Pregnancy in women with systemic lupus erythematosus

INTRODUCTION — 

Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. This topic will use the term "women" to refer to both women and birthing people. We encourage the reader to consider the specific counseling and 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 disease activity of SLE has been quiescent for at least six months prior to the pregnancy. During pregnancy, it may be challenging to distinguish SLE disease flares from physiologic changes related to pregnancy and other conditions that complicate pregnancy (eg, preeclampsia). 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 pregnancy in patients with impaired kidney function, antiphospholipid syndrome (APS), and anti-Ro or anti-La antibodies are also presented elsewhere:

●(See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)

●(See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

●(See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

The use of contraception in women with SLE is also presented separately. (See "Approach to contraception in women with systemic lupus erythematosus".)

RISKS OF PREGNANCY — 

Most patients with systemic lupus erythematosus (SLE) have uncomplicated pregnancies; however, there are a variety of risks during pregnancy, including worsening SLE disease activity and adverse pregnancy outcomes.

Exacerbation of SLE — The reported flare rates during pregnancy and the postpartum period vary widely from 25 to 60 percent [1-4]. Some of this variation may be attributed to the heterogeneous study designs, the nature of patient and control groups, and different definitions of flares used in the studies.

The following factors are associated with an increased risk of SLE flare during pregnancy [5-11]:

●Active disease during the six months prior to conception

●A history of lupus nephritis

●Discontinuation of hydroxychloroquine (HCQ) or other medication

●Primigravidas

●Low C4 prior to conception

As an example, in a retrospective study of 95 pregnancies in patients with SLE, the rate of SLE flare in patients with a history of lupus nephritis was 54 percent, compared with 25 percent in patients without a history of nephritis [8]. However, most kidney flares in this cohort were not severe, responded to high doses of prednisone, and did not lead to pregnancy loss.

Treatment of disease flares during pregnancy is discussed below. (See 'Management of SLE flares' below.)

Adverse pregnancy outcomes — Pregnancy in the setting of SLE is associated with a higher risk of complications compared with those of healthy women. As an example, a large cross-sectional study that included 13,555 pregnancies in patients with SLE identified a two- to fourfold increased rate of various obstetric complications (including preterm labor, unplanned cesarean delivery, fetal growth restriction, preeclampsia, and eclampsia) among women with SLE compared with those without SLE [12]. The rate of pregnancy complications including mortality rates in patients with SLE may be decreasing over time based on data from a large population-based study; however, rates are still higher for those with SLE compared with rates for those without SLE [13].

Several predictors of adverse pregnancy outcomes among women with SLE have been identified and include active disease [1,5,14], being a primigravida [9], use of antihypertensives, lupus nephritis (active or historical) [15], the presence of antiphospholipid antibodies (aPLs), and thrombocytopenia [16,17]. Rates of adverse pregnancy outcomes also vary by race and ethnicity, with higher rates of complications among Black patients compared with White patients [18]. As an example, in an observational study of 385 pregnant patients with SLE (49 percent non-Hispanic White), the risk of adverse pregnancy outcomes was 58 percent in a group of patients with certain risk factors (patients who either had positive lupus anticoagulant testing, or who identified as nonwhite or Hispanic and used antihypertensives), compared with 8 percent in the group without risk factors [17].

Despite these risks, many patients with SLE have uncomplicated pregnancies. As an example, in an observational study of 385 patients, 81 percent of pregnancies were uncomplicated when patients had inactive or mild or moderate SLE disease activity at conception and no history of lupus nephritis [17].

Women with SLE who have received kidney transplants have pregnancy outcomes that are similar to those of other kidney transplant recipients [19], which is discussed separately. (See "Sexual and reproductive health after kidney transplantation", section on 'Pregnancy'.)

More information on specific adverse pregnancy outcomes is provided below:

●Maternal risks

•Preeclampsia – Preeclampsia is one of the most frequent complications of pregnancy in SLE, occurring in 16 to 30 percent of SLE pregnancies, compared with 4.6 percent of pregnancies in the general obstetric population [1,20-22]. Risk factors for preeclampsia in patients with SLE include those seen in healthy people as well as those specific to patients with SLE, such as an active or prior history of lupus nephritis, declining complement levels [10], and thrombocytopenia. The data on whether aPLs predispose to preeclampsia are unclear [20,23], although antiphospholipid syndrome (APS) is associated with preeclampsia. (See "Preeclampsia: Clinical features and diagnosis", section on 'Risk factors'.)

