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Maternal and Fetal Complications of Systemic Lupus Erythematosus
Maternal and Fetal Complications of Systemic Lupus Erythematosus
Maternal and Fetal Complications of Systemic Lupus Erythematosus
x 2012;14:167–174
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Key content To understand the features and associated risk factors which
Systemic lupus erythematosus (SLE) is an autoimmune condition increase the chance of adverse pregnancy outcome in women with
that has multi-organ involvement. SLE.
It is approximately ten times more common in women than in To understand which therapies for SLE can be used safely in
men and is often diagnosed during the childbearing years. pregnancy and while breastfeeding.
SLE is known to increase the risk of spontaneous miscarriage; it To understand the role of the multidisciplinary team in the care of
can also cause fetal growth restriction and increased rates of women with SLE, particularly those with underlying organ
sudden intrauterine death, pre-eclampsia and preterm delivery. impairment.
Management of women with lupus nephritis can be difficult, as the
Ethical issues
disease may mimic and overlap significantly with pre-eclampsia. When should women with SLE be advised against pregnancy?
Multidisciplinary management of pregnant women with SLE
At what point should termination of pregnancy be considered if
ensures optimal surveillance of both mother and fetus.
there is deterioration in maternal health in early pregnancy?
Learning objectives
Keywords antiphospholipid syndrome / drug therapy / fetal growth
To understand how to manage pregnant women with SLE.
restriction / perinatal complications / pre-conception counselling /
To understand the importance of pre-pregnancy counselling for
pre-eclampsia / thromboembolism
women with SLE.
Please cite this paper as: Cauldwell M, Nelson-Piercy C. Maternal and fetal complications of systemic lupus erythematosus. The Obstetrician & Gynaecologist
2012;14:167–174.
Box 1. 1997 update on 1982 American College of Rheumatology classification criteria for systemic lupus
erythematosus2
Criterion Definition
Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older
lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician
Arthritis Non-erosive arthritis of two or more peripheral joints, with tenderness, swelling or effusion
Pleuritis or pericarditis Pleuritis: convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion, or
pericarditis: documented by electrocardiogram or rub or evidence of pericardial effusion
Renal disorder Persistent proteinuria >0.5 g per day or > 3 + if quantification not performed, or
cellular casts: may be red cell, haemoglobin, granular, tubular, or mixed
Neurological disorder Seizures: in the absence of offending drugs or known metabolic derangements; e.g. uraemia, ketoacidosis, or electrolyte
imbalance, or
psychosis: in the absence of offending drugs or known metabolic derangements, e.g. uraemia, ketoacidosis, or electrolyte
imbalance
Haematological disorder Haemolytic anaemia: with reticulocytosis, or
leucopenia: <4000/mm3 on 2 occasions, or
lymphopenia: <1500/mm3 on 2 occasions, or
thrombocytopenia: <100 000/mm3 in the absence of offending drugs
Immunological disorder Anti-DNA: antibody to native DNA in abnormal titre, or
anti-Sm: presence of antibody to Sm nuclear antigen, or
positive finding of antiphospholipid antibodies on:
(i) abnormal serum level of IgG or IgM anticardiolipin antibodies
(ii) positive test result for lupus anticoagulant using a standard method, or
(iii) false-positive test result for 6 months confirmed by Treponema pallidum immobilisation or fluorescent
treponemal antibody absorption test
Positive antinuclear An abnormal titre of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the
antibody absence of drugs
Any combination of four or more of 11 criteria, well documented at any time during a woman’s history, makes it likely that she has SLE (specificity
and sensitivity are 95% and 75%, respectively).
Organ/system Complication/manifestation/investigation
Cardiac Pulmonary hypertension, valvular heart disease, cardiomyopathy: assess with echocardiography
Respiratory Pulmonary fibrosis: may need to consider chest X-ray, CT, lung function tests if there is underlying restrictive respiratory
involvement
Renal Urine dipstick and protein:creatinine ratio to screen for and to quantify any underlying proteinuria.
