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Volume 23 Issue 4 2021

Contents

Editorial 301 Review of advanced energy devices for the minimal access gynaecologist
SBA Gemma L Bentham, Jessica Preshaw
235 Editorial
Jo Morrison

Tips and Techniques

Editor's Pick 310 Excision of endometriosis – optimising surgical techniques
236 Spotlight on… multiple pregnancy Kyle Fleischer, Ahmed El Gohari, Matthew Erritty, Vasileios Minas,
George Attilakos Shaheen Khazali

Commentary Education
237 Working remotely: a perspective on telemedicine in delivery of 318 Improving basic training in obstetric ultrasound: developing a
obstetrics and gynaecology health care framework for specialist trainees
Aditya Bhalla, Rita Bhalla, Suneetha Ganta Robin Hughes, Uma Rajesh

243 Engaging the future generation of obstetricians and

gynaecologists in effective patient safety training CPD
Sophie Walter, Emma Torbé
324 CPD questions for volume 23 issue 4

Review
246 The role of antenatal corticosteroids in improving neonatal outcomes Letters and emails
SBA
Paula Busuulwa, Katie Groom, Lucy C Chappell, Andrew H Shennan
329 Re: Detecting endometrial cancer
258 Trauma and pregnancy Chris Spencer, Colin Partington, Jamal Zaidi
SBA
James Tibbott, Matteo Di Carlofelice, Rashmi Menon, Etienne Ciantar
329 Authors’ reply
265 Adrenal disease and pregnancy: an overview Eleanor R Jones, Helena O’Flynn, Emma J Crosbie
SBA
Mayada Ahmed, Mohammed Bashir, Gbemisola O Okunoye,
Justin C. Konje
278 Peripartum cardiomyopathy
UKOSS update
SBA 331 UKOSS update
Akshatha Kulkarni, Gareth Squire, Kai Hogrefe,
Mohamed Waseem Osman Marian Knight

290 Shared decision making in gynaecological oncology; a challenge

SBA
in an ageing population And finally…
Magda Sbai, Emily Jasper, Fionna Martin, Savithri Rajkumar,
332 Our next book
Ana Montes, Jeyanjali Jeyarajah, Danielle Harari, Judith Partridge
James Drife
295 Update on recurrent vulvovaginal candidiasis
SBA
Amy Borland, Katie Ovens, Ifeoma Offiah, Anupreet Dua,
Robert Freeman
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 DOI: 10.1111/tog.12768 2021;23:246–57
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

The role of antenatal corticosteroids in improving neonatal

outcomes
Paula Busuulwa MBBS BSc,a,b* Katie Groom PhD FRANZCOG CMFM,
c,d
Lucy C Chappell PhD FRCOG FMedSci,
e,f,g

Andrew H Shennan MD FRCOGh,i

a
Clinical Fellow, Department of Obstetrics and Gynaecology, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1
7EH, UK
b
Academic Clinical Fellow in Obstetrics and Gynaecology, Department of Women’s and Children’s Health, Centre for Women’s Health Research,
Institute of Life Course and Medical Sciences, University of Liverpool, UK
c
Associate Professor of Maternal and Perinatal Health and Hugo Charitable Trust Research Fellow, Liggins Institute, University of Auckland,
Building 503, Level 2, 85 Park Road, Auckland 1023, New Zealand
d
Maternal Fetal Medicine Subspecialist and Obstetrician, National Women’s Health, Auckland City Hospital, 2 Park Road, Auckland 1023, New
Zealand
e
Chief Scientific Adviser, Department of Health and Social Care, UK
f
Professor of Obstetrics and NIHR Senior Investigator, Department of Women and Children’s Health, King’s College London, London WC2R 2LS,
UK
g
Honorary Consultant Obstetrician, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK
h
Professor of Obstetrics, Department of Women and Children’s Health, King’s College London, London WC2R 2LS, UK
i
Consultant Obstetrician, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK
*Correspondence: Paula Busuulwa. Email: paula.busuulwa@btinternet.com

Accepted on 17 November 2020. Published online 7 September 2021.

Key content  To understand the rationale for ACS use in specific circumstances,
 Antenatal corticosteroids (ACS) are a key evidence-based as well as current areas of uncertainty.
intervention proven to reduce neonatal morbidity and mortality.
Ethical issues
 ACS should be given in a timely manner to ensure maximal
 For women who receive ACS for threatened preterm labour, there
benefit. This can be challenging, particularly in women presenting
is only benefit if their baby is born within 7 days. Therefore,
with suspected spontaneous preterm labour.
 There is continuing uncertainty about the role of repeat ACS
optimal prediction of risk of preterm delivery is essential.
 Evidence of benefit of ACS does not translate directly from high-
courses in women who remain at high risk of preterm delivery.
 Evidence from long-term follow-up studies has yielded mixed
income settings into low- and middle-income countries because
there are other factors that influence preterm birth outcomes.
findings; further research is needed to determine the impact of  Timing of ACS, in relation to time before delivery, number of
ACS on future health.
courses and gestational age, is likely to be important.
Learning objectives
Keywords: antenatal corticosteroids / preterm / rescue or repeat
 To understand the mechanisms underpinning ACS effectiveness in
ACS
utero and the evidence to support their use.

Please cite this paper as: Busuulwa P, Groom K, Chappell LC, Shennan AH. The role of antenatal corticosteroids in improving neonatal outcomes. The
Obstetrician & Gynaecologist 2021;23:246–57. https://doi.org/10.1111/tog.12768

Introduction
The use of antenatal corticosteroids (ACS) in women at risk
of preterm birth is well established within obstetric
practice.1,2 ACS promote fetal lung maturation3 and reduce
the risk of neonatal morbidity and mortality.4,5 Despite the
benefits of appropriately timed ACS in the management of
women at risk of preterm birth, concerns remain about the
long-term impact on the child.6,7 There are additional
challenges with accurate prediction of preterm birth8 and
the benefits of ACS in less well-resourced settings.9
Background
The use of ACS has been established following the seminal
work of Liggins in the 1960s.10 Liggins observed that
following exposure to the corticosteroid dexamethasone in
utero, the lungs of prematurely delivered lambs were partially
aerated and expanded despite not being artificially
ventilated.10 Liggins hypothesised that ACS administered in
utero accelerated surfactant production in these lambs
leading to improved respiratory outcomes.10 This initial
hypothesis was subsequently tested by Liggins and Howie11 in

246 ª 2021 Royal College of Obstetricians and Gynaecologists


the first of many randomised controlled trials (RCTs)
comparing ACS use with placebo in women at risk of
preterm birth, either because of spontaneous labour or as an
indicated birth associated with maternal and/or fetal
compromise.4,12–14 In this first RCT,11 neonates exposed to
maternal betamethasone were less likely to develop
respiratory distress syndrome (RDS) when ACS were given
at least 48 hours prior to and within 7 days of birth,
compared with placebo use (3.6% versus 33.3%, p = 0.03).
Neonatal and perinatal deaths were also significantly reduced
in the ACS group (early neonatal death: 3.2% ACS-treated
versus 15.2% placebo, p = 0.01; perinatal death: 6.4% ACS-
treated versus 18.0% placebo, p = 0.02). These findings have
since been confirmed in multiple trials and meta-
analyses.4,12–14 ACS are thought to accelerate alveolar
development and maturation of the type II pneumocytes
responsible for surfactant production3 and, in doing so,
prepare the preterm neonate for life ex utero.
Mechanisms
Glucocorticoid receptors (GR) are expressed in numerous
fetal tissues, including the brain and lungs, as well as the
placenta.15 GR signalling pathways are important for the
stabilisation of vascular endothelial cells, which is thought
to help reduce the risk of intraventricular haemorrhage after
preterm birth.16 Additionally, ACS act on neural stem/
progenitor cells, exerting antiproliferative effects that may
contribute to long term behavioural and cognitive outcomes
in infants exposed to ACS.16 ACS are thought to act on the
fetal gastrointestinal tract by strengthening the intestinal
barrier and preventing translocation of bacteria and
bacterial toxins, as well as reducing inflammation, which
all acts to reduce the risk of necrotising
enterocolitis (NEC).17
Transfer of endogenous glucocorticoids from mother to
fetus is limited by the placental enzyme 11b-hydroxysteroid
dehydrogenase type 2 (11b-HSD2). This enzyme limits the
transfer of endogenous glucocorticoids (cortisone and
corticosterone), while synthetic glucocorticoids
(dexamethasone or betamethasone) are able to bypass this
barrier and reach fetal tissues.18 Additionally, 11b-HSD2
converts maternal cortisol to the inactive cortisone.18
Importantly, animal studies have demonstrated a notable
reduction in 11b-HSD2 expression towards parturition,
allowing more maternal glucocorticoid to reach the
fetus.15,18 Additionally, the fetal adrenal axis becomes more
sensitive to adrenocorticotrophic hormone, with a resultant
increase in endogenous fetal cortisol close to term.8,18
Changes in placental 11b-HSD2 and the transporter
molecule P-glycoprotein are also thought to mediate the
different effects of both endogenous and exogenous
glucocorticoids during fetal life.18 Taken together, these
ª 2021 Royal College of Obstetricians and Gynaecologists
Busuulwa et al.
findings might explain how glucocorticoids have differing
effects across gestation,18 which may be most marked for the
fetus exposed to ACS earlier in pregnancy but subsequently
delivered at term and so exposed to both endogenous and
exogenous corticosteroids.
Exposure to ACS leads to acceleration of fetal organ
maturation at the expense of growth.19 Variations in the
expression of 11b-HSD2 may mediate these observed
differences and underlie prenatal glucocorticoid
programming.19 A reduction in fetal growth in utero may
‘programme’ the fetus to future cardiovascular disease,
insulin resistance and hypertension in adult life.20,21 ACS
administration may also programme the fetal hypothalamic–
pituitary axis (HPA) leading to alterations in neurological
and endocrine function in later life.22
The benefits of antenatal corticosteroids
Evidence supporting the use of antenatal
corticosteroids
A Cochrane review on the use of ACS in women at risk of
preterm birth identified 30 studies, including 7774 women
and 8158 infants.4 In this review, treatment with ACS led to a
reduction in RDS (relative risk [RR] 0.66, 95% confidence
interval [CI] 0.56–0.77), need for mechanical ventilation (RR
0.68, 95% CI 0.56–0.84), neonatal death (RR 0.69, 95% CI
0.59–0.81), NEC (RR 0.50, 95% CI 0.32–0.78) and
intraventricular haemorrhage (IVH; RR 0.55, 95% CI 0.40–
0.76).4 RDS, in particular, a key endpoint in ACS trials, was
estimated to affect 116 per 1000 (ACS-treated) compared
with 176 per 1000 (non-ACS-treated) pregnancies in 7764
pregnancies.4 The review authors concluded that there was
little need for further trials examining the benefits of ACS in
singleton pregnancies in high-income settings.4 However,
there is a need for further research in low-income settings
where evidence is limited.9
These findings have been adopted into national and
international recommendations made by the UK’s National
Institute for Health and Care Excellence (NICE)2 and the
American College of Obstetricians and Gynecologists
(ACOG),23 as well as the World Health Organization
(WHO),1 which recommend giving ACS to women for
whom preterm birth is imminent (within 7 days) between
24+0 and 33+6 weeks of gestation. This guidance encompasses
women with preterm prelabour rupture of membranes
(PPROM), spontaneous preterm labour and medically
indicated/iatrogenic preterm delivery (see Table 1). A
complete course of ACS requires multiple doses of either
dexamethasone or betamethasone given intramuscularly. The
two common regimes for a course of ACS are two doses of
intramuscular betamethasone 12 mg, given 24 hours apart,
or four doses of intramuscular dexamethasone 6 mg, given
12 hours apart.24
247
 Antenatal corticosteroids and neonatal outcomes
Table 1. Timing of antenatal corticosteroid administration according
to national and international guidelines
Guideline Recommendation
WHO, 20151 Recommended between 24 and 34 weeks of
gestation where preterm delivery is expected
within 7 days, in the absence of maternal infection
Not recommended in the presence of maternal
chorioamnionitis, planned caesarean section
between 34 and 36+6/7 weeks of gestation
A repeat course may be given if preterm birth does
not occur within 7 days and the risk of preterm
delivery is still considered high within 7 days
NICE 20152 Administer after discussion with the woman and her
family between 23+0 and 23+6/7 weeks of gestation
for women who are in suspected or diagnosed
preterm labour or having planned preterm delivery,
or have PPROM
Single course between 24+0 and 33+6/7 weeks of
gestation for women who are in suspected or
diagnosed preterm labour or having planned
preterm delivery, or have PPROM
Consider a course between 34+0 and 35+6/7 weeks
of gestation for women who are in suspected or
diagnosed preterm labour or having planned
preterm delivery, or have PPROM
Do not routinely administer repeat ACS but take
into consideration the interval since the end of the
last course, gestational age and likelihood of birth
within 48 hours
ACOG, 201723 Administer after discussion with the woman and
her family between 23+0 and 23+6/7 weeks of
gestation for women at risk of preterm delivery
within 7 days
Single course between 24+0 and 33+6/7 weeks of
gestation for women at risk of preterm delivery
within 7 days
Single course between 34+0 and 36+6/7 weeks of
gestation for women at risk of preterm delivery
within 7 days and who have not previously
received a course of corticosteroids
A single repeat course should be considered in
women <34+0 weeks of gestation who are at risk
of preterm birth within 7 days and last received
a course of ACS more than 14 days previously,
although can be within 7 days if clinically indicated
Abbreviations: ACOG = American College of Obstetricians and
Gynecologists; NICE = National Institute for Health and Care
Excellence; PPROM = preterm prelabour rupture of membranes;
WHO = World Health Organization
Choice of antenatal corticosteroid
The choice of corticosteroid to use remains an area of
uncertainty and continuing research.24,25 A Cochrane
review24 comparing betamethasone and dexamethasone
found no significant differences in neonatal death or RDS
248
when either corticosteroid was used, but dexamethasone was
associated with reduced risk of IVH (RR 0.44, 95% CI 0.21–
0.92; four trials, 549 infants).24 Furthermore, one study
included in the review26 reported that one child in the
dexamethasone group had global development delay at
18 months of age. The ASTEROID trial,25 a large
multicentred double-blinded RCT, investigated whether
antenatal betamethasone versus dexamethasone given prior
to 34 weeks of gestation reduced death or neurosensory
disability at 2 years of age. Incidence of the primary outcome
was similar in both groups, as was the number of infants with
RDS, IVH and the severity of lung disease in both groups.25
Infants who had received antenatal dexamethasone also had
significantly lower systolic blood pressure z-scores at 2 years
(p = 0.04) and were less likely to have blood pressure in the
hypertensive range (32% versus 41%, dexamethasone versus
betamethasone, respectively; RR 0.78, 95% CI 0.64–0.95;
p = 0.02). Additionally, betamethasone use was associated
with a higher chance of caesarean birth compared with
dexamethasone; 52% and 43%, respectively (p = 0.0013). This
finding could not be explained by increased rates of fetal
distress or other indications for caesarean birth. While there
remains no clear difference in primary outcomes associated
with dexamethasone and betamethasone use, cost effectiveness
and accessibility may favour the use of dexamethasone.27
However, formal cost analyses are still needed.
Timing of steroid use
Optimal timing of ACS is critical to ensuring efficacy and
limiting potential harm.28,29 Norman et al. (2017)29
demonstrated an overall reduction in infant mortality when
ACS were administered between 24 hours and 7 days prior to
delivery in women presenting between 24 and 31+6 weeks of
gestation (adjusted RR 0.5, 95% CI 0.4–0.6). Crucially, the
greatest benefit appears to be conferred when ACS are given
between 18 and 36 hours prior to delivery; here a 50% reduction
in mortality was noted.29 A similar time-to-delivery effect was
reported by Norberg et al. (2017)28 in extremely premature
infants born between 22 and 26 weeks of gestation, where infant
survival was greatest when ACS were administered within 24–
48 hours (hazard ratio [HR] 1.60, 95% CI 0.73–3.50). Both
studies28,29 were observational in design, and do not account for
infants exposed to ACS but delivered at term, because they
focused on extreme prematurity. Therefore, they might have
underestimated the impact of mistimed ACS. Nevertheless, they
suggest that ACS may have the greatest impact on neonatal
survival when administered within 24–48 hours of delivery.
Repeated multiple courses
After initial trials demonstrating the importance of timing of
ACS in relation to birth, this led to concerns from clinicians
ª 2021 Royal College of Obstetricians and Gynaecologists
 Busuulwa et al.

about women who remained pregnant and still at high risk of
preterm birth but more than 7 days from their original ACS
course.30 Clinicians consequently prescribed multiple ACS
courses for such women.30
Current NICE guidelines do not recommend routine use
of repeat ACS, but advise consideration of their use
depending on the interval since the end of the last course,
gestational age and likelihood of birth within 48 hours.2
Meanwhile ACOG and WHO guidelines recommend a rescue
course if the risk of preterm birth remains high (see
Table 1).1,23 The question of repeat ACS (administration of
ACS repeated every 7–14 days) has been studied in several
large trials.31–33 However, results are inconsistent. Some
conclude additional benefit conferred by repeat courses,33
while others have shown no significant benefit and, indeed,
potential harm (see Table 2).31,32
The Multiple Courses of Antenatal Corticosteroids for
Preterm Birth (MACS) trial31 compared a single course versus
multiple courses (repeated every 14 days) of ACS in women who
remained at high risk of preterm birth. The risk of mortality and
morbidity was similar in both groups31 and there was no
significant benefit from administering multiple courses of ACS
to women after an initial course had been given.31 However, in
contrast, in the the Australasian Collaborative Trial of Repeat
Doses of Steroids (ACTORDS) trial,33 which compared repeat
ACS (repeated every 7 days) with a single course, babies exposed
to repeat ACS were less likely to develop RDS (p = 0.01),
composite serious neonatal morbidity (p = 0.02) or require
oxygen therapy (p = 0.03).33 The National Institute of Child
Health and Human Development (NICHD) study32 on repeat
ACS (weekly) was stopped early because of safety concerns.
Specifically, these concerns related to low birthweight in the

Table 2. Evidence from trials comparing single vs repeat courses of ACS

Gestational age Frequency of

at enrolment repeat ACS
Trial (weeks) (days) Primary outcome Key findings

ACTORDS33 Below 32+0 7 Frequency and severity of RDS,
severity of any lung disease,
need for and duration of
oxygen therapy, need for
and duration of mechanical
ventilation, weight, height
and head circumference at
birth and discharge
Reduction in rate of RDS in repeat ACS group (RR 0.82,
95% CI 0.71–0.95, p = 0.01), reduction in need
for oxygen therapy in repeat group (RR 0.90,
95% CI 0.81–0.99, p = 0.03), reduction in
composite serious neonatal morbidity (p = 0.02)
and shorter duration of mechanical ventilation in
repeat ACS (p = 0.01)
Smaller birthweights (p = 0.04) and head circumferences
(p = 0.03; by z-score) in repeat ACS group but
nonsignificant at discharge (p = 0.29 for weight, and
p = 0.48 for head circumference)

MACS31 25–32 14 Perinatal or neonatal mortality No significant difference in mortality or morbidity

(stillbirth or neonatal death Neonates exposed to multiple courses of ACS weighed
≤28 days) or morbidity significantly less at birth (p = 0.0026), with shorter
(severe RDS, BPD, grade birth lengths (p < 0.001) and had smaller
III or IV IVH, cystic PVL, NEC) head circumferences (p < 0.001)

NICHD32 23+0–31+6 7 (maximum Composite of severe RDS, No significant reduction in the primary outcome
of 4 courses)* grade III or IV IVH, PVL, in the treatment group (RR 0.88, 95% CI
CLD, stillbirth or 0.49–1.57, p = 0.67)
neonatal death Less need for ventilatory support (RR 0.58, 95% CI
0.40–0.84, ip = 0.004), use of surfactant (RR 0.61,
95% CI 0.40–0.94, p = 0.02), pressor or volume
support (RR 0.53, 95% CI 0.30–0.93,
p = 0.02) in repeat ACS group
Reduced birthweight and length associated
with 4 or more courses of ACS (p = 0.01
and p = 0.006, respectively)

Abbreviations: ACS = antenatal corticosteroids; ACTORDS = Australasian Collaborative Trial of Repeat Doses of Steroids; BPD = bronchopulmonary
dysplasia; CLD = chronic lung disease; IVH = intraventricular haemorrhage; MACS = Multiple Courses of Antenatal Corticosteroids for Preterm
Birth; NEC = necrotising enterocolitis; NICHD = National Institute of Child Health and Human Development; PVL = periventricular haemorrhage;
RDS = respiratory distress syndrome
*Decision made to limit to 4 repeat course after first 67 participants

ª 2021 Royal College of Obstetricians and Gynaecologists 249

 Antenatal corticosteroids and neonatal outcomes
repeat ACS group without additional benefit;32 that is, no
reduction in the composite neonatal outcome (RR 0.88, 95% CI
0.49–1.57, p = 0.67), although reductions in specific
cardiovascular and pulmonary outcomes were noted (see
Table 2). While the studies’ main conclusions vary,31–33 they
consistently reported a reduction in infant growth associated
with multiple ACS administration (see Table 2).
A recent individual participant data meta-analysis (including
11 studies) conducted by Crowther and colleagues34 concluded
that repeated ACS led to no significant reduction in serious
adverse infant outcomes (RR 0.92, 95% CI 0.82–1.04, 5893
infants), although they were associated with a reduction in the
need for neonatal respiratory support (RR 0.91, 95% CI 0.85–
0.97, 5791 infants from 10 studies). A Cochrane review of repeat
ACS reported that the risk of RDS in infants exposed to repeat
courses of ACS in utero was reduced compared with those
receiving a single course followed by placebo (RR 0.83, 95% CI
0.75–0.91, 3206 infants), but this was also associated with a
reduction in birthweight (mean difference -75.79 g, 95% CI
-117.63 to -33.96, 5626 infants).35
While there is some evidence that repeat courses of ACS
may reduce early infant morbidity,33 the consistent evidence of
lower birthweight demonstrated across numerous studies31–33
would warrant caution when considering a repeat dose or
course of ACS. The use of ACS in the management of women
at risk of preterm birth has improved outcomes for infants
born preterm.4,5 However, their wide use and, in some cases
repeated use, may have a long-lasting effect on the child,
potentially persisting long after the neonatal period into
adulthood.36–39 Furthermore, a single dose has been suggested
to limit side effects and may still have benefit.40
Rescue course
A ‘rescue course’ is when a second course of ACS is given to
women who remain undelivered more than 1 week from
their original course.41 A rescue course is administered at the
discretion of the clinicians rather than routine repeated
administration.41 A multicentre placebo-controlled RCT
investigating the role of a rescue course of ACS
demonstrated a reduction in composite neonatal morbidity
below 34 weeks of gestational age (odds ratio [OR] 0.45, 95%
CI 0.27–0.45, p = 0.002), where the composite was defined as
one of the following: RDS, bronchopulmonary dysplasia,
severe IVH, periventricular leukomalacia, blood culture-
proven sepsis, NEC, or perinatal death.41 Importantly, Garite
and colleagues41 found no difference in birthweight or head
circumference between the two groups.
Adverse effects of antenatal corticosteroids
ACS use has resulted in improved neonatal outcomes,4 but
may have long-lasting effects on the fetus42 and there are
250
concerns about the long-term consequences of in utero
exposure.6,42 Of the 30 studies included in the Cochrane
review by Roberts et al.,4 only two reported follow-up into
adulthood,36,38,43,44 with 21%38 and 44%36 loss to follow-up.
The results from follow-up studies, including a 30-year
follow-up of adult survivors of the original Antenatal Steroid
Trial,44 have been reassuring in terms of ACS safety, although
small differences in exposed and non-exposed individuals do
exist. Thirty years from the original trial, adult children of the
women who participated in the Auckland Steroid Trial
conducted by Liggins and Howie11 were assessed, providing
further insight into cardiovascular, respiratory and
psychological health (see Table 3).36,43,44 In the
cardiovascular study, individuals exposed to ACS were
more likely to develop insulin resistance, but showed no
other significant differences.36 In the psychological wellbeing
study44 there were no significant differences in cognitive
function, working memory or psychiatric illness,44 and no
differences in lung function at 30 years of age (see Table 3).43
Khalife et al.37 compared children at 8 and 16 years of age
who received ACS to age-matched controls using propensity
score matching, accounting for prematurity status and
gender. Children exposed to ACS were more likely to
demonstrate inattentive behaviours at age 8 (p = 0.02).
These results should be interpreted with caution because
propensity score-matching is not akin to randomisation,
hence the results are open to potential bias.
Additionally, Dessens et al.38 reported on a Dutch cohort
of adults whose mothers had taken part in a double-blind
RCT comparing three groups: orciprenaline (a betamimetic)
and betamethasone (group 1) versus orciprenaline and
placebo (group 2) versus no treatment (group 3).14 Dessens
et al.38 found women exposed to both ACS and placebo were
more likely to report irregular menstrual cycles than the
general population, although this was significantly increased in
the placebo group compared to the ACS group (16% versus
69%, ACS and placebo, respectively, p = 0.005). The authors
propose this might be attributed to a small number of placebo
women in the follow-up group, with some of these women
commencing hormonal contraception early.38 Additionally,
ACS-exposed adults used more medications than placebo
(p = 0.01); commonly these medications were for allergies or
chronic obstructive pulmonary diseases, although these may
be attributable to these conditions also being present in the
families of these individuals.38 Importantly, no other
differences in physical, mental health or body anthropometry
were noted in this study (see Table 3).38
There have also been concerns about ill-timed ACS.
Norman and colleagues29 reported a 40% increase in
mortality when ACS were administered more than 7 days
prior to delivery compared with those administered within
an interval of 1–7 days (adjusted RR 0.7, 95% CI 0.6–0.9 and
adjusted RR 0.5, 95% CI 0.4–0.6 for ACS administered more
ª 2021 Royal College of Obstetricians and Gynaecologists

Table 3. Evidence from follow-up studies (single courses of ACS)
Time to Follow up from
Study follow-up initial study (%)
Auckland Steroid Follow-up study – 30 years 56% presumed to be alive
cardiovascular follow-up36
Auckland Steroid Follow-up study – 30 years 56% presumed to be alive
lung function follow-up43
Auckland Steroid Trial – 30 years 20% (subgroup of those
Psychological follow-up44 from Dalziel et al., 200536)
Dessens et al., 200038 20 years 79%
than 7 days before delivery compared with within 1 and
7 days of delivery, respectively).29 This effect could reflect the
transient effect of ACS, as Norman and colleagues report that
any ACS administration was associated with a reduction in
infant mortality.29 Further evidence of potential harm has
been demonstrated in samples taken at autopsy from preterm
infants (24–32 weeks of gestation)45 who died within 4 days
of life and were exposed to ACS. These samples demonstrated
a significantly lower density of neurons in the hippocampus
of the treated neonates (p = 0.02).45
Importantly, there are potential risks caused by ACS in
those infants delivered at term and exposed to ACS in
utero.46,47 A recent retrospective study investigating
outcomes for infants exposed to ACS in utero compared
with non-exposed infants46 demonstrated that infants
delivered at term were more likely to be referred for
assessment of hearing, visual or cognitive problems (HR
1.12, 95% CI 1.08–1.16). Although the study cannot prove
causality, it highlights that children exposed to ACS and
delivered at term may be at increased risk of future
neurosensory and cognitive problems.46 This evidence
highlights the need to ensure that ACS are only given to
those likely to benefit most, and to limit potentially harmful
exposure to those who are less likely to benefit.
The earlier trials of multiple ACS courses demonstrate the
potential harm that can be caused by repeated ACS
exposure.31,32 A MACS trial follow-up of 2-year-old
children born to mothers who participated in the original
study found infants exposed to repeat ACS were not at
increased risk of death or neurological impairment (OR 1.001,
ª 2021 Royal College of Obstetricians and Gynaecologists
Busuulwa et al.
Key findings
Increased insulin concentrations at 30 min following oral glucose
tolerance testing (60.5 versus 52.0 mIU/L, p = 0.02)
Lower glucose concentrations in the steroid exposed versus
placebo groups (4.8 versus 5.1 mmol/L, p = 0.05) 120 min
following oral glucose tolerance testing
No difference in prevalence of asthma, wheeze or lung function
No significant differences in cognitive function, working
memory or psychiatric illness
Higher rate of irregular menstrual cycles in placebo
group (p = 0.005)
Higher use of medication in treated group (p = 0.01)
Slightly lower blood pressure in treatment group
(systolic blood pressure lower in treatment, p = 0.05)
95% CI 0.75–1.30, p = 0.95).48 However, the 5-year follow-up
study demonstrated that, in the subset of children exposed to
multiple ACS doses and subsequently born at term, there was a
significantly increased risk of death or disability (OR 1.69, 95%
CI 1.04–2.77, p = 0.04) and neurosensory disability (OR 3.70,
95% CI 1.57–8.75, p = 0.004);49 a relationship not related to
number of doses received. This finding of increased risk was
not seen in those children who were born preterm.49 Similarly,
the ACTORDS 2-year follow-up reported no increased risk of
disability at age 2 in children in the repeat ACS group
(ACTORDS-2), but these infants were more likely to have
attention problems (adjusted RR 1.87, 95% CI 1.03–3.42,
p = 0.04).50 However, these problems did not appear to persist
into later childhood,51 possibly suggesting that any effect on
fetal programming in utero was short lived.51 The NICHD 2-
year follow-up study52 also demonstrated a non-significant
increase in the rate of cerebral palsy in infants exposed to
repeat courses of ACS (RR 5.7, 95% CI 0.7–46.7, p = 0.12).
Although repeat ACS may improve short-term neonatal
outcomes, namely RDS, the findings from follow-up studies
suggest that this may be at the expense of neurological
development in childhood.49,52 Moreover, infants exposed to
single or multiple ACS courses and delivered at term appear
to be particularly vulnerable to the effects of ACS
(see Table 4).46,49
Dose effect relationship
Another criticism made of the use of ACS is the challenge of
appropriate dosing to limit side effects while maximising
251
 Antenatal corticosteroids and neonatal outcomes

