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NIH Public Access Author Manuscript Best Pract Res Clin Rheumatol. Author manuscript; available in PMC 2014 June 01. Published in final edited form as: NIH-PA Author Manuscript Best Pract Res Clin Rheumatol. 2013 June ; 27(3): . doi:10.1016/j.berh.2013.07.005. Managing lupus patients during pregnancy
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  Managing lupus patients during pregnancy  Aisha Lateef  a  and Michelle Petri b Aisha Lateef: aisha_lateef@nuhs.edu.sg; Michelle Petri: mpetri@jhmi.edu a Division of Rheumatology, University Medicine Cluster National University Health System 1E,Kent Ridge Road, Singapore 119074 b Division of Rheumatology, Johns Hopkins University, School of Medicine, Johns Hopkins LupusCenter, 1830 E. Monument Street, Suite 7500, Baltimore, MD 21205, USA  Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease, primarily affecting youngfemales. Pregnancy in a woman with SLE remains a high risk situation with higher maternal andfetal mortality and morbidity. Although live births are achieved in majority of the pregnancies,active disease and major organ involvement can negatively affect the outcomes. Higher risk of fetal loss, pre-term birth, intra-uterine growth restriction and neonatal lupus syndromes are majorfetal issues. Mothers are faced with disease flares, pre-eclampsia and other complications. Diseaseflares during SLE pregnancy pose the unique issue of recognition and differentiation betweenphysiologic changes and disease state. Similarly pre-eclampsia and lupus nephritis may lead todiagnostic confusion. Treatment choices during pregnancy are limited to a few safe drugs, furtherrestricting the options. Refractory pregnancy loss associated with anti-phospholipid antibodies andcomplete heart block associated with anti-Ro antibodies remain unresolved issues. Amultidisciplinary approach, with close monitoring, is essential for optimal outcomes. Keywords Systemic lupus erythematosus; anti-phospholipid antibodies; pregnancy; fetal loss; pre-eclampsia;neonatal lupus syndromes Introduction Systemic lupus erythematosus (SLE) is an auto-immune disease with significant femalepredominance. The onset during reproductive years, coupled with improved survival, has ledto increased numbers of pregnancies in SLE. The pregnancy outcomes have alsosignificantly improved. The rate of pregnancy loss has decreased from 43% to 17% in recentyears [1]. However, SLE patients have fewer children than their normal counterparts andSLE pregnancy still carries a high risk of complications [2-4]. A multidisciplinary approach,with close medical, obstetric and neonatal monitoring, is essential for optimal outcomes.This chapter will highlight major issues in SLE pregnancy and discuss the managementstrategies to minimize maternal and fetal risks. © 2013 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Best Pract Res Clin Rheumatol  . Author manuscript; available in PMC 2014 June 01. Published in final edited form as: Best Pract Res Clin Rheumatol  . 2013 June ; 27(3): . doi:10.1016/j.berh.2013.07.005. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    Pregnancy planning in SLE Active SLE at the time of conception is known to be the strongest predictor of adversepregnancy outcomes [5]. Hence, ideally, all pregnancies in women with SLE should beplanned during periods of disease control. Unplanned pregnancies during periods of diseaseactivity highlight the often neglected need of effective contraceptive counseling of all youngwomen with SLE [6]. Natural and barrier methods of contraception have a high failure rateand may not be sufficient in a patient with active disease. Safety of oral contraceptives hasbeen documented in two large randomized controlled trials [7, 8]. However, patients withseverely active disease were excluded from the studies. Patients with anti-phospholipidantibodies (aPL) are at high risk of thrombosis and should avoid estrogen containingcontraceptives [9]. Certain drugs interfere with the oral contraceptive efficacy. This fact hasrecently been added to the FDA labeling of mycophenolate mofetil. Although effective,progesterone-only contraceptives have to be used judiciously. Long term use, especially of depot preparations, leads to negative effects on bone mineral density [10]. The intra-uterinecontraceptive device remains a viable and safe option for many patients with SLE [8]. Pre-conception evaluation Preconception assessment is an essential component of pregnancy planning in SLE. In alimited number of patients, pregnancy may pose an unacceptably high maternal risk, justifying an advice to defer or avoid pregnancy (Table 1). If there are no contra-indications,patient should undergo pre-conception counseling, maternal and fetal risk assessment, andmedication review, before conception (Figure 1). A complete set of autoantibodies should beas certain specific maternal antibodies (aPL and anti-Ro antibodies) in mother poses