Version May 2024
INTRODUCTION — Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. Fertility in SLE patients does not appear to be altered by disease itself; however, a decrease in ovarian reserve can occur in women exposed to cyclophosphamide. This topic will use the term “women” to refer to both women and birthing people. We encourage the reader to consider the specific counseling at treatment needs of transgender and gender-expansive individuals.
Pregnancy in women with SLE carries a higher maternal and fetal risk compared with pregnancy in healthy women. The prognosis for both mother and child is best when SLE has been quiescent for at least six months prior to the pregnancy. Disease flares during SLE pregnancy pose challenges with respect to distinguishing physiologic changes related to pregnancy from disease-related manifestations. Thus, a multidisciplinary approach with close medical, obstetric, and neonatal monitoring is necessary to optimize both maternal and fetal outcomes.
This topic review will discuss the major risks associated with pregnancy in SLE patients, as well as management recommendations. Issues related to the use of contraception in women with SLE are presented separately (see "Approach to contraception in women with systemic lupus erythematosus"). Issues related to pregnancy in patients with impaired renal function or with antiphospholipid syndrome (APS) are also presented elsewhere. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
PREGNANCY PLANNING — Ideally, disease should be quiescent for six months on medications compatible with pregnancy prior to systemic lupus erythematosus (SLE) patients attempting conception. Active SLE at the time of conception is a strong predictor of adverse maternal and obstetrical outcomes [1-3]. In spite of this risk, the majority of such pregnancies still result in live births. The following studies are illustrative:
●The largest observational study, including 385 pregnant lupus patients (49 percent non-Hispanic White) with inactive or mild or moderate disease at conception, found 81 percent of subjects had uncomplicated pregnancies [4]. Adverse pregnancy outcomes were defined as fetal or neonatal death, birth before 36 weeks gestation, placental insufficiency, hypertension, preeclampsia, and birthweight less than the fifth percentile. Among women without risk factors including antihypertensive use, thrombocytopenia, and presence of lupus anticoagulant (LA), the rate of adverse pregnancy outcomes was 7.8 percent. Adverse pregnancy rates in those with risk factors were as high as 58 percent, and fetal and neonatal mortality was 22 percent. However, the study population was limited as it excluded women with high disease activity, active lupus nephritis, uncontrolled hypertension, and diabetes.
●A study of 267 pregnancies in a cohort of lupus patients found that women with high disease activity compared with low disease activity in the first and second trimesters showed a threefold increase in pregnancy loss (miscarriages and perinatal mortality) [1]. However, overall there was no statistically significant difference in the number of live births between the women with high disease activity compared with low disease activity (77 percent versus 88 percent, respectively).
Our approach to pregnancy planning and management in SLE is generally consistent with recommendations developed by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [5] and the American College of Rheumatology (ACR) [6].
Preconception evaluation — A preconception assessment is essential in women with SLE to determine whether pregnancy may pose an unacceptably high maternal or fetal risk, to initiate interventions to optimize disease activity, and to adjust medications to those that are least harmful to the fetus.
Women should be advised that discontinuation of medications used to control disease activity increases the risk of lupus flare and pregnancy complications. Ideally, women considering conception should be maintained on medications that are compatible with pregnancy and should continue these medications in pregnancy. Clinical features specific to pregnancy in the setting of SLE are discussed below. A more general discussion on preconception care and risk assessment in all women is presented separately. (See "The preconception office visit".)
Risk assessment — The preconception evaluation in women with SLE should include an assessment of disease activity and major organ involvement, as well as hypercoagulability or concurrent medical disorders that may impact pregnancy. Previous obstetric outcomes should be reviewed, with particular attention paid to history of small for gestational age fetus, preeclampsia, stillbirth, miscarriage, and preterm birth. An approach to the assessment of disease activity and severity of SLE is discussed separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Assessment of disease activity'.)
Patients with evidence of active SLE, especially lupus nephritis, should be advised to defer pregnancy until the disease is well controlled for at least six months. For those with renal insufficiency, counseling should include an assessment of the risk of temporary or permanent decline in renal function. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)
Increased severity of maternal disease generally correlates with higher maternal and fetal risk in pregnancy. Thus, recent stroke, cardiac involvement, pulmonary hypertension, severe interstitial lung disease, and advanced renal insufficiency can portend poor pregnancy outcome for both the mother and fetus. Women with these or other worrisome medical conditions should be counseled carefully by a Maternal Fetal Medicine specialist as to their individual risk profile, with clear discussion of the morbidity and mortality risks to both mother and fetus associated with pregnancy. Alternatives such as gestational carriers and adoption should be presented. Should they elect to pursue pregnancy, they should be followed in a multidisciplinary fashion in a high-risk center [7,8].
