lupus and pregnancy

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA Category 1 CreditsTM can be earned in 2011. Instructions for how CME credits can be earned appear on thelast page of the Table of Contents.

Lupus and PregnancyAlan N. Baer, MD,* Frank R. Witter, MD,

and Michelle Petri, MD, MPH*Associate Professor, Division of Rheumatology, Department of Medicine, Professor, Department ofGynecology and Obstetrics, and Professor, Division of Rheumatology, Department of Medicine,

Johns Hopkins University School of Medicine, Baltimore, MD

Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive ageyears. Pregnancy in this systemic autoimmune disease has long been associated with poorobstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a levelcommensurate with that of the general US population. The outcomes of lupus pregnancies arebetter if conception is delayed until the disease has been inactive for at least 6 months, and themedication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications,including flares of disease activity during pregnancy or in the postpartum period, preeclampsia,miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritisposes the greatest risk. The recognition of a lupus flare during pregnancy may be difficult becausethe signs and symptomsmaymimic those of normal pregnancy. Monitoring should include baselineand monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-modeechocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs orsymptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxy-chloroquine was in use before conception, it should be maintained throughout pregnancy. If a womanwith SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecularweight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treatedwith hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathio-prine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications butare associated with significant pregnancy-related complications and poor obstetrical outcomes.Target Audience: Obstetricians and Gynecologists and Family PhysiciansLearning Objectives: After completing the CME activity, physicians should be better able to provide

preconception counseling to a woman with lupus, differentiate signs of a lupus flare from symptoms ofpregnancy, differentiate preeclampsia from a flare of lupus nephritis, and differentiate the serious medicalcomplications of pregnancy in a lupus patient.

Systemic lupus erythematosus (SLE) is a multior-gan autoimmune disease, which disproportionately

affects women in their reproductive age years. Thedisease is variable in its organ involvement, but ischaracterized by the particular manner in which itinvolves the skin, joints, serous membranes, kidneys,and central nervous system (Table 1). It is associatedwith the formation of high titers of autoantibodies to

Unless otherwise noted below, the authors, faculty and staff ina position to control the content of this CME activity and theirspouses/life partners (if any) have disclosed that they have nofinancial relationships with, or financial interest in, any commercialorganizations pertaining to this educational activity.Supported by the National Institute of Arthritis and Musculosk-

eletal and Skin Diseases (grant R01-AR43737) and National Insti-tute of Dental and Craniofacial Research (contract NOI DE-32636),Hopkins General Clinical Research Center (grant M01-RR-00052),and the Jerome L. Greene Foundation.

Correspondence requests to: Alan N. Baer, MD, Associate Pro-fessor of Medicine, Johns Hopkins University, Clinical Director,Division of Rheumatology, Good Samaritan Hospital, Suite 508,Russell Morgan Building, 5601 Loch Raven Boulevard, Baltimore,MD 21239. E-mail: [email protected].

CME REVIEWARTICLEVolume 66, Number 10OBSTETRICAL AND GYNECOLOGICAL SURVEYCopyright 2011by Lippincott Williams & Wilkins 29

www.obgynsurvey.com | 639

TABLE 1Major clinical and laboratory features of SLE

Criterion for DiseaseClassification* Frequency in Hopkins Lupus Cohort (%)

CutaneousLupus-specific skin diseaseAcute cutaneous lupus erythematosusMalar butterfly rash X 53

Subacute cutaneous lupus erythematosus 51Discoid lupus X 21

Nonspecific lupus skin lesionsPhotosensitivity X 55Oral/nasopharyngeal ulceration X 51Livedo reticularis 21Nonscarring alopecia

VascularRaynauds 52Cutaneous vasculitis 15

MusculoskeletalArthralgia 93Arthritis (2 peripheral joints) X 74Myositis 8

SerositisPleuritis or pericarditis X

RenalGlomerulonephritisPersistent proteinuria (500 mg/d) or cellular casts X Proteinuria: 41Nephrotic syndrome 18

Tubulointerstitial diseaseNeuropsychiatricSeizures or psychosis X Seizure: 10; psychosis: 4Stroke 4Cranial neuropathy 2Transverse myelitis 1Organic brain syndrome 5Cognitive dysfunction 6

PulmonaryPulmonary fibrosis 8Pulmonary hypertension 8

CardiacEndocarditis 1Myocarditis 2

HematologicHemolytic anemia or leucopenia or thrombocytopenia X Hemolytic anemia: 11; leucopenia: 44;

thrombocytopenia: 21Lymphadenopathy 31

ImmunologicAntinuclear antibodies X 96Lupus autoantibodiesdsDNA antibodies or Sm antibodies or antiphospholipid

antibodies (anticardiolipin antibodies, false-positivetest for syphilis, or lupus anticoagulant)

X dsDNA (57); Sm (16); cardiolipin (48)

RNP antibodies 26SS-A (Ro) antibodies 30SS-B (La) antibodies 12

Hypocomplementemia 54

*To be classified as having systemic lupus erythematosus by the American College of Rheumatology Criteria, a patient must have any4 or more of the 11 listed criteria, serially or simultaneously, during any interval of observation.1,2 Many other important features of lupus,shown in the table, are not included in these criteria because they did not add to their ability to differentiate lupus from other systemicrheumatic diseases.

Frequency of disease manifestations among 1827 consecutive patients in the Hopkins Lupus Cohort.

640 Obstetrical and Gynecological Survey

an array of ubiquitously expressed nuclear antigensas well as to a limited number of cell- or tissue-specific antigens. The 1982 American College ofRheumatology Criteria for Classification of SLE arecommonly used as guidelines for diagnosis (Table1).1,2 However, they were intended for research clas-sification and may not capture patients with earlydisease or limited forms of lupus, such as patientswith isolated lupus nephritis.