Table 4. Evidence from follow-up studies (repeat ACS)

Follow-up
Time to from initial
Study follow-up study (%) Primary outcome Key findings

NICHD52 24–35 months 87.4 Medical history, developmental
milestones, physical and
neurological assessment,
and assessment of psychomotor
and mental development
Reduction in asthma risk in treatment group
(RR 0.6, 95% CI 0.3–1.0, p = 0.05)
Nonsignificant increase in cerebral palsy in
treatment group (RR 5.7, 95% CI 0.7–46.7,
p = 0.12)

MACS – 2 years48 18–24 months 91.3 Death or presence of No significant difference between treatment
neurological impairment group and placebo in primary outcome
(cerebral palsy or cognitive delay) (OR 1.001, 95% CI 0.75–1.30, p = 0.95)
Infants in repeat ACS weighed slightly less
though not significant (11.94 kg versus
12.14 kg in treated and nontreated,
respectively; p = 0.04)

ACTORDS – 2 years50 2 years 96 Survival without major
neurosensory disability
and body size (weight,
height, head circumference)
No significant difference in disability free survival
(aRR 1.04; 95% CI 0.98–1.10, adjusted p = 0.20)
Infants exposed to repeat ACS more likely
to demonstrate attention problems, (aRR
1.87, 95% CI 1.03–3.42, p = 0.04)
No significant difference in z-scores for
weight, height or head circumference

ACTORDS – 6–8 years51 6–8 years 86 Survival free of any No significant difference in disability free survival
neurosensory disability (RR 1.00, 95% CI 0.94–1.08, p = 0.89)
Placebo group performed better in immediate
word recall (p = 0.01), although no
difference in word recall over five trials
No other significant differences in health,
functional or psychological outcomes

MACS – 5 years49 5 years 80.7 Death or neurodevelopmental No significant difference between treatment
disability group and placebo in primary outcome in
study population as a whole (OR 1.02
95% CI 0.84–1.29)
Infants exposed to repeat ACS and born
at term more likely to experience primary
outcome (OR 1.69, 95% CI 1.04–2.77,
p = 0.04) and increased risk of neurosensory
disability (OR 3.70, 95% CI 1.57 8.75;
p = 0.004)

Abbreviations: ACTORDS = Australasian Collaborative Trial of Repeat Doses of Steroids; aRR = adjusted relative risk; CI = confidence interval;
MACS = Multiple Courses of Antenatal Corticosteroids for Preterm Birth; NICHD = National Institute of Child Health and Human Development;
OR = odds ratio; RR = relative risk

benefit to the fetus. A single dose of ACS may be as effective
as two doses in reducing neonatal morbidity and mortality.40
In a group of surfactant-treated premature infants, those
exposed to a single dose of ACS within 24 hours of birth had
comparable outcomes to those who received a full course.
Conversely, in another retrospective study on incomplete
ACS administration,53 an incomplete ACS course (one of two
doses) did not improve outcomes for premature infants. In
some cases, this may have even led to poorer outcomes,
namely increased RDS, longer hospitalisation and increased
need for intubation in the delivery room, although the ACS-
treated infants were approximately 1 week younger by
gestational age. Although inconsistent, these findings raise
interesting questions, particularly about whether current
dosing regimens are effective, especially since they have not
been reviewed in several decades and despite considerable
advances in neonatal care. The planned BETADOSE trial,54 a
non-inferiority RCT comparing the effect of a single dose

252 ª 2021 Royal College of Obstetricians and Gynaecologists


versus a full course of ACS treatment on the diagnosis of
severe RDS, will further clarify this important question. This
may also prove useful in challenging clinical contexts, such as
ACS use in mothers with diabetes, where data are limited and
the risk of maternal effects and neonatal hypoglycaemia
is greater.55
Corticosteroids in specific circumstances
Corticosteroids for threatened preterm labour
Accurate prediction of preterm birth in women at increased
risk is a considerable challenge.56 This is further complicated
by the mixed aetiology associated with spontaneous preterm
birth, including differences in the vaginal microbiome across
ethnic groups, which may account for differences in rates of
spontaneous preterm birth across these ethnic groups,57,58 as
well as pathophysiological differences in asymptomatic versus
symptomatic individuals.59
Currently several predictive tests are available, including
vaginal biomarkers such as fetal fibronectin (fFN), ultrasound
assessment of cervical length, and identification of obstetric
risk factors including previous preterm birth.59 Current NICE
guidance2 advises that women presenting with suspected
preterm labour prior to 30 weeks of gestation should be
treated with tocolytics and ACS, and those presenting at a
gestation of more than 30 weeks should be managed according
to cervical length and fFN. This treat-all policy raises potential
concerns if the woman remains undelivered but has received a
course of ACS. False negative test results are relatively rare and
a treat-all policy may not be justified given the harmful effects
of ACS. Given the mixed aetiology of spontaneous preterm
birth, any predictive or prognostic tool would probably need
to combine more than one test to improve accuracy and
clinical applicability.59
The QUiPP app uses a combination of gestational age,
quantitative fFN, cervical length and prior history to quantify
individual risk of spontaneous preterm birth.56,60,61 A key
strength of the QUiPP app is its high negative predictive
value, which has been demonstrated to be 100% for risk
thresholds 1%, 5% and 10% for delivery within 7 days in 188
women presenting with threatened preterm labour before
30 weeks of gestation.56 Furthermore, using a 5% risk of
delivery as a treatment threshold, the QUiPP app would have
appropriately treated 9/9 women who presented with signs of
preterm labour prior to 34 weeks of gestation and delivered
within 7 days56 – the interval most clinically relevant for ACS
administration. Similarly, the area under the receiver
operating characteristic (AUROC) values for fFN also
demonstrate good test performance values (0.8816 and
0.8262 for delivery before 30 and 34 weeks of gestation,
respectively).60 The recently published QUiPP app toolkit has
been developed to aid clinicians in implementing the QUiPP
app into clinical practice.61
ª 2021 Royal College of Obstetricians and Gynaecologists
Busuulwa et al.
Importantly, the use of prognostic tools enables clinicians
to direct interventions such as ACS, tocolytic therapy and in
utero transfer to those women who are most likely to deliver
within the following 7–14 days, while appropriately
withholding them in those who are unlikely to deliver
imminently.56 In the context of spontaneous preterm labour
this is crucial because many of these women do not deliver
prematurely.7,62 One study reported that, of the infants
exposed to ACS, 44% were delivered at term,7 while another
cites an estimate of greater than 50%.62
Corticosteroids for medically indicated preterm birth
Indicated preterm birth accounts for 30–35% of all preterm
births,8 with pre-eclampsia being among the commonest
indications for preterm delivery.63,64 Pre-eclampsia can only
be cured by delivery of the baby and placenta,65 and the
decision for, and timing of delivery requires a careful balance
between the risks and benefits to the woman and fetus,
particularly at earlier gestations.65 Unlike spontaneous
preterm labour, which is usually unpredictable, clinicians
frequently plan delivery allowing ACS to be given when
delivery is arranged or likely.66 Novel tools, including
biomarkers, which can assist in diagnosing the disease and
predicting time to delivery have been evaluated67 and may
aid timing of ACS when preterm delivery is indicated.
Corticosteroids in the late preterm period
The role of ACS in the late preterm period is uncertain.55,68
The Antenatal Late Preterm Steroids (ALPS) trial,69 a double-
blind RCT, investigated the role of betamethasone in women
at risk of preterm birth between 34+0 and 36+5 weeks of
gestation where risk of preterm birth was defined as ruptured
membranes, cervical dilatation to at least 3 cm with intact
membranes, 75% cervical effacement, induction of labour or
planned caesarean section within 24 hours and 7 days.69
Fewer infants had the primary outcome (a neonatal
composite of need for respiratory support within 72 hours
of birth, or stillbirth or neonatal death) in the ACS group
(165 infants [11.6%] in betamethasone versus 202 infants
[14.4%] in the placebo group; RR 0.80, 95% CI 0.66–0.97,
p = 0.02), with similar rates of RDS, apnoea and pneumonia
in both groups.69
Notably, the incidence of transient tachypnoea of the
newborn (TTN) was lower in the ACS group (RR 0.68, 95%
CI 0.53–0.87, p = 0.002).69 Similarly, in a meta-analysis of
late preterm or term use of ACS, Saccone and Berghella70
found the risk in the late preterm group of severe RDS and
TTN to be significantly reduced in the ACS-treated groups
(RR 0.60, 95% CI 0.24–0.98; and RR 0.72, 95% CI 0.50–0.98,
respectively), although the overall risk of RDS was similar
across both groups. Additionally, subgroup analysis from the
ALPS trial69 demonstrated that ACS use does not reduce
severe respiratory complications in planned vaginal delivery
253
 Antenatal corticosteroids and neonatal outcomes
(RR 1.06, 95% CI 0.73–1.53), but it does in planned
caesarean sections (RR 0.58, 95% CI 0.36–0.94).69 This
implies that the study findings may not be generalisable to all
modes of delivery in the late preterm period.
Another important finding from the ALPS study69 is that
of the increased incidence of neonatal hypoglycaemia in the
ACS treated group (24.0% in betamethasone versus 15.0% in
the placebo group; RR 1.60, 95% CI 1.37–1.87, p < 0.001),
although the lack of standardisation of glucose measurement
may have confounded these findings.69 Similarly, Saccone
and Berghella70 found the incidence of neonatal
hypoglycaemia to be higher in the late preterm ACS treated
groups (RR 1.61, 95% CI 1.16–2.12). These results suggest
that while ACS reduced short-term respiratory complications
in infants born in the late preterm period, their use may
contribute to an increased risk of neonatal hypoglycaemia.
Hypoglycaemia may in turn affect long-term development of
the infant, but requires long-term follow-up for
confirmation. Nonetheless, the positive findings of the
ALPS trial prompted ACOG to update its recommendation
on this topic, advising that women presenting with suspected
preterm birth, who were not previously treated with ACS,
should receive a course between 34+0 and 36+6 weeks of
gestation.23 It should be noted, however, that the inclusion of
a very high risk for delivery group may have also contributed
to the significance of the ALPS study’s findings, thus may not
be applicable to all clinical groups or modes of delivery.69
Corticosteroids for elective caesarean section
The observed risks of respiratory morbidity associated with
caesarean section compared with vaginal birth has prompted
some researchers to evaluate the benefits of ACS in women
undergoing elective caesarean section at term.71 Infants born
following caesarean section have an increased risk of short-
term respiratory morbidity than those born vaginally,72,73
and this risk is higher for those born by elective or prelabour
caesarean section than those born by caesarean section in
labour.72,73 This is thought to be associated with failure of the
lung epithelium to make adaptations from life in utero to life
ex utero.74
The Antenatal Steroids for Term Caesarean
Section (ASTECS) trial75 randomised women to usual care
or a course of betamethasone 48 hours prior to elective
caesarean section at 37 weeks of gestation or beyond. The
trial demonstrated a reduction in the proportion of
admissions to special care baby units (SCBU) with RDS (11
in the treatment group versus 24 babies in the control group;
RR 0.46, 95% CI 0.23–0.93). Notably, the relative proportion
of affected infants was small (35 affected infants from a total
population of 942; that is, less than 5%).75
A subsequent Cochrane review on the use of ACS in
elective caesarean section at term (four trials, 3956 women
and 3893 infants)71 concluded that the administration of
254
ACS in women undergoing elective caesarean section results
in a reduction in the rate of RDS and TTN by 52% and 57%;
respectively. However, the review’s authors deemed all four
trials to have been subject to potential bias and overall low
quality, so the findings should be interpreted with caution.71
Importantly, none of the trials included in the Cochrane
review reported on neonatal hypoglycaemia.71
In the only follow-up study of trials of term and late
preterm ACS use, there were no differences in behaviour or
academic attainment by treatment group at age 8–11 years
seen in the children born to some of the mothers who
participated in the ASTECS trial.76 However, children from
the ACS treatment group were more likely to be in the lower
quartile for academic ability (8.5% in control group versus
17.7% in the ACS group, p = 0.03). Aiken and colleagues77
argued that these differences could suggest that
administration of ACS to women at term has negative
consequences on fetal brain maturation and long-term
development. Indeed, neonatal hypoglycaemia may be the
mechanism by which this occurs.55 Given the relatively low
prevalence of serious morbidity and the large numbers of
women requiring treatment, any harm caused by ACS will
affect many babies who do not benefit from the treatment.
This must be carefully considered and discussed with women
so they can make an informed choice.77
Corticosteroids in low- and middle-income countries
Globally, it is estimated that 15 million babies are born
prematurely, with most of these births occurring in low and
middle-income countries.78 These births are associated with
substantial mortality79 and morbidity80 extending beyond the
neonatal period.80 Importantly, evidence-based interventions
such as ACS may help to address these inequalities, although
results of trials in this context have yielded conflicting
results81 to those from high-income countries.4
The Antenatal Corticosteroids Trial (ACT)81 was a two-
arm, international cluster RCT conducted across six low and
middle-income countries, in which women presenting before
36 weeks of gestation and considered to be at high risk of
preterm delivery were randomised to ACS or standard care.
Birthweight of less than the fifth percentile was used as a
proxy for prematurity. ACT demonstrated no difference in
28-day neonatal mortality among the less-than-fifth
percentile infants in the intervention group compared with
controls, with 225 per 1000 live births and 232 per 1000 live
births, respectively (RR 0.96, 95% CI 0.87–1.06, p = 0.65).81
Importantly, when considering the whole population, 28-day
neonatal mortality was increased in those infants exposed to
ACS compared with controls, at 27.4% and 23.9%,
respectively (RR 1.12, 95% CI 1.02–1.22). These findings
may, in part, be explained by ACS being administered in
more higher birthweight births (defined as ≥25th percentile)
in the intervention arm than the controls (7% and 1%,
ª 2021 Royal College of Obstetricians and Gynaecologists

respectively), and possibly contributing to 30% increased
mortality in the intervention group.81
A recognised limitation of the applicability of findings
from the Cochrane review4 are that most studies were
conducted in high and upper-middle income settings.
Importantly, adequate calculation of gestational age,
childbirth and neonatal facilities must be addressed before
any future implementation of ACS use in low and middle-
income countries.9,82 To address this, two concurrent trials of
ACS use in the early preterm (below 34 weeks of gestation)
and late preterm periods (34+0 to 36+0 weeks of gestation) are
being conducted: the WHO Antenatal CorTicosteroids for
Improving Outcomes in preterm Newborns (WHO
ACTION) trials.83,84 It is hoped that these two trials will
provide more definitive evidence to aid appropriate use in
low and middle-income countries.
Implications for future research
The choice of who should receive ACS and how they should
be timed remains a major clinical challenge. Although ACS
are known to have an overwhelmingly positive impact when
given appropriately, a substantial proportion of women who
receive ACS do not deliver within the following 7 days,
meaning that risks of potential harm are introduced46
without the known, significant benefits occurring. There is
an urgent need to develop and implement reliable prognostic
and diagnostic markers that enable clinicians to appropriately
time ACS administration and avoid unnecessary treatment
with its associated risks.46 Further research into the biological
pathways leading to spontaneous preterm birth will help to
identify reliable biomarkers and improve predictive tools to
ensure treatment is directed appropriately. The obvious way
to avoid mistimed or unnecessary courses, which clearly have
some undesirable effects, is to avoid unnecessary first courses.
A key limitation to ACS use in low and middle-income
settings is the absence of sufficient high-quality evidence
demonstrating benefit, including significant reductions in
neonatal morbidity and mortality, which are observed
elsewhere.4 The continuing WHO ACTION trials will
provide important answers to questions about safety and
efficacy in such countries.83,84 Appropriately powered and
designed follow-up studies to determine the impact of ACS
on adolescent and adult health, particularly where repeat
doses of ACS have been used, would help to address concerns
about the longer-term effects of ACS.
Studies comparing the efficacy of different ACS
formulations would also be helpful in delineating optimal
dosing, limiting unnecessary exposure and aiding choice of
agent and formulation.24,54,85,86
Implications for ACS use are probably similar for all
indicated cases of preterm birth; for example, for other
maternal and fetal conditions. However, future work is
ª 2021 Royal College of Obstetricians and Gynaecologists
Busuulwa et al.
needed to consider whether risks and benefits are different in
subgroups, including different aetiologies such as PPROM.
Fetal growth restriction, an important cause of preterm birth,
is an area in which clinical uncertainty exists, so further
research evidence is needed.87
Finally, work is needed to elucidate the potential benefits
of ACS in the late preterm and early term periods to provide
clarity for clinicians. It is hoped that the continuing
C*STEROID feasibility study and planned C*STEROID
trial55 will help to elucidate the role of ACS in women
undergoing a planned caesarean section between 35+0 and
39+6 weeks of gestation. In the meantime, it is reasonable to
withhold corticosteroids at this time until the risks and
benefits can be evaluated further.
Conclusions
ACS have led to considerable improvements in outcomes for
premature infants. There remains an important need to
ensure this intervention is only given to appropriate groups
(women who are likely to deliver within 7 days) and is
administered close to delivery to optimise benefit. Further
work to assess benefit and potential harm in late preterm
gestations and prior to planned caesarean section is required.
Continuing trials in low and middle-income countries will
provide further evidence to guide ACS use in this context.
Disclosure of interests
PB, KG and LCC report no conflicts. AHS receives funding
from Hologic, paid to the institution, for
biomarker evaluation.
Contribution to authorship
PB researched and wrote the article with assistance from KG,
LCC, AHS. All authors approved the final version.
References
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257
 DOI: 10.1111/tog.12769 2021;23:258–64
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Trauma and pregnancy

James Tibbott BSc (Hons) MBBS MRCOG,a* Matteo Di Carlofelice BSc (Hons) MBBS,
b
Rashmi Menon MBBS MD FRCA,
c

Etienne Ciantar MD MRCOG FHEAd

a
ST6 Obstetrics and Gynaecology, Hull Royal Infirmary, Hull HU3 2JZ, UK
b
Foundation Year 1 Doctor, Mid Yorkshire Hospital Trust, Pinderfields Hospital, Wakefield WF1 4DG, UK
c
Consultant Anaesthetist and Anaesthesia Lead for Major Trauma, Leeds Teaching Hospital Trust, Leeds LS1 3EX, UK
d
Consultant Obstetrician, Leeds Teaching Hospital Trust, Leeds LS1 3EX, UK
*Correspondence: James Tibbott. Email: jmwtibbott@gmail.com

Accepted on 16 November 2020. Published online 30 September 2021.

Key Content
 Trauma accounts for 10% of annual worldwide deaths, and 6–8%
of all pregnancies will experience some form of trauma. Pregnancy
is an independent predictor for mortality.
 Trauma services in the UK were reorganised in 2012. Since then,
the odds of survival from major trauma have increased by 19%
compared with 2008.
 Trauma has maternal complications (for example, haemorrhage,
abruption and disseminated intravascular coagulation) and fetal
complications (such as preterm birth, hypoxic brain injury and death).
 Clinicians should initiate aggressive fluid resuscitation and
strongly consider the possibility of concealed blood loss. Emphasis
should be placed on warmed blood products and tranexamic acid.
 Trauma imaging should not be delayed for fear of risk to the fetus;
we must continue to reinforce the tenet that the mother’s health
takes priority over the fetus in all decision making and the
mother’s condition should be stable prior to the assessment of
fetal wellbeing.
Learning Objectives
 To explore the structure of trauma services in the UK.
 To understand the principles of trauma management and
important considerations in the pregnant patient.
 To appreciate the maternal and fetal outcomes associated
with trauma.
Keywords: maternal fetal outcomes / pregnancy / trauma

Please cite this paper as: Tibbott J, Di Carlofelice M, Menon R, Ciantar E. Trauma and pregnancy. The Obstetrician & Gynaecologist 2021;23:258–64. https://doi.
org/10.1111/tog.12769

major trauma call are listed in Box 1. Mechanisms vary, with

Introduction
motor vehicle collisions being the commonest. Other
Trauma management requires complex multidisciplinary mechanisms include domestic violence and falls,
team involvement. Pregnancy adds an additional dimension particularly in pregnancy.
to trauma because there are, in effect, two patients in one. In 2012, trauma services in the UK were reorganised into
Maternal and fetal needs must both be considered; however, regional trauma networks commissioned to deliver trauma
the mother’s life takes priority. Members of the trauma team care to specified geographical regions. Each network consists
might be unfamiliar with the obstetric complications that can of a major trauma centre (MTC) with associated trauma
occur even after relatively minor trauma. Likewise, many units (TUs). There are 27 MTCs: 11 serve both adult and
obstetricians will be unfamiliar with trauma services in the
UK and the specialty-specific management of common
trauma complications. We outline the major trauma
pathway in the UK and discuss the maternal/fetal outcomes Box 1. Major trauma call examples
and management considerations of trauma in pregnancy.
 High speed road traffic collisions
 Death of an occupant in the same vehicle
 Fall from two storeys or more
Trauma in general  Prolonged entrapments
 Assault with a weapon
Trauma is a leading cause of mortality and disability around  Crush injuries
the world, accounting for up to 10% of deaths annually.1  Blast injuries
Trauma can be classified according to the Injury Severity  Pedestrian or cyclist versus vehicle
 Motorcycle road traffic collisions
Score (ISS) as ‘Minor (<9)’, ‘Moderately Severe (9-15)’ and  Ejection from a vehicle
‘Major (>15)’. Some examples of trauma that would satisfy a

258 ª 2021 Royal College of Obstetricians and Gynaecologists


paediatric patients, 11 solely adult, and five solely paediatric.
MTCs offer the necessary specialties to manage a trauma
patient, such as neurosurgery, in the same hospital. Prior to
the formation of MTCs, patients were taken to their local
hospitals irrespective of the nature of their injuries. The
restructuring of trauma services aimed to improve trauma
outcomes. This has proved successful: trauma victims who
reached English hospitals alive in 2017 had a 19% increased
chance of survival compared with those in 2008.2
Trauma care is broken down into four stages, defined by
NHS England’s Major Trauma Care Pathway:3
1. Pre-hospital care – this is delivered by the ambulance
service, first responders and Helicopter Emergency
Medical Services (HEMS).
2. Acute emergency care and surgery – the receiving hospital
can be either an MTC or a TU. If transfer time will exceed
45–60 minutes, patients are directed to a TU. The function
of a TU is to provide resuscitative care and expert triage to
allow the patient to be stabilised before transfer to
an MTC.
3. Ongoing care and reconstruction – the appropriate
specialties are consulted and the patient’s injuries
(visceral injury, long bone fractures etc.) are managed.
4. Specialised or local rehabilitation – the aim is to identify
those patients with complex rehabilitation needs and offer
a specialised service. These needs may include primary
neurological trauma, secondary neurological injury (for
example, hypoxic brain injury), new cognitive
impairment, acquired limb loss, or behavioural problems
(such as delirium or established cognitive impairment).
Trauma in pregnancy
Why is this important?
Trauma in pregnancy is relatively common. Approximately
6–8% of all pregnancies are complicated by some degree of
trauma.4 The most common forms of trauma are road traffic
collisions (RTCs), falls and assaults of varying degree.5
Pregnancy has recently been shown to be an independent
predictor for mortality after trauma, with pregnant women
being 1.6 times more likely to die than their nonpregnant
counterparts.6 Table 1 summarises maternal and fetal
complications associated with major trauma.
Road traffic collisions
Motor vehicle-related trauma is common, accounting for
more than half of maternal trauma.5 It can range from
low speed car-on-car collisions to catastrophic car-on-
pedestrian accidents.
An Australian population-based study7 of 600 000
pregnant women found that 2147 were admitted to
hospital following motor vehicle accidents (MVAs); a ratio
of 3.5 per 1000 maternities. Of these patients, 88.6% were
ª 2021 Royal College of Obstetricians and Gynaecologists
Tibbott et al.
Table 1. Maternal and fetal major trauma complications
Maternal Fetal
Haemorrhage Preterm birth
Abruption Hypoxic brain injury
Uterine rupture Death
Disseminated intravascular coagulation
Pelvic/long bone fractures
Hysterectomy
Preterm labour
Death
Post-traumatic stress disorder/depression/anxiety
passengers in a car, 3.4% were pedestrians and 0.8% and
0.9% were motorcyclists and cyclists, respectively. Following
MVAs, 96% remained undelivered and had similar pregnancy
outcomes to women who were not involved in an MVA.
Immediate delivery was only required in 3.5% of pregnancies
past 20 weeks of gestation; however, consequent outcomes
were poor: 58% preterm births, 25% placental abruptions,
61% caesarean sections and 31% perinatal deaths.7 Similar
‘severe’ maternal and fetal outcomes were found in 648
women who were involved in MVAs in Kuwait over a 3-year
period. The authors highlighted high complication rates,
including 59% abruptions, 40% preterm labours and 11%
perinatal mortality.8 Those women wearing seatbelts were
more likely to sustain minor injuries; this is supported by
other studies, which convey improper seat belt use is a major
risk factor for poor maternal outcomes.8,9
Pregnant women should be advised on the proper use of
three-point restraints. The lap belt should pass under the
abdomen and over the iliac spines. The shoulder harness
should be displaced adjacent to the uterus, run between the
breasts and cross the midline of the clavicle.10
Domestic violence, homicide and suicide
In the UK, approximately 8% of women experience some
form of domestic abuse during pregnancy.11 This is higher
than in some European countries, such as Sweden, which has
a prevalence of domestic abuse of 2.5% antenatally and 3.3%
in 1–1.5 years postnatally,12 and Germany, which has a rate of
psychological, physical or sexual abuse during pregnancy of
6.7%.13 We know that domestic violence increases in
259
 Trauma and pregnancy
pregnancy and this has been suggested to be almost twice as
high in pregnant women than nonpregnant women (8307 per
100 000 live births versus 5239 per 100 000 women
respectively).14–16
The MBRRACE-UK (Mothers and Babies: Reducing Risk
through Audits and Confidential Enquiries across the UK)
report for 2014–2016 demonstrated that five out of 14
murders had a strong history of domestic abuse and that all
14 women were killed by either their current or ex-partner.17
This is compared with 33% of murdered nonpregnant
women who are killed by partners or ex-partners.18
Similarly, Stockel et al.13 found that in Germany, the main
perpetrators of abuse during pregnancy were partners or
work colleagues. The UK homicide rate in pregnancy is often
quoted as 0.43 per 100 00017 compared with the US rate of
2.9 per 100 000. This is on a background rate of 2.3 per
100 000 in the USA16 and 0.8 per 100 000 in the UK.18
Suicide in the UK is the third largest cause of direct
maternal death and the largest cause of direct late maternal
death. There were 71 deaths between 2014 and 2016,
equalling a rate of 2.8 per 100 000 pregnancies,17 compared
with 5.5 per 100 000 in the nonpregnant population.19 This,
again, is comparable with the USA, which often quotes two
suicides per 100 000 pregnancies versus 8.8 per 100 000 in
the nonpregnant population.16,20,21 Failed suicide attempts
often present as trauma calls, since the methods of suicide in
pregnancy are much more violent than in the nonpregnant
population, for example, jumping from a height rather
than overdose.22
Burns and fractures
Burns can compound trauma. A case series looked at 51
pregnant patients who sustained mostly unintentional burns.
As the size of the burn increased, so did the maternal and
fetal mortality, and when the burn total body surface area
(TBSA) became greater than 40%, maternal and fetal
mortality was 100%. The presence of inhalation burns was
strongly associated with maternal mortality.23 However, the
data are inconsistent – a different study showed that when a
15–25% TBSA burn was present, the risk of fetal loss was
high at 56%, but with no maternal deaths.24
Fractures of the pelvis, in particular acetabular fractures
in the third trimester, are a concern for fetal skull fractures,
with an incidence of 18%. When a fetal skull fracture is
present, the risk of fetal death is 42%.25 A different study
focusing on pelvic fractures found that high mortality
rates were related to the influence of the mechanism
of injury.26
Long-term sequelae
It is important to emphasise that trauma in pregnancy has
not only immediate complications but potentially long-
lasting effects on women. Significant trauma is a known risk
260
factor for post-traumatic stress disorder (PTSD) and long-
term depressive illness.27 This may be the result of reliving
the event, dealing with life-changing injuries, or bereavement
over a pregnancy loss. For example, in the case of a patient
involved in a high-speed RTC with consequent uterine
rupture, fetal demise and major haemorrhage is controlled
with a hysterectomy. Potential ramifications include the
psychological effects of the event, loss of the pregnancy and
loss of reproductive ability.
Trauma management in the pregnant
patient
The Advanced Trauma Life SupportTM (ATLSTM)28 course
provides a basis for a structured approach to the
management of major trauma. The European Trauma
Course (ETC) complements this, with a focus on a team-
based approach and regional requirements.29
The initial principles of trauma management encompass
preparation, triage, primary survey (‘ABCDE’) and
resuscitation. This is followed by a secondary survey
(history and thorough evaluation), continued reassessment
and definitive care. The purpose of the primary survey is to
identify life-threatening injuries and initiate resuscitation in
the first or ‘golden hour’. The ‘ABCDE’ approach28 of
the primary survey is described below, with special
considerations in pregnancy outlined.
A: Airway and cervical spine control
The airway is assessed for actual or impending airway
compromise. A Glasgow Coma Scale (GCS) score of 8 or less
requires the insertion of a definitive airway. In major trauma,
cervical spine injury is assumed until proven otherwise and
protection of the spine and spinal cord is paramount.
A definitive airway is considerably harder to achieve in
pregnant women owing to tissue oedema.30 Combined with
any facial trauma or burns injury, this can lead to a higher
rate of failed tracheal intubation. Mortality of failed
intubation in a pregnant patient can be as high as 1%,
usually secondary to aspiration of gastric contents.30 Front-
of-neck access is a technique explored on the ‘Managing
Medical and Obstetric Emergencies and Trauma (mMOET)’
course, but an increase in neck adiposity and oedema in
pregnant patients adds complexity to this procedure.31 It is
recommended that an experienced practitioner secures a
definitive airway early, following the joint Obstetric
Anaesthetists’ Association and Difficult Airway Society’s
guidelines for difficult and failed intubation in obstetrics.31
B: Breathing
Once airway patency is assured, respiratory ventilation is
evaluated and life-threatening chest trauma is treated. If
ventilation is compromised, supplemental oxygen can be
ª 2021 Royal College of Obstetricians and Gynaecologists