Antibodies to Ro/La should be assessed prior to pregnancy, as these antibodies may predispose to neonatal lupus (NL) [7]. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)
Additionally, one should test for antiphospholipid antibodies (aPLs), although, in the absence of clinical manifestations of antiphospholipid syndrome (APS), positive aPLs can be difficult to interpret. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)
Specific laboratory testing — In addition to routine preconception labs (see "The preconception office visit", section on 'Laboratory assessment'), the following should be reviewed during the preconception evaluation (see "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Laboratory evaluation'):
●Anti-Ro/SSA and anti-La/SSB antibodies
●Renal function (creatinine, urinalysis with urine sediment, spot urine protein/creatinine ratio)
●Complete blood count (CBC)
●Liver function tests
●Anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies
●Complement (CH50, or C3 and C4)
As discussed above, one should test for aPLs (LA, immunoglobulin G [IgG] and IgM anticardiolipin [aCL] antibodies, and IgG and IgM anti-beta2 glycoprotein I [anti-beta2GPI] antibodies). (See 'Risk assessment' above.)
Medications — Medications must be reviewed and adjusted prior to conception with the goal of maintaining disease control with medications with the best safety profile during pregnancy. Although some medications used to treat SLE are potentially harmful or contraindicated during pregnancy, many are safe. Information regarding the use of immunosuppressive agents in pregnant patients with SLE can be found below, and in a separate topic (see "Safety of rheumatic disease medication use during pregnancy and lactation"). The most commonly used medications used to treat patients with SLE are reviewed briefly below.
Recommended during pregnancy
●Hydroxychloroquine – For most pregnant women with SLE, we suggest continuation of hydroxychloroquine (HCQ) to reduce the risk of SLE flares. Several studies have demonstrated fewer disease flares and better outcomes in patients continuing HCQ during pregnancy [9-15]. As an example, a randomized trial including 20 consecutive pregnant patients with SLE found no differences between disease flare rates, but patients in the HCQ group were able to reduce the prednisone dose [12]. In addition, the HCQ group had significantly lower disease activity scores after delivery compared with the placebo group. Findings from a larger prospective study with 257 pregnancies in 197 women also found that discontinuation of HCQ during pregnancy was associated with a higher rate of flare compared with women who either continued HCQ during pregnancy or never took it [9]. In addition, high disease activity occurred in twice as many pregnancies in which HCQ was stopped compared with those who continued taking HCQ. While HCQ has long been considered safe for use in pregnancy, one study showed a small increased risk of congenital anomalies (odds ratio [OR] 1.3) with a daily dose over 400 mg daily in the first trimester, though the association was not seen when the dose was under 400 mg [15,16]. However, no specific pattern of anomaly was identified, and other confounders such as other medications, alcohol, smoking, and illicit drug use were not accounted for in this study [17]. A more detailed discussion regarding the relative safety of HCQ during pregnancy can be found elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine'.)
Additionally, some data suggest a decrease in occurrence of congenital heart block in at-risk fetuses of mothers with anti-Ro/SSA and anti-La/SSB antibodies exposed to HCQ [18]. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Heart block'.)
●Low-dose aspirin – We initiate low-dose aspirin in all women with SLE, unless contraindicated, starting from approximately 12 weeks gestation, to reduce the risk of preeclampsia and its sequelae (eg, fetal growth restriction), regardless of the presence of aPLs. This approach is consistent with the recommendation by the United States Preventive Services Task Force to use low-dose aspirin in women at high-risk of developing preeclampsia, which includes women with SLE [19]. Recommendations for prophylactic use of low-dose aspirin during pregnancy for prevention of preeclampsia are discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs' and "Preeclampsia: Prevention".)
Selective use allowed during pregnancy — The following drugs have a reasonable safety profile during pregnancy, but certain limitations apply to their use. Nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, azathioprine, and some antihypertensive medications are included in this category. They each have a small risk of causing fetal harm, but their use may be acceptable if needed to control manifestations of SLE during pregnancy.