The overall prevalence of SLE in the United Statesis estimated to be in the range of 14.6 to 50.8 per100,000 persons.3 It is 3 to 4 times higher in African-American women compared with white women liv-ing in the United States. The 10-year survival ofpatients with SLE has improved over the past 50years and is now estimated to be 90%.3,4

Pregnancy in the setting of SLE has long beenassociated with poor obstetric outcomes, promptingphysicians in the past to advise their lupus patientsnot to consider childbirth. However, the frequency ofpregnancy loss in SLE has dropped over the last 40years from levels as high as 43% in 19601965 to17% in 20002003, a level now commensurate withthat of the general US population.5 The managementof maternal complications has also improved dramat-ically. Pregnancy is thus an option for many womenwith lupus and can usually be managed successfullyin a high-risk clinic with the close collaboration ofthe obstetrician and rheumatologist. At present, ap-proximately 4500 pregnancies in the United Stateseach year are in women with SLE6,7 and thus an

understanding of the management of these patients isessential for all obstetricians.

Pregnancy in the setting of SLE is prone to compli-cations and must therefore be considered high-risk. In arecent US study of 16.7 million pregnancies, 13,555pregnancies occurred in lupus patients and were as-sociated with a 20-fold increase in maternal mortalityand increased risks for cesarean deliveries (odds ra-tio: 1.7), preterm labor (odds ratio: 2.4), and pre-eclampsia (odds ratio: 3.0).6 In addition, there was ahigher rate of thrombotic, infectious, and hemato-logic complications.

Lupus disease activity may flare during pregnancyor in the postpartum period. Reported rates of suchflares range from 13.5% to 65% of pregnancies in theaffected women.8 The extent to which this occurs hasbeen the subject of 7 prospective comparative studiesthat have used nonpregnant lupus patients as con-trols. Of these studies, 4 did not identify an increasedrate of flares, while 3 did.916 This disparity reflectsvariability in the severity of the lupus among thepatients in the study cohorts and in the criteria fordefining a lupus flare. Some symptoms and labora-tory findings of a normal pregnancy can mimic thoseof SLE, such as malar erythema, joint pain, anemia,and mild thrombocytopenia, making it more difficultto diagnose a lupus flare during pregnancy (Table 2).Most of the manifestations of active lupus duringpregnancy are mild to moderate in severity and in-volve the skin and joints.20,21 Approximately 15% to30% of patients who flare will have severe disease

TABLE 2Assessment of lupus flares in pregnancy

Feature Findings Indicative of a Lupus Flare Findings of Normal Pregnancy That Can Mimic a Flare

Clinical Active rash of lupusInflammatory arthritisLymphadenopathyFever 38C (not related toinfection or drug)PleuritisPericarditis

FatigueArthralgiasBland effusions of kneesMyalgiasMalar and palmar erythemaPostpartum hair lossCarpal tunnel syndromeEdema of hands, legs, and faceMild resting dyspnea

Erythrocycle sedimentation rate Increased 1846 mm/h 20 weeks gestation3070 mm/h 20 weeks gestation 17

Anemia Hemoglobin 10.5 gm/dL Hemoglobin 11 gm/dL during first 20 weeks gestationHemoglobin 10.5 gm/dL h after 20 weeksgestation18

Thrombocytopenia Platelet count 95,000 Mild in approximately 8%19

Urinalysis Hematuria or cellular casts Rare hematuria from vaginal contaminationProteinuria 300 mg/d 300 mg/ddsDNA antibodies Rising titers Negative or stable titersComplement 25% drop Usually increased

Lupus and Pregnancy Y CME Review Article 641

manifestations, with involvement of the kidney andother internal organs.22 The presence of active SLEwithin 6 months before conception is a risk factor fora flare during pregnancy.

Preeclampsia complicates 13% to 35% of lupuspregnancies compared with 5% to 8% of pregnanciesin the general US population.7,21,23 This occurs morecommonly in women with active lupus nephritis atthe time of conception.24 Other risk factors includethe sustained use of prednisone in doses of 20 mgper day or greater during the pregnancy, obesity,thrombocytopenia, and hypertension, and/or renaldisease.21,25,26

Approximately 19% of lupus pregnancies end witha miscarriage or stillbirth.27 Up to 55% of thesepregnancy losses occur as stillbirths in the secondtrimester, a rate much higher than that of the generalpopulation. Clowse et al identified proteinuria (500mg/d), secondary antiphospholipid antibody syn-drome, thrombocytopenia, and hypertension as 4first-trimester risk factors for fetal loss.28

Preterm birth (delivery before 37 weeks) and in-trauterine growth retardation (IUGR) are also morecommon, with reported median prevalences of 33%(range, 8%63%) and 9% (range, 2%40%), respec-tively.27 These outcomes are often associated withactive lupus nephritis with hypertension during thefirst trimester and the subsequent development ofpreeclampsia. Other risk factors include other formsof increased lupus activity at the time of conceptionand during the first trimester, a history of a previouspregnancy loss, and the presence of antiphospholipidantibodies. IUGR occurs even in those mothers withmild disease.29 The neonates of lupus patients arelower in birth weight at every gestational age thannormal controls even when controlling for hyperten-sion and renal disease.30 Lupus may thus have aneffect on fetal growth irrespective of disease activityor complications.