provided and intubation with rapid sequence induction (RSI)
should be considered, as well as chest decompression if
appropriate. Chest decompression is achieved via insertion of
a chest drain but, in a pre-hospital suspected tension
pneumothorax, a chest drain might not be inserted in a
timely fashion. Thus, decompression by a needle
thoracostomy should first be performed.
The gravid uterus compresses lung bases, reducing the
functional residual capacity and hence oxygen stores. This
feature, coupled with increased oxygen requirement in
pregnancy, makes pregnant patients prone to rapid
desaturation, with shorter durations of hypoxia. Splinting
of the diaphragm that occurs with the gravid uterus makes
pregnant patients harder to ventilate.32 There are
recommendations that, owing to this visceral displacement,
the incision for a chest drain should be one to two intercostal
spaces higher than the usual fifth intercostal space.33
C: Circulation and haemorrhage control
Efforts are made to minimise haemorrhagic shock. Any
external haemorrhage should be ceased and tissue perfusion
assessed. Adequate intravenous access is required to facilitate
fluid resuscitation.
A recent shift in fluid replacement strategy has been to give
blood products earlier and, in particular, not just red cells.
Each unit usually has its own major haemorrhage packs but,
predominantly in trauma, plasma, platelets and red blood
cells are now given in a 1:1:1 ratio.34 This is often guided by
point-of-care coagulation tests such as ROTEM. This
specifies which component of the coagulation pathway is
deficient and aids a tailored approach to replacement therapy
in close liaison with haematology.35
After trauma, coagulopathy is a major concern because
trauma-induced coagulopathy (TIC) is exacerbated by
trauma-associated coagulopathy (TAC).36 TIC is caused by
the assault of trauma itself on the patient, which alters the
dynamic equilibrium of platelets, the endothelium,
procoagulant factors and anticoagulant factors. A
consumptive coagulopathy with hyperfibrinolysis ensues,
with the underlying pathophysiology being synonymous
with disseminated intravascular coagulation with
fibrinolytic phenotype.37 In contrast, TAC is associated
with the physiological conditions of a trauma patient.
These can be broadly divided into acidosis, hypothermia
and haemodilution.36 In major trauma, large volumes of
fluid are lost, but also given. The use of rapid infusers that
warm blood, and fluid products, can help to negate
the potential hypothermia caused by high-volume
fluid resuscitation.
Obstetricians will be well versed with the findings from the
WOMAN trial, which showed that the use of tranexamic acid
in postpartum haemorrhage led to a reduction in death by
bleeding.38 However, fewer may be as aware of the results of
ª 2021 Royal College of Obstetricians and Gynaecologists
Tibbott et al.
the CRASH-2 trial.39 Tranexamic acid was given to
nonpregnant patients as a 1-g bolus given over 10 minutes,
followed by an infusion of 1 g over 8 hours, and this also
showed a reduction in death by bleeding. Since the
publication of this trial, tranexamic acid is used routinely
in trauma patients.
Aortocaval compression becomes increasingly important
after 20 weeks of gestation. Care should be given to displace
the gravid uterus or consider delivery of the fetus to aid
maternal resuscitation.40 A perimortem caesarean section
(PMCS) is primarily for maternal survival. In women over 20
weeks of gestation, this should be commenced after no
response to correctly performed cardiopulmonary
resuscitation (CPR) within 4 minutes of witnessed collapse,
and be achieved within 5 minutes of witnessed collapse.41
Consideration here should be given to revealed (per vagina)
bleeding or concealed (retroplacental or intra-abdominal)
bleeding. If the patient is more unstable than the visual
amount of blood loss would suggest, an intra-abdominal
source should be considered. This can be from a surgical
cause (for example, splenic or hepatic rupture) or an
obstetric one (such as abruption, uterine rupture or broad
ligament haematoma). Anti-D immunoglobulin must be
given to all Rh D-negative women and a Kleihauer–Betke
(KB) test should be taken to determine the need for further
anti-D.
D: Disability
A brief neurological examination is conducted to ascertain
level of consciousness, pupillary responses and lateralising
signs. A traumatic injury to the head can lead to intracranial
hypertension. This should be managed early with
conservative and medical measures, while requesting a
neurosurgical consultation. Strategies aim to prevent
progression to eventual brain stem herniation.
If traumatic brain injury is suspected, maternal
hyperventilation is a therapeutic strategy to induce
hypocapnia and cerebral vasoconstriction, thus reducing
intracranial hypertension. However, hypocapnia can also lead
to a maternal alkalosis, causing uterine vasoconstriction and
a left shift in the maternal oxygen dissociation curve, thus
reducing uteroplacental oxygen transfer.32
E: Exposure and environment
Clothing should be removed to aid prompt access and
examination of the patient. Particular attention should be
given to evaluating any revealed or nonrevealed bleeding.
Abdominal signs on examination may guide clinical
diagnoses and subsequent management (for example, hard
woody abdomen in placental abruption). Temperature
should be measured and normothermia maintained with a
warm environment and specific management considerations,
such as forced-air warming and warmed fluids.
261
 Trauma and pregnancy
Imaging
In major trauma in the UK, early imaging is the gold-
standard investigation, recommended by the National
Institute for Health and Care Excellence (NICE). It usually
takes the form of whole-body computed tomography (CT).
This has been shown to improve survival outcomes in the
trauma patient compared with no CT or focused CT.42 In the
pregnant patient, concerns for the fetus can lead to delays in
diagnosis and treatment, resulting in morbidity and mortality
to both mother and fetus.43 The Royal College of Radiologists
(RCR) addresses this by stating that the life of the mother
takes precedent over the fetus.44 A single trauma CT is not
thought to have detrimental effects on the fetus in utero, so –
if indicated – a trauma CT should not be delayed.4 Fetal
radiation exposure of <50 mGy has not been associated with
fetal anomalies, growth restriction or miscarriage, and
diagnostic imaging in trauma will likely expose the fetus to
less than this this amount.45,46 For reference, Table 2 outlines
the expected fetal radiation dose ranges in various
CT studies.45
Ultrasound extended focused assessment of trauma
(eFAST) is used in some parts of the world for initial
trauma, but in the UK, the RCR suggests that it is unlikely to
add more to a CT so should not delay transfer to a CT
scanner. The RCR comments that it is a poor discriminator
for the need for a laparotomy because the negative predictive
value of a FAST scan is 50–63% in unstable patients.44
The fetus
In the context of trauma, the mother’s life takes priority over
that of the fetus. Benefits to the fetus should only be
considered when the mother is stabilised. A hysterotomy may
be required if trauma is sufficiently extensive and maternal
life is in danger. At 21 weeks of gestation, this will condemn
the fetus; however, neonatal outcomes have improved
significantly at the extremes of viability. MBRRACE-UK
Table 2. Fetal radiation dose ranges in computed tomography studies
Type of imaging Fetal radiation dose (mGy)
Head and neck CT 0.001–0.01
Chest CT 0.01–0.66
Abdominal CT 1.3–35
Pelvic CT 10–50
Abbreviations: CT = computed tomography
262
reported that in 2017, 29.6 % of babies born between 22 and
23 weeks of gestation survived up to 28 days, rising to 85.5%
at 24–27 weeks of gestation.47 The improvements in
survivability have largely been associated with developments
such as continuous positive airway pressure (CPAP) and
mechanical ventilation in the 1980s, exogenous surfactant
and antenatal corticosteroids in the mid-1990s and targeted
oxygen therapy in the 2000s.48
If there is time and opportunity, several interventions may
benefit the fetus. If preterm labour should occur, efforts to
transfer to a unit that can provide adequate neonatal support,
in addition to the mother’s ongoing care needs, may improve
fetal survival. The EPICure 2 study showed that extremely
preterm infants born at a level 3 neonatal unit had better
survival than if they were born at a level 2 unit.49
Nevertheless, establishment of labour or a deterioration of
clinical state may mean there is insufficient time to transfer
the mother.
Consideration should be given to antenatal corticosteroid
administration, particularly in infants who are likely to be
born vaginally and preterm before 36 weeks of gestation, or
by a caesarean section before 39 weeks of gestation. The
known benefits include reduction in respiratory distress
syndrome, intraventricular haemorrhage and perinatal death
with a single course of steroids given antenatally.50 In
children born before 32 weeks of gestation, magnesium
sulphate significantly reduces the incidence of cerebral palsy
and severe motor dysfunction at the age of 2 years, with the
number needed to treat to prevent one case of cerebral palsy
being 63.51 In trauma, administration of magnesium sulphate
should occur before delivery of the fetus; however, this may
not always be practicable. For example, in maternal cardiac
arrest occurring after 20 weeks of gestation, delivery of the
fetus cannot be delayed to administer magnesium sulphate.
Fetal monitoring
Stabilisation of the mother must occur before fetal
monitoring can take place. If evacuation of the uterus
would stabilise the mother (for example in a case of maternal
cardiac arrest after 20 weeks of gestation), then this should be
the priority, not monitoring the fetus.52 An obstetric
assessment should occur only once the mother is stable.
Viability can be assessed using ultrasound scanning or fetal
heart auscultation, and a cardiotocograph (CTG) can be
performed after 26 weeks of gestation. In the context of
trauma, abnormal antenatal CTGs may be the first sign of an
abruption, especially if the mother is intubated.
A normal antenatal CTG is reassuring, but there is
uncertainty about the duration of monitoring. One small
case study noted no abruptions when uterine activity was less
than one contraction every 10 minutes and the CTG had
been normal for 4 hours. Subsequently, as a guide, it is
ª 2021 Royal College of Obstetricians and Gynaecologists

recommended that CTG monitoring can be discontinued
after 4 hours if uterine activity is less than one contraction
in 10 minutes, there is no vaginal bleeding and no
abdominal pain.16
Conclusion
Although trauma may differ substantially in its presentation
and severity, the approach to management is structured.
Priority is always given to the mother in decision making and
hesitant imaging or fetal monitoring should not delay
resuscitation of the mother in favour of the fetus. Despite the
improved outcomes resulting from trauma service
restructuring in the UK, pregnancy remains an independent
predictor for mortality. An appreciation of the scope of trauma
in the pregnant patient, as well as the effect of obstetric
physiology on trauma management, is vital for all team
members to ensure the best possible outcomes for our patients.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
JT researched the literature and wrote the manuscript. MDC
researched the literature and contributed to the content and
reviewed the draft manuscript. RM and EC contributed to
the content and reviewed the draft manuscript. All authors
approved the final version.
Supporting Information
Additional supporting information may be found in the
online version of this article at http://wileyonlinelibrary.com/
journal/tog
Infographic S1. Trauma and pregnancy
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ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12761 2021;23:265–77
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Adrenal disease and pregnancy: an overview

Mayada Ahmed MBBS CABOG,a Mohammed Bashir MBBS MD FRCP(Ir),b Gbemisola O Okunoye MBBS FWACS FRCOG
MBA, Justin C. Konje MD FWACS FMCOG (Nig) FRCOG MBA*
c d

a
Specialist in Obstetrics and Gynaecology, Women Wellness and Research Centre (WWRC), Hamad Medical Corporation, Doha, Qatar
b
Senior Consultant Endocrinologist, Women Wellness and Research Centre (WWRC), Hamad Medical Corporation, Doha, Qatar
c
Senior Attending Physician and Assistant Professor of Obstetrics and Gynaecology, Weill Cornell Medicine, Sidra Medicine, PO Box 26999, Doha,
Qatar
d
Emeritus Professor of Obstetrics and Gynaecology, University of Leicester, UK
*Correspondence: Justin Konje. Email: jck4@leicester.ac.uk

Accepted on 12 October 2020. Published online 13 August 2021.

Key content Learning objectives

 Although uncommon, adrenal disorders in pregnancy are
associated with severe complications, especially if undiagnosed or
poorly managed.
 Some women are on long-term steroids (especially those known to
suffer from adrenal insufficiency) that suppress endogenous
adrenal function. Under stress, these can become insufficient –
particularly around labour and the puerperium.
 Adrenal insufficiency, for example, has been associated with
maternal and fetal morbidity and mortality if untreated, while
phaeochromocytoma is associated with considerable
maternal mortality.
 Clinical features, diagnosis and management of the disorders of the
adrenals in pregnancy are discussed, including Cushing’s
syndrome, adrenal insufficiency, phaeochromocytoma and
paragangliomas, primary aldosteronism and congenital
adrenal hyperplasia.
 To understand the physiological changes in the adrenal system
during pregnancy.
 To understand the clinical features of common adrenal problems
in pregnancy and how they can be diagnosed and managed to
minimise complications, especially acute adrenal insufficiency.
 To understand how the management of adrenal disorders is altered
in pregnancy and the effect of adrenal diseases on pregnancy.
Ethical issues
 Is there a role for in utero therapy if a prenatal diagnosis is made?
 Does treatment of the mother affect the fetus?
 Is optimal treatment of the mother limited by concerns for
the fetus?
Keywords: adrenal insufficiency / corticosteroids / Cushing’s
syndrome / hyperaldosteronism / phaeochromocytoma

Please cite this paper as: Ahmed M, Bashir M, Okunoye GO, Konje JC. Adrenal disease and pregnancy: an overview. The Obstetrician & Gynaecologist 2021;23:265–
77. https://doi.org/10.1111/tog.12761

previously associated with reduced fertility (e.g. Cushing’s

Introduction
Adrenal disease complicating pregnancy is rare1 and, as such,
presents considerable challenges for timely diagnosis and
treatment.2 Delay in recognition and diagnosis during
pregnancy has been responsible for the increased fetal and
maternal morbidity and mortality associated with these
disorders.3,4 The average practising obstetrician has limited
experience in the management of pregnancies complicated by
adrenal disease, underscoring the need for increased awareness
of the differentiating features of the major adrenal disorders
encountered. These disorders include primary adrenocortical
insufficiency (Addison disease), Cushing’s syndrome, primary
aldosteronism (PA), congenital adrenal hyperplasia (CAH)
and phaeochromocytoma and paraganglioma (PPGL). In
addition, developments in assisted reproduction and
advances in medical diagnostics and treatment of disorders
syndrome) have led to more women achieving pregnancy with
coexisting adrenal disorders. Therefore, timely recognition,
diagnosis and involvement of clinicians with appropriate
expertise are essential for optimising fetal and maternal
outcomes in these high-risk pregnancies.5 This article
presents an overview of adrenal diseases complicating
pregnancy, highlighting differentiating features, diagnosis
and risk reduction management approaches during pregnancy.
Primary adrenal insufficiency (Addison
disease)
Adrenal insufficiency (AI) can be classified into primary,
secondary and tertiary.6 Primary AI in pregnancy is
uncommon, with an estimated prevalence of about 1 in
3000 to 5.5 in 100 000 pregnancies.1,4,6,7 It results from

ª 2021 Royal College of Obstetricians and Gynaecologists 265

 Adrenal disease and pregnancy

adrenocortical disease, while secondary and tertiary AI are
associated with adrenocorticotropic hormone (ACTH) and
corticotropin-releasing hormone (CRH) secretion disorders,
respectively. Primary AI results from both glucocorticoid
(GC) and mineralocorticoid (MC) deficiencies, whereas
secondary and tertiary AI result mainly from cortisol
deficiency; this is because the hypothalamic–pituitary–
adrenal axis does not regulate MC production.
Autoimmune atrophy of the adrenal gland accounts for
70–90% of primary AI.8 Other causes include haemorrhage
secondary to sepsis, or major burns, lymphoma, metastasis
and infections such as tuberculosis.8,9
Figure 1 shows the changes in cortisol secretion during
pregnancy. Cortisol levels increase to a peak, on average at
the 26th week of pregnancy.10 Estrogen increases the
production of corticosteroid-binding globulin (CBG), while
the placenta increases the production of both CRH and
ACTH, thus increasing their circulating levels, as well as free
and total cortisol levels.11,12 Importantly, the diurnal
rhythmic variation in cortisol levels is maintained, with the
nadir around bedtime.13
Diagnosis
Women with primary AI tend to have lower fertility rates;
hence, most are diagnosed before pregnancy and are therefore
likely to be on established doses of both GC and MC
replacements.14 Diagnosing primary AI for the first time in
pregnancy is challenging, especially as the symptoms – such as
nausea, vomiting, lethargy and increased pigmentation –
overlap with those of pregnancy.15,16 However, features highly
suggestive of primary AI include significant weight loss,
prolonged vomiting, hyperpigmentation in skin folds,
hypoglycaemia, hyponatraemia and hyperkalaemia.1 The
hyperpigmentation in AI is commonly on mucous
membranes, extensor surfaces and nonexposed regions of the
body. This differentiates it from pregnancy-associated
changes.17 Symptoms of adrenal crisis could also be triggered
by stress, induced, for example, by hyperemesis, infections,
vaginal delivery or caesarean sections.14
The physiological changes associated with pregnancy make
the interpretation of biochemical tests for diagnoses of AI
problematic. These physiological changes include increased
circulating cortisol levels (2 to 3-fold higher at term than in
nonpregnant women), estrogen-induced increased
corticosteroid binding globulin (CBG), increased cortisol
half-life secondary to decrease in hepatic clearance and
placental production of cortisol-releasing hormone (CRH),
which induces adrenal hypertrophy and enhances its
responsiveness to synthetic ACTH administration.18 In
nonpregnant cases, the diagnosis is highly likely if morning
cortisol level is <140 nmol/L in combination with an elevated
plasma ACTH concentration (>2-fold above the upper limit
of the reference interval).19 A short Synacthen stimulation
test (SST) should be performed in suspected cases unless
basal results are unequivocal. The test involves the
intravenous or intramuscular administration of
250 micrograms (ug) of a synthetic ACTH, preferably in
the morning. A normal response to the SST is a rise in serum
cortisol concentration after either 30 or 60 minutes to
≥500–550 nmol/L. This cut-off value is, however, unreliable
in pregnancy: following stimulation with 250 ug synthetic
cortisol, Suri et al.18 showed that all second and third
trimester women had values exceeding 20 ug/dl (555 nmol/L),
implying that using this will result in underdiagnosis of AI
in pregnancy.18 Furthermore, such a response (of serum
cortisol >20 ug/dl (555 nmol/L) from the SST) also excludes
primary and secondary AI.17 It has been suggested that
salivary free cortisol may be consistent, generalisable and a
physiologically rational measure of adrenal function in
pregnancy, rather than total cortisol. Its use offers

Total and free cortisol The peak is at 26 weeks

levels are increased
Total and free Diurnal variation is maintained
cortisol

ACTH directly acts on the adrenal gland

Placenta increases the
ACTH-CRH secretion of ACTH and CRH CRH stimulates the adrenal gland
directly and indirectly

CBG Estrogen stimulates Pituitary ACTH levels increase

the production of CBG Increase in adrenal cortisol secretion

Figure 1. Changes in the pituitary–adrenal physiology with pregnancy.Abbreviations: ACTH = adrenocorticotropic hormone; CBG =
corticosteroid-binding globulin; CRH = cortisol-releasing hormone

266 ª 2021 Royal College of Obstetricians and Gynaecologists


advantages such as it is noninvasive and can be performed in
an outpatient setting. However, owing to the increase in
CBG, pregnant women with highly suggestive clinical
features but an indeterminate SST should be offered
treatment during pregnancy and retested after delivery.
The presence of adrenal antibodies is suggestive of an
autoimmune aetiology.8 Radiological imaging is not
routinely used in investigating pregnant women with
suspected primary AI and should be deferred till
after delivery.
Management
Management of primary AI is best provided by a joint team
of obstetricians and endocrinologists.7 The replacement
regimen for primary AI in pregnancy is like that for
nonpregnant patients. Hydrocortisone (HC) is the
preferred GC because it is short acting and does not cross
the placenta. Besides, a typical dose between 15–25 mg in two
to three divided doses mimics the physiological diurnal
variation in cortisol secretion.19 Fludrocortisone at a dose of
between 0.05 mg and 0.1 mg/day is sufficient for MC
replacement in most patients. Prednisolone at a dose of 3–
5 mg once daily could be used for GC replacement in
patients with poor compliance. There are no data and no
widely accepted recommendations for managing GC doses in
pregnancy. There is an overlap between symptoms of AI and
pregnancy, including postural hypotension and fatigue.
However, the occurrence of these symptoms during
pregnancy from the 24th week of gestation onwards might
prompt an increase in the doses of GC and/or
fludrocortisone.19 HC has an MC effect: 40 mg of HC
equals 0.1 mg of fludrocortisone. Hence, an increase in
fludrocortisone is not essential. However, prednisolone does
not have an MC effect and the fludrocortisone dose might be
increased by 20–30%.
Acute adrenal insufficiency
Acute AI (Addisonian crisis) in pregnancy is a rare, life-
threatening emergency. It could be confused with a surgical
acute abdomen, owing to the presenting symptoms of
abdominal pain, vomiting and shock.2 Therefore, a high
index of clinical suspicion is required. Adrenal crisis may
occur in patients with primary or secondary AI, especially in
the setting of severe hyperemesis with decreased absorption
of medications. In patients not previously known to have
adrenal disease, it may result from sudden bilateral adrenal
necrosis caused by haemorrhage, sepsis or adrenal vein
thrombosis.9 It may also occur in women who are being
treated with pharmacological doses of steroids20,21 during
pregnancy; for example, if their GC or MC requirements are
acutely unmet during stressful events such as illness, labour
or surgery. Sudden withdrawal of therapeutic doses of
systemic GCs (both oral and inhaled) during pregnancy
ª 2021 Royal College of Obstetricians and Gynaecologists
Ahmed et al.
may precipitate adrenal crisis, hence systemic steroids should
always be tapered off gradually. Therefore, patients who have
used 5–20 mg or more of prednisolone (or equivalent) per
day for 3 weeks or more during pregnancy should have
intravenous HC intrapartum at a dose of 50–100 mg 8-
hourly for up to 24 hours to reduce the risk of acute AI.
Prompt evaluation and concurrent treatment is needed to
reduce morbidity and mortality following diagnosis.
Intravenous access should be secured, and blood samples
taken for ACTH, cortisol, glucose and serum electrolytes,
while treatment is initiated promptly with intravenous saline
as well as intravenous HC. Two to three litres of 0.9% saline
or 5% dextrose in 0.9% saline should be administered as
quickly as possible for patients in shock. Fluid rate should be
subsequently adjusted based on urine output and volume
status. HC is administered at a dose of 100 mg every 6–
8 hours, or as a continuous infusion of 200–300 mg in
24 hours, with monitoring of vital signs and serum
electrolytes. Recovery is typically quick, usually within
24 hours of commencing treatment. Parenteral HC should
be tapered over 1–3 days; after this, most patients can be
switched to oral treatment with HC and fludrocortisone.1,4
The precipitating cause of acute adrenal crisis should be
carefully investigated and treated to prevent a recurrence.
Box 1 summarises the management of this medical
emergency. The ‘sick day rules’ have been developed to
reduce the risk of acute AI.
Sick day rules and stress doses
The ‘sick day rules’ are a set of measures aimed to prevent the
occurrence of adrenal crisis. Women with primary AI should
be educated on these rules. During pregnancy, hyperemesis,
infections, delivery and surgery could trigger adrenal crisis.
Figure 2 summarises the sick day rules that should be
reviewed in every single visit.22 When there is a birth partner,
we recommend they are also trained on the use of
intramuscular HC injections. Women with primary AI who
Box 1. Treatment of acute adrenal insufficiency (adrenal crisis) in
pregnancy1
1. Prompt intravenous access with wide bore cannula
2. Take blood samples for serum electrolytes, glucose,
adrenocortocotropic hormone (ACTH) and cortisol
3. Administer 2–3 litres of 0.9% saline or 5% dextrose saline and
titrate rate based on urine output and improvement of shock
4. Give intravenous hydrocortisone 100 mg administered 6–8 hourly,
or a continuous infusion of 200–300 mg/24 hours
5. Monitor vital signs using the modified obstetric early warning scores
parameters
6. Search for the cause of the adrenal crisis and treat appropriately
7. Fetal assessment and monitoring (gestation dependent)
8. Taper intravenous hydrocortisone over 1–3 days as the patient
recovers and start oral replacement therapy
267
 Adrenal disease and pregnancy

Sick day rules

Double the dose of Provide IM HC for

Always wear a medical
oral GC in cases of self-administration in
alert bracelet or
fever or illness cases of gastroenteritis
necklace
requiring bedrest or during fasting

Management of GC and MC during delivery and postnatally

1 Delivery day 4 Discharge 5 Follow-up

• Give 200 mg/day of HC in • Discharge of HC • Arrange follow-up in

divided doses, IV or oral 30–35 mg/day endocrine clinic
• Hold fludrocortisone • Restart fludrocortisone • Dose of HC could be
dose brought down to
prepregnancy levels
• Dose of fludrocortisone
2 Day 1 postnatal 3 Day 2 postnatal could be adjusted
• Encourage breastfeeding
• Give 100 mg/day of HC in • Give 50 mg/day of HC in
divided doses, IV or oral divided doses, IV or oral
• Hold fludrocortisone • Hold fludrocortisone

Figure 2. Management of glucocorticoids and mineralocorticoids during delivery and in the puerperium. Abbreviations: GC = glucocorticoids; HC
= hydrocortisone; IM = intramuscular; IV = intravenous; MC = mineralocortocoids

present with hyperemesis should receive intravenous HC,
typically at a dose of between 100 and 200 mg/day, together
with appropriate fluid resuscitation.18 During labour and
delivery, stress doses of GCs should be administered, but
there are no controlled studies on optimal dosing. Figure 2
summarises a proposed approach to labour and delivery.23
Pregnancy outcomes and breastfeeding
Vaginal delivery should be encouraged in women with
primary AI, and caesarean delivery should be reserved for
obstetric indications. Close attention should be paid to risk
assessment for venous thromboembolism, especially in the
peripartum period, and appropriate prophylaxis instituted.7
The outcome for patients with adequately treated primary AI
is good, but there is an increased risk of adverse fetal
outcomes, such as fetal growth restriction (FGR). There is
also an increased risk of maternal morbidity in untreated
patients or those with delayed diagnosis during pregnancy.1,7
Suboptimal replacement therapy, especially in stressful
scenarios, as well as poor maternal education and
compliance can also increase maternal risks. These risks
include preterm delivery, caesarean section, poor wound
healing, thromboembolism and acute adrenal crisis.2,7,10
Although maternal adrenal antibodies cross the placenta,
there is no significant effect on the fetal adrenal gland. Both
HC and prednisolone are excreted in breast milk in very low
amounts that are unlikely to harm the baby.24,25
Cushing’s syndrome
Cushing’s syndrome is characterised by increased cortisol
levels and, in the ACTH-dependent types and some adrenal
cancers, elevated androgens. It is rare for untreated women to
be pregnant because most will be amenorrhoeic, anovulatory