Document and quantify presence of haematuria, hypertension and/or renal impairment (lupus nephritis)
Renal function tests to assess pre-existing renal dysfunction
Haematology/ Thrombosis: assessment of risk and need for anticoagulation. Full blood count to determine any anaemia, neutropenia or
immunology thrombocytopenia
Autoantibody profile: antiphospholipid (aPL), anticardiolipin (aCL), lupus anticoagulant (LA), anti-dsDNA and anti-Ro/anti-
La antibodies, complement C3/C4 levels
CT = computed tomography
Obstetric management
Perhaps the most difficult discussions concern when to
It is important to appreciate that not all pregnancies in women
advise women not to conceive or when to terminate a
with SLE need to be considered as high risk. Careful
pregnancy. Of great concern are women with SLE and
identification and stratification should take place to allow
associated pulmonary arterial hypertension who wish to
women to be managed on an individual basis. Women with
conceive: maternal mortality rates have been quoted as being
quiescent skin and/or joint disease who have no other underlying
as high as 40%, but recent data have shown that this rate is
organ impairment and who do not require multidrug therapy or
~33%.13 The point prevalence of pulmonary arterial
an incremental increase in their current drug dosage are very
hypertension in patients with lupus is 4.2%, with most cases
different from those with a history of nephritis/hypertension or
being defined as mild (systolic pulmonary arterial
concurrent APS.
pressure <40 mmHg).14 This was determined for a non-
Pregnant women with active SLE/lupus nephritis or anti-Ro/
pregnant cohort of patients, but the mean age was 41 years,
La/antiphospholipid antibodies shouldbe consideredas a higher
highlighting the importance of selectively screening women for
risk group and managed in centres with appropriate experience.
underlying pulmonary arterial hypertension prior to
Care should be carried out in a multidisciplinary setting where
pregnancy. Women should also be advised not to conceive
obstetricians/midwives and physicians/haematologists work
during a period of active disease, particularly with lupus
closely together to optimise care. It is difficult to recommend
nephritis, because of worse maternal and fetal outcomes.15 In
precisely how often these women should be reviewed, but those
very general terms, women with SLE have two to four-fold
with more active disease need closer monitoring and often
higher rates of complications compared with those without
require hospital admission. For those individuals with stable
the disease: this includes pre-eclampsia, preterm delivery and
disease, 4-weekly reviews of disease activity and regular
fetal growth restriction, all of which are discussed in this
assessment of fetal growth, blood pressure and proteinuria are
article.5,10,16
appropriate. For those at particular risk of fetal growth
Termination of pregnancy or preterm delivery should be
restriction and/or pre-eclampsia because of active disease or
considered in the presence of uncontrolled hypertension and/
previous history, more frequent assessment is indicated.
or worsening renal function despite optimal pharmacological
For those women who are anti-Ro/La positive the fetal
therapy. This may be related to a flare of lupus nephritis
heart rate should be monitored and recorded at each visit and
or severe early-onset pre-eclampsia, particularly if there is
fetal echocardiography assessments made at 18–20 and
associated APS. In active lupus nephritis with worsening
~28 weeks of gestation.
renal function, increasing proteinuria and hypertension,
Careful obstetric management involves an awareness of the
it may be necessary to use such treatments as
possibility of lupus flare and an understanding of how this
cyclophosphamide and mycophenolate mofetil, which are
can overlap with normal pregnancy-related changes and with
associated with congenital malformations if used in the first
pre-eclampsia. Pregnancy and SLE-related changes are
trimester, in which case appropriate counselling should be
summarised in Box 3.
offered.
they should be appropriately counselled regarding this in the Neonatal lupus rash
pre-pregnancy period. This forms part of the neonatal lupus erythematosus
spectrum, manifesting as annular inflammatory lesions,
Scanning and Doppler ultrasound which appear much like lesions of subacute cutaneous SLE.
There is no definitive guide stipulating the absolute timing of The lesions are most commonly seen on the face and scalp
fetal scans and the frequency between scans in pregnancies and appear typically after ultraviolet exposure in the first
complicated with SLE. It is important for the obstetrician to 2 weeks of life, but up to 3–6 months postpartum. The rash
be aware of the risks of congenital heart block, fetal growth generally appears spontaneously and can persist for up to
restriction and increased rates of preterm delivery and 6 months postnatally until the neonate clears the maternal
pre-eclampsia.24 These must all be taken into account when antibodies. It is rare for neonatal cutaneous lupus and
deciding whether increased fetal scanning is indicated. congenital heart block to occur together in the same
Scanning at least every 4 weeks to screen for fetal growth individual.29 Skin biopsy shows histopathology and
restriction in those women at risk is generally accepted and immunofluoresence typical of that of cutaneous lupus.