Active lupus nephritis poses the greatest risk to theoutcome of pregnancy in women with lupus.24 Therates of pregnancy loss range from 8% to 36% amongpatients with a history of lupus nephritis before preg-nancy23,31,32 and may reach as high as 52% in womenwith active lupus nephritis during pregnancy.31,33Women with a serum creatinine of 2.8 mg/dL atthe time of conception are at significant risk of pre-eclampsia and have only 20% to 30% pregnancysuccess.34

Neonatal lupus occurs in 3.5% to 8% of lupuspregnancies.20,35 This disease is associated with ma-ternal anti-SS-A (Ro) (anti-52 kd and anti-60 kd) andSS-B (La) (anti-48 kd) antibodies. The most serious

complication, in utero heart block (first-, second-, orthird-degree), occurs in 2% of the fetuses of womenwith anti-SS-A (Ro) antibodies with a recurrence rate of20% in subsequent pregnancies.3639 The most commonmanifestation is a rash that typically develops severalweeks into neonatal life. It is photosensitive, tends toinvolve the face and scalp, and comprises annular orelliptical erythematous plaques. It resolves within thefirst 6 to 8 months of life, coincident with the clearanceof maternal autoantibodies from the infants circulation.Other manifestations include thrombocytopenia, myo-carditis, and hepatitis. Hydroxychloroquine use in preg-nancy may reduce the risk of the cardiac manifestationsof neonatal lupus in mothers with anti-SS-A (Ro)and/or SS-B (La) antibodies.40

PathophysiologyThe potential worsening of lupus during pregnancy

has generally been attributed to the associated alter-ations of sex hormone levels. Estrogen levels in-crease progressively in the maternal circulationduring pregnancy, especially in the third trimester.Estrogens augment immunologic reactivity and havebeen implicated as the cause of the increased risk ofautoimmune disease in women.41 Thus, increasedestrogen levels during pregnancy have been postu-lated to lead to an increased risk of lupus flare.However, such an increase in estrogen levels was notdocumented in a study of 17 pregnant lupus patients,possibly as a result of placental compromise.42 Ad-ditionally, a recent study of transgenic SJL mice witha common gonadal type showed that the XX sexchromosome complement, when compared with thatof the XY chromosome, augments the expression ofSLE.43 Thus, there seems to be a direct role for thesex chromosome complement, independent of thesex hormone milieu, in the female bias noted in lupusand other autoimmune diseases.

Placental pathology underlies the poor gestationaloutcomes of lupus pregnancies. The primary lesionsrelate to the placental vasculature and include decid-ual vasculopathy, decidual thrombi, and extensiveinfarction.44,45 Placental weight is generally reduced.These lesions are evident in lupus pregnanciesirrespective of the presence of antiphospholipid an-tibodies. The placental injury may stem from hyper-coagulability, hypertension, and immune-mediatedvessel damage.

Complement activation may play a key role in thegenesis of preeclampsia, fetal loss, and intrauterinegrowth restriction. The induction of fetal loss andgrowth restriction requires complement activation in


a murine model of antiphospholipid antibody syn-drome.46 Phosphatidylserine, externalized on theouter leaflet of the trophoblast, serves as a target forantiphospholipid antibodies. The binding of theseantibodies to the trophoblast, with subsequent acti-vation of complement, is thought to promote an in-flammatory response with placental injury andadverse effects on the fetus. The complement activa-tion product Bb, detected in the serum of pregnantwomen (with or without lupus) in their first trimester,was a strong predictor of the subsequent develop-ment of preeclampsia.47 Thus, complement activationin early pregnancy of women not affected by lupusmay also play a role in the genesis of preeclampsia.This complement activation may occur as part of amaternal immune-mediated inflammatory responseto paternally derived fetal antigens on the surface oftrophoblasts. Its role in lupus pregnancies, indepen-dent of the presence of antiphospholipid antibodies,is being explored in the PROMISSE study.48

Neonatal lupus results from the transplacental pas-sage of maternal SS-A (Ro) and SS-B (La) antibodiesthat bind to fetal tissue.49 In the heart, these antibod-ies trigger immune-mediated inflammation of theatrioventricular nodal and myocardial tissues. Fibro-sis then develops in the targeted tissues, resulting invarying degrees of heart block and occasionally acardiomyopathy.

Fertility and Contraception in SLE PatientsWomen with SLE have normal fertility, unless they

have advanced renal disease, are amenorrheic as aresult of very active disease, or have received cyclo-phosphamide therapy for more severe organ mani-festations.50 Cyclophosphamide therapy, given eitheras intravenous pulse therapy once a month or orallyon a daily basis, is associated with a high rate ofovarian failure.5153 The prevention of ovarian toxic-ity during intravenous cyclophosphamide therapy isoften attempted with the parallel administration ofgonadotropin-releasing hormone agonists (e.g., leu-prolide, 3.75 mg, 2 weeks before each cyclophosph-amide infusion).54 However, the efficacy of thisapproach has not been established,55 and the initia-tion of these agonists in the follicular phase of themenstrual cycle may increase estrogen levels and therisk for thrombotic events. Egg, embryo, or ovariancryopreservation techniques are additional optionsfor fertility preservation before cytotoxic chemother-apy.56 Because the ovarian stimulation before oocyteretrieval has the potential to increase the risk ofthrombotic events, alternative approaches should

be considered in lupus patients.57,58 Ovulation in-duction with or without in vitro fertilization is anoption for infertile women with SLE. However,such treatment is only applicable to women withintact ovarian function and must be approachedcarefully because it has been associated with anincreased risk of maternal (lupus flare and throm-bosis) and fetal complications.5961

All women with lupus in their reproductive yearsof life should be counseled by their gynecologistsand rheumatologists as to the potential risks of preg-nancy, the need for pregnancy planning, and theefficacy and safety of various modes of contracep-tion. In a recent survey, 23% of women with lupusreported engaging in frequent unprotected inter-course, emphasizing the need for women with lupusto receive counseling about pregnancy planning andappropriate contraception methods.62 Contraceptivecounseling is often not provided to lupus patients atrisk of pregnancy.63