268 ª 2021 Royal College of Obstetricians and Gynaecologists


and suffer from irregular periods.15, 26,27 A timely diagnosis,
early initiation of treatment and individualised care by a
multidisciplinary team of specialists are therefore critical for
optimising pregnancy outcomes because, when improperly
treated, these are invariably poor.
Aetiology
Adrenal adenomas account for 60% of reported cases in
pregnancy, whereas pituitary-dependent Cushing’s syndrome
accounts for 70% of those outside pregnancy.28 Adrenal
adenomas do not cause excess androgen secretion hence are
less likely to cause menstrual irregularities. On the other
hand, adrenal hyperplasia and some adrenal carcinomas
produce large amounts of androgens and spontaneous
pregnancy is very unlikely. Pregnancy-associated Cushing’s
syndrome is defined as onset occurring during gestation or
within 12 months of delivery or miscarriage.29 This may
result from nodular hyperplasia of the adrenals stimulated by
placentally produced ACTH, or as a result of stimulation of
ACTH receptors in a pre-existing but undiagnosed adrenal
adenoma by ACTH from the placenta.28,30
Diagnosis
The timely diagnosis of Cushing’s syndrome in pregnancy
presents a unique challenge. As shown in Figure 1, pregnancy
is associated with elevated cortisol levels, which affect the
results of some diagnostic tests, especially the low-dose
dexamethasone suppression test.30 In addition, pregnancy-
associated features, such as weight gain, hypertension, striae,
fatigue and glucose intolerance, overlap with features of
Cushing’s syndrome.15,17 Differentiating clinical features of
Cushing’s syndrome include proximal myopathy, easy
bruising, osteopenia/osteoporosis-induced fractures and
hirsutism from increased androgens, early onset
hypertension in pregnancy and the presence of red or
purple striae (instead of pale striae of normal pregnancy).15,26
A composite of diagnostic tools should be considered in
pregnant women who present with features suggestive of
active Cushing’s syndrome. A midnight plasma cortisol level
could be used as the preliminary screening test because the
diurnal variation of cortisol is maintained during pregnancy,
although with a higher nadir than in the nonpregnant
population.26 The use of salivary cortisol at night, in
combination with urinary free cortisol (UFC), are reliable
confirmatory diagnostic tools in pregnancy. Late-night
salivary cortisol and UFC values greater than three times
the upper limit of normal are diagnostic of Cushing’s
syndrome in pregnancy.26,30 Recommended thresholds for
salivary cortisol for the first, second and third trimesters are
<6.9 nmo/l, <7.2 nmol/l and <9.1 nmol/l, respectively;
however, this may vary depending on the assay.12,31 The
low dose (1 mg) dexamethasone suppression test may lead to
false positive results because of pregnancy-induced
ª 2021 Royal College of Obstetricians and Gynaecologists
Ahmed et al.
hypercortisolism, but failure to suppress cortisol following
a high dose of dexamethasone (8 mg) is in keeping with a
diagnosis of Cushing’s syndrome in pregnancy.15,26 However,
the usual postdexamethasone ACTH suppression in
Cushing’s syndrome (which is confirmatory of diagnosis) is
often not observed in pregnancy, probably because placental
ACTH production is not suppressed by dexamethasone.26
Patients without cortisol suppression after high doses of
dexamethasone and with a normal to low ACTH (<4.4 pmol/
l) level are likely to have adrenal Cushing’s syndrome, while
patients with cortisol suppression following dexamethasone,
but with a high ACTH (>4.4 pmol/l) are likely to have
pituitary dependent Cushing’s syndrome. Magnetic
resonance imaging (MRI) is a useful imaging modality for
suspected pituitary lesions, as well as adrenal masses. Indeed,
it is better than ultrasound scan for imaging the adrenals.32 It
is important to note that gadolinium-based MRI is
contraindicated in pregnancy. There is no useful guide on
the use of CRH as a diagnostic tool during pregnancy.26
Management
Previously well-treated Cushing’s syndrome in complete
remission does not significantly alter the course of pregnancy.
However, untreated or poorly treated Cushing’s syndrome
and Cushing’s syndrome diagnosed during pregnancy are
associated with significantly more maternal and fetal adverse
outcomes.15 Maternal complications include gestational
diabetes, gestational hypertension, pre-eclampsia, wound
infection, heart failure, psychiatric disorders and – rarely –
maternal death.9,28 The fetus is relatively shielded from
maternal hypercortisolism through the enzymatic conversion
of cortisol to the biologically inactive cortisone by the
placental enzyme 11-b hydroxysteroid dehydrogenase type 2.
Despite this relative protection, active Cushing’s syndrome is
associated with significantly more fetal risks including
miscarriage, FGR, preterm delivery, stillbirth and
neonatal AI.14,28,31
Pregnancies in women with Cushing’s syndrome should be
managed by a team of specialists including obstetricians,
endocrinologists, anaesthetists, neonatologists and surgeons.
This provides a holistic approach with an individualised
timely treatment decision. Ideally, prepregnancy treatment of
known cases of Cushing’s syndrome should be undertaken to
achieve successful treatment before conception. Once
diagnosis is made during pregnancy, early initiation of
treatment for Cushing’s syndrome is associated with
improvement in the live birth rate.30
Surgical treatment, which is more successful than medical
treatment for both adrenal and pituitary dependent
Cushing’s syndrome, is regarded as the treatment option of
first choice.15,26 Successful laparoscopic unilateral
adrenalectomy and trans-sphenoidal surgery have been
reported with good outcomes in the second trimester of
269
 Adrenal disease and pregnancy
pregnancy and, for refractory cases, bilateral adrenalectomy
may be considered.26,28,30,31 Adequate preoperative
assessment and close monitoring in a critical care setting in
the immediate postoperative period are essential to reduce
maternal and fetal morbidity. The role of empirical tocolysis
in the perioperative period is uncertain and should be
decided on an individualised basis. Surgically treated patients
who are in remission should be managed as having AI and
should receive HC supplementation to maintain urinary
cortisol in the normal pregnancy range. This
supplementation is particularly important in the
intrapartum and immediate postpartum period.
Medical treatment is a reasonable second-line option in
those patients who are not fit or suitable for surgery.
Metyrapone, a steroidogenesis inhibitor, is the most widely
used. It reduces cortisol level by inhibiting the conversion of
11-hydroxycortisol to cortisol.26 Metyrapone use increases
the risk of hypertension through the accumulation of MC
precursors, so careful monitoring is required. Ketoconazole,
which has a theoretic risk of teratogenicity,33 and mitotane,
should be avoided in pregnancy because of the risk of
teratogenicity.1,2 Cabergoline can be used as an alternative to
metyrapone in pituitary-dependent Cushing’s syndrome.
Optimal treatment of gestational hypertension, adequate
glycaemic control and prompt assessment and management
of preterm labour are all equally important in improving
pregnancy outcomes in patients with Cushing’s syndrome. In
the absence of specific contraindications, vaginal delivery
should be encouraged, particularly because of the increased
risks associated with caesarean delivery, including poor
wound healing. A plan for follow-up in the endocrinology
service should be made postpartum to ensure a seamless
transition of care.
Primary aldosteronism (Conn’s disease)
In primary aldosteronism (PA) disorders, aldosterone
production is inappropriately high for sodium status,
relatively autonomous of the major regulators of secretion
(angiotensin II and plasma potassium concentration), and
non-suppressible by sodium loading.34 The inappropriately
elevated aldosterone leads to tissue damage, suppression of
plasma renin and hypokalaemia, sodium retention,
hypertension, cardiovascular and renovascular diseases.34
The most common causes of PA are bilateral idiopathic
hyperaldosteronism (60–70%) and unilateral adrenal
adenoma (30–40%). Unilateral adrenal hyperplasia, familial
hyperaldosteronism type I, and pure aldosterone-producing
adrenocortical carcinoma are rare causes.
In the nonpregnant state, PA was estimated to account for
<1% of hypertension, owing to the detection method that
required the presence of hypokalaemia.35 Since hypokalaemia
is no longer a prerequisite, PA is currently estimated to
270
account for 3–15% of all patients with hypertension.36 In
pregnancy, establishing a diagnosis of PA is challenging, as
detailed below. While general hypertensive disorders
complicate 5–10% of pregnancies, the estimated reported
prevalence of PA in pregnancy is between 0.6% and 0.8%.37
However, as only about 50 pregnant cases have been reported
in the literature, PA in pregnancy is likely to be
underreported owing to the challenging detection methods.38
Clinical features and pregnancy outcomes
The classical presentation of nonpregnant patients is with
hypertension and hypokalaemia (present in less than 40% of
patients).39 In a review of 40 pregnancies in women
diagnosed with PA during pregnancy, 81% had
hypertension for the first time in pregnancy, while 19%
had been previously diagnosed with hypertension but not
screened for PA.40 Hypokalaemia was common, occurring in
68% of the cases.40 Hypertension was controlled in 19% (two
on diuretics), uncontrolled despite medical treatment in 32%
of cases, and 16% of cases required adrenalectomy during the
pregnancy.40 Besides, 23% developed pre-eclampsia, 61% had
labour induced, 44% had a caesarean section and 9.3% had a
stillbirth. The median gestational age at delivery was 35 weeks
for those treated with diuretics and 31 weeks for those not
receiving diuretics. A review of 35 pregnancies in 16 women
with GC-remediable aldosteronism (GRA; an autosomal
recessive disorder) showed no increased risk of pre-
eclampsia.41 However, 39% of women experienced
aggravated hypertension and the birthweights of the infants
were lower than in those women without aggravated
hypertension. The caesarean section rate was approximately
double that seen in the general population.41
Diagnosis of primary aldosteronism during
pregnancy
The diagnosis of PA during pregnancy can be challenging
because of the physiological changes that lead to extrarenal
stimulation of the renin angiotensin aldosterone system
(RAAS). Figure 3 summarises the physiological changes in
the RAAS system during pregnancy, which are crucial to
maintaining circulating blood volume, blood pressure and
uteroplacental blood flow.42 Renin activity increases 4-fold in
the first 8 weeks of gestation and by 7-fold in the third
trimester, while aldosterone levels increase 3 to 8-fold in the
first and second trimesters and plateau in the third
trimester.30 However, progesterone antagonises the
vasopressor effects of the RAAS and reduces urinary
potassium excretion.40 Therefore, despite the marked
increase in blood volume necessary to obtain an adequate
placental perfusion, pregnant women are usually
normotensive and normokalaemic.43
The diagnosis of PA during pregnancy should be
considered as a differential in women presenting with (1)
ª 2021 Royal College of Obstetricians and Gynaecologists

hypertension associated with hypokalaemia and (2) resistant
hypertension – especially before 20 weeks of gestation. The
diagnosis of PA in pregnancy is based on suppressed renin
and elevated aldosterone-to-renin ratio (ARR). Confirmatory
testing is not only needed in the presence of hypokalaemia,
but is also not recommended in normokalaemic subjects
because saline infusion could lead to critical volume
expansion.44,45 MRI may be performed during the second
or third trimesters to determine the subtype of PA, whereas
adrenal vein sampling is not performed because of high
radiation exposure. If surgery is not considered as a
treatment for PA during pregnancy, both MRI of adrenals
and adrenal veins sampling, which helps localise the site of
tumour for surgery, should be postponed until
after delivery.46,47
Treatment of primary aldosteronism during
pregnancy
Control of the blood pressure during pregnancy is essential
for favourable maternal and fetal outcomes. There are
currently no formal recommendations for the management
of these patients. Hence, a multidisciplinary team approach is
essential for their care. Approved antihypertensive
medications, such as alpha-methyldopa and labetolol, are
the first options during pregnancy. The choice of further
treatment in those with uncontrolled hypertension requires
understanding of the current evidence and proper
counselling of the patients.
Spironolactone crosses the placenta and its anti-androgen
effects can lead to feminisation of male offspring. It has also
been linked to increased risk of FGR.48 There are only five
case reports of male offspring who were exposed to high-dose
Cholesterol
17-hydroxylase
Pregnenolone 17-hydroxypregnenolone
3β-dehydrogenase 3β-dehydrogenase
17-hydroxylase
Progesterone 17-hydroxyprogesterone
21-hydroxylase 21-hydroxylase
11-deoxycorticosterone 11-deoxycorticosol
11β-hydroxylase 11β-hydroxylase
Corticosterone
18-hydroxylase
Hydroxycorticosterone
Aldosterone
Figure 3. Pathway for biosynthesis of glucocorticoids and mineralocorticoids and the enzymes involved with consequences of their deficiency.
Abbreviation: DHEAS = dehydroepiandrosterone sulphate
ª 2021 Royal College of Obstetricians and Gynaecologists
Ahmed et al.
spironolactone in-utero.49 Contrary to animal data, which
showed high prevalence of male feminisation, all five cases
had normal genitalia. Yet, until further data are available, we
do not recommend the use spironolactone in pregnancy.
Eplerenone is a selective MC receptor antagonist that does
not have anti-androgen activity. So far, no teratogenic effects
have been reported and eplerenone is considered as class B by
the US Food and Drug Administration.47 Few cases of
successful use of eplerenone during pregnancy have been
reported.47,50,51 Based on this limited evidence, eplerenone is
preferred to spironolactone, if needed. The use of potassium-
sparing diuretics, such as amiloride and thiazides, have been
suggested in the literature; however, their safety in pregnancy
remains a concern. A reasonable approach is to use drugs
known to be safe during pregnancy in the first trimester and,
in cases of poor control of hypertension and/or
hypokalaemia, use of thiazides, amiloride or eplerenone
could be considered during the second and third trimesters.
Laparoscopic unilateral adrenalectomy is the treatment of
choice for adrenal adenomas and can be performed safely
after strict control of blood pressure. However, adverse
pregnancy outcomes were reported in four out of nine cases
who had adrenalectomy during pregnancy despite
biochemical cure.52 There was one case of FGR at 26 weeks
of gestation, two deliveries at 26 weeks of gestation because of
FGR associated with fetal distress and one delivery at 34
weeks of gestation.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of
autosomal recessive disorders characterised by impaired
17-hydroxylase
Dehydroepiandrosterone DHEAS
3β-dehydrogenase
17-hydroxylase
Androstenedione
Testosterone
Cortisol
271
 Adrenal disease and pregnancy
cortisol synthesis secondary to enzyme deficiency.22 Based
on national neonatal screening data, the worldwide
incidence ranges between 1 in 14 000 and 1 in 18 000
births.22 The most common enzyme deficiency is 21-
hydroxylase deficiency (21-HD), with an incidence of
about 1 in 500 to 1 in 1000 live births. In 95% of cases,
CAH is caused by mutations in CYP21A2, the gene
encoding the enzyme 21-HD.53 As shown in Figure 3,
deficiency in 21-HD leads to blockage of cortisol and
aldosterone synthesis, resulting in the accumulation of
cortisol precursors that are diverted to sex hormone
biosynthesis. Other rare defects include 11b-hydroxylase
deficiency and 17a-hydroxylase deficiency.54,55
Clinical manifestations: fecundity and fertility
Classical CAH secondary to 21-HD deficiency can present at
birth. In girls, the enhanced ACTH levels drive excess adrenal
androgen production, leading to clitoral enlargement and
labial fusion, presenting as sexual ambiguity at birth and even
inappropriate sex assignment. Seventy-five percent of
patients of both genders present at birth with severe
hyponatraemia caused by salt wasting as a result of severe
aldosterone deficiency.54 Non-classical CAH (NCCAH)
secondary to 21-HD deficiency have features similar to
polycystic ovary syndrome, including hirsutism, primary or
secondary amenorrhea or anovulatory infertility.56
There are no long-term cohort studies on fertility rates in
women with CAH. Mulaikal et al.57 reported on 80 women
with CAH; 40 of whom were sexually active, with a
pregnancy rate of 40%. Most of these women had features
suggestive of poor disease control, including hirsutism and
irregular periods. In the 40 nonsexually active women,
vaginal introital anatomical problems appeared to be the
main barrier for engaging in sexual intercourse. On the other
hand, Conway et al.58 reported a fertility rate of 91%, similar
to the rate in the background population, in women with
well-controlled CAH.
As outlined above, fertility rates depend on disease control
and genital structural changes from reconstruction surgery.
The effects of excessive androgen production are thought to
include anovulation from suppression of follicular
development; induction of endometrial changes, which
could have a negative impact on implantation; and
increased luteinising hormone (LH)-to-follicle stimulating
hormone (FSH) ratio through an increase in the
gonadotrophin-releasing hormone (GnRH) pulse
frequency.23 Besides, the reported high progesterone levels
in women with poorly controlled CAH could lead to
anovulation, unfavourable cervical mucus, inhibited sperm
migration, disruption of endometrial thickening and can
negatively affect implantation.59 In the past, clitoroplasty was
regularly performed in early childhood, often together with
vaginoplasty. Women who underwent clitoroplasty have
272
reported lower rates of sexual satisfaction, likely because of a
loss of sensitivity.60 Almost 50% of those who underwent
vaginoplasty had inadequate vaginal opening.59
Management of CAH and optimisation for pregnancy
Before planning pregnancy, the woman with CAH and the
biological father (where present) should receive genetic
counselling.22 Women with classical CAH have a 1:120
probability of having a child with classical CAH, while
women with nonclassical CAH have a 1:250 probability of
having a child with classical CAH.22 These risks will increase
if the biological father is a carrier of the gene defect.
As outlined above, in sexually active women, optimising
treatment can result in normal fertility rates. For those who
do not conceive spontaneously on their routine steroid dose
within 6 months of trying, follicular phase (days 2–8 of the
cycle) progesterone should be measured and could be
suppressed to <2 nmol/l using three divided doses of
prednisolone.58 Additionally, plasma renin activity could be
suppressed to within the normal range, with an increase in a
single daily dose of fludrocortisone.58 In cases that are
resistant to the above measures, bilateral adrenalectomy
could be considered. Bilateral adrenalectomy was effective in
treating primary infertility in three women, with successful
post treatment pregnancies; an additional successful
pregnancy was also achieved following bilateral
adrenalectomy for difficult-to-treat hyperandrogenism.61
However, adrenalectomy should be the treatment of last
resort, after trying standard ovulation induction measures.
Choice of glucocorticoids during pregnancy
Two critical issues should be discussed during the first
antenatal visit: (1) the choice of GC replacement and (2) GC
stress dosing during pregnancy in intercurrent illness, in case
of hyperemesis and during labour and delivery. As outlined
above, women with CAH could require large doses of GC
therapy to be able to conceive. HC and prednisolone are both
inactivated by placental 11-b hydroxysteroid dehydrogenase
type 2 (11bHSD2), therefore the fetus is protected from
potentially supraphysiological GC doses taken by the
mother.59 On the other hand, dexamethasone is not
inactivated by 11b-HSD2 and can cross the placenta freely,
so can affect the fetal adrenal gland. The placenta aromatises
androgens into estradiol and estrone, so the fetus is protected
from excess androgens in women with CAH.5
The pituitary–adrenal axis is fully functional by 6 weeks of
life. The production of adrenal androgens starts between
weeks 6 and 7 of fetal life and the critical time for sexual
differentiation of external genitalia occurs between weeks 7
and 12.62 During this time, excess production of fetal
androgens can lead to varying degrees of virilisation.
Dexamethasone crosses the placenta and can suppress the
high androgen production in affected females; however, it
ª 2021 Royal College of Obstetricians and Gynaecologists

does this by suppressing the pituitary–adrenal axis. One
proposed approach is to treat all women with CAH with
dexamethasone until the gender of the fetus is confirmed to
be male or an unaffected female by amniocentesis performed
from 15 weeks of gestation.62 With the advent of noninvasive
prenatal testing (NIPT)/noninvasive prenatal diagnosis
(NIPD), such gender confirmatory testing can now be done
by 8-10 weeks from maternal blood using free fetal DNA. A
meta-analysis including 365 pregnancies of women with
CAH treated with dexamethasone showed a reduction in
virilisation in female offspring, with no adverse maternal or
neonatal outcomes.63 However, the unnecessary exposure of
fetuses to dexamethasone at 7–8 weeks is an ethical dilemma.
Despite this, termination is not usually considered an option
for fetuses affected by CAH.
There are a few concerns with the use of dexamethasone
during pregnancy. Possible maternal side effects of
dexamethasone therapy include excessive weight gain,
cushingoid features, hypertension, gestational diabetes,
excessive striae and mood lability. While several studies
have reported these side effects, they appear to be modest.62
Possible fetal side effects are cleft palate and adrenal
suppression. With the ensuing resetting of the fetal
pituitary–adrenal axis, there is an increased risk of
cardiometabolic disorders in adulthood. There has
however, been no reported increased risk of cleft palate in
CAH pregnancies treated with dexamethasone (there are no
robust published data) and no long-term data on adrenal
suppression risks.63 The current recommendation is that
dexamethasone should not be used during pregnancy.22 HC
is the commonest medication for CAH management; the
pre-pregnancy dose should be continued during
pregnancy.22 As outlined, some women require treatment
with prednisolone to conceive and it can also be continued
during pregnancy. However, neither treatment reduces the
risk of virilisation in affected females. Hence, we think the
advantages and disadvantages of each GC agent should be
discussed with the pregnant woman (and her partner,
where present).
The need for GC therapy is uncertain in women with
nonclassical CAH in the absence of strong evidence; however,
those with a history of infertility or miscarriage may benefit
from treatment. The resulting pregnancies should be
closely monitored.
Monitoring of hormone therapy during pregnancy
Monitoring of hormone therapy during pregnancy is mostly
clinical. Both androgen and cortisol levels increase gradually
during pregnancy owing to increases in sex hormone-
binding globulin (SHBG) and corticosteroid-binding
globulin (CBG). Maternal 17-hydroxyprogesterone (17-
OHP) is elevated in normal pregnancy, hence cannot be
used to monitor GC treatment.22 Renal function should be
ª 2021 Royal College of Obstetricians and Gynaecologists
Ahmed et al.
monitored for hyponatraemia and/or hyperkalaemia. The
treatment should otherwise follow the same principles
described above for the management of primary AI.
Women should be educated on the sick day rules, as
outlined in Figure 2.
Pregnancy outcomes
Pregnancy outcome in women with CAH is reasonably
good, with a slightly increased rate of small for gestational
age.59 Women with CAH are at increased risk of
gestational diabetes and should be screened during
pregnancy with an oral glucose tolerance test (OGTT).64
However, the timing of the OGTT should be clinically
judged. We recommend an early screening at 15 weeks of
gestation and, if normal, to be repeated between 24 and
28 weeks of gestation. Most women with classical CAH
deliver by caesarean section because of the high prevalence
of previous vaginal surgery and cephalopelvic
disproportion.64,65 That said, vaginal delivery has been
reported in 16–42% of cases, most of whom had a non-
salt-wasting phenotype. GC management during labour is
similar to that of primary AI (Figure 2).
Breastfeeding should be encouraged in women on cortisol
replacement therapy. Both HC and prednisolone are excreted
in breast milk in low amounts that are unlikely to harm
the baby.24,25
Phaeochromocytoma and paragangliomas
PPGLs are rare neuroendocrine tumours arising from
neural crest-derived cells of the sympathetic and
parasympathetic nervous systems.66 A phaeochromocytoma
is a tumour causing excessive production of catecholamines
(adrenaline [epinephrine], noradrenaline [norepinephrine]
and dopamine) by the chromaffin cells of the adrenal
medulla. A paraganglioma results from excessive production
of catecholamines by the chromaffin cells located in the
extra-adrenal sympathetic paraganglia, typically in the
abdomen and pelvis. The prevalence of PPGL is variable,
from 0.2–0.6% in patients with hypertension, to as high as
3–5% in patients with adrenal mass.67 In pregnancy,
however, the prevalence of PPGL is estimated to be 1 in
15 000 to 1 in 54 000 pregnancies.68 Although PPGL can be
sporadic, it can also form part of hereditary syndromes,
such as Von Hippel–Lindau syndrome, multiple endocrine
neoplasia-type 2 (MEN-2) and neurofibromatosis type 1
(NF1) – all of which have autosomal dominant patterns
of inheritance.69
Catecholamines: basic physiological features and
effects on pregnancy
There are three catecholamines: adrenaline (epinephrine),
noradrenaline (norepinephrine) and dopamine. Adrenaline is
273
 Adrenal disease and pregnancy

produced and stored in the medulla of the adrenal gland, Both adrenaline and noradrenaline are important in
from where it is released into the circulation, whereas adaptation and response to stress stimuli during pregnancy
noradrenaline is produced and stored both in the adrenal and childbirth.66 During healthy pregnancy, the levels of
medulla and peripheral sympathetic nerves. Dopamine is a catecholamines are not increased. In women with eclampsia
precursor of noradrenaline and is an important and pre-eclampsia, slight increases in the levels of
neurotransmitter.56 Catecholamines affect many metabolic catecholamines have been reported.68 The placenta
processes in the body, through the seven receptors listed in produces COMT, hence the fetus is protected from
Table 1. They induce an increase in heart rate and blood maternal catecholamines.
pressure, as well as myocardial contractility. They are
metabolised by catechol-O-methyltransferase (COMT) into Clinical features
metanephrines and normetanephrines. The clinical presentation of PPGL during pregnancy is similar
to that in nonpregnant women. The classic triad of symptoms
(headache, sweating and tachycardia) are not very common
Table 1. Catecholamine receptors
in pregnancy.70 Less common symptoms and signs include
orthostatic hypotension, arrhythmia, chest pain, convulsions,
Receptors Location Function syncope, blurring of vision, weight loss, papilloedema, insulin
resistance, hyperglycaemia, high erythrocyte sedimentation
rates, psychiatry disorders and erythrocytosis.71,72 Most
a1 Postsynaptic sympathetic Stimulation leads to
nerve endings vascular smooth muscle
patients become symptomatic with increasing gestation,
contraction, most likely because of mechanical factors from the growing
vasoconstriction and uterus and fetal movements.73 Nevertheless, some patients
elevated blood pressure can remain asymptomatic until they experience major stress,
a2 Presynaptic sympathetic Stimulation inhibits like birth or caesarean section.
nerve ending norepinephrine release, Certain factors could help differentiate between pre-
suppresses the eclampsia and PPGL.68,73 PPGL should be suspected in any
sympathetic nervous
patient with a previous or family history of PPGL, or any
system and reduces the
blood pressure other associated condition such as MEN-2, Von Hippel–
Lindau, neurofibromatosis, and familial paraganglioma
b1 Mostly in the heart Stimulation causes positive syndromes. Pre-eclampsia is extremely rare before 20 weeks
inotropic and
of gestation, while PPGL can present at any gestation. PPGL
chronotropic effects on
the heart, increased renin is not associated with proteinuria, ankle oedema or elevated
secretion in the kidney uric acid levels, while pre-eclampsia often is. Most
and lipolysis in adipocytes importantly, paroxysmal hypertension and orthostatic
b2 Bronchial, vascular and Stimulation causes positive
hypotension do not occur in women with pre-eclampsia.
uterine smooth muscles inotropic and PPGL should be suspected in all pregnant women who
chronotropic effects on present with life-threatening catastrophes, such as an acute
the heart, increased renin coronary syndrome, cardiomyopathy, arrhythmias, stroke,
secretion in the kidney
and lipolysis in adipocytes
syncope and shock. The risk of hypertensive crises during
delivery appears to be lower in those with paraganglioma
b3 Adipose tissue Regulates energy than those with phaechromocytoma.74
expenditure and lipolysis

D1 Cerebral, renal, mesenteric
and coronary vasculatures
D2 Presynaptic sympathetic
nerve endings,
sympathetic ganglia and
the brain
Stimulation causes
vasodilation in these
vascular beds
Stimulation of D2
receptors in these
locations inhibits the
release of noradrenaline,
inhibits ganglionic
transmission, and inhibits
prolactin release,
respectively
Effect of PPGL on pregnancy and fetal outcomes
While the fetus is protected from high maternal
catecholamines, nonetheless these elevated levels cause
uteroplacental vasoconstriction leading to FGR, fetal
hypoxia and – possibly – fetal death. Moreover, paroxysmal
increases in blood pressure may lead to placental abruption
and rebound hypotensive episodes may lead to severe
intrauterine hypoxia and adverse fetal outcomes.73 Fetal
mortality rates have been declining in recent years, from 50%
in the 1960s to 25% in the late 1990s. In the last decade, fetal
mortality has fallen to 9.5%. The fetal and neonatal mortality
rate was 7% when PPGL was diagnosed antenatally; however,