●Nonsteroidal antiinflammatory drugs – NSAID use is not associated with congenital anomalies. There is conflicting evidence as to whether exposure to NSAIDs during the first trimester increases the risk of spontaneous abortion; in women having difficulty conceiving, one can consider avoiding these medications during the first trimester. There is a small increased risk of oligohydramnios when NSAIDs are used beyond 20 weeks; the US Food and Drug Administration (FDA) recommends that the lowest dose and shortest duration of NSAID be used between 20 and 30 weeks of gestation. Use of NSAIDs after 30 weeks of gestation may cause premature closure of the ductus arteriosus, as well as other complications, and should be avoided altogether from the third trimester on. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)
●Glucocorticoids – Glucocorticoids are used for a wide range of maternal diseases in pregnancy. We suggest control of disease with the lowest possible dose of prednisone, ideally less than 10 mg/day. While there were some reports of glucocorticoid use during the first trimester being associated with cleft lip, with and without cleft palate, subsequent studies have failed to consistently demonstrate an increased risk of this malformation. Maternal and fetal adverse effects of glucocorticoids are discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)
●Azathioprine – Azathioprine is compatible with pregnancy, but doses should not exceed 2 mg/kg/day. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)
●Cyclosporine – Limited observations suggest that children exposed in utero to cyclosporine have normal renal function and blood pressure. The manufacturer suggests that use in pregnancy should be limited to when maternal benefit outweighs fetal risk. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclosporine'.)
●Tacrolimus – Tacrolimus has been used as induction and maintenance therapy in SLE nephritis [20]. A small case series of nine pregnant lupus patients reported successful disease maintenance or control of lupus nephritis flares with tacrolimus [21]. A subsequent series of 54 deliveries in 40 patients with SLE found that pregnancy outcomes were similar between pregnancies that were tacrolimus versus non-tacrolimus exposed [22]. Tacrolimus use has been reported in over 200 pregnancies for varying indications. Overall pregnancy outcomes were normal; however, hypertension, preeclampsia, and preterm birth occurred more frequently than would be expected. A causal relationship between tacrolimus use and congenital anomaly has not been found, though the number of fetuses exposed in utero has been small. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tacrolimus'.)
●Antihypertensive medications – Methyldopa, labetalol, nifedipine, and hydralazine are the most commonly used antihypertensives in pregnancy. By comparison, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are contraindicated during pregnancy due to fetal risks associated with their use. Diuretics may be used with caution. Nitroprusside is the agent of last resort for urgent control of refractory severe hypertension; its use should be limited to a short period of time in an emergency situation. (See "Treatment of hypertension in pregnant and postpartum patients" and "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
Selective use with caution in pregnancy
●Biologic medications – Data regarding the use of biologic medications such as the B-cell depleting antibody, rituximab, or the BAFF inhibitor, belimumab, during pregnancy are limited. Given that IgG does not cross the placenta in significant amounts until week 15 of gestation, we continue these medications through conception (ie, the first missed menstrual period in a woman with regular cycles). In our practice, while we do not encourage rituximab use if there is another option, we will continue to support its use throughout pregnancy as preferable to a flare of SLE. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)
Contraindicated in pregnancy
●Cyclophosphamide – Cyclophosphamide is associated with congenital (or fetal) malformations and should be avoided during the first 10 weeks of gestation, when the fetus is most susceptible to teratogens (figure 1). However, in life-threatening clinical situations, this medication has been used in late pregnancy. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)
●Mycophenolate mofetil – Congenital anomalies have been reported in infants exposed to mycophenolate mofetil during pregnancy. This medication should be avoided during pregnancy. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)
Azathioprine or tacrolimus can be substituted for mycophenolate prior to and during pregnancy, or, alternatively, glucocorticoids may be used at the lowest dose that controls disease activity. Ideally, this transition in medication should take place four to six months prior to conception. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)
●Methotrexate – Methotrexate is teratogenic and should not be used during pregnancy. It should be discontinued one to three months prior to conception. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)
●Leflunomide – While not a definitive teratogen, this medication should be avoided during pregnancy. Patients taking this medication who would like to conceive should do a cholestyramine washout until blood levels are undetectable. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)
Ideally, conception should only be attempted in a state of disease remission or stable disease on medications compatible with pregnancy. However, if pregnancy occurs during a period of disease activity, medications will need to be adjusted for fetal and maternal safety. Active disease is suggested by rising dsDNA, decreased complement levels, and increases in disease activity scales such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and physician global assessment.
SPECIFIC CONSIDERATIONS DURING PREGNANCY
Exacerbation of SLE — Although it is generally accepted that pregnancy and the postpartum period are associated with a higher rate of systemic lupus erythematosus (SLE) disease flares, widely variable rates have been reported ranging from 25 to 60 percent [3,8,23,24]. Some of this variation may be attributed to the heterogeneous study designs, patient, and control groups, as well as different definitions of flares used in the studies. For comparison, the background rate of flare of SLE is approximately 30 percent per year.