uniquefetal risks. Every effort should be made to ensure optimal disease control for at least 6months prior to conception. Medications should be reviewed and adjusted to achieve gooddisease control on permitted medication. Thyroid function should be assessed ashypothyroidism in SLE is associated with poorer outcomes [11]. Pre-pregnancy Counseling SLE pregnancies are considered to be high risk. All patients should be counseled about thepossible issues including risk of disease flares, higher rates of pregnancy complications, sub-optimal obstetric outcomes, and the risk of neonatal lupus syndromes. The need for optimaldisease control with safe medications during pregnancy should be explained. Disease activity during pregnancy One of the major issues is SLE pregnancy is the risk of disease exacerbation. Although it isgenerally agreed that pregnancy may lead to higher rates of disease flares, widely variableflare rates of between 25-65% have been reported [12-17]. Different organ systems mayhave variable response to pregnancy; musculoskeletal flares are less common while renaland hematologic flares are more common [18]. Majority of the flares in pregnancy are mild-to-moderate, with only small percentage of patients developing severe flares [16]. Activedisease during the 6 months prior to conception, history of lupus nephritis anddiscontinuation of anti-malarial significantly increase the risk of flares during the pregnancy[14, 19-21]. Pregnancy Complications Pregnancy in the setting of SLE is associated with a higher risk of complications, comparedto normal women. A large national data base study of 16.7 million deliveries reported manyfold increased risk of maternal death, preeclampsia, preterm labor, thrombosis, infection,and hematologic complications during SLE pregnancy [2]. However, these results have to be Lateef and PetriPage 2 Best Pract Res Clin Rheumatol  . Author manuscript; available in PMC 2014 June 01. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    interpreted with caution. Non- pregnant SLE patients also have higher risk of medicalcomplications and mortality rate. In addition, women with SLE in this study were older andhad significantly higher rates of co-morbidities.The biggest issue is the 3-5 times higher risk of pre-eclampsia, complicating 16-30% of SLEpregnancies [22-24]. The predisposing factors for pre-eclampsia include advanced maternalage, previous personal or family history of preeclampsia, pre-existing hypertension ordiabetes mellitus, and obesity [25]. In SLE, additional specific risk factors include active orhistory of lupus nephritis, presence of anti-phospholipid antibodies, declining complementlevels, and thrombocytopenia [22-24, 26]. A genetic predisposition with heterozygousmutations in complement regulatory proteins was reported in the PROMISSE cohort, butneeds further evaluation [27]. Obstetric Outcomes The main obstetric issues in SLE pregnancy are higher rates of fetal loss, preterm birth,intra-uterine growth restriction (IUGR), and neonatal lupus syndromes. However, the rate of fetal loss has declined and live births rates of 80-90% have recently been reported [12, 14,15]. Active disease and lupus nephritis increase the risk of fetal loss and other adverseoutcomes [13, 20, 28, 29]. Proteinuria, hypertension, thrombocytopenia, and presence of anti-phospholipid antibodies are other negative predictors for fetal survival [13, 28, 30].Pre-term births, and the morbidity associated with it, are the most frequent problems of SLEpregnancy. Variable rates have been reported but in the presence of the mentioned adverseprognostic factors, up to half of the pregnancies may end in premature delivery. Thyroiddisease is also associated with higher risk of pre-term birth in SLE pregnancy [11]. About10-30% of SLE pregnancies are complicated with fetal growth restriction and small forgestational age babies [14, 21]. Neonatal Lupus Syndromes Neonatal Lupus Syndromes (NLS) is a form of passively acquired fetal autoimmunity frommaternal antibodies, anti-Ro and anti-La antibodies. Majority of the manifestations, such asrash, hematologic and hepatic abnormalities, parallel the presence of maternal antibodies inthe neonatal circulation. They tend to resolve with the clearance of the antibodies by six toeight months of life. In contrast, cardiac complications are a result of permanent damage tothe fetal cardiac conduction system by maternal antibodies.The cardiac manifestations of NLS include conduction defects, structural abnormalities,cardiomyopathy and congestive cardiac failure [31]. However, the most common issue iscongenital heart block (CHB). CHB leads to high fetal mortality; rates of 15-30% have beenreported. The majority of survivors require pacemakers, adding to the significant morbidity[32, 33]. CHB affects about 2% of children born to primigravid women with anti-Roantibodies [34]. However, the risk rises to about 16-20% in subsequent pregnancies, afterthe birth of an affected child [35, 36]. Other suggested risk factors include higher levels of maternal antibodies, maternal hypothyroidism, and fetal genetic polymorphisms [36, 37]. Medication use during pregnancy An essential component of pre-pregnancy counseling is discussion about the use of appropriate medications during the pregnancy. Unfortunately, concerns over presumedtoxicity often lead to discontinuation of necessary therapy with resultant increase in diseaseactivity, worsening the outcomes. The United States Food and Drug Administration (FDA)categories are often not helpful as they are mostly derived from animal data or are outdated. Lateef and PetriPage 3 Best Pract Res Clin Rheumatol  . Author manuscript; available in PMC 2014 June 01. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    Although majority of SLE therapeutics are potentially harmful and contra-indicated, safeoptions exist and should be continued during the pregnancy (Table 2).Non-steroidal anti-inflammatory drugs (NSAIDS) were considered safe during the first andsecond trimesters [38]. However, moderate associations between NSAID use in firsttrimester and specific birth defects were recently reported [39, 40]. There is also anincreased risk of impaired fetal renal function with use after 20 weeks of gestation. Hence,caution needs to be exercised when using NSAIDs during early pregnancy. Continued useafter the 32 week of gestation can increase the risk of premature closure of the ductusarteriosus by almost 15-fold, and should be avoided [41]. The data on the cyclooxygenase 2inhibitors in pregnancy is very limited, and they are best avoided during pregnancy.Steroid exposure should be limited to a minimum during the pregnancy. High doses duringpregnancy are associated with an increased risk of diabetes, hypertension, pre-eclampsia andpremature rupture of membranes [38]. However, in the case of disease flares, short coursesof high doses and/or intravenous pulse methylprednisolone can be used. Patients on longterm steroid therapy should also receive stress doses at the time of delivery. Use of fluorinated compounds, such as dexamethasone and betamethasone should be limited to asingle course for fetal lung maturity, in cases of premature delivery. Repeated use has beenassociated with impaired neuro-psychological development of the child in later life, andshould be avoided [42].Hydroxychloroquine should be continued in all pregnant women with SLE. Multiple studieshave proven the beneficial effects of hydroxychloroquine in SLE, including duringpregnancy. Reduction in disease activity was noted with no harmful effects on the baby withuse during pregnancy, while discontinuation led to an increase in disease flares [19, 43, 44].The risk of CHB and neonatal lupus syndromes was also significantly reduced in at-risk pregnancies with sustained use of hydroxychloroquine [45, 46].Azathioprine is one of the only few immunosuppressive agents that has documented safetyduring pregnancy [38]. The dose should be limited to maximum of 2mg/kg/day, to avoidrisk of fetal cytopenias and immune suppression [38]. An association between maternalazathioprine therapy during pregnancy and late developmental delays in offspring wassuggested by a recent study [47]. However, the confidence intervals were very wide and thestudy had serious limitations (small sample size, retrospective nature, lack of validatedmeasures). Azathioprine can still be considered safe during pregnancy but it is prudent tocounsel the women about the possible association. Other immunosuppressive drugs with noreported increase in fetal risk are the calcineurin inhibitors, tacrolimus and cyclosporine[48]. Leflunomide was considered to be teratogenic and traditional advice has been todiscontinue for 2 years or perform a wash out procedure before conception. Recently, 2cohort studies reported no increase in risk of malformations after inadvertent exposureduring pregnancy [49, 50]. However, caution needs to be exercised and routine use of leflunomide during pregnancy is not recommended. Most other agents, such ascyclophosphamide, methotrexate, and mycophenolate, are contraindicated during pregnancyand should be discontinued at least 3 months before conception. Data on the biologics, suchas rituximab or belimumab, during pregnancy are very limited, and they should bediscontinued before conception.Most of the commonly used antihypertensive drugs have to be either avoided or used withextreme caution during pregnancy [51, 52]. Angiotensin-converting-enzyme (ACE)inhibitors and angiotensin II receptor blockers can cause specific malformations, the ACE-inhibitor fetopathy. In addition, neonatal arterial hypotension, renal failure, and death havebeen reported. Beta-adrenergic blockers have been associated with IUGR and fetal Lateef and PetriPage 4 Best Pract Res Clin Rheumatol  . Author manuscript; available in PMC 2014 June 01. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  
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