274 ª 2021 Royal College of Obstetricians and Gynaecologists


it was 17% when an antenatal diagnosis was missed.73 In a
more recent case series and review of the literature, Wing
et al.74 concluded that there were differences in the maternal
and perinatal mortality rates between those presenting with
paraganglioma and phaechromocytoma: these rates were
lower in those with paraganglioma.
Diagnosis
The diagnostic work-up outside and during pregnancy is
largely similar. Once PPGL is suspected, the first step is to
undertake biochemical testing for catecholamine excess; the
recommended test is a 24-hour urine collection for plasma
free metanephrines or urinary fractionated metanephrines.67
This test has a sensitivity of 97%; hence, if normal, it rules
out PPGL. Nevertheless, the specificity is quite low.67 A
combined measurement of fractionated metanephrines and
catecholamines in a 24-hour urine collection has a sensitivity
and specificity of 98%.75 Plasma free metanephrines has a
high sensitivity of almost 100%, but a specificity of 85%.75 It
is critical that all women are given written instructions on
how to collect, store and deliver the 24-hour urine sample.
Furthermore, the following medications can cause a false
positive result and should be stopped: tricyclic antidepressants,
resperine, phenoxybenzamines, clonidine, levodopa,
amphetamines, ethanol, most antipsychotics, decongestants
and prochlorperazine.
Once the biochemical presence of PPGL is confirmed,
localising imaging is required. Both computed
tomography (CT) of the abdomen and functional meta-
iodobenzylguanidine (MIBG) scans deliver large doses of
radiation; hence MRI is the imaging mode of choice for the
adrenal gland.68
Management during pregnancy
Surgical resection is the treatment of choice. A
multidisciplinary team including surgeons, obstetricians,
endocrinologists and anaesthetics should deliver the care.
However, the timing of resection should be planned carefully.
Based on the available literature, the optimum timing of
resection is before 24 weeks of gestation.68 Beyond that, the
anatomical changes of pregnancy are less favourable for
surgical removal and the operation could be delayed until
after delivery.
Medical therapy is required at all times, regardless of the
timing of surgery. Treatment with a-adrenergic receptor
blockers can counteract the effects of catecholamines on the
uteroplacental blood flow; nonetheless, it can induce
hypotension, which can itself compromise this blood flow.
The aim of the treatment is therefore to alleviate the effects
of catecholamines and avoid hypotension. Two a-blockers
are used during pregnancy: phenoxybenzamine and
doxazocin. Phenoxybenzamine blocks both a-1 and a-2
receptors, while doxazocin is a selective a-1 receptor blocker.
ª 2021 Royal College of Obstetricians and Gynaecologists
Ahmed et al.
Phenoxybenzamine use can lead to nasal congestion,
orthostatic hypotension and reflex tachycardia, while
doxazocin has fewer side effects. Both agents can cross the
placenta; phenoxybenzamine has been associated with
neonatal hypotension and respiratory depression, while
doxazocin was not.68,73 Beta-blockers can be added to
reduce orthostatic hypotension and reflex tachycardia. Beta-
blockers, including labetalol, can induce a hypertensive crisis
if used without alpha-blockers. If more agents are needed to
control the blood pressure, calcium channel blockers may be
added. All women should be advised to increase salt and
fluid intake. It is important to note that the long-term
effects of these agents are not known; nonetheless, the
maternal and fetal benefits outweigh these risks.
Mode of delivery
Delivery can be associated with acute haemodynamic
instability, so requires careful planning and timing. In
addition, neonates are at risk of hypotension and respiratory
depression. Hence, a well-timed and planned delivery by
caesarean section has been the preferred method of delivery
because of the associated increased stress. Besides, agents like
syntocinon75 can cause adverse haemodynamic effects, such as
hypotension and tachycardia. Nonetheless, vaginal delivery
combined with epidural analgesia has been successful.75
The attending physician should be prepared to manage any
hypertensive crises that can occur during labour. The three
agents of choice are intravenous nitroprusside, phentolamine
or nicardipine. Sodium nitroprusside is a rapid-acting
vasodilator and is the treatment of choice; phentolamine is
a non-selective a-blocker, while nicardipine is a calcium
channel blocker.
Disclosure of interests
JCK is Lead CPD Editor for The Obstetrician & Gynaecologist;
he was excluded from editorial discussions regarding the
article and had no involvement in the decision to publish.
The other authors have no other conflicts of interest.
Contribution to authorship
JCK conceived the idea. MME wrote the first draft. MB and
GOO restructured the article and wrote the second draft. JCK
contributed to the design of the article and revised the second
draft. All authors revised and approved the final version.
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virilization in pregnancies at risk for classical congenital adrenal hyperplasia
because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and
meta-analyses. Clin Endocrinol (Oxf) 2010;73:436–44.
64 Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, Frisen L,
et al. Fertility and pregnancy outcome in women with congenital adrenal
hyperplasia due to 21-hydroxylase deficiency. Hum Reprod
2008;23:1607–13.
65 Conway GS, Casteras A, De Silva P, Rumsby G. Reassessing fecundity in
women with classical congenital adrenal hyperplasia (CAH): normal
pregnancy rate but reduced fertility rate. Clin Endocrinol (Oxf)
2009;70:833–7.
66 Plouin PF, Amar L, Dekkers OM, Fassnacht M, Gimenez-Roqueplo AP,
Lenders JWM, et al. European Society of Endocrinology Clinical Practice
Guideline for long-term follow-up of patients operated on for a
phaeochromocytoma or a paraganglioma. Eur J Endocrinol 2016;174:
G1–10.
67 Lenders JWM, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SKG,
Murad MH, et al. Pheochromocytoma and paraganglioma: an Endocrine
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2014;99:1915–42.
68 Lenders JWM, Langton K, Langenhuijsen JF, Eisenhofer G.
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69 Lenders JWM, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma.
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70 Stein PP, Black HR. A simplified diagnostic approach to pheochromocytoma:
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 DOI: 10.1111/tog.12770
The Obstetrician & Gynaecologist
http://onlinetog.org
Peripartum cardiomyopathy
Akshatha Kulkarni MS DNB MRCOG,a* Gareth Squire
Mohamed Waseem Osman MBChB MRCOG MDd
a
Specialty Trainee in Obstetrics and Gynaecology, Kettering General Hospital NHS Foundation Trust, Rothwell Road, Kettering NN16 8UZ, UK
b
Specialty Registrar in Cardiology, Northampton General Hospital NHS Trust, Cliftonville, Northampton NN1 5BD, UK
c
Consultant Cardiologist, Kettering General Hospital NHS Foundation Trust, Rothwell Road, Kettering NN16 8UZ, UK
d
Consultant Obstetrician and Gynaecologist, Kettering General Hospital NHS Foundation Trust, Rothwell Road, Kettering NN16 8UZ, UK
*Correspondence: Akshatha Kulkarni. Email: axek.007@gmail.com
Accepted on 3 November 2020. Published online 7 September 2021.
Key content
 The increasing incidence of peripartum cardiomyopathy (PPCM)
is associated with advancing maternal age, multiple gestation,
obesity and increasing awareness of the implications of
the disease.
 A ‘two-hit’ model of pathogenesis has been proposed, wherein a
vascular insult secondary to hormonal effects of advanced
pregnancy prompt cardiomyopathy changes in women with
underlying genetic predisposition.
 The emphasis should be on making a diagnosis, and not simply
excluding a diagnosis.
 Early involvement of a multidisciplinary team and senior clinicians
is imperative in managing these women effectively.
 Newer pharmacotherapeutic agents to treat PPCM lack adequate
evidence, making their use experimental.
Please cite this paper as: Kulkarni A, Squire G, Hogrefe K, Waseem Osman M. Peripartum cardiomyopathy. The Obstetrician & Gynaecologist 2021;23:278–89.
https://doi.org/10.1111/tog.12770
Introduction
Cardiovascular disease continues to be the leading cause of
direct and overall maternal deaths in the UK. The 2019
MBRRACE (Mothers and Babies: Reducing Risks through
Audit and Confidential Enquiries) report states that, among
the women who died from cardiac causes, nearly one-third of
them were associated with cardiomyopathy.1
Peripartum cardiomyopathy (PPCM) is a form of
cardiomyopathy that is distinctly related to pregnancy. In
2010, the European Society of Cardiology (ESC) defined
PPCM as “idiopathic cardiomyopathy presenting with heart
failure secondary to left ventricular systolic dysfunction
towards the end of pregnancy or up to 6 months following
delivery, where no other cause of heart failure is found. It is a
diagnosis of exclusion. The left ventricle may not be dilated
but the ejection fraction is nearly always reduced below 45%.”2
Epidemiology and risk factors
The estimated incidence in Western health care ranges from 1
in 1000–4000 pregnancies, but certain areas have a greater
278
2021;23:278–89
Review
MA MBChB MRCP AFHEA,
b
Kai Hogrefe MD FRCP,
c
Learning objectives
 To understand the principles of clinical assessment, which
sometimes mimic physiological symptoms of pregnancy.
 To understand how to manage women with PPCM in a
multidisciplinary setting and become familiar with the various
pharmacotherapies available.
 To understand the importance of counselling women on long-term
prognosis and implications on future pregnancy.
Ethical issues
 The unexpected presentation of the disease and the acuity of illness
profoundly affects women at an early stage of their lives.
 Sparse knowledge means there is uncertainty on the long-term
prognosis, which poses a challenge in counselling for
future pregnancies.
disease burden. The highest incidence has been noted in
Nigeria and Haiti, where it occurs in 1 in 100 live births and 1
in 300 live births, respectively.3 The disease more commonly
manifests in women of Afro-Caribbean lineage and carries a
poor prognosis. Other risk factors include multiparity,
multiple pregnancy, obesity, chronic hypertension, pre-
eclampsia and advanced maternal age.3,4 Even though the
disease can strike women of any age, those older than 30
years of age are at higher risk.5 There is a close association
between pre-eclampsia and PPCM, which is hypothesised to
be associated with a synchronous pathophysiology. A 2013
meta-analysis of 22 studies detected pre-eclampsia in 22% of
women with PPCM, which – notably – was four times greater
than the 5% prevalence of pre-eclampsia in the general
worldwide population.6
Pathogenesis
A comprehensive understanding of the exact pathogenesis of
PPCM continues to elude clinicians and scientists.
Historically, a viral-induced myocarditis proved a popular
theory; however, subsequent testing of endocardial biopsies
ª 2021 Royal College of Obstetricians and Gynaecologists
 Kulkarni et al.

at autopsy demonstrated comparable viral serologies between
PPCM biopsies and control groups. In addition, the
increasing use of cardiac magnetic resonance imaging
(MRI) has not demonstrated imaging characteristics
consistent with myocarditis.7 There are adaptive changes to
the maternal heart and systemic circulation during pregnancy
and it has been speculated that the associated haemodynamic
stress placed upon the heart may contribute to PPCM.
However, the compensatory changes occur mainly in the
second trimester, while the signs and symptoms of PPCM
arise late in the third trimester, as well as into the postpartum
period. Therefore, the disease timeline does not correlate.7,8
The true overarching pathophysiology is now considered to
be multifactorial, with a single theory unlikely to provide
unification. Recent attempts at exploring PPCM aetiology
have proposed a ‘two-hit’ model9 of genetic predisposition
combined with a vascular hormonal insult to the maternal
heart in and around term, as illustrated in Figure 1.
Genetic factors
Strong regional and familial patterns exist in the prevalence
of PPCM, implying a strong genetic basis to the condition.
Multiple genetic targets are associated with the condition
including TTN, TTNCI, BAG3, PTHLH and PGC‑1a. Many
of these genes regulate myocyte function, with mutations
predisposing to PPCM.9,10
Vascular hormonal models
Transcription factor STAT3 becomes activated to a large
extent within the normal heart during pregnancy and the
postpartum period. Mirroring this toward the end of
pregnancy, there is a large increase in prolactin secretion

Figure 1. Two-hit hypothesis explanation for pathogenesis of peripartum cardiomyopathy.9 Secretion of prolactin by the anterior pituitary,
enhanced production of endothelial microRNA-146a (miRNA-146a) and placental secretion of soluble fms-like tyrosine kinase receptor 1 (sFlt-1) on
a background of genetic susceptibility ultimately leads to endothelial dysfunction and cardiomyocyte apoptosis. Abbreviations: VEGF = vascular
endothelial growth factor. Figure reproduced with permission. [Colour figure can be viewed at wileyonlinelibrary.com]

ª 2021 Royal College of Obstetricians and Gynaecologists 279

 Peripartum cardiomyopathy
from the maternal pituitary. When there is reduced
expression of STAT3, there is an associated increase in
reactive oxidative species (ROS). This, in turn, increases the
levels of cathepsin D.11 Cathepsin D cleaves prolactin into a
16-kDa fragment, which ultimately results in greater cardiac
endothelial and capillary dysfunction. Reduced expression of
STAT3 and higher levels of the 16-kDa fragment have been
found on biopsy and transplant samples from women with
PPCM.9 Administration of bromocriptine, a prolactin
antagonist, appeared to reverse systolic impairment in
STAT3 deficient mice; the current clinical use of
bromocriptine is based upon this theory.8,12 The 16-kDa
fragment also increases levels of microRNA‑146a, which
blocks several signalling cascade pathways, eventually
contributing to cardiac myocyte death.9
The placenta secretes exponentially increasing con-
centrations of soluble fms‑like tyrosine kinase receptor 1
(sFlt‑1) towards the end of pregnancy as part of the adaptive
process to minimise the likelihood of haemorrhage in
labour.12 In healthy women, sFlt-1 levels drastically reduce
following childbirth (following removal of the placental
source of sFlt-1), but persist in women with PPCM. Raised
sFlt-1 alters systemic angiogenesis by inhibiting vascular
endothelial growth factor (VEGF) and placental growth
factor (PlGF), resulting in further endothelial damage. There
is a well-known association between sFlt‑1 and preeclampsia.
The resultant endothelial dysfunction is thought to be a
common factor between hypertension and PPCM
co-existence.9
Clinical presentation
PPCM mimics other forms of systolic heart failure in its
clinical presentation.13 It can manifest clinically in a variable
pattern, ranging from mild symptoms to a swift progression
resulting in end stage heart failure and death. Reassuringly, it
is also not uncommon for symptoms to abate and result in a
spontaneous recovery. In around 78% of women with the
condition, symptoms manifest in the 4 months after
childbirth. Around 9% of women with PPCM present in
the last month of pregnancy, and the remaining 13% present
either prior to a month before delivery or 4 months after
delivery.2 PPCM can present with dyspnoea, orthopnoea,
unexplained cough (particularly when lying down),
palpitations, dizziness and swelling in the legs. Additionally,
there can be abdominal discomfort caused by hepatic
congestion and precordial pain.2 Examination may reveal
signs of heart failure such as sinus tachycardia, a raised
jugular venous pressure, and lung crepitations.9 Other
uncommon findings include a third heart sound and
displaced apex beat (Box 1). The 2019 MBRRACE report
highlights that tachypnoea, chest pain, persistent tachycardia
and orthopnoea are red flag signs that could be indicative of
280
Box 1. Diagnostic approach for peripartum cardiomyopathy
(PPCM)
Symptoms of heart failure
 Dyspnoea
 Orthopnoea
 Paroxysmal nocturnal dyspnoea
 Pedal edema
 Unexplained cough, particularly when lying down or which
produces frothy pink sputum
 Dizziness
 Palpitation
 Fatigue
 Chest pain
 Abdominal discomfort
Initial evaluation
 History: known congenital or acquired heart disease? Family history
of ischaemic/non-ischaemic heart failure?
 Physical examination: tachypnoea, tachycardia, peripheral oedema,
jugular venous distension.
 Electrocardiogram: no specific pattern in PPCM but may rule out
ischaemic or thromboembolic cause.
 Blood tests: haemoglobin, C reactive protein, white cell count,
natriuretic peptides, troponin T, blood gas analysis if unstable.
 Echocardiography: crucial in diagnosing PPCM. Left ventricular
ejection fraction (LVEF) <45%, ventricles may or may not be dilated.
 Other investigations: chest X-ray, cardiac magnetic resonance
imaging and rarely endomyocardial biopsy.
cardiac disease and should always be fully investigated. The
emphasis should be on making a diagnosis, and not simply
excluding a diagnosis.1 The presenting features of PPCM can
be similar to the physiological symptoms of pregnancy and
the postpartum period,14 which can sometimes lead to a
diagnostic delay. The differential diagnosis (Table 1) includes
pre-existing cardiomyopathy and valvular disease, with
mitral stenosis and aortic stenosis being the commonest
encountered valvular defects in pregnancy.9 Since both
plasma volume and cardiac output increase by 50% by the
late second trimester and then plateau for the rest of
pregnancy, women with the above conditions become
symptomatic earlier on in their pregnancy than women
with PPCM.9 The risk of myocardial infarction, from
atherosclerotic plaque rupture or spontaneous coronary
artery dissection, is three to four times higher in the early
postpartum period than in nonpregnant women. Other
conditions to consider include pulmonary embolism, the risk
of which is five to 10 times higher during pregnancy and the
postpartum period, and – more rarely – amniotic fluid
embolism, a condition marked by shock and respiratory
failure during childbirth or immediately postpartum.9
Among the noted complications of the disease, ventricular
arrhythmias are known to occur in 20% of women with
PPCM. There have been cases of arrhythmia leading to
sudden cardiac death during both the initial and later stages
ª 2021 Royal College of Obstetricians and Gynaecologists
 Kulkarni et al.

Table 1. Differential cardiovascular diagnoses of peripartum cardiomyopathy.2,9

Condition Distinguishing features Diagnostic investigations for the condition

1. Benign dyspnea of Gradual onset mild breathlessness, with no associated None needed; however, CXR and echocardiography will
pregnancy cough; normal heart rate and Spo2, no jugular venous be normal.
distension.

2. Arrhythmias Palpitations, followed by acute heart failure presentation; Tachyarrhythmia on ECG; pulmonary oedema on CXR;
tachycardia, pulmonary rales, peripheral oedema. diffuse hypokinesis typically seen on echocardiography.

3. Amniotic fluid embolism
Sudden respiratory failure and circulatory collapse during Blood tests show raised D-dimer, schistocytes, low
or immediately after delivery, often accompanied by fibrinogen and thrombocytopenia.
bleeding from disseminated intravascular coagulation;
on examination:tachypnea, tachycardia, hypotension
and crackles are typically present.

4. Asthma History of asthma; wheezing or decreased air entry on Pulmonary function testing with positive provocation test
examination and use of accessory muscles for breathing. or response to bronchodilator challenge.

5. Pre-existing (IDC) PPCM presents commonly in the postpartum period, Detailed history, ECG, brain natriuretic peptide,
while IDC presents by the end of the second trimester. echocardiography, cardiac MRI.
Usually larger cardiac dimensions are noted in IDC
compared with PPCM.

6. HIV cardiomyopathy HIV cardiomyopathy presents often with nondilated History, HIV antibody testing.
ventricles

7. Pre-existing valvular heart PPCM presents commonly in the postpartum period, History, examination, ECG may show chamber
disease unmasked by while valvular heart disease presents by the end of the enlargement, CXR shows pulmonary oedema plus left
pregnancy (e.g. rheumatic second trimester, along with associated murmur of atrial and pulmonary artery enlargement in mitral
valve disease) valvular stenosis or regurgitation. stenosis, echocardiography shows culprit valve lesion.

8. Hypertensive heart disease Pre-existing severe hypertension. Proteinuria may be present on urine analysis, CXR shows
pulmonary oedema, echocardiography shows preserved
or mildly decreased LVEF, left ventricular hypertrophy
may be present in chronic hypertension.

9. Cardiac dysfunction
secondary to ischemia (e.g.
atherosclerosis, coronary
dissection, vasospasm,
coronary embolism)
History (but can present atypically), antecedent chest
pain, shortness of breath, followed by acute heart failure
symptoms.
History, ECG shows ischemic changes; cardiac biomarkers
raised (troponin T). CXR shows pulmonary oedema;
echocardiography shows segmental wall motion
abnormality; coronary angiography may show stenosis/
occlusion or dissection.

10. Pulmonary embolus History, sudden onset of shortness of breath, often with History, ECG, CXR, ventilation/perfusion scan, CT
pleuritic chest pain, may or may not be accompanied by pulmonary angiogram.
deep vein thrombosis.

Abbreviations: CT = computed tomography; CXR = chest X-ray; ECG = electrocardiogram; IDC = idiopathic dilated cardiomyopathy; LVEF = left
ventricular ejection fraction; MRI = magnetic resonance imaging; PPCM = peripartum cardiomyopathy.

of the disease.15 Another serious complication is the risk of
developing intracardiac thrombus, particularly when the left
ventricular ejection fraction (LVEF) is less than 35%.2 The
resultant thrombus can dislodge into the bloodstream and
embolise to other organs, resulting in acute myocardial
infarction, pulmonary embolism, stroke, bowel ischaemia, or
limb ischaemia, based on the area of involvement. Rarely,
some women can present in the first instance itself with acute
cardiogenic shock requiring inotropic or mechanical
circulatory support.9
Investigations
PPCM is often a diagnosis of exclusion.16,17 In this regard, a
detailed investigation for other cardiac and noncardiac causes
of heart failure should be undertaken. A high index of

ª 2021 Royal College of Obstetricians and Gynaecologists 281

 Peripartum cardiomyopathy

suspicion and a timely work-up is helpful in arriving at an

early diagnosis.

Electrocardiogram
Electrocardiography (ECG) is advised in any pregnant
woman who presents with unexplained or new onset
cardiac symptoms.1 There are no ECG findings that are
specific to PPCM. However, common features in these
women include sinus tachycardia with nonspecific ST-
segment and T-wave abnormalities.15 Since an ECG is not
routinely offered to pregnant women, it is not always
possible to compare with previous tracings to note any
difference over time. Nevertheless, the ECG can be an
important discriminating tool for conditions presenting in a
similar manner, such as pulmonary embolism and
acute ischaemia.18

Laboratory tests
Inflammatory markers, such as C-reactive protein and
leucocyte count, although nonspecific, are often elevated,
while haemoglobin levels are frequently decreased. Brain
natriuretic peptide (BNP) or N-terminal pro-brain natriuretic
peptide (NT-proBNP) is an established marker for heart
failure. Although not specific for PPCM, both types of
natriuretic peptide levels would be expected to be elevated15
(normal ranges are values less than 100 pg/ml for BNP and less
than 300 pg/ml for NT-proBNP).19 However, cardiac enzyme
troponin T, a marker for cardiac myocyte injury, is often in the
normal range in these women.18
Chest X-ray
Although chest X-ray is nonspecific for PPCM, it may
show typical features of cardiac strain, such as alveolar
shadowing, septal lines, cardiomegaly, pulmonary oedema,
or pleural effusion.15
Echocardiography
The most helpful tool among all investigations for PPCM is
echocardiography. The absence of radiation risk and the ease
of access has made this a useful imaging modality.9,15 By
definition, an essential criterion to diagnose PPCM is a left
ventricular (LV) ejection fraction of below 45%2 (Figure 2).
However, echocardiography does not only help in making a
diagnosis, but also provides valuable prognostic information.
Although right ventricular dysfunction is not a common
association, its coexistence results in a poorer outcome.
Nevertheless, the best predictors for recovery of LV function
are left ventricular size and ejection fraction at the point of
diagnosis. Left ventricular end diastolic diameter (LVEDD)
>6 cm and LVEF <30% are indicative of a decreased prospect
of spontaneous recovery and an increased likelihood of
mechanical support, transplant and death.9
Figure 2. Flow chart for evaluating suspected acute peripartum
cardioomyopathy.2 Abbreviations: BNP = brain natriuretic peptide;
EF = ejection fraction; NT-proBNP = N-terminal prohormone brain
natriuretic peptide; PPCM = peripartum cardiomyopathy.
Cardiac magnetic resonance imaging
Cardiac MRI is a useful tool for cardiac imaging.2 It can
accurately assess cardiac chamber volume and systolic function
and is more sensitive in identifying intracardiac thrombus than
echocardiography. Additionally, cardiac MRI evaluates features
of cardiac tissue injury, such as intracellular and interstitial
injury, hyperaemia, capillary leakage, necrosis and fibrosis.15 It
is not used as an initial investigation owing to the risk of
gadolinium contrast in pregnant women and the difficulty in
accessing this service in all areas. The European Society of
Radiology recommends that gadolinium should be used in
pregnancy only if necessary. Breastfeeding, however, does not
need to be interrupted after administration of gadolinium.20
Endomyocardial biopsy
Endomyocardial biopsy (EMB) is rarely performed to
exclude other causes of LV dysfunction, particularly when
there is diagnostic uncertainty.21
Management
Principles of comprehensive PPCM management include a
planned interdisciplinary patient-centred approach, optimal
medical therapy and, rarely, mechanical augmentation of
both circulation and ventilation (Figure 3).
Pharmacotherapy
The mainstay of pharmacological management in PPCM is
broadly the same as that for generalised heart failure with

282 ª 2021 Royal College of Obstetricians and Gynaecologists

 Kulkarni et al.

Acute heart failure in pregnancy

Confirm diagnosis:
ECG, blood tests (natriuretic peptides), chest X ray, ECHO

Antenatal corticosteroids for fetal lung maturation (after 23 weeks and 6 days gestation,
consider for women between 23+0 and 23+6 weeks of gestation) along with transfer to tertiary centre

Multidisciplinary team meeting involving obstetrician, cardiologist, neonatologist, anaesthetist and intensivist.

Assess heart failure severity: SBP <90 mmHg; HR >130/min or <45/min; RR >25/min; SpO2 <90%; lactate >2.0 mmol/L;
ScvO2 <60%; altered mental state, cold skin; oliguria

Severe acute heart failure/cardiogenic shock Severe acute heart failure/cardiogenic shock

Maintain optimal preload: Antepartum Postpartum

Volume vs diuretics, vasodilators if
SBP >110mmHg
MDT approach: Heart failure
therapy:
Optimise oxygenation: Timing of delivery
Consider non-invasive ventilation, invasive balanced between ACE-I (or ARB)
ventilation if SpO2 <95% deteriorating maternal Beta-blocker
condition and
prematurity in fetus MR antagonist
Add inotropes and/or vasopressors Diuretics
Consider levosimendan 0.1 mcg/kg/min
Deterioriating Stable maternal
maternal condition condition Consider
Urgent delivery bromocriptine

Recommend Heart failure

Consider bromocriptine delivery therapy:
Hydralazine

Consider mechanical circulatory support Advanced acute heart Nitrate

failure therapy Beta blocker
Consider diuretics
Recovery?

Delivery planning
Transplantation Weaning
(MDT approach)
Vaginal route
preferred

Consider wearable cardioverter-defibrillator if LVEF ≤35%

Continue heart failure therapy

Figure 3. Management of acute heart failure during/after pregnancy.27 Abbreviations: ACE-I = angiotensin-converting enzyme inhibitor; ARB =
angiotensin receptor blocker; ECG = electrocardiogram; ECHO = echocardiogram; HR = heart rate; LVEF = left ventricular ejection fraction; MDT =
multidisciplinary team; MR = mineralocorticoid receptor; RR = respiratory rate; SBP = systolic blood pressure; ScvO2 = central venous oxygen
saturation; SpO2 = peripheral oxygen saturation. [Colour figure can be viewed at wileyonlinelibrary.com]

ª 2021 Royal College of Obstetricians and Gynaecologists 283

 Peripartum cardiomyopathy
reduced ejection fraction (HFrEF). This is typically seen to
include ACE inhibitors (ACEi) or angiotensin receptor
blockers (ARB) as an alternative, mineralocorticoid receptor
antagonists/aldosterone antagonists (MRA; for example,
spironolactone, eplerenone), and b-blockers.22 These agents
inhibit the overactivation of various neurohormonal
signalling pathways, including the renin–angiotensin–
aldosterone system (RAAS), the sympathetic nervous system
and reduced systemic sensitivity to natriuretic peptides.
Angiotensin receptor nephrilysin inhibitors (ARNI) act on
the same neurohormonal pathways and, in recent trials, have
been shown to be superior to ACEi/ARB.23 Their use
globally as a replacement to ACEi/ ARB in unselected
HFrEF is increasing. Sodium-glucose co-transporter-2
(SGLT2) inhibitors are a new therapy aimed at managing
glucose control in type 2 diabetes. However, they have also
been shown to have a significant benefit in HFrEF through an
unknown mechanism.24
Pharmacological therapy should consider the placenta
during pregnancy and potential breastfeeding postpartum.
The optimal length of time for pharmacological management
is not known. Prognostic therapies should be given at least
until the ejection fraction recovers, but no evidence exists for
continuing treatment beyond this. If anticoagulation has
been started, this should be continued for 6–8 months
postpartum, unless there is an indication for continuing
treatment.7 Table 2 provides a list of commonly used drugs
with their safety profile in pregnancy and breastfeeding.
Treatments can be broadly split into four groups.
1. Pregnant and haemodynamically stable
Salt restriction is an important first measure and
demonstrates sound efficacy for improving volume control.
A loop diuretic, such a furosemide or bumetanide, is useful
in managing symptomatic breathlessness and pedal oedema
through reduced preload, though caution is needed to avoid
overdiuresis with resultant maternal hypotension and
uterine hypoperfusion. Beta-blockers can be safely initiated;
preference is for selective b-1 antagonists, such as metoprolol,
to avoid unwanted systemic side effects. Both ACEi and ARB
are contraindicated in pregnancy, as are MRA. Hydralazine
in combination with nitrates can be used instead as a
form of vasodilatory therapy, which reduces afterload.
Anticoagulation, if needed, should be undertaken with low-
molecular-weight heparin (LMWH) because warfarin is
contraindicated in pregnancy and no data exist on use of
the direct oral anticoagulants (DOACs) in pregnancy. The
overall venous thromboembolism (VTE) rate within the
PPCM population is high at 2.2–6.8%.12 If arrhythmia arises
as a problem and cannot be managed with b-blockers, other
anti-arrhythmics, such as adenosine, verapamil, flecainide
and procainamide, can be used. However, there is limited
evidence of their safety.9
284
2. Postpartum breastfeeding and haemodynamically
stable
Postpartum, several ACEi and ARBs are compatible with
breastfeeding, as is MRA therapy. Beta-blocker therapy can
be continued, as can hydralazine and nitrate therapy,
although preference is to establish ACEi/ARB, so nitrates
and hydralazine may need to be stopped to accommodate
this. LMWH can continue if needed, but warfarin is also
compatible with breastfeeding.
3. Postpartum and not breastfeeding
Within this cohort, all pharmacological options are open to
the clinician, including ARNI, SGLT2 and DOAC, although
their use is based on data from undifferentiated management
of HFrEF.9
4. Haemodynamically unstable
Patients with signs of haemodynamic instability need rapid
and aggressive therapy, usually requiring admission to the
intensive care unit.21 Initial therapy is centred around the
following principles:
 Optimisation of preload. This can be achieved by
administering intravenous diuretics, particularly when
there are signs of congestion, such as pulmonary
oedema. Intravenous vasodilators (for example, nitrates)
can be safely started in women with systolic blood
pressure >110 mmHg.21
 Adequate oxygenation. Oxygenation should be maintained
in the optimal range (SpO2 >95%) and, where possible, the
patient’s thorax should be kept upright. The use of
noninvasive ventilation with continuous positive airway
pressure (CPAP) may decrease intubation rate; however,
intubation and ventilation should be considered in the case
of refractory hypoxia.21
 Circulatory support with inotropic and/or vasopressor
therapy. In the presence of cardiogenic shock (defined as
ineffective cardiac output caused by cardiac dysfunction
resulting in inadequate end-organ perfusion), circulatory
stability should be quickly achieved to prevent permanent
organ damage. Inotropes and vasopressors are useful to
establish this stability. Catecholamines, such as adrenaline
and dobutamine, may be less favourable in PPCM patients
because they increase the myocardial oxygen demand,
which, in turn, adds further compromise. For patients
needing inotropic support, there is weak evidence from
retrospective analysis that levosimendan (a calcium
sensitising agent) is preferable to catecholamines, although
this has not been proved in randomised control trials.25
 Urgent delivery if heart failure occurs during pregnancy.
Ideally, when feasible, patients with severe manifestation of
the disease should be transferred to and treated in an
experienced tertiary unit. Maternal safety takes precedence
ª 2021 Royal College of Obstetricians and Gynaecologists
 Kulkarni et al.