Effective contraception is a key element of preg-nancy planning. The safety of estrogen-containingoral contraceptives in lupus has not been fully estab-lished.64 Two randomized placebo-controlled trialsdid not show an increased rate of flares amongwomen with mild, stable lupus, who were receivingoral contraceptives.65,66 Both studies excluded pa-tients with active lupus, precluding the assessment ofthe safety of these pills in patients with more activedisease. The study of Petri et al examined only com-bined oral contraceptives and precluded patients withantiphospholipid antibodies or a history of thrombo-sis.66 The study of Sanchez-Guerero et al also exam-ined progestogen-only pills and copper intrauterinedevices (IUDs) and included women with antiphos-pholipid antibodies, but not those with antiphospho-lipid syndrome.65 Alternative forms of contraceptionare acceptable. The progesterone-only contraceptive,Depo-Provera, is commonly used in lupus patients,but its use for more than 2 years may increase the riskof osteoporosis. Pregnane progestins may be an ac-ceptable alternative, but are not available in theUnited States and are not marketed as contracep-tives.67 A levonorgestrel-containing IUD is appropri-ate for a woman in a monogamous relationship whois not receiving potent immunosuppressive therapythat might predispose to infection.68 For most lupuspatients, an IUD would be the optimal choice ofcontraception, combining the greatest efficacy withthe least risk. However, IUDs were in use by only 3%of the women in their reproductive age years, attend-ing the lupus clinic at the University of Pittsburgh.62


Preconception Counseling and ManagementPregnancy planning is essential for women with

SLE because the outcomes of such pregnancies arefar better if conception is delayed until the diseasehas been inactive for at least 6 months, and thepatients medication regimen has been adjusted inadvance (later discussion). Before considering preg-nancy, a woman with SLE should meet with both herrheumatologist and a maternal-fetal medicine spe-cialist to be apprised of the risk of both maternal andfetal problems, to receive advise about the advisabil-ity and timing of pregnancy, and receive a specificmanagement plan concerning alterations in their medi-cation regimen (if necessary) and monitoring. The stepsin monitoring and managing pregnancy in lupus pa-tients are summarized in the algorithm (Fig. 1).

Conception should be delayed until the patient hashad quiescent SLE for at least 6 months. A smallminority of lupus patients should be advised not to

conceive; these include those with severe pulmonaryhypertension (estimated systolic pulmonary arterypressure 50 mm Hg), advanced renal insufficiency(creatinine 2.8 mg/dL), severe restrictive lung dis-ease (forced vital capacity 1 L), heart failure, ahistory of severe preeclampsia, or a history withinthe past 6 months of a severe lupus flare, active lupusnephritis, or stroke.26 In the absence of any signs orsymptoms of active SLE, affected patients require nospecific treatment during pregnancy.69 Drug use duringpregnancy is summarized in Table 3. Immunosuppres-sive medications with potential teratogenicity, includ-ing methotrexate, leflunomide, mycophenolate, andcyclophosphamide, should be stopped at least 3 monthsbefore conception. A more rigorous protocol is requiredfor the elimination of leflunomide from the patientbefore attempted conception. This uses oral cholesty-ramine for a period of 11 days, followed by a measure-ment of the blood level. Hydroxychloroquine is safe

Fig. 1. Steps in managing and monitoring a lupus pregnancy.


TABLE 3Use of drugs in lupus pregnancy

DrugFDA Pregnancy-Risk

CategoryMaternal and Fetal Outcomes

Related to Use During PregnancyRecommendation for Use During

Pregnancy

Nonsteroidal anti-inflammatorydrugs (NSAIDs)

C May lead to constriction of fetalductus arteriosus.

Avoid, especially in thirdtrimester

Hydroxychloroquine C Considered safe in doses used totreat lupus

Continue to prevent lupus flares

Nonfluorinated corticosteroids(e.g., prednisone,methylprednisolone)

B Associated with a small risk of oro-facial clefts

Treatment of severe flares

Fluorinated corticosteroids (e.g.,betamethasone anddexamethasone)

C Cross the placenta Use only if intent is to treat fetus

Intravenous pulsemethylprednisolone

B May reach the fetus Treatment of severe flares

Leflunomide X High rate of fetal anomalies in ro-dent studies but 9.3% in registryof rheumatoid arthritis pa-tients (compared with 13% forcontrol RA group and 3.5% forhealthy women)70

Contraindicated

Methotrexate X Estimated congenital anomaly rateof 10%15% with doses used forrheumatic disease.71 Discontinueat least 3 menstrual cycles beforeattempting to conceive

Contraindicated

Cyclophosphamide D Use in first trimester associated withmalformations and miscarriageUse in second and third trimes-ters associated with growthretardation, suppression of fetalhematopoiesis, impaired neuro-logical development.

Use only when mothers life is atrisk and other optionsexhausted.

Cyclosporine C No increased risk of congenitalanomalies. May be associatedwith increased rates of prematu-rity. Often used during pregnancyby women with organ transplants

May be used for treatment oflupus

Azathioprine D May be associated with IUGR Long track record of use in lu-pus pregnancies

Intravenous immunoglobulin C Studies in women with multiplesclerosis and antiphospholipidantibody syndrome have not re-vealed any fetal risk.

May be used for certain lupusmanifestations

Mycophenolate mofetil D Increased risk for congenital anoma-lies, including facial dysmorphiaand malformation of the ears

Contraindicated

Bisphosphonates C Cross the placenta; effects on neo-natal bone metabolism areunknown.