•Other maternal complications – Rates of maternal mortality and other maternal complications from pregnancy are increased among those with SLE. In a large cohort study that included 13,555 pregnancies in patients with SLE between 2000 and 2003, maternal mortality was 20-fold higher among patients with SLE compared with those without SLE [12]. Patients with SLE also had a significantly higher risk of thrombosis, infection, thrombocytopenia, and transfusion. Several other retrospective studies have found that pregnant patients with SLE had increased rates of hypertension, preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, maternal venous thromboembolism, and acute kidney failure compared with those without SLE [24,25]. Subsequent studies have shown improved pregnancy outcomes [25].

●Adverse pregnancy outcomes

•Fetal loss and infant death – Patients with SLE have historically had higher rates of both early and late pregnancy loss, although fetal loss rates in this population has declined over the last decades [5,15,26]. 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. An estimated 5 to 23 percent of pregnancies in patients with SLE end in fetal loss or neonatal death [17,27]. For comparison, estimates of the general population's risk of pregnancy loss range from 8 to 20 percent [28,29].

The effect of SLE on early pregnancy loss (embryonic death) is controversial, with a possible slight increase in risk. However, patients 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) [3]. In patients with high disease activity (as measured by physician global assessment) the risk of pregnancy loss may be three times higher compared with those who have low disease activity [5].

Infant mortality may also be higher in children born to patients with SLE, although the absolute risk appears to be low and likely related to complications of prematurity. In one retrospective cohort study of infants born between 1987 and 2014, 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 patients without SLE or rheumatoid arthritis (relative risk [RR] 2.11, 95% CI 1.21-3.67) [30].

•Preterm birth – Preterm birth is the most common obstetric complication in patients with SLE. Reported rates of preterm birth range from 15 to 50 percent, with increased incidence in pregnant people with lupus nephritis and/or high disease activity, compared with 12 percent of pregnancies in the general United States obstetric population [5,8,20]. One systematic review and meta-analysis of studies published between 1995 and 2021 reported an average preterm birth rate of 31 percent (95% prediction interval 0.14-0.50) of pregnancies in women with SLE; an approximately equal number of preterm births were spontaneous versus indicated [31]. This study has significant limitations, including lack of reporting on SLE disease activity or medication exposures, as well as inclusion of non-contemporary data. For patients with SLE, the majority of preterm births result from preeclampsia or maternal SLE activity [32]. The presence of lupus nephritis and active disease are the strongest predictors for early delivery [3,15,21]. Rates of preterm birth are likely better among those without such risk factors [17].

•Fetal growth restriction and low birthweight – Approximately 10 to 30 percent of pregnancies in patients with SLE are complicated by fetal growth restriction and small-for-gestational-age babies compared with approximately 10 percent of pregnancies in the general obstetric population [3,8,33]. As with the other complications, the risk is higher in the presence of active SLE, hypertension, and lupus nephritis [7]. Lower birth weight at every gestational age is also more prevalent in patients with SLE [24,30].

●Neonatal lupus (NL) – 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 disease. The major manifestations of NL are cutaneous and cardiac, but other manifestations of NL include hematologic and hepatic abnormalities. The most serious complication in NL is congenital complete heart block, which occurs in approximately 2 percent of children born to primigravid women with anti-Ro/SSA antibodies [34] and appears to be most frequent in the setting of anti-Ro52 antibodies. When a patient has a history of a prior pregnancy complicated by cutaneous NL or congenital complete heart block, the risk of complete heart block in subsequent pregnancies increases to 10 to 15 percent and 16 to 18 percent, respectively [35-37]. More information on anti-Ro/SSA and anti-La/SSB antibodies and the pathogenesis, clinical manifestations, screening, prevention, and treatment of NL is provided separately:

•(See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Neonatal lupus'.)

•(See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

•(See "Congenital third-degree (complete) atrioventricular block".)

●Additional fetal and infant risks – Data are mixed on whether SLE confers additional risks for fetuses and infants. Several studies have not found an increased rate of identifiable congenital abnormalities [38,39]. 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 born to mothers with SLE, while others report similar neurodevelopmental outcomes in children of mothers with SLE and in children of mothers without SLE [40-43].

PREGNANCY PLANNING — 

Planning for pregnancy in patients with systemic lupus erythematosus (SLE) allows time to determine whether pregnancy may pose an unacceptably high maternal or fetal risk, minimize factors that may adversely impact pregnancy outcomes (eg, active disease, use of certain medications), and ensure that protective factors are in place (eg, use of hydroxychloroquine [HCQ]) (algorithm 1).