Table 2. Safety profile of drugs for heart failure.18

Safety during Absence of full recovery of LV Complete recovery

Drug pregnancy Safety during lactation function of LV function

Beta blocker Safe, metoprolol is the Safe Essential for all patients. Titrate to Continue for at least
recommended beta maximally tolerable dose. 12 months.
blocker.

ACE inhibitor Avoid. Teratogenic Low transfer of enalapril and Essential for all patients. Titrate to Continue for at least
due to risk of fetal captopril, hence relatively safe. maximally tolerable dose. 12 months.
kidney injury.

Angiotensin receptor Avoid, teratogenic. Limited data, so best to avoid. Recommended for women who Continue for at least
blocker cannot tolerate ACE inhibitor. 12 months.
Titrate to maximally tolerable dose.

Mineralocorticoid No data, so best Limited data, so best avoided. Recommended for all patients with Continue for at least 6
receptor antagonist avoided. LVEF <40%. Eplerenone may be months. After this,
considered because it is associated discontinue if there is
with fewer hormonal side effects. sustained recovery of
the structure and
function of left
ventricular structure
and function.

Diuretics Use sparingly as they Thiazides are the best-studied Continue only when symptom Discontinue as soon as
can cause decreased drug during lactation and are control is needed (for oedema and symptom control for
placental blood flow. well tolerated. congestion). Early tapering of oedema and
Thiazides and doses when there is good congestion is
furosemide are most symptom control even before achieved.
commonly used. complete recovery of LV function.

Vasodilators Includes nitrates and Safe Continue only when symptom relief Discontinue when
hydralazine. Use with is needed. asymptomatic.
caution, may
precipitate uterine
hypoperfusion.

Abbreviations: ACE inhibitor = angiotensin-converting enzyme inhibitor; LV = left ventricle; LVEF = left ventricular ejection fraction.

over fetal interest. Therefore, in an unstable patient, a
decision for urgent delivery – irrespective of the stage of
pregnancy – should be undertaken by a multidisciplinary
team with due consideration to the woman’s wishes. For
patients with no improvement in circulatory stability
despite optimal medical treatment, mechanical circulatory
support should be offered.21
 Consideration of ancillary support with bromocriptine.
The use of bromocriptine, a dopamine D2 agonist, within
this cohort of patients is increasing.26 In 2018, the
European Society of Cardiology27 recommended its use
as a IIb recommendation. However, in 2016, the American
Society of Cardiology28 classed its use as experimental. If
bromocriptine is commenced, anticoagulation should also
be started because its use has been associated with risk of
thrombosis.7 A dose of 2.5 mg once daily for at least
1 week is advised in uncomplicated cases, whereas
extended treatment (2.5 mg twice daily for 2 weeks, then
2.5 mg once daily for 6 weeks) is advised when the
ejection fraction is less than 25%, with or without
associated cardiogenic shock.27
Mechanical circulatory support
Usually, in HFrEF, where inotropic support fails, mechanical
circulatory support can be indicated. This should be
discussed with the centres able to offer these treatments.
Short-term initial therapies may include temporary
ventricular support devices, such as intra-aortic balloon
pump (IABP) and intraventricular pump (for example,
Impella), which can be inserted via peripheral arterial
access (for example, the femoral artery). IABP devices
augment circulation by reducing afterload and improving

ª 2021 Royal College of Obstetricians and Gynaecologists 285

 Peripartum cardiomyopathy
coronary flow, and intraventricular pumps maintain cardiac
output, but neither has any effect on oxygenation. In cases
involving continuing pulmonary dysfunction, extracorporeal
membrane oxygenation (ECMO) may be an option.21 A
prolonged period of support may require long-term
ventricular assist devices such as BiVAD (biventricular
assist device) or LVAD (left ventricular assist device).
Conventionally, these are used as a bridge to definitive
management, usually transplant; however, as the possibility
for recovery in this condition remains high it may be
considered as a bridge to recovery.9 Unfortunately no metric
exists to accurately predict recovery and roughly 5% of
PPCM patients need mechanical support or transplant.29
Women who receive transplant for PPCM have poorer
outcomes than recipients for other conditions. These women
have had a higher mortality rate, greater incidence of
rejection, with shorter graft survival and greater rates of
repeat transplantation.21 For serious arrhythmia or cardiac
arrest, cardioversion and defibrillation remain safe options, if
needed, across pregnancy and breastfeeding.
Advanced heart failure therapy
Traditionally, in severe HFrEF, there is strong evidence for
implantable cardiac defibrillator devices for primary and
secondary prevention of arrhythmia. However, with optimal
medical therapy, PPCM often recovers sufficiently that such
devices are no longer indicated, so avoiding implantation
where possible seems sensible. The European Society of
Cardiology (ESC) and the American Heart Association
(AHA) recommend consideration of these devices in
severely impaired PPCM patients as a bridge to ejection
fraction recovery or, if needed, to full intracardiac device
implantation after 3–6 months.9
Pregnancy-specific consideration
Box 2 presents a checklist for the management of acute heart
failure caused by PPCM.21 Most cases of PPCM present
postnatally. Antenatally occurring cases usually present in the
latter part of pregnancy. When prescribing, the effect of
medication on the fetus must be considered. Fetal growth
monitoring with serial growth scans is essential. These
women should be managed in a high-risk obstetric unit
with additional input from cardiology.1 The biggest
consideration is the timing of delivery, which requires
maternal status to be balanced against fetal prematurity. In
women with advanced heart failure or haemodynamic
instability, urgent delivery must be considered, irrespective
of the gestation age.21 In the absence of overt cardiac failure
symptoms, supportive medical therapy and a spontaneous
vaginal delivery is an acceptable approach. Caesarean section
should be reserved for an obstetric reason or if there is severe
maternal compromise. Induction of labour is similarly
286
Box 2. Checklist for the management of acute heart failure caused
by peripartum cardiomyopathy21
 Multidisciplinary approach to managing women with peripartum
cardiomyopathy.
 Avoidance of heart failure drugs with teratogenic risks during
pregnancy and breast feeding (for e.g. ACE inhibitors/ARBs,
mineralocorticoid receptor antagonists)
 Consideration of bromocriptine (2.5 mg twice daily for 2 weeks,
followed by 2.5 mg per day for 6 weeks).
 Anticoagulation with low molecular weight heparin especially in
women with left ventricular ejection fraction (LVEF) ≤35% and/or
those women being treated with bromocriptine.
 In the case of cardiogenic shock, consideration of levosimendan (0.1
lg/kg/min for 24 h) instead of catecholamines as first-line inotropic
drug.
 Early transfer to a specialist care centre with evaluation for
mechanical circulatory support where necessary.
considered for an obstetric indication for delivery or for
deteriorating cardiac function.30 If the fetus needs to be
delivered prematurely, intramuscular corticosteroids are
administered between 24 weeks of gestation and 35 weeks
and 6 days gestational age to promote fetal lung
maturation.31 A detailed intrapartum plan should be
available in the woman’s maternity record for staff to
follow when she presents in labour.
Optimal intrapartum care is important. The fetus should
be monitored with continuous cardiotocography. In
accordance with guidelines published by the National
Institute for Health and Care Excellence (NICE) on
intrapartum care,32 hourly monitoring of fluid balance
(with a 4-hourly assessment by a senior clinician), blood
pressure, pulse, respiratory rate and oxygen saturation is
recommended. Continuous ECG, pulse oximetry and
assessing cardiac output with non-invasive techniques are
crucial aspects of monitoring cardiac function. Women who
need more comprehensive monitoring will need to be in an
intensive care unit where the necessary equipment and
expertise is available. This will include continuous invasive
intra-arterial pressure monitoring, central venous pressure
monitoring and advanced cardiac output monitoring. A 30°
left tilt is essential to avoid aortocaval compression.30 Low-
dose regional analgesia is safe because it avoids cardiac
instability during labour and birth. Limiting the active phase
of the second stage of labour with the aid of instrumental
delivery helps to negate the cardiovascular effects of
prolonged pushing.30 In the third stage, slow infusion of
oxytocin is the first-line recommended drug to avoid
sudden haemodynamic change. Misoprostol and carboprost
(PGF2a) are used as second-line treatment to reduce risk
of haemorrhage. Long-acting oxytocin analogues and
ergometrine should be avoided because of the risk of heart
failure secondary to medication-induced hypertension.32
ª 2021 Royal College of Obstetricians and Gynaecologists

Breastfeeding
There is no clear consensus on breastfeeding in women with
PPCM; existing evidence is sparse. Notably, since prolactin
has been associated with causing PPCM, it would be a
reasonable argument to avoid breastfeeding altogether.
However, there is no clinical evidence to substantiate a
poor prognosis associated with breastfeeding.33 The current
approach, when a woman is haemodynamically stable, is to
not discourage breastfeeding, taking into consideration the
woman’s preference. Another practical aspect involved in
the decision of breastfeeding in developing countries is the
availability of clean water and milk formula. While several
pharmacotherapies for managing chronic heart failure are
safe during breastfeeding (captopril, enalapril and quinapril),
others such as long-acting carvedilol and spironolactone are
not recommended owing to concerns about their safety
profiles.34 However, the onus should be on optimal treatment
of cardiomyopathy and heart failure to achieve the fastest
possible recovery. Therefore, in women who are symptomatic
and haemodynamically unstable, or if the LVEF <45%,
breastfeeding should be actively deterred.33,34
Prognosis
Around 50–80% of women diagnosed with PPCM achieve
recovery in their left ventricular function (LVEF ≥50%),
mostly within the first 6 months after manifesting the
disease. There has been a significant improvement in
mortality rate since the early 1970s, when it was reported
to be around 30–50%.9 Currently, the overall mortality rate
has been estimated to be 10%.30 Afro-Caribbean lineage is
associated with a reduced likelihood of recovery.9 In contrast,
PPCM associated with hypertension has been associated with
a more successful recovery.9
Subsequent pregnancy
There is a risk of relapse of PPCM in subsequent pregnancies.
In women with persistent left ventricular dysfunction, there is
a 50% chance of further deterioration in left ventricular
function and increased morbidity and mortality rates
(mortality may be as high as 20%).34 In women with
complete recovery of left ventricular function, prognosis
appears to be better, although 20% of women may have a
further relapse.34,35 For women who recover their normal left
ventricular function, long-term outcome is largely unknown,
with regard to late onset heart failure, progressive ventricular
dysfunction and the need for advanced heart failure therapy
or transplant. If the LVEF <25% at initial diagnosis, or when
the LVEF has not normalised over a course of time following
adequate medical care, the woman should be counselled not
to become pregnant again.34 Both the ESC27 and the AHA28
ª 2021 Royal College of Obstetricians and Gynaecologists
Kulkarni et al.
guidelines advise against a subsequent pregnancy if the
woman has not achieved a normal LVEF.
Management in subsequent pregnancy
Pre-conceptional counselling with a multidisciplinary team of
experts (cardiologist, obstetric physicians and obstetricians
with an interest in maternal medicine or fetal/maternal,
anaesthetist, neonatologist and other allied specialties), ideally
in a tertiary care centre, should be arranged prior to embarking
on a subsequent pregnancy. A review of medications should be
undertaken, with a plan to stop ACEi, ARB blockers and MRA
in the prepregnancy period and convert to alternative
hydralazine-nitrate combination. Following confirmation of
pregnancy, early booking and consultant-led care should be
arranged with frequent antenatal visits. The patient should
continue treatment with b-blockers and followed closely with
echocardiography and brain natriuretic peptide (BNP)
levels.34 The proposed timing of offering echocardiograms
has been discussed in Figure 4.
In pregnant women with PPCM, particularly those with
LV dysfunction, anticoagulation with LMWH should be
considered.36 Serial scans to monitor fetal growth should be
offered from 24 weeks of gestation. Timing of the delivery is
guided by obstetric indications (such as fetal growth
restriction or pre-eclampsia) or for cardiac reasons (such as
worsening cardiac function). Ideally the target would be to
reach 37 weeks of gestation. However, the best outcome will
be achieved by a consensus with the team of experts to
balance maternal health against fetal prematurity. Vaginal
birth is recommended, unless there is a need for caesarean
section for obstetric indications or because of acute
haemodynamic compromise. Anticoagulation should be
considered for 6 weeks after the delivery because of the
thrombotic risk during this period.37
Contraception
A safe and dependable contraceptive is recommended for
women with PPCM to avoid an unplanned pregnancy,
especially when adequate recovery of cardiac functions has
not been achieved. This was highlighted in the recent
MBRRACE 2019 report.1 Simple barrier methods are not
recommended because they are not reliable (failure rate can be
as high as 18% with typical use of male condoms).38
Intrauterine devices (copper and progestogen-releasing
IUDs) are not just effective and long-lasting, but also have
no added risk of thromboembolism. Women with PPCM have
a high risk of cardiac arrhythmias. Arrhythmias tend to cause
vasovagal collapse because the heart rate is too fast-paced to
allow satisfactory filling, or too slow to enable adequate
outflow. For this reason, hospital is a safer place for IUD fitting.
Although invasive contraceptives can theoretically increase the
287
 Peripartum cardiomyopathy
Figure 4. Recommended schedule of screening echocardiography for women with a history of peripartum cardiomyopathy and subsequent
pregnancy.9 Following delivery echocardiography is recommended prior to discharge from hospital. Figure reproduced with permission. [Colour
figure can be viewed at wileyonlinelibrary.com]
risk of infective endocarditis, prophylactic antibiotics are not
recommended as they have no effect on the rates of
endocarditis.39 Combined hormonal contraceptives should
be avoided because estrogen, in particular, is known to increase
the risk of thromboembolism.40 Long-acting reversible
contraceptives (LARC) containing progesterone (such as
intramuscular, subcutaneous and subdermal forms) are a
safe alternative. Sterilisation options include vasectomy and
tubal ligation. Because of the psychological impact of the
disease, uncertainty about the long-term prognosis and the
permanent nature of sterilisation, women and their
partners should be carefully counselled about these options.
In addition, the anaesthetic risk involved in female
sterilisation should be considered in women with persisting
LV dysfunction.2
Conclusion
PPCM is a rare but serious disorder affecting otherwise healthy
women in their childbearing age. Despite a dramatic
improvement in the understanding of this disease, there are
some unanswered questions. Apart from bromocriptine, no
other treatment specific for PPCM is yet in use. Further work is
needed in several areas, including the long-term prognosis in
women with complete and incomplete recovery, required
treatment length for medical therapy, PPCM-specific
diagnostic biomarkers and PPCM-specific treatment options.
National multicentre and worldwide registers on PPCM,
together with continued research activities, are needed to
further broaden our understanding of PPCM and
its management.
288
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
AK instigated, wrote, and revised the article; GS wrote and
edited the article. MWO and KH critically revised it for
important intellectual content. All authors approved the
final version.
Acknowledgements
The authors would like to thank Margaret Theaker, the
Library and Knowledge Services Manager at Kettering
General Hospital, for her contribution to literature search.
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 DOI: 10.1111/tog.12771 2021;23:290–4
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Shared decision making in gynaecological oncology; a

challenge in an ageing population
Magda Sbai MBBS BSc (Hons) MRCP,a* Emily Jasper MBBS (Hons),b Fionna Martin BA (Hons) MBBS MRCP,a
Savithri Rajkumar MRCOG,c Ana Montes LMS PhD,d Jeyanjali Jeyarajah MBBS BSc FRCA,e
Danielle Harari MD FRCP,f,g Judith Partridge MSc PhD FRCPa,h
a
Consultant Geriatrician, Perioperative Medicine for Older People undergoing Surgery (POPS), Guy’s and St Thomas’ NHS Foundation Trust,
New City Court, 20 St. Thomas Street, London SE1 9RT, UK
b
Research Fellow, Perioperative Medicine for Older People undergoing Surgery (POPS), Guy’s and St Thomas’ NHS Foundation Trust,
New City Court, 20 St. Thomas Street, London SE1 9RT, UK
c
Consultant Oncology Gynaecologist, Gynaecology, Guy’s and St Thomas’ NHS Foundation Trust, New City Court, 20 St. Thomas Street, London
SE1 9RT, UK
d
Consultant Medical Oncologist, Guy’s Cancer Centre, Guy’s and St Thomas’ NHS Foundation Trust, New City Court, 20 St. Thomas Street,
London SE1 9RT, UK
e
Consultant Anaesthetist, Guy’s and St Thomas’ NHS Foundation Trust, New City Court, 20 St. Thomas Street, London SE1 9RT, UK
f
Consultant Geriatrician, Geriatric Oncology Liaison Development (GOLD) team, Guy’s and St Thomas’ NHS Foundation Trust, New City Court,
20 St. Thomas Street, London SE1 9RT, UK
g
Honorary Academic Reader in Geriatric Medicine, King’s College London, London, UK
h
Honorary Senior Lecturer, Division of Primary Care and Public Health Sciences, Faculty of Life Sciences and Medicine, King’s College London,
London, UK
*Correspondence: Magda Sbai. Email: magda.sbai@nhs.net

Accepted on 3 November 2020. Published online 14 September 2021.

Key content
 Gynae-oncology patients are increasingly older and living with
frailty and multimorbidity, resulting in higher rates of
perioperative or treatment-associated adverse outcomes.
 Collaborative shared decision making (SDM), where healthcare
professionals and patients work in partnership to reach a treatment
decision, can be used to engage patients in treatment decisions.
 Comprehensive geriatric assessment (CGA), a multidimensional,
interdisciplinary process assessing medical, psychological and
functional capabilities, can inform individualised management
and SDM in older gynae-oncology patients with
complex conditions.
 Evidence is emerging for the use of CGA to inform individualised
management and underpin integrated care pathways and SDM for
older people. This methodology is advocated in NHS England’s
Cancer Strategy through integrated pathways for older cancer
patients with geriatrician involvement.
 Using clinical case studies, this review contextualises the
application of SDM through CGA in older patients with
gynaecological malignancy.
Learning objectives

Know that SDM takes proposed risks and benefits into account,
together with projected disease progression with and without
treatment and patient preferences.
 Understand that limitations to SDM in older people include the
effects of multimorbidity, cognitive impairment and frailty, limited
data on long-term clinician and patient-reported outcomes and
frequent exclusion of older people from research trials.
Keywords: geriatric / gynae-oncology / shared decision making

Please cite this paper as: Sbai M, Jasper E, Martin F, Rajkumar S, Montes A, Jeyarajah J, et al. Shared decision making in gynaecological oncology; a challenge in an
ageing population. The Obstetrician & Gynaecologist 2021;23:290–4. https://doi.org/10.1111/tog.12771

coupled with the relative exclusion of older patients from

Introduction
Gynaecologists and oncologists are increasingly managing
women with complex, multimorbidities. This older surgical
population experiences higher rates of adverse postoperative
outcomes and oncological treatment complications than
their younger counterparts.1,2 Such adverse outcomes relate,
in part, to multimorbidity and frailty, which are commonly
observed in older patients. An awareness of these issues,
research, might explain why older cancer patients are less
likely to receive the most clinically effective treatments.3
Potential under treatment of disease may also contribute to
poorer outcomes in older patients. Shared decision making
(SDM) is important to ensure that the patient is supported in
making well-informed investigation and treatment choices,
taking into account their needs and preferences, within the
short timeframes of cancer pathways. SDM, in the context of

290 ª 2021 Royal College of Obstetricians and Gynaecologists


gynaecological malignancy in the older population, can be
complex, given the paucity of evidence in this patient group,
particularly with relation to functional status and long-
term outcomes.
Shared decision making
SDM is a collaborative process in which healthcare
professionals and patients (or their appointed/nominated
deputies) work in partnership to reach a treatment decision
based on a clinician’s expert knowledge and the patient’s
values.4 The clinician’s role in SDM is to inform the patient
of the diagnosis and predicted risks and benefits of the
available treatment options. These might range from the
most invasive options through to the best supportive care to
provide realistic and comprehensible choices to the patient,
taking health literacy (the ability to use healthcare
information to make appropriate healthcare decisions)
into account. The patient’s role lies in articulating the
impact of the condition and proposed treatments on their
life and outcome preferences. The clinician and patient are
then able to come to a shared decision on the most
appropriate intervention and ongoing care. Within the
oncological context, this process may require multiple
consultations as patients come to terms with a new,
potentially life-altering diagnosis. Subsequently, this may
require re-evaluation of continuing health and life goals.
While SDM has been recognised as an ideal model of care
for several years, its importance was highlighted in 2016
through the Choosing Wisely initiative. This focused on
improving patient–physician conversations, ensuring access
to appropriate interventions and reducing unnecessary
treatments. The initiative advocates use of the BRAN tool,
a four-question decision aid that patients and healthcare
professionals can use to facilitate SDM
conversations (Figure 1).
There is a common perception among healthcare
practitioners that SDM already constitutes routine practice
in the UK.5 Despite this, a Kings Fund report highlights that
What are the Benefits?
What are the Risks?
What are the Alternatives?
What if we do Nothing?
Figure 1. BRAN: Shared decision making decision aid advocated by
the Choosing Wisely UK initiative.
ª 2021 Royal College of Obstetricians and Gynaecologists
Sbai et al.
SDM is not yet the norm, with patchy implementation and a
perception among clinicians that SDM is more resource-
intensive than standard care. Regardless of such perceptions,
it is clear from national surveys that patients do desire
increased involvement in their care.5 Addressing this
imbalance through SDM may empower patients to be equal
partners in care decisions, resulting in greater satisfaction and
reduced patient–physician conflict. Such benefits may be seen
independently of patients’ preferred decision roles,
emphasising the importance of involving patients in SDM.6
Shared decision making in older
gynae-oncology patients
In keeping with the international Choosing Wisely
programme, there is growing advocacy for SDM in gynae-
oncology. Gynaecological cancer care involves a team of
specialists (including gynaecologist, oncologist, anaesthetist
and palliative care), each with an inherent bias. Therefore,
patients may receive variable information from each
specialist, leading to decisional conflict. Decisional conflict
arises when there is uncertainty about the course of action to
take. It can be harmful: patients are more likely to delay
decisions, blame clinicians for adverse outcomes, or regret a
decision.7 This uncertainty has been demonstrated in the
endometrial cancer population, where 45% of women felt
inadequately involved in decisions, with increasing age
associated with this view.8 In older people, SDM can
be additionally challenging, owing to concurrent
multimorbidity, cognitive impairment and geriatric
syndromes (conditions that are typical, but not specific, to
ageing), such as frailty. Communication difficulties can also
add a layer of complexity through sensory impairment
(visual and hearing), language barriers and involvement of
carers/next of kin who may hold conflicting views. Decision
aids can be used to assist with SDM in the oncology setting
and, while these are potentially beneficial in older people,
they have not yet been validated within this cohort.
Common barriers to SDM include time pressures,
perceived lack of training and fears about managing risk,
in addition to patient factors such as low health literacy and
cognitive impairment.5
Multidisciplinary team (MDT) meetings are an established
component of cancer pathways, allowing a collaborative
interspecialty approach for clinicians to confirm diagnoses,
discuss management options and establish the recommended
treatment path. The acknowledged deficiency in this model of
care is the focus on a pathological diagnosis, without sufficient
attention afforded to the patient’s values and biopsychosocial
profile. Therefore, the utility of an MDT meeting is diminished
because it lacks – arguably – the most important information:
the patient’s preferences. This approach can limit effective SDM,
through beginning the care trajectory with clinician-led
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 Shared decision making in gynaecological oncology

decisions that may be incongruent with the patient’s

Table 1. Components of comprehensive geriatric assessment
values. These clinician-made, disease-based decisions are
predominantly influenced by diagnosis and patient age, rather Domain Intervention
than comorbidities and support networks. The effect of this was
illustrated in an ovarian cancer study, in which only 10% of
Medical Assessment and optimisation of:
patients aged over 75 years received best practice care according  Known co-morbidity
to guidelines (although the degree of patient involvement in  Medication review
these decisions was not specified).9 This disconnect is  Nutrition and skin integrity
acknowledged in NHS England’s Cancer Strategy, which  FrailtyDiagnosis of previously unrecognised co-
morbidity
advocates a need to assess integrated pathways for older cancer
patients, as well as better outlining the role of geriatricians and Psychological Assessment and optimisation of:
their input into the MDT.10  Cognitive function and capacity
 Anxiety and depression
 Concerns and expectations
What can comprehensive geriatric
Functional Assessment and optimisation of:
assessment offer?  Personal activities of daily living
 Instrumental activities of daily living
Comprehensive geriatric assessment (CGA) is a
 Gait and balance
multidimensional, interdisciplinary process that assesses a  Falls assessment and bone health
patient’s medical, psychological and functional capabilities,
to inform individualised management (Table 1). It identifies Social Assessment and optimisation of:
 Informal support network (friends and family)
risk factors, such as medical comorbidity and geriatric  Social support network (visitors and
syndromes (frailty, falls, cognitive impairment and activity centres)
functional impairment), which affect surgical and treatment  Formal care provision
outcomes, thus providing a tailored framework for SDM  Lifestyle modification (smoking and alcohol)
conversations with patients. There is emerging evidence for Environmental Assessment and optimisation of:
the utility of CGA in cancer care, both in patients undergoing  Home environment and necessary
surgical and oncological treatment.11,12 Operationalising safety equipment
CGA in the surgical management of cancer patients is  Telehealth technologies
 Access to local resources (e.g. taxicard)
described by one UK model: the Perioperative medicine for
Older Patients undergoing Surgery (POPS) service at Guy’s
and St Thomas’ NHS Foundation Trust.10 Similarly, the
Geriatric Oncology Liaison Development (GOLD) model at
the same Trust uses CGA methodology to underpin the co-
management of oncology patients.12 These geriatrician-led
Case 1
MDTs assess and optimise patients’ presurgical or
oncological cancer treatment and deliver inpatient An 88-year-old woman was referred for preoperative
management through a shared care model with surgical or assessment prior to total abdominal hysterectomy (TAH) as
oncological teams. CGA-trained clinicians have experience in curative surgery for Grade 1 endometrial adenocarcinoma.
eliciting the views of patients with multimorbidity and Comorbidities included hypertension and osteoarthritis,
geriatric syndromes and identifying premorbid views of managed with amlodipine and paracetamol.
patients lacking capacity through discussion with their
relatives. In the UK, the Mental Capacity Act 2005 (MCA) Assessment
is used to appraise capacity and direct best interest CGA identified severe frailty, falls, mild cognitive impairment
decisions.13 Similar frameworks exist in other countries. (MCI) and dysphagia. The patient’s understanding of the
Application of such legal frameworks requires specific skill diagnosis and proposed treatment was explored, revealing
and training, which is incorporated in CGA practice. that she attributed her gradual functional decline to the
The following clinical examples aim to contextualise the recently diagnosed malignancy. She believed that surgery
application of CGA and SDM in older patients with would reverse her functional deterioration. The patient had
gynaecological malignancy and demonstrate how common capacity despite MCI. Treatment options were presented;
barriers can be addressed. In each of these cases, assessment first, curative surgery accepting surgical risk, medical risk
was performed by a CGA-trained healthcare professional (delirium, falls, aspiration pneumonia) and functional risk
within a geriatrician-led MDT and SDM conversations were such as failure to return home. Second, conservative
directly facilitated by a consultant geriatrician. management accepting disease progression with the option