Discontinue before conception

Warfarin X Teratogenic in the first trimester Switch to heparin beforeattempting to conceive

Rituximab C Associated with transient B-cell de-pletion in fetus if administered tomother in second or third trimester

May be used for certain lupusmanifestations

FDA pregnancy-risk categories: A, no risk in adequate controlled trials of pregnant women; B, no risk to fetus demonstrated in animalreproduction studies or adverse effect noted in animal studies but no risk evident in controlled trials of pregnant women; C, no data inhumans are available and animal studies either positive for fetal risk or have not been conducted; D, evidence of human fetal risk exists,but the potential benefit outweighs the potential risk to the fetus; X, risk associated with the use of the drug clearly outweighs anypositive benefit.72,73

IUGR indicates intrauterine growth retardation.


and should be continued during pregnancy. In fact, itsdiscontinuation may place the patient at greater risk ofincreased lupus disease activity during her preg-nancy.74,75 If there is a need for continued therapy witha nonsteroidal immunosuppressive agent, azathioprineis considered the safest to use because the fetal livercannot metabolize azathioprine into its active form.76,77Low-dose maintenance therapy with corticosteroids canbe maintained if needed for disease control, but the doseshould be kept at levels equivalent to prednisone 10 mgdaily or less. Higher corticosteroid doses have beenreported to increase the risk of hypertension, pre-eclampsia, preterm birth, premature rupture ofmembranes, IUGR, and gestational diabetes in lu-pus patients. However, this has not been evident inthe therapy of other conditions and has been assessedto cause a small risk to the developing fetus.72

If a woman with SLE has antiphospholipid anti-bodies, prophylactic treatment is prescribed to pre-vent fetal loss. In a first pregnancy, a woman withantiphospholipid antibodies and with no history ofthrombosis should be treated with low-dose (81 mg)aspirin alone. A woman with antiphospholipid anti-bodies and a history of obstetric complications, suchas late (10 weeks) fetal death, IUGR, or preeclamp-sia should be treated with low-dose aspirin plus low-molecular weight heparin as soon as the pregnancy isdiagnosed. Enoxaparin 30 mg every 12 hours ordalteparin 2500 units every 12 hours is used mostcommonly. Unfractionated heparin (5000 units every12 hours) is an acceptable alternative. Low-molecularweight heparin should be switched to unfraction-ated heparin 4 weeks before the anticipated deliv-ery date. Unfractionated heparin is discontinued atthe onset of labor or 8 hours before planned ce-sarean delivery. Heparin is continued for 6 weekspostpartum. Low-dose aspirin alone may be anoption for a woman with antiphospholipid antibod-ies and recurrent early (10 weeks gestation) mis-carriages,78,79 but many clinicians would prescribeconcomitant heparin.

Diagnostic Testing During PregnancyThe prenatal care of the pregnant woman with SLE

requires close collaboration between the obstetricianand the rheumatologist, and management in a high-risk clinic. Recommendations for monitoring the pa-tient during pregnancy are detailed in Table 4 andFigure 1. The rheumatologist should evaluate thepatient every 46 weeks,25 while the obstetricianshould evaluate her every 4 weeks until 20 weeks ofgestation, then every 2 weeks until 28 weeks, and

then weekly until the time of delivery.80 A lowerfrequency of obstetrical visits is appropriate ifthere are few risk factors for poor obstetrical out-comes.81 The obstetrical visits should include mea-surement of the womans blood pressure, weightgain, uterine size, fetal heart rate, urinalysis, andurine protein-to-creatinine ratio. Additionally, theobstetrician should ask about symptoms of lupusflares at every visit.

At the onset of pregnancy, baseline laboratory testsshould include, in addition to the standard registra-tion labs, a complete blood count and chemistrypanel as well as measures of lupus activity (C3, C4,CH50, anti-dsDNA antibodies), risk for neonatal lu-pus (anti-SS-A (Ro), anti-SS-B (La)), risk for fetalloss (anticardiolipin antibodies, lupus anticoagulant[e.g., Russell Viper Venom Test]), and measures ofrenal function (urinalysis and spot urine protein-to-creatinine ratio). Because an elevation in the serumurate level can be a marker of preeclampsia, a base-line level should be obtained. On a monthly basisthroughout the pregnancy, laboratory studies shouldinclude a complete blood count, chemistry panel withserum urate level, urinalysis, spot urine protein/cre-atinine ratio, C3, C4, CH50, and dsDNA antibodies.If there is protein by urine dipstick and/or an elevatedspot urine protein-to-creatinine ratio, then a 24-hoururine protein-to-creatinine ratio should be mea-sured.82 Additionally, first and/or second trimesteraneuploidy screening should be offered and routine28-week laboratory tests should be drawn.

A sonogram with measurement of crown-rump dis-tance should be performed early in pregnancy to con-firm gestational dating. First trimester nuchal translu-cency screening should be offered. Another sonogramshould be performed at 1620 weeks of gestation tosurvey for fetal anomalies and to monitor fetal growth.Subsequent sonograms should be done at 4 week inter-vals or every 3 weeks in the setting of preeclampsia orsuspected IUGR to monitor fetal growth and measureamniotic fluid volume. The combination of abdominalcircumference 10th percentile and an estimated fetalweight 50th percentile is predictive of IUGR whendetected by an ultrasound examination within 5 weeksof delivery.83 Uterine artery Doppler studies serve todefine the adequacy of uteroplacental blood flow andmay have utility as a predictor of preeclampsia.84 Thefirst such study may be done around the 20th week ofgestation, and if abnormal, repeated 4 weeks later.85

Fetal surveillance tests should be started at 2628weeks and continued weekly until birth. These in-clude the nonstress test (NST), which can begin at 28weeks, the biophysical profile, which can begin at 26


weeks without the NST, and fetal umbilical arteryDoppler velocimetry, which can begin at 26 weeks.The NST evaluates the fetal heart rate response tofetal motion. The criteria for an acceleration vary bygestational age. Between 28 and 32 weeks, it is 10beats per minute lasting 10 seconds. After 32 weeks,it is 15 beats per minute lasting 15 seconds. Thebiophysical profile provides a score of fetal wellbeing and includes a NST as well as ultrasoundassessments of fetal breathing motion, fetal body orlimb movement, fetal tone and posture, and determi-nation of an amniotic fluid pocket free of umbilicalcord that is greater than 2 cm in depth. It requires upto a 30-minute real-time 2-dimensional ultrasound ex-amination of the fetus. Abnormal umbilical and uterinearterial blood flow assessed with Doppler velocimetryduring the second trimester may be predictive of pre-

eclampsia and IUGR.81,86,87 Detection of IUGR withthese fetal surveillance tests should prompt closer mon-itoring and consideration of early delivery.