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) [44] and the American College of Rheumatology (ACR) [45].

A more general discussion on preconception care and risk assessment in all women is presented separately. (See "The prepregnancy office visit".)

Baseline evaluation — A preconception assessment is essential in patients with SLE to determine whether pregnancy may pose an unacceptably high maternal or fetal risk. Our evaluation focuses on the following elements:

●Patient history

•Previous obstetrical outcomes – Previous obstetric outcomes should be reviewed with particular attention paid to any history of a small for gestational age fetus, preeclampsia, stillbirth, miscarriage, or preterm birth.

•SLE disease activity – Clinicians should assess the patient's history of SLE disease activity and any recent symptoms suggestive of active disease. Increased severity of maternal disease, specifically leukopenia and thrombocytopenia, hypertension, or kidney, lung, or cardiac involvement, generally correlates with higher maternal and fetal risk in pregnancy. Active SLE at the time of conception is a strong predictor of adverse maternal and obstetrical outcomes [1,5,14]. An approach to the assessment of disease activity and severity of SLE is discussed separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Assessment of disease activity'.)

•SLE complications and comorbid conditions – Clinicians should ask about a history of certain SLE complications that may predispose to adverse pregnancy outcomes, such as antiphospholipid syndrome (APS) and lupus nephritis. Comorbid medical conditions such as recent stroke, cardiac disease, pulmonary hypertension, severe interstitial lung disease, and advanced kidney function impairment can portend poor pregnancy outcomes for both the mother and fetus.

●Physical examination – We perform a comprehensive physical examination looking for evidence of active SLE and potential complications. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'History and physical examination'.)

●Laboratory studies – In addition to routine preconception labs (see "The prepregnancy office visit", section on 'Laboratory assessment'), we check the following laboratory tests to assess disease activity and screen for the presence of antibodies that may impact pregnancy management (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Laboratory evaluation'):

•Complete blood count (CBC)

•Kidney function tests (creatinine, urinalysis with examination of the urine sediment, spot urine protein/creatinine ratio)

•Liver function tests

•Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

•Anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies

•Complement (CH50, or C3 and C4)

•Anti-Ro/SSA and anti-La/SSB antibodies, as these antibodies may predispose to neonatal lupus (NL) [46]

•Antiphospholipid antibodies including lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta2 glycoprotein I (anti-beta2GPI) [45]

Preconception counseling — Patients with SLE who are considering pregnancy should be counseled about the common issues that arise during pregnancy, the morbidity and mortality risks to both mother and fetus associated with pregnancy, and their individual risk profiles. Ideally, counseling is provided by a rheumatologist, maternal fetal medicine specialist, and, if necessary, other relevant subspecialists (eg, hematology for those with APS, nephrology for those with lupus nephritis).

Preconception counseling should address the following issues:

●Fertility – Fertility in patients with SLE does not appear to be altered by the disease itself; however, a decrease in ovarian reserve can occur in women exposed to cyclophosphamide. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Gonadal dysfunction'.)

●Timing of conception – Ideally, disease activity in SLE should be quiescent for six months on medications compatible with pregnancy before a patient with SLE attempts to conceive.

●Management of medications – We review the potential risks of any medications that the patient is taking and modify therapy as needed to minimize fetal risk. We also counsel patients about the importance of taking medications regularly during pregnancy, especially HCQ. (See 'Medication management' below.)

●Pregnancy outcomes – We discuss the risks of adverse pregnancy outcomes such as preterm birth, fetal growth restriction, and fetal loss. For patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, we also discuss the risk of NL. (See 'Adverse pregnancy outcomes' above.)

●Maternal risks – We discuss the maternal risks of pregnancy and delivery, such as SLE flare, preeclampsia, and unplanned cesarean deliveries. (See 'Risks of pregnancy' above.)

●Impact of comorbid conditions – Certain manifestations of SLE may increase the likelihood of various adverse pregnancy outcomes and require changes in monitoring and/or therapy, including lupus nephritis, the presence of certain autoantibodies (eg, anti-Ro/SSA, anti-La/SSB, and/or aPL), and APS. For patients with chronic kidney disease, counseling should include the risk of temporary or permanent decline in kidney function. These issues are discussed in detail separately:

•(See "Pregnancy and contraception in patients with nondialysis chronic kidney disease", section on 'Preconception counseling'.)