292 ª 2021 Royal College of Obstetricians and Gynaecologists


of progestins and/or radiotherapy. The patient was
counselled on radiotherapy risk, including urinary and
faecal incontinence. The assessing clinician communicated
that surgery would not reverse her functional deterioration
because this was attributable to severe frailty and, given that
it would lead to further functional decline, surgery would
probably not be in her best interests. She elected to discuss
further with her family and a follow-up appointment
was made.
Outcome
Between appointments, the patient was hospitalised for
aspiration pneumonia. At follow-up, the patient declined
surgery, understanding that the endometrial cancer was
unlikely to result in death. Instead, she opted for progestin
therapy. Advanced care planning was undertaken with
her GP.
Case 2
An 81-year-old woman referred for preoperative assessment
prior to vulvectomy with lymph node (LN) clearance for a 6-
cm vulval carcinoma with expected LN invasion. The
diagnosis was made following presentation with localised
symptoms of pain. Documented comorbidities included
stable ischaemic heart disease and osteoporosis. The patient
was currently living in a one-level adapted environment as
she was unable to climb stairs.
Assessment
Cognitive assessment performed by a consultant geriatrician
confirmed dementia. The patient did not have capacity to
consent to treatment and had a pre-appointed lasting power
of attorney (LPA). According to the MCA, the team
discussed the treatment options with the patient and LPA.
These included vulvectomy with LN clearance, wide local
excision (WLE) without LN clearance, radiotherapy, or
palliative care. Surgical risks included impaired lower limb
lymph drainage, infection and likelihood of requiring
adjuvant radiotherapy. Medical risks included delirium
with dementia progression, functional decline (potentially
resulting in long-term institutionalisation) and death.
Despite lacking capacity, the patient’s understanding was
further explored to elicit any understanding or opinion on
treatment. However, the only priority voiced and echoed by
the appointed LPA was for the patient to continue living in
her own home.
Outcome
Taking the patient’s views into account, the clinical team and
LPA agreed that radical surgery was not in her best interests.
WLE without lymphadenectomy was undertaken, primarily
to achieve symptom control. Advance care planning was
ª 2021 Royal College of Obstetricians and Gynaecologists
Sbai et al.
undertaken with the patient and LPA, and the patient was
referred to the community palliative care team.
Case 3
An 83-year-old woman was referred for preoperative
assessment for hysteroscopy and biopsy under general
anaesthetic, with view to proceeding to TAH if proven
malignancy. Comorbidities included hypertension, cardiac
failure and chronic kidney disease. Previously prescribed
medications were ramipril, amlodipine, bisoprolol
and frusemide; however, the patient reported non-
adherence secondary to her belief that she did not
need them.
Assessment
The patient had a 3-month history of worsening shortness of
breath and paroxysmal nocturnal dyspnoea, with impaired
mobility. She lived in a two-storey home. CGA identified
mild frailty, intact cognition, a new diagnosis of mild chronic
obstructive pulmonary disease (COPD) and decompensated
biventricular cardiac failure. The patient was educated
regarding medication non-adherence, which had resulted in
decompensated heart failure and uncontrolled hypertension.
Proceeding without medical optimisation carried a risk of
further cardiac decompensation, stroke, respiratory
complications and functional decline. SDM resulted in
delaying surgery to facilitate medical optimisation and
modification of the perioperative risk profile. Optimisation
involved reintroduction and up-titration of medications, new
inhaled treatment for COPD and education
regarding adherence.
Outcome
Ten days following medication reintroduction there was no
evidence of decompensated heart failure, and blood pressure
was within normal limits. She subsequently underwent
hysteroscopy and biopsy, confirming malignancy. A
successful TAH was undertaken with curative intent.
These cases illustrate the benefit of CGA informing SDM
perioperatively. In the first case, a disease-centred decision
regarding curative surgery made in a traditional surgical-
oncological meeting was reversed on discussion with the
patient. The process of CGA identified frailty, which predated
any deterioration attributable to the early gynaecological
malignancy. Incorporating this information into SDM allowed
better information provision by the healthcare, thus team
informing the final patient-led decision. The second case
illustrates the process of SDM in the presence of cognitive
impairment, with reference to legal frameworks and the role of
advocacy in reflecting the patient’s pre-specified wishes. In the
third case, CGA was used to identify multidomain issues,
allowing medical optimisation to reduce perioperative risk. In
293
 Shared decision making in gynaecological oncology
this case, SDM centred more on the role of optimisation, as
opposed to whether surgery should be undertaken. The second
and third cases both highlight the importance of SDM for
advance care planning and discussions around resuscitation
and escalation of treatment.
Conclusion
There are continuing challenges in the delivery of optimal
patient-centred cancer care, particularly in view of an ageing,
multimorbid population. SDM in this group requires thorough
assessment, medical optimisation and risk modification; the
communication of benefits, risks, alternatives and doing
nothing; and the application of relevant legal frameworks.
CGA can be used to underpin such processes by providing an
evidenced-based approach. National initiatives in support of
such approaches to pathway development include the Choosing
Wisely campaign and collaborative working, such as the Centre
for Perioperative Care. Strategies that can be employed locally by
the gynaecologist to improve shared decision making in the
complex older patient include the use of decision aids in
clinician–patient interactions, the inclusion of patient
preferences in MDT discussions, utilisation of established roles
like the clinical nurse specialist in facilitating some of these
discussions, collaborative working with perioperative physicians
and anaesthetists who have expertise in SDM, and the design of
integrated care pathways for older cancer patients.
Disclosures of interests
There are no conflicts of interest.
Contribution to authorship
MS wrote the first and final draft of the manuscript and
contributed to editing. EJ, FM, SR, AM, JJ and DH reviewed
and edited the manuscript. JP conceived the idea for the
manuscript and edited the manuscript.
294
References
1 Iyer R, Gentry-Maharah A, Nordin A, Burnell M, Liston R, Manchanda
R, et al. Predictors of complications in gynaecological oncological
surgery: a prospective multicentre study (UKGOSOC-UK gynaecological
oncology surgical outcomes and complications). Br J Cancer
2015;112:475–84.
2 Urban R, He H, Alfonso R, Hardesty M, Gray H, Goff B. Ovarian
cancer outcomes: Predictors of early death. Gynecol Oncol
2016;140:474–80.
3 National Cancer Intelligence Network. Older people and cancer. London:
Public Health England; 2015 [http://www.ncin.org.uk/publications/older_pe
ople_and_cancer].
4 Choosing Wisely UK. Shared decision making. London: Choosing Wisely UK;
2019 [https://www.choosingwisely.co.uk/shared-decision-making/].
5 Coulter A, Collins A. Making shared decision making a reality – no decision
about me, without me. London: Kings Fund; 2011 [https://www.kingsfund.
org.uk/sites/default/files/Making-shared-decision-making-a-reality-paper-Angela-
Coulter-Alf-Collins-July-2011_0.pdf].
6 Kehl KL, Landrum MB, Arora NK, Ganz PA, van Ryn M, Mack JW, et al.
Association of actual and preferred decision roles with patient-reported
quality of care: shared decision making in cancer care. JAMA Oncol
2015;1:50–8.
7 McAlpine K, Lewis K, Trevena L, Stacey D. What is the effectiveness of
patient decision aids for cancer-related decisions? A systematic review
subanalysis. JCO Clin Cancer Inform 2018;2:1–13.
8 Kunnemann M, Pieterse AH, Stiggelbout AM, Nout RA, Kamps M, Lutgens
LCHW, et al. Treatment preferences and involvement in treatment decision
making of patients with endometrial cancer and clinicians. Br J Cancer
2014;111:674–79.
9 Van Walree IC, van Soolingen NJ, Hamaker ME, Smorenburg CH, Louwers
JA, van Huis-Tanja LH. Treatment decision-making in elderly women with
ovarian cancer: an age-based comparison. Int J Gynecol Cancer
2019;29:158–65.
10 NHS England. Achieving World-Class Cancer Outcomes – a strategy for
England 2015–2020. Redditch: NHS England; 2015 [https://www.england.
nhs.uk/wp-content/uploads/2016/10/cancer-one-year-on.pdf].
11 Partridge JS, Harari D, Martin FC, Peacock JL, Bell R, Mohammed A, et al.
Randomised clinical trial of comprehensive geriatric assessment and
optimization in vascular surgery. Br J Surg 2017;104:679–87.
12 Kalsi T, Babic-Illman G, Ross PJ, Maisey NR, Hughes S, Fields P, et al.
The impact of comprehensive geriatric assessment interventions on
tolerance to chemotherapy in older people. Br J Cancer
2015;112:1435–44.
13 NHS England. Mental Capacity Act. London: NHS England; 2019 [https://
www.nhs.uk/conditions/social-care-and-support-guide/making-decisions-
for-someone-else/mental-capacity-act/].
ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12772 2021;23:295–300
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Update on recurrent vulvovaginal candidiasis

Amy Borland MRCOG,a* Katie Ovens MRCP DipGUM DipHIV DTMH,b Ifeoma Offiah MRCPI PhD MRCOG,
c

Anupreet Dua MD MRCOG,d Robert Freeman MD MRCOGe

a
Registrar in Obstetrics and Gynaecology, University Hospitals Plymouth NHS Trust, Plymouth PL68DH, UK
b
Registrar in Genitourinary Medicine, University Hospitals Plymouth NHS Trust, Plymouth PL68DH, UK
c
NIHR Clinical Lecturer in Obstetrics and Gynaecology and Subspecialty Trainee in Urogynaecology, University Hospitals Plymouth NHS Trust,
Plymouth PL68DH, UK
d
Consultant Obstetrician and Gynaecologist and Subspecialist Urogynaecologist, University Hospitals Plymouth NHS Trust, Plymouth PL68DH,
UK
e
Consultant Urogynaecologist, University Hospitals Plymouth NHS Trust, Plymouth PL68DH, UK
*Correspondence: Amy Borland. Email: amyborland@nhs.net

Accepted on 16 November 2020. Published online 23 September 2021.

Key Content  This review combines the current literature on VVC, incorporating
 Recurrent vulvovaginal candidiasis (RVVC) affects millions of data on novel therapies with established standard
women worldwide. Defined as four or more episodes per year of management protocols.
vulvovaginal candidiasis (VVC), it is a cause of significant morbidity,
Learning objectives
affecting quality of life, relationships and ability to work. 
 RVVC is uncommon in prepubertal girls and the incidence
To be able to assess risk factors and correctly diagnose VVC.
 To know the current management strategies for RVVC and the
markedly declines following menopause.
 Some gynaecologists and trainees have unmet training needs in the
efficacy of novel therapies.
 To be aware of the common differentials of bacterial
optimal assessment and management of RVVC.
 A multifaceted approach is often required, including vulval skin
vaginosis and trichomonas vaginalis and their recommended
management.
care, avoidance of triggers and induction and suppression regimes
with antifungal drugs.

Please cite this paper as: Borland A, Ovens K, Offiah I, Dua A, Freeman R. Update on recurrent vulvovaginal candidiasis. The Obstetrician & Gynaecologist
2021;23:295–300. https://doi.org/10.1111/tog.12772

Introduction
Vulvovaginal candidiasis (VVC) is considered the second
commonest genital infection in women after bacterial
vaginosis.1 Worldwide, recurrent VVC (RVVC) affects
around 130 million women annually, with a global annual
prevalence of 3871 per 100 000 women.2 Seventy-five percent
of women will have at least one episode of VVC in their
lifetime, with around 6% developing recurrent disease.3
Treatment is best achieved using a multifaceted approach
of lifestyle change, avoidance of triggers and improving
chronic disease, alongside antifungal medication. In both
acute and recurrent VVC, Candida albicans is the most
common pathogen. Acute infections usually respond well to
oral or topical antifungals, while women who develop RVVC
require longer term suppression therapy.3 Although
antifungal agents are widely available in the UK, clinical
resistance is uncommon. Elsewhere in the world (China,
Uganda, Ethiopia) reports of decreased susceptibility and
clinical resistance are increasing.4–7
Definition
Acute VVC is a first or an isolated episode of VVC. RVVC is
diagnosed when a woman has four or more reported episodes
of VVC over 12 months. Two of these episodes should be
confirmed by culture or microscopy (one must be by culture).3
Quality of life
RVVC is a long-term condition that can be debilitating and,
in some cases, severely affects quality of life.2 A study of
women in Europe and the USA showed that subjective health
status and quality of life was significantly worse in women
with RVVC than the general population and comparable with
those with chronic obstructive pulmonary disease or
asthma.8 The survey also revealed a significant loss of
productivity associated with RVVC (33 hours per year).
A systematic review by Denning et al.2 found that women’s
lives are not only affected by the continuing discomfort and
pain from RVVC. They also report:

ª 2021 Royal College of Obstetricians and Gynaecologists 295

 Update on recurrent vulvovaginal candidiasis
 Psychological burden (feeling dirty, lost
self-esteem/confidence)
 Days off from work
 Psychosexual problems
 Effects on interpersonal relationships (particularly with
sexual partners)
 Associated stigma: many partners believed it was linked
with sexually transmitted infections.
Aetiology
Candidiasis is a fungal infection caused by yeasts. Yeasts are
unicellular microorganisms belonging to the fungi kingdom.
Yeasts are present in low numbers on healthy skin in moist
areas and are part of the normal flora of the mucous
membranes of the respiratory, gastrointestinal, and female
genital tracts. Overgrowth of these organisms can cause both
superficial and systemic infections to develop. Candida
infections in the genital tract do not cause serious systemic
infections. Most cases of acute VVC and RVVC are caused by
C. albicans (80–89%); the remainder of infections are caused
by other Candida species or yeasts such as Candida glabrata,
Candida krusei and Saccharomyces cerevisiae.3
Risk factors
Many cases of RVVC are thought to be related to the host
rather than the fungus. For many women, a cause for
infection recurrence is never identified. Risk factors for
RVVC include:
 Estrogen exposure (puberty, pregnancy, hormone
replacement therapy and hormonal contraception)
 Use of broad-spectrum antibiotics within the
last 3 months
 Poorly controlled diabetes mellitus
 Local irritants (perfumed soaps, wet wipes, fabric
conditioner and douches)
 Immunocompromised state
 New sexual partner
 Spermicidal gel/creams
 Noncompliance with antifungal therapy
 Resistance to antifungal therapy
 Iron deficiency anaemia.9
Diagnosis
History and examination
 Symptoms including duration, severity and exacerbating/
relieving factors (Box 1)
 Treatment history, including over-the-counter and
complementary or alternative remedies
 Risk factors (see above)
 Other symptoms that may suggest a differential diagnosis.
296
Differential diagnosis
While women may have a dual pathology, many women have
other conditions rather than RVVC, such as:
 Eczema
 Dermatitis
 Lichen sclerosus/planus
 Bacterial vaginosis (see Table 1)
 Trichomonas vaginalis infection (see Table 1)
 Aerobic vaginitis (if primary complaint is purulent, non-
offensive discharge)
 Cytolytic vaginosis (consider if microscopy and fungal
cultures are negative)
 Vulvodynia
 Vestibulodynia (in some women this has been triggered
by VVC)
 Vulvar intraepithelial neoplasia and vulval cancer.
Up to 20% of women may be colonised with Candida spp.
during their reproductive years.3 Without clinical features,
they do not need treatment for VVC.6 This will, of course,
include many women with the conditions listed above. In these
women, Candida may not be contributing to the symptoms.
Investigations
 A high vaginal swab for culture testing. In many
laboratories, swabs must be accompanied by a specific
request for species identification and to test sensitivities in
patients with RVVC. Some species are inherently azole
resistant; for example, C. glabrata.10
 Microscopy. The presence of blastospores, pseudohyphae
and neutrophils is indicative of infection caused by
Candida spp.3
 Vaginal pH testing (if possible). To assess the likelihood of
symptoms being caused by VVC (pH ≤ 4.5), bacterial
vaginosis or Trichomonas vaginalis (pH >4.5), secretions
should be collected from the lateral sides of the vaginal
wall using a swab.10 A tiny amount of discharge is put onto
litmus paper.
 Consider an HbA1c test to exclude diabetes mellitus,
especially in prepubertal girls and postmenopausal women,
who rarely have VVC without other risk factors.
 Consider full blood count to rule out anaemia.
Box 1. Signs and symptoms
 Persistent vulval itch
 Non-offensive vaginal discharge (curdy or thin)
 Soreness or burning
 Superficial dyspareunia
 Erythema
 Fissuring
 Swelling/oedema
 Satellite lesions and excoriation marksSymptoms may be cyclical in
nature.
ª 2021 Royal College of Obstetricians and Gynaecologists
 Borland et al.

Table 1. Bacterial vaginosis and Trichomonas vaginalis: overview of diagnosis and management

Bacterial vaginosis11 Trichomonas vaginalis20

Definition An imbalance in the vaginal flora causing a rise in pH levels to A sexually transmitted infection caused by a flagellated
4.5–6.0 protozoon, Trichomonas vaginalis
There are fewer lactobacilli and an increase in anaerobic bacteria

Risk factors Smoking12,13 Older age21 (>24 years)

Douching14 Nonwhite ethnicity (particularly Afro-Caribbean)21
Black ethnicity13,15 Concurrent Chlamydia trachomatis or Neisseria gonnorhoea21
New sexual partner16 People living with HIV22
Concurrent sexually transmitted infection, e.g. herpes13
Receptive cunnilingus17

Signs and Offensive fishy discharge, which is typically thin and white/grey Vaginal discharge (can be malodourous)
symptoms Up to 50% asymptomatic Vulvovaginal itch
Dysuria
Vulvovaginitis
Vulval ulceration
Low abdominal pain
Up to 50% asymptomatic

Investigations pH test using litmus paper or Vision Vaginal Infection Swab (if Vaginal swabs taken from the posterior fornix then tested
available) using (depending on availability):
Microscopy Wet prep microscopy
There are diagnostic criteria available to aid diagnosis such as Nucleic acid amplification test (NAAT)
Amsel’s or Hay/Ison criteria Point of care test
Culture (T. vaginalis [TV] culture broth)
First choice would be triple NAAT if available, but if not then
send as separate sample for NAAT, TV culture or TV point-of-
care test, depending on availability of testing in your trust/site
Remember to test for other sexually transmitted infections

Management Metronidazole 400 mg orally twice a day for 5–7 days or; Metronidazole 2 g orally stat, or metronidazole 400–500 mg
Metronidazole 2 g orally stat or; orally twice a day for 5–7 days
Intravaginal metronidazole gel (0.75%) once daily for 5 days or; Alternative: tinidazole 2 g orally stat
Intravaginal clindamycin cream (2%) once daily for 7 days
Alternatives: tinidazole 2 g orally stat, or clindamycin 300 mg orally
twice a day for 7 days

Other Give vulval skin advice Must ensure the partner is treated and both avoid sex until
information Probiotics have demonstrated reduced recurrence rates18,19 they have both completed treatment

In women with RVVC who also suffer from other
recurrent infections (for example, upper respiratory tract
infections or recurrent otitis media) consider testing for
mannose binding lectin (MBL) deficiency. MBL deficiency is
a genetic condition affecting the immune system and is
associated with both acute and recurrent VVC.3 This does
not aid in the treatment of RVVC, but may give the patient a
better understanding of their condition.
Management
Management of RVVC commences with the general advice
given to patients for all vulval skin conditions.
 Avoid local irritants such as perfumed soap, shampoo,
bubble bath, fabric softener and wipes
 Simple emollients can be used as a soap substitute and
general moisturiser
 Wash just once a day
 Avoid tight fitting garments that might irritate the area
 If possible, avoid pads or panty liners as these
prevent aeration
 Avoid vaginal douching.
Vaginal douching, the process of washing out the vagina
with water or other fluid mixtures, is common around the
world. It is significantly associated with both acute and
recurrent VVC, probably because of disruption of the normal

ª 2021 Royal College of Obstetricians and Gynaecologists 297

 Update on recurrent vulvovaginal candidiasis

Table 2. Treatment regimens for acute and recurrent vulvovaginal candidiasis

Recurrent VVC

Acute VVC Induction Maintenance

Oral Fluconazole 150 mg, oral, Fluconazole 150 mg, oral, every 72 hours for three Fluconazole 150 mg, oral, once per
single dose doses week for 6 months

or or

Topical Clotrimazole pessary 500 mg, Clotrimazole pessary 500 mg, per vagina, 7–14 days Clotrimazole pessary 500 mg, per
per vagina, single dose according to response vagina, once per week for 6 months

Non-C. albicans spp. Nystatin pessaries 100 000 Nystatin pessaries 100 000 units, per vagina, 14 nights per month for 6 months
and azole resistance units, per vagina, 12–14
nights

Abbreviations: VVC = vulvovaginal candidiasis.

vaginal flora.14,23,24 A discussion of daily hygiene regime is
recommended as other potential irritants may be identified.
No link between intercourse and RVVC has been identified
and intercourse does not need to be avoided. However, some
women prefer not to have sex until symptoms have
improved, particularly if they have fissuring of the skin.3
Those reporting a correlation between intercourse and
worsening symptoms might wish to consider using a water-
based or silicone-based lubricant; patients should try both
and see which works best (the silicone ones are more
protective). Psychosexual and emotional issues should be
discussed because these are common in women with
vulvovaginal conditions.3
Treatment
Treatment for RVVC comprises an initial induction followed
by maintenance therapy. Table 2 summarises the regimes
recommended in the most recent guidelines published by the
British Association for Sexual Health and HIV (2019).3
A recent observational study from the USA showed that
fluconazole suppression therapy was highly effective in
preventing VVC symptoms (93%).5 However, 80% of
women reported relapse after discontinuing maintenance
therapy. In this group, the development of drug resistance in
Candida albicans isolates after long-term fluconazole
maintenance therapy was 7.5%.
Pregnancy and breastfeeding
RVVC poses specific challenges in pregnancy. There is a
higher rate of asymptomatic colonisation of Candida spp. in
pregnant women (30–40%), and symptomatic candidiasis is
commoner.3 There is conflicting evidence over the safety of
fluconazole and other oral azoles in pregnancy, with five case
reports of skeletal malformations in infants whose mothers
took high doses of fluconazole (400–1200 mg/day) for
extended periods (weeks to months). By contrast,
epidemiological studies of almost 9000 pregnant women
taking short courses of lower dose (150 mg stat) showed no

Table 3. Treatment for vulvovaginal candidiasis in pregnancy

Acute VVC Recurrent VVC

Clotrimazole pessary 500 mg, Induction Maintenance

per vagina, once a night for up
to 7 consecutive nights Clotrimazole pessary 500 mg, per vagina, Clotrimazole pessary 500 mg, per vagina, once a week
once a night for 10–14 nights according to response

Abbreviations: VVC = vulvovaginal candidiasis.

298 ª 2021 Royal College of Obstetricians and Gynaecologists


increased risk of congenital malformation.25 These
conflicting data mean the advice is to avoid. The BASHH
guidelines recommend an extension to the treatment regime
in pregnant women. This is based on the results of a
Cochrane review, which reported improved cure rates of 90%
after a 7-day course of clotrimazole 500 mg pessaries
compared with 50% cure following the routine 4-day
course.26 Table 3 displays the first-line treatments for
pregnant and breastfeeding women.
Fluconazole enters breastmilk in small doses, and
breastfeeding can continue following a single dose of
150 mg; however, higher or repeated doses should be
avoided. Topical treatments are safe and effective and are
therefore the treatment of choice in pregnancy
and breastfeeding.
Important to note
 Topical/intravaginal treatments can affect condoms and
put women at risk of unwanted pregnancy.
 Fluconazole and other azoles can react with other
medication when given in multiple dose regimes,
particularly in relation to their association with
hypokalaemia and prolongation of QT interval. A clear
medication history should be sought.
 If not responding to treatment, consider testing for species
other than C. albicans or revisiting alternative diagnoses.
 Small studies have shown that using breathable underwear
with antimicrobial protection reduces symptoms and
recurrences compared with cotton briefs in women with
recurrent VVC suppressive regimens.27
Supplementary treatments
Despite antifungal therapy, some women still have residual
symptoms. Supplementary therapies have been shown to be
of benefit to some. The antihistamine cetirizine 10 mg taken
orally, daily, for 6 months alongside maintenance azole
therapy may cause remission in atopic women with
refractory symptoms.28
Probiotics are live bacteria and yeasts often added to yogurts
or taken as oral supplements to improve gut and skin flora. The
use of probiotics (mainly lactobacilli) in combination with
antifungal therapy is shown to improve short and long-term
cure rates and reduce relapse rates at 1 month by >50%
compared with antifungal therapy alone. However, the evidence
is low quality, with non-standardised methodologies, small
sample sizes and short follow-up times.1,3
The future: early-stage research
Vaginal laser therapy and other phototherapies are on the rise
in private clinics as part of ‘vaginal rejuvenation’ treatments.
ª 2021 Royal College of Obstetricians and Gynaecologists
Borland et al.
Electromagnetic radiation has been shown to have
antimicrobial properties associated with disruption of
DNA. Currently, there are studies both in animal models
and pilot studies in humans investigating the efficacy of using
this mode of treatment for VVC.29,30
Conclusion
The worldwide burden of RVVC is significant. There is a high
recurrence rate (80%) and worldwide drug resistance is on the
rise.4–7 RVVC has the ability to seriously affect a woman’s
quality of life, with grave consequences on her mental health,
relationships and working life. We have provided up-to-date
diagnostic and treatment recommendations. Further work
must be done to educate women on the risk factors associated
with the condition and the importance of vulval skin care.
Disclosure of interests
AD is Vice Chair of the British Society of Urogynaecology
Training Committee, Royal College of Obstetricians and
Gynaecologists (RCOG) assessor for subspecialty assessments
and an RCOG tutor.
Contribution to authorship
AB researched, wrote, and edited the article. KO researched,
wrote, and edited the article. IO instigated, researched, wrote,
and edited the article. AD instigated and edited the article. RF
instigated and edited the article. All authors approved the
final version.
References
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vulvovaginal candidiasis in non-pregnant women. Cochrane Database Syst
Rev 2017;(11):CD010496.
2 Denning DW, Kneale M, Sobel JD, Rautemaa-Richardson R. Global burden
of recurrent vulvovaginal candidiasis: a systematic review. Lancet Infect Dis
2018;18:e339–47.
3 British Association for Sexual Health and HIV (BASHH). British Association for
Sexual Health and HIV national guideline for the management of
vulvovaginal candidiasis. Lichfield: BASHH; 2019 [https://www.bashhguide
lines.org/media/1223/vvc-2019.pdf].
4 Collins LM, Moore R, Sobel JD. Prognosis and long-term outcome of women
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5 Wang FJ, Zhang D, Liu ZH, Wu WX, Bai HH, Dong HY. Species distribution
and in vitro antifungal susceptibility of vulvovaginal Candida isolates in
China. Chin Med J 2016;129:1161–5.
6 Mukasa KJ, Herbert I, Daniel A, Sserunkuma KL, Joel B, Frederick B.
Antifungal susceptibility patterns of vulvovaginal Candida species among
women attending antenatal clinic at Mbarara Regional Referral Hospital,
South Western Uganda. Br Microbiol Res J 2015;5:322–31.
7 Bitew A, Abebaw Y. Vulvovaginal candidiasis: species distribution of
Candida and their antifungal susceptibility pattern. BMC Womens Health
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8 Aball
ea S, Guelfucci F, Wagner J, Khemiri A, Dietz JP, Sobel J, et al.
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9 Naderi N, Etaati Z, Rezvani Joibari M, Sobhani SA, Tashnizi SH. Immune
deviation in recurrent vulvovaginal candidiasis: correlation with iron
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10 National Institute for Health and Care Excellence (NICE). Candida – female-
genital. London: NICE; 2017 [https://cks.nice.org.uk/candida-female-genita
l#!topicSummary].
11 Hay P, Patel S, Daniels D. UK National Guideline for the management of
bacterial vaginosis 2012. Lichfield: British Association for Sexual Health and
HIV; 2012 [https://www.bashhguidelines.org/media/1041/bv-2012.pdf].
12 Hellberg D, Nilsson S, Mardh PA. Bacterial vaginosis and smoking. Int J STD
AIDS 2000;11:603–6.
13 Cherpes TL, Hillier SL, Meyn LA, Busch JL, Krohn MA. A delicate balance: risk
factors for acquisition of bacterial vaginosis include sexual activity, absence
of hydrogen peroxide-producing lactobacilli, black race, and positive herpes
simplex virus type 2 serology. Sex Transm Dis 2008;35:78–83.
14 Ness RB, Hillier SL, Richter HE, Soper DE, Stamm C, McGregor J, et al.
Douching in relation to bacterial vaginosis, lactobacilli, and facultative
bacteria in the vagina. Obstet Gynecol 2002;100:765.
15 Ness RB, Hillier S, Richter HE, Soper DE, Stamm C, Bass DC, et al. Can known
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16 Hawes SE, Hillier SL, Benedetti J, Stevens C, Koustsky L, Wolner-Hanssen P,
et al. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal
infections. J Infect Dis 1996;174:1053–63.
17 Verstraelen H, Verhelst R, Vaneechouette M, Temmerman M. The
epidemiology of bacterial vaginosis in relation to sexual behaviour. BMC
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19 Darmayanti AT, Murti B, Susilawati TN. The effectiveness of adding probiotic
on antimicrobial for bacterial vaginosis: a systematic review. Indonesian J
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Kingdom National Guideline on the management of Trichomonas vaginalis
2014. Int J STD AIDS 2014;25:541.
21 Mitchell H, Lewis D, Marsh K, Hughes G. Distribution and risk factors of
Trichomonas vaginalis infection in England: an epidemiological study using
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2009–2011. Epidemiol Infect 2013;142:1678–87.
22 Mavedzenge SN, Van der Pol B, Cheng H, Montgomery E, Blanchard K,
de Bruyn G, et al. Epidemiological synergy of Trichomonas vaginalis and
HIV in Zimbabwean and South African women. Sex Transm Dis
2010;37:460–6.
23 Heng LS, Yatsuya H, Morita S, Sakamoto J. Vaginal douching in Cambodian
women: its prevalence and association with vaginal candidiasis. J Epidemiol
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24 Martino JL, Vermund SH. Vaginal douching: evidence for risks or benefits to
women’s health. Epidemiol Rev 2002;24:109–24.
25 Kaplan YC, Koren G, Bozzo P. Fluconazole exposure during pregnancy. Can
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26 Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in
pregnancy. Cochrane Database Syst Rev 2001;(4):CD000225.
27 D’Antuono A, Baldi E, Bellavista S, Banzola N, Zauli S, Patrizi A. Use of
Dermasilk briefs in recurrent vulvovaginal candidosis: safety and
effectiveness. Mycoses 2012;55:e85–9.
28 Neves NA, Carvalho LP, Lopes ACV, Cruz A,
Carvalho EM. Successful
treatment of refractory recurrent vaginal candidiasis with cetirizine plus
fluconazole. J Lower Genital Tract Dis 2005;9:167–70.
29 Robatto M, Pavie MC, Garcia I, Porto Menezes M, Bastos M, Dourado Leite
HJ, et al. Ultraviolet A/blue light-emitting diode therapy for vulvovaginal
candidiasis: a case presentation. Lasers Med Sci 2019;34:1819–27.
30 Simo~es Onofre de Santi ME, Prates RA, Francßa CM, Garcia Lopes R, Silva
Sousa A, Ferreira LR, et al. Antimicrobial photodynamic therapy as a new
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ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12774
The Obstetrician & Gynaecologist
http://onlinetog.org
Review of advanced energy devices for the minimal access
gynaecologist
Gemma L Bentham MChem (Oxon) MBBS Hons MRCOG,*
a
Specialist Trainee Obstetrics and Gynaecology, Royal United Hospitals Bath, BA1 3NG, UK
b
Consultant Gynaecologist, Southmead Hospital, Bristol BS10 5NB, UK
*Correspondence: Gemma L Bentham. Email: g.bentham@nhs.net
Accepted on 17 November 2020. Published online 27 September 2021.
Key content
 Contemporary energy devices utilise advanced bipolar, ultrasound,
hybrid technology, plasma beam and laser energy.
 Each energy modality has specific characteristics influencing its
particular benefits and disadvantages.
 Gynaecologists must be aware of the available energy modalities to
select the optimum device.
 Minimal access surgeons must demonstrate a comprehensive
understanding of their instruments to ensure surgical success
and safety.
Learning objectives
 To understand the biophysics of advanced energy devices and their
practical applications.
Please cite this paper as: Bentham GL, Preshaw J. Review of advanced energy devices for the minimal access gynaecologist. The Obstetrician & Gynaecologist
2021;23:301–9. https://doi.org/10.1111/tog.12774
Introduction
The progression of energy technology has brought to the
market various devices delivering safe and efficient
haemostasis and dissection. Consequently, minimal access
surgeons have many devices at their fingertips. The choice is
no longer simply between conventional monopolar or
bipolar; a surgeon can choose from advanced bipolar,
ultrasound, hybrid, plasma beam and laser energy. This
poses an exciting challenge for trainees in gynaecology, who
can expect to encounter various devices within their training.
The article published in The Obstetrician & Gynaecologist by
El-Sayed et al.1 presents a thorough review of safety issues
associated with electrosurgery, specifically in relation to
conventional devices (CD). This article presents a second
chapter in the review of laparoscopic energy devices with
emphasis on advanced modalities.
Our aim is to equip gynaecologists with the essential
theoretical and practical knowledge required to safely and
confidently utilise advanced energy devices. This includes the
biophysics underpinning each energy modality, their safety
considerations, the advantages and disadvantages of each
ª 2021 Royal College of Obstetricians and Gynaecologists
2021;23:301–9
Review
a b
Jessica Preshaw MBChB BSc Hons MRCOG
 To review advantages, disadvantages and safety issues associated
with each modality and offer practical tips and problem-solving for
commonly available devices.
 To enable surgeons to select the optimal device for their
surgical tasks.
Ethical issues