In utero heart block develops as a manifestation ofneonatal lupus after 16 weeks of gestation. Most casesoccur between 16 and 24 weeks, but some occur as lateas 3840 weeks. Because the early recognition of heartblock in the fetus may allow for therapeutic interven-tion, close monitoring of at-risk fetuses is mandatory.The fetal heart rhythm should be monitored by m-modeechocardiography weekly from 16 weeks onward.80

Differential Diagnosis of Medical ComplicationsDuring a Lupus Pregnancy

The close collaboration of a maternal-fetal medi-cine specialist and a rheumatologist is a key to the

TABLE 4Monitoring of the pregnant lupus patient

Type of Monitoring Timing During Gestation Testing

Clinic visit: obstetrician Conception to 20 weeks: monthly2028 weeks: every 2 weeks28 weeks to delivery: every week

Standard prenatal visitStandard registration and 28 week labsAssessment at each visit for signs and symptomsof lupus

Clinic visit: rheumatologistLaboratory

Monthly Clinical assessmentInitial assessment Complete blood count

Chemistry panelSerum urate levelUrinalysisSpot or 24-h urine protein-to-creatinine ratioC3, C4, CH50

dsDNA antibodiesSS-A and SS-B antibodiesCardiolipin antibodiesLupus anticoagulant assay (e.g., Russell vipervenom test)

Monthly Complete blood countChemistry panelSerum urate levelUrinalysisC3, C4, CH50dsDNA antibodies24-h or spot urine protein to creatinine ratio if urinedipstick positive

Sonography 713 wk1620 wkThen every 4 weeks (or every 3weeks in setting of preeclamp-sia or suspected IUGR)

Assessment of crown-rump lengthFetal anatomy scanMonitoring for fetal growth disturbances andoligohydramnios

Fetal surveillance At 2628 weeks, and then weeklyuntil birth

Nonstress test to start at 28 weeksBiophysical profile to start at 26 weeksFetal umbilical artery Doppler velocimetry to start at26 weeks

Fetal m-mode echocardiography(in setting of maternal SS-A(Ro) and/or SS-B (La)antibodies)

Weekly beginning at 16 weeksand continuing till delivery

Assessment for heart block

IUGR indicates intrauterine growth retardation.


differential diagnosis of medical complications thatmay arise in the course of a lupus pregnancy. Theseinclude lupus flares with or without glomerulone-phritis, hypertension, preeclampsia, and the HELLP(hemolysis, elevated liver enzymes, and low plateletcounts) syndrome. The availability of serial labora-tory tests (such as serum urate, complement anddsDNA antibody levels, obtained at booking andmonthly during the pregnancy) greatly facilitates thisdiagnostic process.

The recognition of a lupus flare during pregnancymay be difficult because the signs and symp-toms may mimic those of normal pregnancy. Suchflares may occur at any time during pregnancy or inthe immediate postpartum period. However, severalprospective studies have suggested that the frequencyof these flares may be lowest in the third trimes-ter.11,12,88 Severe fatigue, facial and palmar ery-thema, melasma, postpartum hair loss, dyspnea,arthralgias, and headaches frequently accompanynormal pregnancy (Table 2).89 Bland joint effusionsoccur in late pregnancy.90 In a normal pregnancy, thematernal blood volume increases by 50%, and the redcell mass increases by 35%.91 As a result of thehemodilution, a mild anemia is present in up to 50%and mild thrombocytopenia is present in up to 8%.19Renal blood flow and the glomerular filtration rateincrease by more than 50% to accommodate theincreased blood volume, resulting in a decreasedserum creatinine level.34 A serum creatinine level of0.8 mg/dL and blood urea nitrogen (BUN) level of13 mg/dL are considered indicative of renal im-pairment in pregnancy.91 A creatinine level that re-mains stable throughout pregnancy and does not de-crease can also be a sign of renal insufficiency. Theincreased renal blood flow results in increased tubu-lar flow and may increase urine protein spillage.Levels of proteinuria up to 300 mg/d are considerednormal in pregnancy. In women with prior renaldamage from lupus nephritis, the degree of urineprotein loss may increase. However, a doubling inthe amount of the baseline urine protein should be acause for concern. Hepatic protein synthesis alsoincreases in pregnancy, and this can result in higherlevels of the serum complement components as wellas fibrinogen.92,93 The latter may lead to a substantialincrease in the erythrocyte sedimentation rate in anormal pregnancy.

The differentiation of preeclampsia from lupus glo-merulonephritis is notoriously difficult. Both maypresent with increasing proteinuria, hypertension,lower extremity edema, deterioration in renal func-tion, and thrombocytopenia. In addition, the 2 con-

ditions may coexist. Preeclampsia is defined by thepresence of a blood pressure 140/90 and protein-uria 0.3 g in a 24-hour urine specimen detected forthe first time after 20 weeks of gestation. However, apregnant woman with more severe lupus may havehypertension and/or proteinuria in the first half ofpregnancy, thereby obscuring early recognition ofthis complication. The risk of preeclampsia is higherin any woman with a prior or family history ofpreeclampsia, body mass index of 35 kg/m2 orhigher, antiphospholipid antibodies, and/or preexist-ing diabetes, renal disease, or hypertension.94 Ele-vated serum levels of soluble FMS-like tyrosinekinase 1 (FLT-1, also known as vascular endothelialgrowth factor receptor-1) at 2232 weeks of gesta-tion are associated with the subsequent developmentof preeclampsia in SLE.95 Features of preeclampsia,which serve to distinguish it from active lupus ne-phritis are summarized in Table 5 and include aserum uric acid 5.5 mg/dL, a urine calcium level of195 mg/d,96 and rising liver enzyme levels. Uterineartery Doppler ultrasonography may help define in-adequate uteroplacental blood flow in preeclampsia.An increased pulsatility index with notching predictspreeclampsia in high-risk patients with a positivelikelihood ratio of 21, but is less accurate in cases ofsevere preeclampsia.84