•(See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

•(See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Prenatal'.)

●Contraception – If needed, we review potential options for contraception (eg, when patients are not yet ready to conceive, or to consider postpartum). (See "Approach to contraception in women with systemic lupus erythematosus".)

Women with active SLE or other worrisome comorbid conditions should be counseled carefully about the risks of pregnancy. We present alternatives such as gestational carriers and adoption and offer contraception. Should the patient elect to pursue pregnancy, they should be followed in a multidisciplinary fashion in a high-risk center [2,46].

Medication management — All medications must be reviewed and adjusted prior to conception with the goal of maintaining disease control with medications that have the best safety profile during pregnancy. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'General principles regarding medication use in pregnancy'.)

General approach — Although some medications used to treat SLE are potentially harmful or contraindicated during pregnancy, many are safe. Women considering conception should ideally be maintained on treatment that is compatible with pregnancy and continue this treatment during pregnancy. We advise patients that discontinuation of medications used to control disease activity increases the risk of SLE flare and pregnancy complications.

An overview of common medications used in patients with SLE is provided in the table (table 1), which groups medications based on their risk of harm into the following categories:

●Selective use allowed during pregnancy – These drugs have a reasonable safety profile during pregnancy, and their use may be acceptable if needed to control manifestations or complications of SLE during conception and pregnancy. However, they each have a small risk of causing fetal harm and there may be certain limits to their use.

●Selective use with caution during pregnancy – Many medications have limited data during pregnancy and/or are associated with increased risks to the fetus. In certain scenarios, these medications may still be used during pregnancy if the potential benefit (ie, maintaining disease control or treating a disease flare) outweighs the risk.

●Contraindicated in pregnancy – Some medications are clearly associated with adverse fetal outcomes and should be avoided during pregnancy. Very rarely, certain medications may still be used in life-threatening scenarios.

Detailed information regarding the use of common medications in pregnant patients with SLE is provided separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Hydroxychloroquine — For most pregnant patients with SLE, we suggest continuation of HCQ to reduce the risk of SLE flares. The dosing, adverse effects, contraindications, and monitoring for HCQ, including the potential for checking drug levels, are discussed elsewhere. (See "Antimalarial drugs in the treatment of rheumatic disease".)

Several studies have demonstrated fewer disease flares and better outcomes in patients continuing HCQ during pregnancy [6,47-52]. Examples include the following:

●In a randomized trial including 20 consecutive pregnant patients with SLE, patients receiving HCQ had greater reductions in their prednisone requirements and lower postpartum disease activity scores compared with those receiving placebo [49]. However, there were no differences in the rate of disease flare between the groups.

●In a prospective study of 257 pregnancies in 197 patients with SLE, discontinuation of HCQ during pregnancy was associated with a higher rate of flare compared with continuation or nonuse of HCQ [6]. High disease activity occurred in twice as many pregnancies in which HCQ was stopped compared with those in which HCQ was continued.

●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 [53].

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 in the first trimester, though the association was not seen when the dose was under 400 mg [52,54]. 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 [55]. 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'.)

MANAGEMENT DURING PREGNANCY — 

Issues related to the management of systemic lupus erythematosus (SLE) during pregnancy are presented below (table 2). Optimal care for patients with SLE during pregnancy requires coordination and collaboration across the patient's entire medical team, including a rheumatologist and an obstetrician experienced in caring for high-risk mothers, such as a maternal fetal medicine specialist.

Monitoring SLE activity — Once pregnancy is confirmed, patients with SLE should be regularly monitored for disease activity.

●Frequency of monitoring – Disease activity should be assessed by a rheumatologist at least once each trimester and more frequently if they have active disease.

●Clinical assessment – We perform a detailed history and comprehensive physical examination, including measurement of blood pressure, to look for evidence of SLE disease activity and complications. This is described in detail separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'History and physical examination'.)

●Laboratory testing – While we generally send the same set of laboratory tests to assess SLE disease activity in pregnant and nonpregnant patients, results of several tests in pregnant patient must be interpreted with caution. This is because physiologic changes of pregnancy may overlap with or mask features of active SLE on laboratory evaluation. For patients who show evidence of increased dsDNA or decreased complement levels, but who remain asymptomatic, we monitor closely but do not initiate therapy for serologic findings alone.