Trainee minimal access surgeons should have solid theoretical
knowledge of energy devices before performing hands-on surgery.
 Consideration of the safety aspects of energy devices will enable
surgeons to minimise harm to their patients.
 Potentially high investment costs necessitate consideration of the
anticipated benefits of energy devices to ensure value for money.
Keywords: bipolar / energy devices / laser / ultrasound
device, and tips to facilitate usage. It may require several visits
to the operating theatre before this familiarity can be
achieved. Presenting the information in a summarised form
will arm trainees with the theoretical background they
require to correctly and appropriately select an instrument
and enable them to excel in their minimal access surgery
(MAS) experience.
Drive to develop new devices
The evolution of laparoscopic surgery has driven the
development of advanced energy devices. Minimal access
surgeons are expanding the boundaries of laparoscopic surgery
and, correspondingly, manufacturers are striving to deliver
safer and more efficient instruments. Advanced devices convey
benefits to surgeons throughout the spectrum of technical
proficiency. For those embarking upon their MAS training,
advanced devices dramatically reduce operating times for
laparoscopic hysterectomies.2 The same reduction in
operating times is not seen for surgeons with advanced
laparoscopic skills performing standard procedures.3
However, advanced devices enable experienced surgeons to
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complete technically complex surgery; for example, radical
hysterectomy with pelvic lymphadenectomy, in less time, with
the same perioperative outcomes.4
Economics of energy devices
The use of advanced energy devices requires consideration of
the financial implications. On face value, the purchasing price
of advanced energy devices is significantly greater than for
CDs and varies between modalities and manufacturers.
However, as outlined by Munro,5 the issue of cost in health
care is far more complex. The net increase in cost of using a
particular device is equal to the additional capital cost per
procedure, compared with the alternative, minus the cost
savings. The additional capital cost includes purchasing of
energy generators, staff training, device maintenance and cost
of single-use components. Examples of cost savings include
reduction in operating time, lower complication rates and
shorter hospital stays. Evidently, these costs will vary from
hospital to hospital, with considerable regional and
international variations. Given the complex economics, we
have chosen to include a price range for the single-use
component of each device for interest only; see Table 1.
Types of advanced energy devices
Advanced bipolar
Advanced bipolar devices (ABDs) combine bipolar
electrocoagulation with an integral blade to deliver haemostasis
and cutting in one device. Commonly encountered models

Table 1. Comparison of advanced energy devices

Advantages Disadvantages Cost** Examples

ABD Consistent vessel seal Two-step cut and coagulation £££ Ligasure
Haemostasis feedback Less suitable for fine dissection £££ Enseal
Seals vessels up to 7 mm in diameter Greater LTS PK Cutting Forceps
Cut with blade only Caiman 5
Independent coagulation

UD Fine dissection Less reliable seal for vessels >5 mm in diameter* ££££ Harmonic
Haemostasis feedback Residual heat £££ Sonicision
No radiofrequency energy Sonicbeat
Avoids neuromuscular activation Lotus
Reduced surgical plume
Reduced LTS vs ABD

HD Consistent vessel seal Residual heat ££££ Thunderbeat

Seals vessels up to 7 mm in diameter
Fine dissection
Reduced instrument traffic
Improved efficiency
Haemostasis feedback

PD Precise tissue effect Small vessels only £ Helica TC

Minimal LTS Raised intra-abdominal pressure ££££ PlasmaJet SS
No residual heat Potential for gas emboli ABC
No smoke production

LD Extremely precise tissue effects Small vessels only £££££ Lumenis AcuPulse
Minimal LTS Inefficient dissection
Minimal tissue penetrance Staff training
Optical damage
Implementation cost
Maintenance
Fire hazard
Surgical plume

Abbreviations: ABD = advanced bipolar device; HD = hybrid device; LD = laser device; LTS = lateral thermal spread; PD = plasma device; UD =
ulstrasonic device.
*Harmonic Ace +7 Shears can seal vessels up to 7 mm in diameter
**Cost of single-use component excluding VAT. £ = £0–150, ££ = £150–300, £££ = £300–450, ££££ = £450–600, £££££ = £600+. All prices £GBP.
CO2 laser price includes fibre.

302 ª 2021 Royal College of Obstetricians and Gynaecologists


include Ligasure (Covidien), Enseal (Ethicon), PK Cutting
Forceps (Olympus) and Caiman 5 (B. Braun) (Figure 1). All
ABDs require a specialist energy generator. Most handpieces are
single use, except for the reusable Marseal device (KLS Martin).
ABDs are licensed to seal vessels up to 7 mm in diameter.
Biophysics
ABDs exert their haemostatic effect by combining high
current, low voltage electrocoagulation with mechanical force
to denature collagen and elastin in the vessel walls and
generate a haemostatic seal (Figure 2).6
A key feature of ABDs is the incorporation of technology
capable of detecting tissue impendence. Impedance is the
opposition to flow of electrical current. The impedance of
tissues is a complex concept and depends upon multiple
variables. Usually, tissues with higher water content have
decreased resistance to electrical current; for example, skin
and adipose demonstrate high resistance, whereas muscle,
tendon and blood have a relatively lower resistance.
Additionally, tissue damage, such as scarring, oedema and
eschar, results in higher impedance. The integrated feedback
system within the device monitors the tissue impedance to
determine when the seal is complete. Subsequently, the
generator terminates delivery of energy to the device or
signals the surgeon with an audible tone. Computer-
controlled feedback systems enable ABDs to deliver
consistent and reliable vessel sealing.
How to use
Tissue is grasped between the jaws. Activation of the device
results in generation of heat and mechanical compression of
the tissue held in the jaw. The device control unit alerts the
surgeon, through an audible tone change, when haemostasis
has been achieved. Within the handheld unit is an integral
Figure 1. A) Enseal (Ethicon) and B) PK Forceps (Olympus) advanced
bipolar devices.
ª 2021 Royal College of Obstetricians and Gynaecologists
Bentham and Preshaw
blade that can be advanced to cut tissue held in the device. In
this way, the device can be used for haemostasis and dissection.
Evidence demonstrates little or no difference between the
leading ABDs in terms of surgical outcomes and measurable
variables.7 The choice of ABD will depend upon the surgeon’s
preference, availability of equipment and cost.
Advantages of advanced bipolar devices
ABDs provide reliable vessel sealing at supraphysiological
burst pressures. Burst pressure is defined as the maximal
pressure required to overcome the vessel seal. It is important
to note that despite producing very high burst pressures, not
all devices can consistently provide this seal.7,8 ABDs can
provide coagulation without cutting, such as that required in
spot haemostasis. Furthermore, ABDs allow the surgeon to
cut tissue without radiofrequency energy; this conveys the
advantage of allowing dissection in areas where thermal
energy may result in injury. Compared with ultrasound
devices (UD), ABDs are less expensive.
Disadvantages of advanced bipolar devices
The jaw design and energy delivery of ABDs leads some
surgeons to select alternative devices for finer dissection.
Additionally, there is evidence to suggest that ABDs can
result in greater lateral thermal spread (LTS) than other
advanced energy modalities.8,9 Haemostatic transection is a
two-step process requiring activation of energy followed by
deployment of the blade. This can make dissection
more cumbersome.
When to use
ABDs are useful when reliable vessel sealing is required,
particularly of larger vessels. These devices are an excellent
choice when complex dissection is not anticipated, such as
basic adnexal surgery or routine hysterectomy.
Tips and tricks
The jaws of ABDs are coated in nonstick material to prevent
tissue and eschar from adhering to the device. If tissue does
become stuck, it can affect the delivery of energy to the tissue,
with a subsequent haemostatic effect. Furthermore, tissue
sticking may dislodge a haemostatic seal. Therefore, it is
important to keep the instrument tip clean to maximise the
function of the device.
Placing the grasped tissue under tension during device
activation will reduce the coagulation effect. Therefore,
maximum coagulation is best achieved by relaxing the
tension on the tissue. Subsequently, the tissue is then placed
under tension to optimise the cutting effect of the blade.
Safety issues specific to advanced bipolar devices
All ABDs generate heat with potential dissipation to nearby
tissues. Tissue damage occurs at temperatures above 42°C
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 Advanced energy devices

(see Table 2). Heat can spread deep and lateral to the The ultrasound scalpel effect is a consequence of
intended target, known as LTS.1 ABDs can result in LTS up cavitation. At higher energy settings the mechanical energy
to 7 mm from the intended target.10 Surgeons should causes the production of small vapour cavities, which
endeavour to maintain a safe margin of 0.5–1.0 cm from collapse to cause cell destruction and tissue dissection. The
vital tissue and use the minimum power setting and energy generator is controlled by a microprocessor capable of
activation time required to avoid unintended sensing changes in the acoustic system and subsequently
thermal damage.7 altering energy delivery.

Ultrasound How to use

Ultrasonic devices (UDs) were first used for haemostasis in
1988. These instruments utilise ultrasound to seal vessels and
cut tissue without the need for an integral blade. These are
single-use instruments; examples include Harmonic
(Ethicon), Sonicision (Covidien) and Lotus (BOWA
Medical) (Figure 3). UDs are licensed to seal vessels up to
5 mm in diameter, except for the Harmonic Ace+ 7 Shears,
which can seal vessels with a diameter of 7 mm.
Biophysics
Ultrasonic waves are high frequency sound waves inaudible
to the human ear. Piezoelectric materials generate ultrasonic
energy when they are placed under mechanical stress. The
handpiece of an ultrasound device contains a piezoelectric
transducer, which converts electrical energy to ultrasonic
energy. This mechanical energy, in the form of ultrasonic
waves, is transferred to the active blade of the device causing
it to vibrate or oscillate. Depending on the UD, oscillations
are torsional, angular or longitudinal at rates from 36 000 to
55 500 Hz. At low energy settings, the mechanical vibrations
result in breakage of hydrogen bonds and subsequent
denaturation of proteins. The proteins are converted to a
coagulum that ‘welds’ vessels together to form a haemostatic
seal. This is known as coaptive coagulation (Figure 2).
Tissue is grasped between the jaws of the device. The lower
blade is active and generates the mechanical energy. The
upper, inactive blade is immobile and holds the tissue in
apposition. The surgeon utilises higher energy to cut tissue
for the purpose of dissection and lower energy settings to
simultaneously coagulate and dissect tissue.
Advantages of ultrasonic devices
A considerable benefit of UDs over bipolar devices is the
avoidance of the inherent complications of electrosurgery,
such as coupling effects.1 Furthermore, ultrasound energy
does not result in neuromuscular stimulation. Surgeons
recognise that UDs demonstrate precise dissection with a
small thermal footprint,8 thus potentially minimising the risk
of damage to adjacent structures. In contrast to ABDs,
cutting and haemostasis is achieved in one step, resulting in
improved ergonomics. UDs tend to generate less smoke
plume than ABDs,9 conveying the benefit of improved
visibility and reduced risks of exposure for the surgical
team.11 Sonicision is cordless, with a reusable handheld
generator and rechargeable battery. Some surgeons find the
absence of a power cable improves freedom of movement,
although this comes at the cost of an approximate additional
150 g of weight compared with the Harmonic Ace.

Table 2. Biothermal effects

Disadvantages of ultrasonic devices
UDs may be less reliable for haemostasis of larger vessels than
Temperature (°C) Tissue effect CDs and ABDs.7-9 UDs usually have more expensive
operating costs than ABDs.
37 Normal temperature
When to use
45–50 Hyperthermia UDs are versatile instruments suitable for a variety of
Reduced enzyme activity procedures, including total laparoscopic hysterectomy and
Necrosis
adnexal surgery. However, UDs are particularly favourable
60–80 Denaturation of proteins and collagen for cases requiring complex dissection, such as excision of
Coagulation and desiccation deeply infiltrating endometriosis, ureterolysis and
laparoscopic myomectomy.12
100 Vaporisation
Ablation
Tips and tricks
>100 Carbonisation Like ABDs, placing tissue under tension during activation
will result in quicker cutting with less coagulation; relaxing
>300 Melting
tissue tension has the opposite effect. The force of the
surgeon’s grip will also affect the balance between cutting and
coagulation of tissue. With lighter pressure on the trigger, the

304 ª 2021 Royal College of Obstetricians and Gynaecologists


surgeon can achieve better coagulation with slower cutting.
Conversely, a firmer grip will deliver higher energy and
subsequent efficient cutting with less haemostatic effect.
Subtle use of instrument rotation can create tension, enhance
cutting while improving exposure, and allows fine movement
in a tight space. Applying tension to the active blade by
twisting will also lift the hot blade away from underlying
vulnerable structures.
Energy can be delivered without the need to grasp tissue
between the jaws of the device. This is known as ‘back-
scoring’; a unique feature of UDs. With jaws open, the
surgeon places the back of the lower blade in contact with
tissue while activating and moving the device.
Safety issues specific to ultrasonic devices
All energy devices generate heat when activated, so have the
potential to cause inadvertent tissue damage as a result of
residual heat. Residual heat is the temperature of the tip of the
device postactivation. It varies with length of activation, the
type of device and the device’s settings. Ex vivo evidence
demonstrates that UDs have significantly higher tip
temperatures postactivation and demonstrate residual heat
for longer than monopolar, bipolar and argon beam devices.13
The following steps are recommended to avoid
tissue damage:
 Minimise activation time
 Use the minimal energy setting required
 Use irrigation to cool the tip
 Keep the device in view or remove it from the port and
store safely in a surgical quiver when not in use
 Wait before manipulating tissue
Hybrid energy device
Thunderbeat (Olympus) is a hybrid device (HD) combining
ultrasound and bipolar energy (see Figure 4). It is currently
the only device with this capability. The manufacturers aim
to provide a device that combines the optimum vessel sealing
of bipolar energy with the efficiency of dissection of
ultrasonic energy. The Thunderbeat is licensed for use on
vessels up to 7 mm in diameter.14
Biophysics
The lateral edge of the upper and lower jaw conducts bipolar
energy and a central band on the active blade generates
ultrasound. The biophysics of each modality is explained in
the ABD and UD sections above. As with other advanced
energy devices, Thunderbeat contains an integral feedback
mechanism for detecting tissue impedance and moderating
energy delivery.
How to use
Tissue is grasped between the toothed jaws. The device has
two modes: ‘seal and cut’ and ‘seal’. In ‘seal and cut’ mode,
ª 2021 Royal College of Obstetricians and Gynaecologists
Bentham and Preshaw
both ultrasound and bipolar energy are active; this setting is
used for dissection and coagulation of vessels up to 7 mm in
diameter. In ‘seal’ mode, only bipolar energy is active; this
setting is used for coagulation only and will not cut tissue. It
is not possible to activate ultrasound energy independently.
The device microprocessor detects when tissue has been
sealed or transected and automatically terminates
energy delivery.
Advantages of Thunderbeat
Thunderbeat is a versatile instrument with the capacity for
effective dissection and reliable haemostasis. Incorporation of
multiple functions in a single device results in reduced
instrument traffic and consequent improved surgical
efficiency. This is demonstrated by the significant reduction
in operating times for complex laparoscopic procedures.4
Disadvantages of Thunderbeat
Thunderbeat results in high residual tip heat,15 as
demonstrated by all devices exploiting ultrasound energy.
Thunderbeat costs more per single-use instrument and
requires a specialist generator.
When to use
Its inherent versatility means Thunderbeat can be used for a
variety of surgical procedures. However, it conveys greatest
advantage when applied in advanced laparoscopic surgery, such
as that encountered in gynaeoncology, performing excision of
severe endometriosis or laparoscopic myomectomy.12
Tips and tricks
Thunderbeat provides dual energies in one platform, which
offers the surgeon superior versatility.15 With tissue grasped
between the jaws, it is not possible to activate the ultrasonic
energy independently of bipolar energy. However, the surgeon
can ‘back-score’ in the same way as with a UD, thus delivering
ultrasound energy independently. To perform fine dissection
and minimise tissue sticking caused by coagulum formation, it
is important to move the device through the tissues during
activation via the ‘seal and cut’ button. Like ABDs and UDs,
applying the correct tissue tension during activation is key to
operating the device skilfully.
Safety issues specific to Thunderbeat
Thunderbeat generates higher tip temperatures and takes longer
to cool than CDs and ABDs owing to the effect of ultrasound
energy.15 Therefore, it is recommended that surgeons exert the
same level of caution as when operating UDs to avoid
inadvertent tissue damage as a consequence of residual heat.
Plasma devices
Plasma devices (PDs) utilise radiofrequency energy to create
a plasma jet capable of causing superficial haemostasis and
305
 Advanced energy devices
cutting. Examples include the PlasmaJet SS (Plasma
Surgical), the Helica TC (Helica Instruments) and the ABC
(ConMed). These systems include a console with surgeon-
controlled settings and a single-use hand-piece (Figure 5).
The devices can be used for shallow, unified haemostasis,
tissue ablation and superficial tissue cutting.
Biophysics
Plasma is a gas containing free ions and electrons. It can be
generated by applying high voltage energy to an inert gas. The
handheld component of PDs contains electrodes that ionise a
stream of gas as it passes over them (Figure 6).16 This generates
a plasma beam that can be directed to the surgical site.
The highly conductive plasma beam can generate light,
kinetic and thermal energy. The light energy illuminates the
surgical site and enables the surgeon to visualise the point of
application. Kinetic energy from the flow of gas clears fluid or
debris from the surface of tissue, creates tissue planes and opens
Figure 2. Coaptive coagulation: collagen and elastin fibres crosslink
to seal vessel wall.
Figure 3. A) Harmonic (Ethicon) and B) Lotus (BOWA) ultrasonic
devices.
306
adhered areas. Transmission of highly focused thermal energy
predominantly results in tissue ablation and can generate
haemostasis through coagulation or desiccation. Additionally,
the plasma beam can conduct radiofrequency energy to tissue.
The electrical energy principally causes coagulation and
desiccation. As desiccated tissue forms, energy is diverted to
areas of lower resistance, such as superficial exposed vessels. A
superficial layer of coagulation therefore forms.
Surgeons must appreciate how different PDs operate to
ensure optimum and safe usage; not all PDs exert their tissue
effect through generation of thermal energy, and some
devices do not conduct radiofrequency energy. More recently
developed PDs, such as the PlasmaJet SS, generate an
electrically neutral, thermal plasma beam at very low argon
gas flow. Thermal plasma is generated through multiple
collisions between electrons in the plasma generating
extremely high temperatures (10 000–20 000°C).18 The
Figure 4. Thunderbeat (Olympus) hybrid device.
Figure 5. Helica TC (Helica Instruments) plasma device.
Figure 6. Plasma beam generation.
ª 2021 Royal College of Obstetricians and Gynaecologists

plasma jet discharges the thermal energy directly to the tissue
without conducting electrical energy.
The depth of tissue effect depends upon the penetration of
energy. This will vary depending upon the mode of action of
the PD, tissue impedance, generator and gas settings and the
distance from the tissue.19
How to use
The handheld devices can be used in open and laparoscopic
procedures. The device is activated in a non-touch method.
The beam is emitted from the tip of the device upon
activation by a hand switch (PlasmaJet), foot pedal (Helica)
or both (ABC). To achieve haemostasis or tissue ablation, the
device is held approximately 5 mm from the intended target.
To achieve superficial cutting, for example of the
peritoneum, the device is held in closer proximity to the
tissue. The radiofrequency energy is delivered in a monopolar
circuit and requires a dispersive pad (this is not necessary
for PlasmaJet).
Advantages of plasma devices
PDs can deliver energy with minimal penetration depths,
resulting in superficial thermal effects (up to 2 mm) and
minimal LTS (less than 8 mm).17,20 Altering the power
setting and gas flow allows the surgeon to accurately control
the depth of penetration. The degree of LTS does not depend
upon duration of activation or power settings.20
Furthermore, the tip of the device will always remain cool,
negating any complications caused by residual heat. PDs
produce little or no smoke, improving visibility and
minimising the surgical team’s smoke exposure. Gas is
expelled from the device at pressure, pushing debris and
blood away from the intended target, resulting in improved
visibility and coagulation effects.
Disadvantages of plasma devices
PDs are limited to superficial tissue effects. They cannot
coagulate large vessels or efficiently cut dense tissue. PDs with
high gas flows can elevate intra-abdominal pressures and
necessitate frequent evacuation of pneumoperitoneum.21
When to use
The commonest use of PDs is to treat superficial
endometriosis, either through ablation or excision of
peritoneal endometriotic deposits. PDs may result in better
preservation of ovarian function when used to treat ovarian
endometrioma compared with cystectomy.22 PDs are used
for devitalisation and shrinkage of tumours and treating
tissue overgrowth.
Tips and tricks
This modality performs surgical tasks in a precise ‘no touch’
manner. Adjusting the ‘tip-to-tissue’ distance alters the
ª 2021 Royal College of Obstetricians and Gynaecologists
Bentham and Preshaw
subsequent effect on the tissue. The spectrum of results
ranges from superficial surface coagulation through dispersed
surface vaporisation, and ultimately focused tissue
vaporisation and cutting as the distance is closed.
Safety issues specific to plasma devices
PDs with high gas flows can significantly elevate intra-
abdominal pressures during laparoscopy. High intra-
abdominal pressures can result in harmful physiological
effects; in particular, reduced ventilatory capacity and cardiac
output. Surgeons must maintain safe pressure limits. In
addition, high flow gases have the potential to result in gas
emboli. Case reports have cited incidences of pressurised
argon gas entering large open vessels during laparoscopic
procedures.23 As argon and helium gas are not readily
soluble, they can potentially pass into the systemic
circulation, resulting in fatal gas emboli. To minimise the
risk of gas emboli and excessive intra-abdominal pressures,
manufacturers recommend the following:
 Use the lowest flow rate required to achieve haemostasis
 Remove the instrument when not in use
 Use gas insufflators with non-defeatable pressure alarms
 Never touch the tissue while the device is active
 Follow the manufacturer’s recommendations for use and
staff training
Laser devices
‘LASER’ is an acronym for Light Amplification by Stimulated
Emission of Radiation. The gynaecologist is probably most
familiar with laser for treatment of cervical intraepithelial
neoplasia, emerging vaginal therapies and for treatment of
condyloma accuminata. Laser devices (LDs) for use in MAS
are less popular than other advanced energy devices because
of their high costs and considerable operational
requirements. However, some surgeons favour their use
when operating close to vital structures, such as the ureter,
because of the highly accurate application of energy. Most
gynaecologists probably have limited exposure to this
modality; therefore, we focus on the commonest
encountered CO2 LDs, such as the Lumenis AcuPulse.
Biophysics
A laser is an instrument that projects a highly concentrated
beam of light through the stimulated emission of photons.
These photons have the same wavelength, travel in
synchrony, and move in the same direction. This results in
monochromatic, highly focused and very bright light. The
wavelength of the photon, and therefore the colour of light
emitted, depends upon the laser medium.
For laser light to exert a tissue effect, cells must first absorb
the light. Light energy not absorbed by cells will be
transmitted and penetrate deeper tissue. The wavelength of
the laser determines which tissue will absorb the light energy.
307
 Advanced energy devices
Additionally, surgeons can vary the amount of energy
transmitted to tissue by changing the output wattage, beam
focus (the narrower the beam the higher the energy density)
and duration of application.24 The light energy absorbed by
the tissue is converted to thermal energy. Subsequent thermal
effects on the tissue will depend upon the temperature
generated (see Table 2).
CO2 LDs operate in the infrared spectrum (10 600 nm).
They are paired with a low-energy aiming laser to enable
surgeons to visualise the beam position. Modern CO2 LDs
use a flexible fibre optic cable to transmit the laser. At long
wavelengths (>10 000 nm) light is absorbed by water. This
means CO2 laser energy is readily absorbed by cells.
Accordingly, CO2 LDs demonstrate limited thermal
penetrance (0.1–0.5 mm) with minimal LTS (0.5 mm).25
How to use
A focusing beam is emitted from the probe, which must be
aligned before use. The laser is emitted by activating a foot
pedal. As with PDs, this is a no-touch technique, with the
probe held at a distance to tissues. To vary the laser action,
the surgeon can alter the beam focus to result in vaporisation
(narrow beam) or desiccation (wide beam). The power of the
laser can be varied with a typical setting of around 30 watts.
Finally, the laser can be delivered continuously or in a
pulsed mode.
Advantages of laser devices
CO2 lasers generate minimal thermal penetrance and LTS
enabling highly accurate tissue effects.
Disadvantages of laser devices
Equipment, theatre modifications and set-up, device
maintenance and staff training are very expensive. There
are also important safety issues that must be considered to
prevent harm to theatre staff (see below). LDs are less
versatile than ABDs and UDs, offering only superficial
dissection and haemostasis of vessels up to 1 mm in
diameter. CO2 LDs produce large amounts of surgical plume.
When to use
CO2 LDs are capable of precise cutting and haemostasis, with
limited adjacent tissue damage. Consequently, they are
particularly useful for excision of lesions; for example,
endometriosis or malignancy close to ureters, bladder and
bowel serosa. The superficial haemostatic effect is useful for
ablation of endometrioma cyst walls.
Tips and tricks
Varying the speed of movement alters the tissue effect; slow
strokes cause cutting, whereas quicker strokes result in
ablation. The suction-irrigation instrument can be used to
protect distant structures in the line of the laser beam.
308
Additionally, suction-irrigation is required for intermittent
evacuation of surgical plume and removal of carbon debris.
Pulsed modes are typically used to allow more controlled
application of energy when close to vital structures.
Safety issues specific to laser devices
All LDs, including aiming beams, can cause optical
damage, ranging from mild corneal burns to irreversible
retinal damage. High-power LDs pose a considerable fire
hazard through their potential to ignite flammable
materials in the operating room. In addition, LDs,
especially CO2 lasers, generate large amounts of surgical
plume, posing a further health risk to theatre staff.11
Departments utilising LDs must adhere to strict safety
protocols, including appointing a laser safety officer to
supervise all aspects of risk management.26
Conclusion
Advanced devices can reduce the learning curve for novice
surgeons.2 For the expert surgeon, advanced devices can
improve surgical efficiency.4 These advances can deliver the
benefits of MAS to a greater number of patients.
The surgeon’s instrument of choice will depend upon
various factors, including the suitability of a device for the
intended operation and the surgeon’s experience.7 An
awareness of all available energy modalities allows operators
to select the optimum device. Additionally, gynaecologists
have an obligation to their patients to demonstrate a
comprehensive understanding of their instruments to
ensure surgical success and safety.
Trainee minimal access surgeons require solid theoretical
foundations to optimise their hands-on surgical training. The
next step for trainees is to undertake simulator-based
laparoscopic training to reinforce this knowledge and
embed the practical elements.27 A curriculum that delivers
theoretical and practical components is required to cultivate
surgeons capable of safe and successful MAS.1
Disclosure of interests
JP is a member of faculty for the BSGE/Olympus Blended
Learning Laparoscopic Gynaecology Skills Development
Programme 2021.
Contribution to authorship
GB conceived, researched and co-wrote the article. JP
researched, co-wrote and critically revised the article. Both
authors read and approved the final version.
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