The following factors are associated with an increased risk of SLE flare during pregnancy [1,9,25-27]:
●Active disease during the six months prior to conception
●A history of lupus nephritis
●Discontinuation of hydroxychloroquine (HCQ) or other medication
●Primigravidas
Low C4 may also be a risk factor for SLE flare during pregnancy. In a multivariate analysis of 246 pregnancies in 172 patients with SLE, a low C4 prior to conception was associated with an increased risk of relapse during pregnancy (76 versus 23 percent, odds ratio [OR] 13.8) [28]. Patients who experienced flare during pregnancy were more likely to have a low C4 during each trimester compared with patients who did not flare. However, there was considerable overlap in the complement levels between those who flared and those who did not, suggesting that while monitoring changes in complement levels in an individual patient over the course of pregnancy may be useful, an absolute level of concerning complement level has not been established. (See 'Monitoring SLE activity' below.)
Impact of lupus on pregnancy — Pregnancy in the setting of SLE is associated with a higher risk of complications compared with healthy women. The largest study to evaluate maternal and pregnancy complications associated with SLE included 13,555 pregnancies [29]. Women with SLE also had a two- to fourfold increased rate of obstetric complications including preterm labor, unplanned cesarean delivery, fetal growth restriction, preeclampsia, and eclampsia. Patients with SLE also had a significantly higher risk of thrombosis, infection, thrombocytopenia, and transfusion. This study also reported that maternal mortality was 20-fold higher among women with SLE; however, mortality amongst similar-aged SLE patients who were not pregnant was even higher. Another study found that increased rates of hypertension during pregnancy, preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism were all more frequent in women with SLE compared with pregnancies of women without SLE [30]. A large population-based study suggested that pregnancy complications including mortality rates are decreasing in SLE, although still higher compared with those without SLE [31].
Several predictors of adverse pregnancy outcomes among women with SLE have been identified and include active disease, use of antihypertensives, prior lupus nephritis, the presence of antiphospholipid antibodies (aPLs), and thrombocytopenia [4,32]. Moreover, primigravidas are at higher risk for pregnancy complications [27].
Preeclampsia — Preeclampsia is one of the most frequent complications of pregnancy in SLE, occurring in 16 to 30 percent of women with SLE, compared with 4.6 percent of pregnancies in the general obstetric population [3,33-35]. Risk factors for preeclampsia in women with SLE are the same as those in healthy women and are discussed separately (see "Preeclampsia: Clinical features and diagnosis", section on 'Risk factors'). Additional risk factors for preeclampsia that are specific to SLE patients include an active or prior history of lupus nephritis, declining complement levels, and thrombocytopenia. The data on whether aPLs predispose to preeclampsia is unclear, although some studies suggest an association [33,36].
Preterm birth — Preterm birth is the most common obstetric complication in women with SLE. Rates of preterm birth from 15 to 50 percent are reported, with increased incidence in women with lupus nephritis or high disease activity. This compares with 12 percent of pregnancies in the general United States obstetric population [1,26,33]. In women with SLE, the majority of preterm births are medically indicated due to preeclampsia or maternal SLE activity [37]. The presence of lupus nephritis and active disease are the strongest predictors for early delivery [23,34,38]. The rates of preterm birth are likely better among women without such risk factors [4].
Fetal complications — Fetal complications during pregnancy in patients with SLE include fetal loss, growth restriction, neonatal lupus (NL) syndromes, and complications of prematurity.
●Fetal loss and infant death – Historically, significantly elevated rates of both early and late pregnancy loss have been seen in women with SLE. Many contemporary studies group all losses from the embryonic stage (up to 9 to 10 weeks gestation) to stillbirth (fetal death at 20 or more weeks) under the term “fetal loss,” making it challenging to interpret the risk of early miscarriage versus later fetal death.
The effect of SLE on embryonic losses is controversial, with a possible slight increase in risk. Women with SLE are at increased risk of fetal death beyond 10 weeks, particularly in the presence of active SLE, lupus nephritis, and antiphospholipid syndrome (APS). Overall, fetal loss rates amongst SLE patients have been declining over the last decades, with increased rates of livebirths [1,38,39]. A large observational cohort of patients with inactive lupus or mild to moderate disease activity at conception found that 5 percent of pregnancies ended in fetal or neonatal death [4]. For comparison, the population risk of miscarriage at less than 20 weeks gestation ranges from 8 to 20 percent [40,41].
One large population-based retrospective cohort study of infants born between 1987 and 2014 described increased infant mortality for children born to patients with SLE, although the absolute risk was low and likely related to complications of prematurity [42]. Death at less than two years of age occurred in 1.1 percent of children born to patients with SLE versus 0.6 percent of children born to women without SLE or rheumatoid arthritis (relative risk [RR] 2.11, 95% CI 1.21-3.67).