Findings indicative of active lupus nephritis in-clude a rise in dsDNA antibody titer, low or droppingcomplement levels, clinical evidence of lupus flare inother organs, and an active urinary sediment. Duringnormal pregnancy, there is a 10% to 50% increase inthe level of the complement components, probably asa result of increased hepatic synthesis. Thus, a lupusflare during pregnancy may be associated with com-plement levels that have dropped, but still remain inthe normal range. Accordingly, a 25% or moredrop in serum complement levels during pregnancycan be considered indicative of a lupus flare.89 An

TABLE 5Differentiation of active lupus nephritis from preeclampsia

Active Lupus Nephritis Preeclampsia

Hypertension Onset before 20 weeks Onset after 20weeks

Proteinuria 300 mg/d 300 mg/dLUrinary sediment Active InactiveUric acid 5.5 mg/dL 5.5 mg/dLDNA antibody levels Rising Stable or

negative24-h urine calcium 195 mg/d 195 mg/dComplement levels 25% drop NormalSoluble FMS-liketyrosine kinase 1

Normal Elevated


increased level of complement split products, such asC3a, may also indicate a flare, but measurement ofsuch split products is not routinely available. A renalbiopsy may be needed to assist in the differentia-tion,97 although the risk of bleeding after the biopsyis higher in pregnancy. On occasion, delivery or atrial of empiric therapy is needed to resolve thisdiagnostic challenge.

Several forms of microangiopathy may complicatepregnancy in lupus, and their differentiation may bedifficult (Table 6), in part because of the potentialoverlap of these conditions. However, such differen-tiation of these microangiopathies is critical becausethe management will vary depending on the type(vide infra). The HELLP syndrome is a complicationof pregnancy, characterized by microangiopathic he-molytic anemia, thrombocytopenia, and liver injury.It occurs in 0.5% to 0.9% of all pregnancies and in10% to 20% of cases of severe preeclampsia,102 witha peak frequency between the 27th and 37th weeks ofgestation. It may develop postpartum in 30% ofcases. Acute fatty liver of pregnancy is a rare com-plication of pregnancy, which occurs in the thirdtrimester and is characterized by a conjugated hyper-bilirubinemia, elevated hepatic transaminases, andevidence of disseminated intravascular coagulation.

The occasional presence of hypertension, proteinuria,and thrombocytopenia may lead to confusion withpreeclampsia and/or the HELLP syndrome. How-ever, the presence of hypoglycemia would favoracute fatty liver. Thrombotic thrombocytopenicpurpura is characterized by microangiopathic hemo-lytic anemia, severe thrombocytopenia, fever, andcentral nervous system and renal disease. It mayoccur rarely in conjunction with systemic lupus.103Lupus patients with high titers of antiphospholipidantibodies are at risk of thrombotic disease, includingthrombotic microangiopathies affecting the kidneys,hearts, and lung.104 Pregnant lupus patients with an-tiphospholipid antibodies may also develop hepaticinfarcts, often in association with the HELLP syn-drome.104 Catastrophic antiphospholipid antibodysyndrome (CAPS) is a rare entity, characterized byan acute thrombotic microangiopathy affecting thesmall vessels of at least 3 organ systems. In a seriesof 15 patients who developed CAPS in associationwith pregnancy, 7 had systemic lupus. The CAPSoccurred during pregnancy in 7 patients, during thepuerperium in 6 patients, and 2 days after a dilatationand curettage for fetal death at 18 weeks of gestationin 1 patient.98 The kidneys, lungs, and brain were the

TABLE 6Differentiation of microangiopathies in lupus pregnancy

Features* HELLP AFLP TTP CAPS

Usual time of onset 34 weeks, includ-ing postpartum

27 weeks Late second to earlythird trimester

Second or third trimesteror postpartum

Fever Absent 25%32% 20%50% 10%Abdominal pain and othersymptoms

60%80% 35%50% Common Common

Jaundice 5%10% 40%90% Rare Not reportedCentral nervous systeminvolvement

40%60% 30%40% 66% 60%

Lung involvement Rare Rare Rare 73%Elevated liver enzymes 100% 100% Usually mild Not reportedElevated bilirubin 50%60% 100% 100% Not reportedHepatic infarcts With antiphospholipid

antibodiesNot reported

Hypertension 80% 50% 20%75% Not reportedProteinuria 90%95% 30%50% Common CommonDIC 5%56% 73% Rare 20%Microangiopathic hemolyticanemia

50100% 1520% 100% With concomitant HELLP

Thrombocytopenia Usually 20,000 None initially Usually 20,000 60%Hypoglycemia Absent Common Absent AbsentADAMTS-13 5% Absent Absent 33%100% Not reported

Adapted from references.98101Hemolysis, elevated liver enzymes, and low platelets.Acute fatty liver of pregnancy.Thrombotic thrombocytopenic purpura.Catastrophic antiphospholipid antibody syndrome.


most commonly affected organs. The HELLP syn-drome occurred in 8 of these patients.