The general approach to laboratory testing to monitor SLE disease activity and interpretation of tests is provided separately; issues relevant to pregnancy are summarized below (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Laboratory evaluation'):

•Complete blood count (CBC) – Patients with active SLE may develop one or more cytopenias, which range from mild to severe. Pregnant patients might also develop mild anemia and/or mild thrombocytopenia. The white blood cell (WBC) count can be a helpful distinguishing feature as leukopenia (especially lymphopenia) is common in SLE flares, while mild neutrophilia is typically seen in pregnant patients. (See "Maternal adaptations to pregnancy: Hematologic changes" and "Anemia in pregnancy" and "Thrombocytopenia in pregnancy".)

•Kidney function tests – We typically check creatinine, urinalysis with examination of the urinary sediment, and a spot urine protein/creatinine ratio (or 24-hour urine collection). Protein excretion increases during normal pregnancy but should remain below 300 mg/24 hours. A baseline urine protein/creatinine ratio (or 24-hour urine collection) can be helpful in distinguishing a flare of SLE from preeclampsia and normal changes later in pregnancy. (See 'Differentiating preeclampsia from SLE flares' below and "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome".)

•Liver function tests – Elevated liver function tests in pregnant patients with SLE may indicate a SLE disease flare or complications of pregnancy such as intrahepatic cholestasis, acute fatty liver, or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). (See "Approach to evaluating pregnant patients with elevated liver biochemical and function tests".)

•Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) – Patients with active SLE typically have elevations in ESR and, to a lesser extent, CRP. Both ESR and CRP may also be elevated during pregnancy; ESR typically rises with increasing gestational age, while the pattern for CPR is more variable. (See "Acute phase reactants", section on 'Increased ESR'.)

•Anti-double stranded DNA (dsDNA) antibodies – An elevated anti-dsDNA titer frequently signifies an increase in SLE disease activity. Levels are not affected by pregnancy.

•Complement (CH50, or C3 and C4) – Complement levels are typically higher during pregnancy [56]. This physiologic increase may mask the expected drop in complement caused by active SLE. Consequently, the trend in complement levels is generally more helpful than the actual value for monitoring SLE disease activity.

If they were not previously checked during a preconception evaluation, we also obtain anti-Ro/SSA and anti-La/SSB antibodies and antiphospholipid antibodies (LA, immunoglobulin G [IgG] and IgM anticardiolipin [aCL] antibodies, and IgG and IgM anti-beta2 glycoprotein I [anti-beta2GPI] antibodies) once at the initial evaluation. (See 'Baseline evaluation' above.)

We do not approach screening for vitamin D deficiency differently in pregnant patients with SLE, since the relationship of vitamin D levels to SLE disease activity is unclear. Although one observational study of pregnant patients with SLE showed that low or high levels of vitamin D were associated with an increased risk of adverse pregnancy outcomes, this U-shaped relationship with both low and high levels and potential confounders limit the generalization of this study [57].

Maternal-fetal monitoring — The optimal monitoring schedule to ensure maternal and fetal health during pregnancy is not known. Patients with risk factors or poor prognostic indicators will require more frequent monitoring. In addition to routine prenatal care, fetal monitoring for patients with SLE includes:

●Ultrasound evaluation for an anatomic survey and assessment of fetal growth and amniotic fluid volume early in the second trimester. This is performed before 20 weeks of gestation, typically around 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 will typically 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 patients with SLE, with individual surveillance plans based on fetal and maternal assessment. (See "Fetal assessment: Overview of antepartum tests of fetal well-being".)

●Patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies have a slightly increased risk for congenital heart block (approximately 2 percent) [58]. Fetal surveillance for heart block is controversial and is discussed in detail separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for atrioventricular block'.)

Medication management — Medications should be reviewed for compatibility with pregnancy and adjusted as needed, as is done during preconception counseling (table 1). It is also important to review adherence, especially as pregnancy may present new challenges around taking medications regularly (eg, nausea and vomiting of pregnancy). Hydroxychloroquine (HCQ) is typically continued and aspirin is added for most pregnant patients with SLE. (See 'Medication management' above and 'Aspirin for primary prevention' below.)

Preeclampsia

Aspirin for primary prevention — Low-dose aspirin (81 to 162 mg/day) is often given to pregnant patients with SLE to reduce the risk of developing preeclampsia and its sequelae (eg, fetal growth restriction), as well as to any pregnant person with antiphospholipid antibodies (aPLs). Aspirin is typically used between weeks 12 and 36 of gestation; however, it may be used for longer in patients with a history of certain types of thrombosis related to antiphospholipid syndrome (APS; eg, stroke, myocardial infarction). It is used regardless of the presence of aPLs.