fetal echocardiography referral should be arranged for those
with anti-Ro/La antibodies or if any cardiac abnormalities are Preterm delivery
detected on ultrasound scan. This is more common in pregnancies complicated by SLE30
Doppler studies can be used to estimate placental function and is often compounded by obstetric intervention and a
and can be an aid to predicting outcomes such as pre-eclampsia tendency to deliver once the fetus is mature. Review of the
and fetal distress. A uterine artery Doppler should be first literature suggests that the most common indication for
carried out at 20 weeks and repeated 4 weeks later if any delivery is pre-eclampsia, followed by fetal distress and fetal
abnormality is found. A raised pulsatility index or diastolic growth restriction. Premature rupture of membranes is also
notching are associated with increased risk for developing regarded as being more frequent in pregnancies complicated
pre-eclampsia, as they can indicate underlying placental by SLE; rates vary and are generally quoted as ~20%.31
dysfunction. Nevertheless, not all women with an abnormal Interestingly, this risk does not appear to be related to disease
uterine artery Doppler will develop complications, so it status or serology, although women on steroid treatment
is important not to treat abnormal Doppler in isolation. appear to have a greater risk.32
Second trimester Doppler has been shown to predict late
pregnancy outcome in SLE and/or APS in some25,26 but not Drug therapy in SLE
all studies.27
Box 4 lists the majority of the pharmacological agentsused in the
Fetal growth restriction treatment of SLE, their mechanism of action, some of the
Since this is common in the context of pregnancies contraindications to use and safety in pregnancy and
complicated by hypertension, APS and pre-eclampsia, it is breastfeeding. Drug therapy is an important consideration, as
not surprising that pregnant women with SLE are also at risk it is often necessary to manage women with a combination of
of fetal growth restriction. It may affect nearly one in four different therapies. This is where the experience of clinicians who
pregnancies with maternal SLE and has been reported as treat pregnant women with SLE on a regular basis is invaluable.
occurring in as many as 35%, particularly with concurrent Glucocorticoids, mainly in the form of prednisolone, are
lupus nephritis.28 frequently but not exclusively used as one of the first-line
treatments in pregnancy. The dosage used does not vary
Congenital heart block greatly between pregnant and non-pregnant patients. The risk
This is associated with maternal anti-Ro/La autoantibodies. of adverse effects of steroids on the fetus is thought to be low,
Antibodies cross the placenta and destroy the Purkinje with little evidence for congenital malformations or neonatal
system. The usual presentation is a fixed fetal bradycardia of adrenal suppression. Prednisolone, methylprednisolone and
60–80 beats per minute on ultrasound scan. It occurs in hydrocortisone are more efficiently metabolised by placental
2–3% of fetuses of women with the anti-Ro/La antibody and enzymes than dexamethasone and betamethasone and
there is a recurrence rate of 16% in subsequent pregnancies. therefore cross the placenta in small amounts only. The
It is associated with significant perinatal morbidity and adverse effects of steroids on the mother, however, are more
mortality, with about half of infants requiring pacing by the numerous. These include weight gain, immunosuppression
first year of life. Congenital heart block develops between 18– (and therefore increased risk of infections), acne,
28 weeks of gestation and fetal echocardiography should be gastrointestinal irritation and, probably the most important
performed around this period to detect it. Hydrops fetalis can adverse effect in pregnancy, increased glucose intolerance.
occur in utero and is thought to be due to the degree of Women on moderate to high dosages of steroids should
endomyocardial fibrosis and associated myocarditis. therefore be screened regularly for gestational diabetes.33
Corticosteroids Anti-inflammatory Betamethasone and Long-term follow-up May breastfeed safely as Continue during
and dexamethasone shows no significant only small amounts pregnancy
immunosuppressive cross placenta neurodevelopmental found in breast milk
readily. delay34
Prednisolone and
hydrocortisone
cross less well
Non-steroidal anti- Inhibit Yes Premature closure of Use with caution in first Ideally, discontinue
inflammatory cyclooxygenase ductus arteriosus if and second trimester. prior to
drugs taken beyond Avoid after 32 weeks of conception
32 weeks gestation.35,36 Safe post-
delivery provided no renal
involvement
Azathioprine Immunosuppressive Crosses placenta but No cases of congenital Safe in pregnancy and Do not stop