●Fetal growth restriction and low birthweight – About 10 to 30 percent of pregnancies in women with SLE are complicated by fetal growth restriction and small-for-gestational-age babies compared with about 10 percent of pregnancies in the general obstetric population [23,26,43]. As with the other complications, the risk is higher in the presence of active disease, hypertension, and lupus nephritis. Lower birth weight at every gestational age is also more prevalent in women with SLE [30,42].
●Neonatal lupus – NL is a passively transferred autoimmune disease that occurs in some babies born to mothers with anti-Ro/SSA or anti-La/SSB antibodies, who may or may not carry the diagnosis of SLE or Sjögren’s. The major manifestations of NL are either cutaneous or cardiac, but other manifestations of NL include hematologic and hepatic abnormalities.
The most serious complication in the neonate is congenital complete heart block, which occurs in approximately 2 percent of children born to primigravid women with anti-Ro/SSA antibodies [44]. In women who have had a child with congenital complete heart block, the risk of complete heart block increases to approximately 16 to 18 percent for subsequent pregnancies, or 10 to 15 percent when a previous infant had cutaneous NL [45-47]. Data suggest that congenital heart block may occur more frequently in the setting of anti-Ro52, as opposed to anti-Ro60 or anti-La antibodies; however, at this time, neonatal surveillance should not be altered by antibody type, and Ro antibody differentiation is not routinely performed to guide obstetric care [48,49]. The pathogenesis, clinical manifestations, screening, prevention, and treatment of NL are discussed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Congenital third-degree (complete) atrioventricular block".)
Data are mixed on whether SLE confers additional risks for fetuses and infants. Several studies have not noted an increased rate of other identifiable congenital abnormalities [50,51]. However, one large population-based analysis of hospital discharge records showed that billing codes for congenital malformations were more common among infants born to people with SLE than among infants born to people without SLE or rheumatoid arthritis (9.1 versus 6.3 percent, respectively). Some studies have found that learning disabilities may be more frequent in children, particularly sons, of SLE mothers, while others support similar neurodevelopmental outcomes in children of women with and without SLE [52-55].
Special considerations
Lupus nephritis — Women with active lupus nephritis should be encouraged to delay pregnancy until the disease is inactive for at least six months to optimize maternal outcomes. As discussed above, a previous history of lupus nephritis or active lupus nephritis during pregnancy is associated with higher rates of maternal and fetal complications. The following examples are illustrative:
●An observational study with 193 pregnancies of 104 women with SLE, among which 81 occurred in the presence of active renal disease, found that low birth weight was observed more frequently in pregnancies with renal disease [25]. The presence of active renal disease during pregnancy was also associated with an increased frequency of pregnancy-induced hypertension and lupus flares.
●Another retrospective study of 95 pregnancies among women with SLE found that a previous history of lupus nephritis was a predictor for adverse maternal outcomes [26]. Pregnancies of women with previous nephritis were associated with a higher risk of maternal complications (88 percent versus 43 percent, respectively) and a higher rate of flares (54 percent versus 25 percent, respectively), most of which were renal flares. However, most renal flares in this cohort were not severe, responded to high doses of prednisone, and did not lead to pregnancy loss.
●A retrospective study of 90 pregnancies among 58 lupus patients found significantly lower rates of preeclampsia, preterm birth, and pregnancy loss among women with lupus nephritis in remission compared with women with active lupus nephritis (35, 30, and 25 percent versus 57, 52, and 35 percent, respectively) [38].
Thus, these women require careful monitoring during pregnancy, and may require medication to control their disease. A detailed discussion of pregnancy in women with underlying renal disease is presented separately (see "Pregnancy and contraception in patients with nondialysis chronic kidney disease"), and the approach to therapy of a flare of lupus during pregnancy is discussed below. (See 'Management during pregnancy' below.)
Women with SLE who have received renal transplants have pregnancy outcomes that are similar to those of other transplant recipients [56]. Management of pregnancy following renal transplantation is discussed separately. (See "Sexual and reproductive health after kidney transplantation", section on 'Pregnancy'.)
Presence of antiphospholipid antibodies — aPLs are present in about a quarter to a half of patients with SLE; however, few patients develop thrombotic or obstetric complications related to APS.
Pregnant women with SLE who have an obstetric history suggestive of APS (fetal death after 10 weeks or three or more consecutive miscarriages, or premature birth <34 weeks due to preeclampsia or placental insufficiency) or unexplained venous or arterial thrombotic event, should be tested for the presence of aPLs (ie, lupus anticoagulant [LA], IgG and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2 glycoprotein I [anti-beta2GPI]). The clinical manifestations, diagnosis, and management of women with aPL who are contemplating pregnancy or who are pregnant are discussed in more detail separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Diagnosis of antiphospholipid syndrome".)
