AOGS EDIT ORS M ES SAGE
Clinical trials in preeclampsia: implications for practice
GANESH ACHARYA1 € ANEN
, AMARNATH BHIDE2 & JUHA RAS €
1
Department of Clinical Science, Intervention and Technology, Karolinska Institute and Centre for Fetal Medicine,
Karolinska University Hospital, Stockholm, Sweden, 2Fetal Medicine Unit, St. Georges University Hospital, London, UK,
and 3Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland
DOI: 10.1111/aogs.13227
Preeclampsia is a relatively common complication of preg-
nancy worldwide, although its prevalence varies widely.
Although less common in Nordic countries, it is an impor-
tant condition encountered by every obstetrician in their
clinical practice and it still remains a significant cause of
maternal and neonatal morbidity/mortality. Despite exten-
sive basic and clinical research in the field, the etiology of
preeclampsia remains elusive. However, our understanding
of its pathophysiology is improving and its prediction,
diagnosis and management is continuously evolving and
getting better. This has resulted in a substantial reduction
in serious complications, such as eclampsia, cerebral hem-
orrhage, renal failure, coagulopathy, pulmonary edema
and maternal death. Recognition of Magnesium sulfate as
the preferred therapy for the treatment and prevention of
seizure in preeclampsia can be considered to be a major
advancement in this regard (1).
The Magpie trial, which compared Magnesium sulfate
with placebo for preeclampsia, was an important interna-
tional multicentre RCT which showed that Magnesium
sulfate is safe and more than halves the risk of eclampsia
(2). A number of randomized clinical trials addressing
the issues related to screening, diagnosis, treatment and
prevention of preeclampsia have been completed recently
and there have been several breakthroughs in research
that have clinical implications.
Traditional antenatal care involves measuring blood
pressure and checking urine for proteinuria at every ante-
natal visit with the hope of identifying preeclampsia early
enough to avoid serious morbidity and mortality.
Recently, self-monitoring of blood pressure by women at
home has also been advocated. However, these methods
have clear limitations which have been further compli-
cated by changing definitions of preeclampsia and a lack
of a general consensus among different professional soci-
eties regarding screening, prevention and treatment strate-
gies. Historically, preeclampsia was defined as a triad of
hypertension, edema, and proteinuria in pregnancy. Later,
edema was excluded as an essential criterion. In 2014, the
ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017) 1157–1158
3
International Society for the Study of Hypertension in
Pregnancy (ISSHP) revised its definition of preeclampsia
as “hypertension developing after 20 weeks of gestation
and the coexistence of one or more of the following new
onset conditions: proteinuria, other maternal organ dys-
function and utero-placental dysfunction/fetal growth
restriction” (3). However, whether proteinuria needs to
be a requirement for the diagnosis of preeclampsia still
remains controversial and some professional societies do
not require presence of proteinuria to make the diagnosis.
Studies have shown that the biochemical markers may be
altered weeks before signs and symptoms of preeclampsia
develop. Triage, using biochemical markers in cases of
suspected preeclampsia, seems to reduce unnecessary hos-
pital admissions. It is quite plausible that early diagnosis
based on biochemical markers will be possible in future.
Another key issue has been the screening and prevention
of preeclampsia. Unfortunately, lack of an effective screen-
ing method and an appropriate intervention to prevent
preeclampsia has been a caveat. Rationale for early detection
of women at increased risk of developing preeclampsia is
compelling, as Aspirin given at a dose of 150 mg/day from
12 to 36 weeks of gestation has been shown to be effective
in preventing preeclampsia (by 62% before 37 weeks and by
82% before 34 weeks) in a large randomized controlled trial
published recently (4). Nevertheless, an optimum screening
approach is yet to be determined (5). Different approaches
to screening and preventive therapy may be required for dif-
ferent populations since Aspirin does not seem to prevent
preeclampsia in all women at increased risk, such as preg-
nant women with pre-existing hypertension (6). This find-
ing supports the conclusion of an earlier publication (7)
where low-dose Aspirin given to women with chronic
hypertension did not reduce the rate of preeclampsia. Crit-
ics also point out that Aspirin benefitted just one out of
1233 women in this trial. However, first trimester uterine
artery Doppler in combination with maternal characteristics
and mean arterial pressure appears to be the most effective
screening method, although including biochemical markers,
1157
Editors Message
such as maternal serum pregnancy-associated plasma pro-
tein-A and placental growth factor, does seem to improve
its screening performance. The latter approach has been
shown to reach a detection rate of 76.6% for preterm
preeclampsia and 38.3% for term preeclampsia for a 10%
false positive rate (8).
Screening for preeclampsia is not a routine in many
countries and Nordic countries also do not have a uniform
policy on screening. For example, first trimester ultra-
sound screening is regularly performed in some countries,
such as Denmark and Finland, whereas this is not the case
in Norway and some regions of Sweden, which makes it
more difficult to introduce screening for preeclampsia. It
could also be argued that setting healthcare priorities for
allocating resources needs serious consideration before
introducing screening in countries where the prevalence of
preeclampsia is low. Additionally, the performance of
screening is poor for late-onset preeclampsia, which is
more common compared to early-onset preeclampsia. Is
there a need to reproduce the results of Aspirin versus Pla-
cebo in Pregnancies at High Risk for Preterm Preeclampsia
(ASPRE) trial in Nordic population before introducing
universal screening for all pregnant women? Policy debate
should not be restricted to medical communities; we must
also consider the opinions of pregnant women and involve
our patients in the debate and decision-making processes.
Some trends have emerged recently regarding the man-
agement of preeclampsia. There seems to be tendency
towards starting Magnesium sulfate earlier to prevent sei-
zures in severe preeclampsia rather than to just treat
eclampsia and prevent seizure recurrence. Although there
is no international consensus on the level of blood pres-
sure at which antihypertensive treatment should be started,
or the target blood pressure following antihypertensive
therapy, there is inclination towards having a lower thresh-
old for treating hypertension and achieving tighter blood
pressure control following publication of the results of the
CHIPS (Control of Hypertension in Pregnancy Study) trial
(9). Several clinicians have also started to consider antihy-
pertensive therapy and fluid management based on hemo-
dynamic stratification of preeclamptic women.
Results of the recently completed Statins to Ameliorate
early onset Pre-eclampsia (StAmP) trial (http://www.isrc
tn.com/ISRCTN23410175) are eagerly awaited. Removal
of soluble Fms-like tyrosine kinase-1 by dextran sulfate
apheresis has been evaluated as a treatment method in
preeclampsia and has shown some promise, as it appears
to prolong pregnancy in severe preeclampsia (10).
Increasing recognition that women who develop
preeclampsia during pregnancy are at increased risk of
cardiovascular and renal diseases later in life has moti-
vated clinicians to develop follow up strategies which
could have potential health benefits for these women.
1158 ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017) 1157–1158
Overall, important evidence has been generated in
recent years by research regarding the screening, preven-
tion and treatment of preeclampsia, which has resulted in
some positive trends that may contribute to reduced bur-
den of the disease and better patient care.
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