agent—prevents fetal liver lacks abnormalities breastfeeding, but use at without
cell proliferation enzyme to convert minimum effective guidance from
and inhibits to active metabolite dose37 rheumatology
lymphocyte staff. Safe to
function continue
Methotrexate Antimetabolite. Does not cross Neural tube defects if Contraindicated in Stop prior to
Inhibits cell- placenta used in early pregnancy. No data on conception
mediated immunity pregnancy effects in breastfeeding
Mycophenolate Inhibitor of purine Crosses placenta and Associated with Avoid in pregnancy and in Stop (change to
mofetil (MMF) synthesis is excreted in breast miscarriage and breastfeeding azathioprine)
milk congenital prior to
malformations36 conception but
seek guidance
from
rheumatology
staff
Cyclophosphamide Alkylating agent Crosses placenta and Teratogenic. Increased Excreted in breast milk, so Stop prior to
is excreted in breast rates of miscarriage should be avoided conception but
milk and congenital altogether in pregnancy in a woman with
abnormalities36 flare consult
rheumatology
staff
Ciclosporin T-cell mediated Crosses placenta and Main problems Treatment used extensively Seek advice from
response prevents found in fetal reported: in transplant patients and rheumatology/
formation of blood prematurity and low autoimmune disease. nephrology staff
interleukin-2 birthweight38 but Breastfeeding probably regarding usage
this may relate to safe
underlying disease
Hydroxychloroquine Disrupts lysosome Does cross placenta No increase in Withdrawal in non- Continue
presentation and congenital pregnant patients may throughout
the processing of abnormalities39 precipitate flare, so safe pregnancy, do
antigens to continue. May not withdraw
breastfeed safely
Other immunosuppressant agents that are frequently hydralazine, procainamide, quinidine, isoniazid, diltiazem
used and are generally considered safe during and minocycline. The pathophysiology of drug-induced
pregnancy include azathioprine and hydroxychloroquine. lupus is not completely understood, but in the case of
There is no indication to discontinue them during hydralazine it is thought to be caused by the formation of
pregnancy. antinuclear antibodies to H1 and the H3–H4 complex
It is also worth noting that several drugs can cause a (antihistone). However, these drugs do not cause disease
lupus-like syndrome. The most common of these are flare in women with established lupus.
antiphospholipid syndrome. Lupus 2010;19:58–64 [http://dx.doi.org/ of Child Health and Human Development Research Network.
10.1177/0961203309347794]. Pediatrics 2000;105:1216–26 [http://dx.doi.org/10.1542/
28 Lima F, Buchanan NM, Khamashta MA. Obstetric outcomes in peds.105.6.1216].
systemic lupus erythematosus. Semin Arthritis Rheum 1995;25: 35 Li DK, Liu L, Odouli R. Exposure to non steroidal anti-inflammatory
184–92 [http://dx.doi.org/10.1016/S0049-0172(95)80030-1]. drugs during pregnancy and the risk of miscarriage: population based
29 Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res cohort study. Br Med J 2003;237:368–73 [http://dx.doi.org/10.1136/
2009;301:107–10 [http://dx.doi.org/10.1007/s00403-008-0896-4]. bmj.327.7411.368].
30 Yasmeen S, Wilkins EE, Field NT. Pregnancy outcomes in women with 36 Ostensen M, Khamashta M, Lockshin M. Anti-inflammatory and
systemic lupus erythematosus. J Matern Fetal Med 2001;10:91–6 immunosuppressive drugs and reproduction. Arthritis Res Ther
[http://dx.doi.org/10.1080/jmf.10.2.91.96]. 2006;8:209–28 [http://dx.doi.org/10.1186/ar1957].
31 Clowse MEB, Jamison M, Myers E, James AH. A national study of the 37 Sau A, Clarke S, Bass J, Marinaki A, Nelson-Piercy C. Azathioprine and
complications of lupus in pregnancy. Am J Obstet Gynecol breast feeding: is it safe? BJOG 2007;114:498–501 [http://dx.doi.org/
2008;199:127. 10.1111/j.1471-0528.2006.01232.x].
32 Chakravarty E, Colon I, Langen E, Nix D, El-Saved Y, Genovese M, 38 Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome
Druzin M. Factors that predict prematurity and pre-eclampsia in after cyclosporine therapy during pregnancy: a meta-analysis.
pregnancies that are complicated by systemic lupus erythematosus. Transplantation 2001;71:1051 [http://dx.doi.org/10.1097/00007890-
Am J Obstet Gynecol 2005;192:1897–1904 [http://dx.doi.org/ 200104270-00006].
10.1016/j.ajog.2005.02.063]. 39 Clowse ME, Magder L, Witter F. Hydroxychloroquine in lupus
33 Yildirim Y, Tinar S, Oner RS, Kaya B, Toz E. Gestational diabetes pregnancy. Arthritis Rheum 2006;54:3640–7 [http://dx.doi.org/
mellitus in patients receiving long-term corticosteroid therapy during 10.1002/art.22159].
pregnancy. J Perinat Med 2006;34:280–4 [http://dx.doi.org/10.1515/
JPM.2006.053].
34 Vohr Br, Wright LL. Neurodevelopmental delay and functional
outcomes of extremely low birth weight infants in National Insititute