Therapy of Lupus Flares During PregnancyThe management of lupus flares during pregnancy

depends on the severity and type of organ involve-ment. Joint pain can be managed with acetamino-phen. NSAIDs should be avoided during pregnancy.Their use has been reported to cause reversible oli-gohydramnios as a result of decreased fetal renalexcretion, prolongation of labor, and premature clo-sure of the patent ductus arteriosus.77 Hydroxychlo-roquine is generally effective for arthritis and skinmanifestations of lupus. As noted earlier, this drugdecreases the incidence of flares and should be main-tained throughout pregnancy, particularly if it wasbeing used before conception.75

Lupus manifestations that are not adequately con-trolled with acetaminophen and hydroxychloroquine re-quire corticosteroids. Anemia (hemoglobin 8 g/dL),sustained fever (38.5C), and low serum albuminlevels (3 g/dL) threaten the developing fetus anddemand more aggressive therapy.105 Prednisone is thepreferred corticosteroid because it is largely inactivatedby the placenta. The fluorinated glucocorticoids, dexa-methasone, and betamethasone, easily cross the pla-centa, and therefore should only be used if there isintent to treat the fetus, such as treating in utero heartblock or inducing fetal lung maturation before pretermdelivery. Low-dose prednisone (20 mg/d) can be usedto treat mild lupus activity, and higher doses, includingpulse intravenous methylprednisolone, can be used totreat more severe lupus activity.106 There may be a2-fold increased risk for cleft lip or palate with systemiccorticosteroid use in the first trimester, although theabsolute risk remains low (approximately 2/1000 babieswith corticosteroid exposure).107,108

Moderate to severe lupus activity may requirelong-term management with a second-line agent inaddition to prednisone. This often facilitates taperingthe prednisone to a lower dose and is thus steroid-sparing. Azathioprine is the preferred drug in thiscategory, although its use during pregnancy has beenassociated with IUGR and an increased rate of preg-nancy loss.76,109 Cyclosporine is safe for the fetus andcan be used to treat renal disease during pregnancy,but poses risks of maternal nephrotoxicity. Intrave-nous immunoglobulin has an accepted indication forthe treatment of thrombocytopenia during pregnancy.Mycophenolate is teratogenic and should be avoidedduring pregnancy.110,111 Cyclophosphamide is occa-sionally used for severe manifestations of lupus that

have not responded to other therapies, with the un-derstanding that the fetus may not survive withouttreatment of the mother. Its use in the first trimesteris associated with fetal malformation and in the sec-ond and third trimesters with growth retardation andsuppression of fetal hematopoiesis.110

The treatment of chronic hypertension in preg-nancy is reserved for patients with diastolic bloodpressures greater than 90 mm Hg. Methyldopa andlabetalol are the preferred agents, but nifedipine canalso be used. Angiotensin-converting enzyme (ACE)inhibitors and angiotensin receptor blockers are con-traindicated in pregnancy because of their associationwith irreversible renal damage in the fetus and fetalloss. Diuretics are usually avoided because they candecrease intravascular volume. Furosemide is theloop diuretic with the best track record in the man-agement of chronic renal failure in pregnancy.

The management of microangiopathy in a lupuspregnancy varies by diagnosis and gestational age.The HELLP syndrome should be managed with im-mediate delivery at 34 weeks of gestation or later.112At 27 to 34 weeks of gestation, delivery should bewithin 48 hours, but an initial attempt should bemade to stabilize the patient in a tertiary care unit,with close maternal and fetal surveillance, and toadminister corticosteroids (e.g., 2 doses of 12 mgbetamethasone 24 hours apart or 6 mg of dexameth-asone 12 hours apart) to promote fetal lung matura-tion. Before 27 weeks of gestation, an attempt tomanage the patient expectantly for more than 4872hours may be considered, but immediate delivery isindicated if the condition of the mother or fetusdeteriorates. Corticosteroids do not seem to reducematernal morbidity in the HELLP syndrome, butmay serve to increase the platelet count and allowvaginal delivery. Women with acute fatty liver ofpregnancy require delivery after stabilization, withadministration of fresh frozen plasma and otherblood products for those with bleeding and/or severecoagulopathies.99 Thrombotic thrombocytopenicpurpura is treated with plasma exchange or plas-mapheresis.113 Catastrophic antiphospholipid syn-drome that develops during pregnancy is managedwith prompt delivery. Before delivery, heparin anti-coagulation should be maintained and fetal lung mat-uration should be promoted, if necessary. High-dosecorticosteroids, intravenous immunoglobulin ther-apy, and plasma exchange were commonly adminis-tered in the reported cases of this rare entity.98

The optimal treatment for in utero heart block in amother with anti-SS-A (Ro) or SS-B (La) antibodieshas not been established. A retrospective case-control


study has suggested that hydroxychloroquine may re-duce the risk of its occurrence.40 In 2 recent trials,intravenous immunoglobulin therapy did not reduce theexpected 20% incidence of fetal heart block in high-riskpregnant women with a previous pregnancy compli-cated by this disease.114,115 The initiation of maternaloral dexamethasone therapy at the first indication ofheart block is recommended. In a recent retrospectivereview of 37 consecutive cases of fetal complete atrio-ventricular heart block observed between 1990 and2003, Jaeggi et al noted a significant reduction in mor-bidity and improved outcome for those fetuses andneonates treated routinely after 1996 with maternaldexamethasone (48 mg/d for 2 weeks, followedby 4 mg/d) and a beta- sympathomimetic agent (ifthe average heart rate declined below 55 bpm)compared with those who did not routinely receivetransplacental therapy between 1990 and 1996.116 How-ever long-term use of a beta-sympathomimetic agent at thelevel that increases fetal heart rate may be associated withadverse neurobehavioral outcomes in the infant and iscontraindicated.117

SummaryThe majority of lupus pregnancies have good out-

comes for both the mother and the fetus, but theseoutcomes can only be achieved with careful preconcep-tion planning, assessment of risk factors, and closemanagement and monitoring of both the disease and thehealth of the fetus. Women with quiescent lupus shouldnot be discouraged from becoming pregnant, but willstill need to be monitored closely during pregnancy.The optimal management of the pregnant woman withlupus should be in a high-risk clinic and involve theclose collaboration of the obstetrician or maternal-fetalmedicine specialist with a rheumatologist.

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