It is unclear whether women with aPLs without an APS diagnosis are at increased risk of pregnancy loss [57]. Issues associated with the presence of these autoantibodies in pregnant women and the management of such patients is discussed separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Management'.)
Presence of anti-Ro and anti-La antibodies — As mentioned above, a fetus exposed to anti-Ro/SSA and/or anti-La/SSB antibodies is at an increased risk of developing congenital complete heart block or NL (see 'Fetal complications' above). In most cases, congenital heart block develops between 18 and 24 weeks of gestation. Thus, in some centers, women who have antibodies to Ro/SSA and/or La/SSB undergo increased fetal surveillance for heart block, with differing surveillance protocols at different sites. While there is no therapeutic intervention proven to prevent progression, early detection allows for increased monitoring. The monitoring and management of congenital heart block associated with neonatal lupus is discussed in detail separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Heart block' and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block' and "Neonatal lupus: Management and outcomes", section on 'In utero management'.)
HCQ use during pregnancy has been associated with reduced rates of congenital heart block [18,58,59]. (See "Neonatal lupus: Management and outcomes", section on 'Prevention of NL in subsequent pregnancies'.)
Women with anti-Ro/SSA and anti-La/SSB may have detectable amounts of these antibodies in breast milk, but there is no evidence that NL results from breast feeding [60].
MANAGEMENT DURING PREGNANCY — Management of pregnant women with systemic lupus erythematosus (SLE) should involve close collaboration between a rheumatologist and an obstetrician experienced in caring for high-risk mothers. An approach to monitoring pregnant women with SLE as well as treating active SLE during pregnancy is presented below.
Monitoring SLE activity — Women should be assessed by a rheumatologist for disease activity at least once each trimester, and more frequently if they have active systemic lupus erythematosus (SLE). The schedule for monitoring includes:
Initial evaluation — At the first visit after (or at which) pregnancy is confirmed, the following investigations are recommended [61]:
●Physical examination, including blood pressure
●Renal function (creatinine, urinalysis, spot urine protein/creatinine ratio)
●Complete blood count (CBC)
●Liver function tests
●Anti-Ro/SSA and anti-La/SSB antibodies if not previously evaluated
●Antiphospholipid antibodies (lupus anticoagulant [LA], IgG and IgM anticardiolipin [aCL] antibodies, and IgG and IgM anti-beta2 glycoprotein [anti-beta2GPI] antibodies)
●Anti-double stranded DNA (dsDNA) antibodies
●Complement (CH50, or C3 and C4)
Some physiological changes of pregnancy may overlap with features of active SLE, making differentiation difficult. As an example, laboratory findings that may be observed during a normal pregnancy include mild anemia, mild thrombocytopenia, elevated erythrocyte sedimentation rate (ESR), and proteinuria. Protein excretion increases in the course of normal pregnancy but should remain below 300 mg/24 hours. A baseline 24-hour urine collection or urine protein to creatinine ratio can be helpful in distinguishing lupus flare from preeclampsia and normal changes later in pregnancy (see 'Preeclampsia versus lupus nephritis' below). Also, during normal pregnancy, complement levels may rise by 10 to 50 percent, and may appear to remain normal despite active SLE. Thus, the trend of complement levels is generally more informative than the actual value.
Thus, laboratory testing must be interpreted in the clinical context and women who show evidence of increased serologic activity but who remain asymptomatic should be monitored more closely. We do not initiate therapy for serologic findings alone.
Laboratory testing — In addition to a physical examination with blood pressure testing, the following laboratory tests are recommended at regular intervals during pregnancy:
●CBC
●Creatinine
●Urinalysis with examination of urinary sediment
●Spot urine protein/creatinine ratio or 24-hour urine collection
The following laboratory tests should be performed in patients with active disease or who have previously manifested changes in these levels with a flare:
●Anti-dsDNA antibodies
●Complement (CH50, or C3 and C4)
Ordering additional laboratory tests such as liver function tests and serum uric acid should be guided by the clinical presentation. The frequency of laboratory testing is individualized and varies with disease activity. Patients with stable disease should ideally undergo laboratory testing each trimester, but those with active lupus will require more frequent testing.
Postpartum laboratory testing — Some women will experience exacerbations of SLE in the postpartum period. Those who have had active disease at conception and those with significant end-organ damage are at greater risk of disease flares in the postpartum period compared with women with inactive disease [62]. Thus, periodic assessment of disease activity is warranted postpartum. The following laboratory tests are recommended at one month following an uncomplicated delivery [61]:
●Urinalysis, urine protein/urine creatinine ratio
●Renal function if the urinalysis is abnormal
●CBC
We also check the following laboratory tests in patients with severe disease or in those in whom the anti-dsDNA and complement levels correlate well with disease activity:
●Anti-dsDNA
●Complement (CH50, or C3 and C4)
Treatment of postpartum women with active SLE is the same as that of nonpregnant women. Some medications used for the management of active SLE are not compatible with breastfeeding; thus, breastfeeding women will require thoughtful discussions with their clinicians as to the risks and benefits of various treatment approaches. Breastfeeding carries short- and long-term health benefits to mothers and babies and should be supported when possible [63]. Medication safety in pregnancy differs in many instances from medication safety in lactation. (See 'Breastfeeding' below.)
Maternal-fetal monitoring — The optimal monitoring schedule to ensure maternal and fetal health during pregnancy is not known. Women with risk factors or poor prognostic indicators will require more frequent monitoring. In addition to routine prenatal care, fetal monitoring for women with SLE includes:
●First-trimester ultrasound evaluation to establish the estimated date of delivery. A fetal anatomic survey is performed at approximately 18 weeks of gestation.
●Ultrasound evaluation for fetal growth and placental insufficiency in the third trimester. Frequency of surveillance for fetal growth will depend upon maternal and fetal wellbeing, but typically will be performed approximately every four weeks. More frequent monitoring, including Doppler velocimetry, is also recommended if growth restriction or placental insufficiency is suspected. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Prenatal care'.)
●Fetal testing with nonstress tests and/or biophysical profile during the final four to six weeks of pregnancy is indicated in most women with lupus, with individual surveillance plans based on fetal and maternal assessment. (See "Overview of antepartum fetal assessment".)
●In patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, increased surveillance for congenital heart block is recommended. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block' and 'Presence of anti-Ro and anti-La antibodies' above.)
Preeclampsia — Females with SLE are at higher risk of preeclampsia than females in general. These patients require additional vigilance, as the presentation of hypertension, proteinuria, or end-organ dysfunction after 20 weeks of gestation is concerning for development of preeclampsia. Severe, early-onset growth restriction of the fetus is similarly concerning for developing preeclampsia. While preeclampsia presenting later in pregnancy can often be managed expectantly, in pre-and peri-viable gestations, delivery is indicated to prevent catastrophic maternal complications. For this reason, early diagnosis is essential.
Risk of preeclampsia in patients with SLE is between 16 and 30 percent. In women at elevated risk of preeclampsia, including all women with SLE, low-dose aspirin has been shown to reduce the absolute risk of disease by approximately 2 to 5 percent when initiated between 12 to 16 weeks gestation [19,64]. The use of low-dose aspirin for preeclampsia prophylaxis is discussed in detail separately (see "Preeclampsia: Prevention", section on 'Candidates' and 'Recommended during pregnancy' above). Preeclampsia in women with antiphospholipid syndrome (APS) is also discussed separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)
Preeclampsia versus lupus nephritis — Differentiating preeclampsia from lupus nephritis or a lupus flare can be challenging. Lupus nephritis flares during pregnancy can mimic preeclampsia, presenting with increasing proteinuria, hypertension, thrombocytopenia, and a deterioration in renal function. Active lupus nephritis and preeclampsia can also occur at the same time. Evidence of lupus activity in other organs can sometimes help distinguish SLE from preeclampsia.
Laboratory testing may be, but is not always, useful in distinguishing preeclampsia from nephritis or a lupus flare:
●Lupus nephritis is often associated with proteinuria and/or an active urine sediment (red and white cells and cellular casts), whereas only proteinuria is seen in preeclampsia.
●Flares of SLE are likely to be associated with low or decreasing complement levels and increased titers of anti-dsDNA antibodies; by comparison, complement levels are usually, but not always, normal or increased in preeclampsia [65-67].
●Thrombocytopenia, elevated serum levels of liver enzymes and an elevated or rising level of uric acid are more prominent in preeclampsia than lupus nephritis. However, thrombocytopenia may also be seen in association with antiphospholipid antibodies (aPLs), thrombotic thrombocytopenic purpura, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.
The onset of these overlapping symptoms before 20 weeks of gestation is more consistent with lupus nephritis. Renal biopsy can help differentiate the two conditions, but the higher risk of complications during pregnancy limits the use in pregnancy. (See "Acute kidney injury in pregnancy".)
Treating active SLE — The treatment of active SLE during pregnancy is guided by the severity and degree of organ involvement, similar to the approach for patients in the nonpregnant state. Treatment should not be withheld due to pregnancy; however, some medications used to treat SLE may cross the placenta and cause fetal harm. Thus, the risks and benefits of treatment during pregnancy must be weighed against the risk of SLE activity having a deleterious effect on the mother and the fetus. The most commonly used medications used to treat patients with SLE are reviewed above (see 'Medications' above). The use of immunosuppressive drugs during pregnancy is discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)
A detailed discussion regarding the treatment of active lupus is presented separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults".)
Lupus nephritis in pregnancy requires special consideration because of its potential morbidity and possible confusion with preeclampsia. (See 'Lupus nephritis' above and 'Preeclampsia versus lupus nephritis' above.)
BREASTFEEDING — Breastfeeding is encouraged for most women with systemic lupus erythematosus (SLE). The safety of medications in lactation should be discussed on an individual level and specific risks reviewed. Premature or ill infants may be at increased risk of some medication exposures.
Hydroxychloroquine (HCQ), prednisone, cyclosporine, azathioprine, and tacrolimus are considered compatible with breastfeeding. Methotrexate, mycophenolate mofetil, cyclophosphamide, and leflunomide are not compatible with breastfeeding. Safety data for tofacitinib is not yet available. Biologics, given their large size, are unlikely to be transferred into breast milk in significant concentration and are compatible with breastfeeding. Detailed information regarding compatibility of medications with lactation is provided by the United States National Library of Medicine (LactMed drug and lactation database) [68]. A more detailed discussion on the use of immunosuppressive drugs during lactation can be found elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Lupus and pregnancy (The Basics)" and "Patient education: Lupus and kidney disease (The Basics)")
●Beyond the Basics topic (see "Patient education: Systemic lupus erythematosus and pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Pregnancy planning – Ideally, all pregnancies in women with systemic lupus erythematosus (SLE) should be planned during periods of disease quiescence for six months prior to conception. Active SLE at the time of conception is a strong predictor of adverse maternal and obstetrical outcomes. In spite of this risk, the majority of such pregnancies still result in live births. (See 'Introduction' above and 'Pregnancy planning' above.)
●Preconception evaluation – A preconception assessment is essential in women with SLE to determine whether pregnancy may pose an unacceptably high maternal or fetal risk, to initiate interventions to optimize disease activity, and to adjust medications to those with the best safety profile during pregnancy. (See 'Preconception evaluation' above and 'Specific laboratory testing' above and 'Medications' above.)
●Specific considerations during pregnancy – Women who are primigravidas and women with a history of lupus nephritis or active nephritis are at highest risk of flare. Higher rates of complications such as preeclampsia, preterm birth, fetal loss, growth restriction, and neonatal lupus (NL) syndromes are seen in lupus pregnancy. (See 'Exacerbation of SLE' above and 'Impact of lupus on pregnancy' above and 'Fetal complications' above and 'Special considerations' above.)
●Management during pregnancy – Management of pregnant women with SLE should involve close collaboration between a rheumatologist and an obstetrician experienced in caring for high risk mothers. Periodic assessment for disease activity should occur throughout pregnancy and the postpartum period. (See 'Management during pregnancy' above and 'Monitoring SLE activity' above.)
•For most pregnant women with SLE, we suggest continuation of hydroxychloroquine to reduce the risk of SLE flares (Grade 2C). (See 'Recommended during pregnancy' above.)
•Females with SLE are at higher risk of preeclampsia than females in general. Recommendations for prophylactic use of low-dose aspirin for preeclampsia is discussed in detail separately (see "Preeclampsia: Prevention", section on 'Candidates'). Lupus nephritis flares during pregnancy can mimic preeclampsia, and differentiating one from the other can be challenging. (See 'Preeclampsia' above and 'Recommended during pregnancy' above.)
●Maternal-fetal monitoring – Women with risk factors or poor prognostic indicators may require more frequent maternal-fetal monitoring. In patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, increased surveillance for congenital heart block is appropriate. (See 'Maternal-fetal monitoring' above.)
●Treating active SLE – The treatment of active SLE during pregnancy is guided by the severity and degree of organ involvement, similar to patients in the nonpregnant state. Treatment should not be withheld due to pregnancy; however, some medications used to treat SLE may cross the placenta and cause fetal harm. Thus, the risks and benefits of treatment during pregnancy must be weighed against the risk of SLE activity having a deleterious effect on the mother and the fetus. (See 'Treating active SLE' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.
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