The risk of preeclampsia in patients with SLE is between 16 and 30 percent. In patients at elevated risk of preeclampsia, including all patients 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 [59,60]. The use of aspirin for pregnant patients with SLE is consistent with the recommendation by the United States Preventive Services Task Force [59]. More information on low-dose aspirin for prevention of preeclampsia and preeclampsia in patients with APS are discussed in detail separately. (See "Preeclampsia: Prevention" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

Differentiating preeclampsia from SLE flares — Differentiating preeclampsia from a flare of SLE, especially a flare of lupus nephritis, can be challenging. Lupus nephritis flares during pregnancy may mimic preeclampsia, with increasing proteinuria, deterioration in kidney function, hypertension, and thrombocytopenia. Active lupus nephritis and preeclampsia can also occur at the same time. Early diagnosis of both preeclampsia and SLE flare is essential to avoid potentially catastrophic maternal complications.

Clinical features that can help differentiate preeclampsia and lupus nephritis include the following:

●The onset of proteinuria, hypertension, thrombocytopenia, and/or worsening kidney function before 20 weeks of gestation is more consistent with lupus nephritis.

●Evidence of disease activity in other organs can sometimes help distinguish SLE from preeclampsia.

●Laboratory testing may be, but is not always, useful:

•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 [61-63].

•Thrombocytopenia, schistocytes, elevated serum levels of liver enzymes, and an elevated or rising level of uric acid are more prominent in preeclampsia than in lupus nephritis. However, thrombocytopenia may also be seen in association with aPLs, thrombotic thrombocytopenic purpura, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.

●Kidney biopsy can help differentiate the two conditions, but the higher risk of complications during pregnancy limits its use. (See "Acute kidney injury in pregnancy".)

More information on the clinical presentation, diagnosis, and management of preeclampsia is presented separately. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Antepartum management and timing of delivery".)

Management of SLE flares

Approach to treatment — The treatment of active SLE in pregnant patients is guided by the severity and degree of organ involvement, as it is for nonpregnant patients. However, the therapeutic options are more limited because certain immunosuppressive therapies can cross the placenta and potentially cause fetal harm. Thus, the risks of treatment must be weighed against the risks of uncontrolled SLE negatively impacting the mother and/or fetus. Risks related to SLE disease activity depend on the specific organ involvement (eg, lupus nephritis) and the severity of the flare.

For the purposes of this topic, we have categorized common types of SLE disease manifestations into mild, moderate, and severe flares to give general guidance on when the benefit of using certain types of immunosuppressive therapies during pregnancy might outweigh the potential risks. However, patients may develop other disease manifestations and/or multiple complications, and treatment must be individualized for each patient. Categories of flare severity in pregnant patients include the following, which are similar to those that we have outlined elsewhere in nonpregnant patients (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Escalation of therapy based on disease activity and severity'):

●Mild flare

•Arthralgia or mild inflammatory arthritis

•Mild mucocutaneous disease (eg, oral ulcers, rash)

●Moderate flare

•Moderate to severe inflammatory arthritis

•Moderate to severe mucocutaneous disease (eg, discoid lupus)

•Mild to moderate hematologic disease (eg, one or more mild to moderate cytopenias)

●Severe flare

•Lupus nephritis

•Pericarditis

•Pulmonary disease

•Severe hematologic disease (eg, any severe cytopenia or pancytopenia)

•Central nervous system disease

•Catastrophic antiphospholipid syndrome (CAPS)/thrombotic microangiopathy (TMA)

Our general approach to treatment of SLE flares during pregnancy is outlined in the algorithm (algorithm 2). This approach is based on expert opinion [64] and is generally consistent with recommendations for the use of rheumatic disease medications in pregnancy developed by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [44] and the American College of Rheumatology (ACR) [45]. There are no trials comparing the use of various immunosuppressive regimens in pregnant patients with SLE. Observational data describing the safety of these medications during pregnancy are provided elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Mild flares — For patients with a mild flare of SLE during pregnancy, we start nonfluorinated oral glucocorticoids. The exact dose and duration will depend on the type and severity of disease flare but is typically less than 20 mg/day of prednisone or its equivalent. Due to potential adverse drug effects, we aim to use the lowest dose of glucocorticoids that controls symptoms for the shortest duration possible (ideally <10 mg/day of prednisone or the equivalent). Fluorinated glucocorticoids (eg, dexamethasone) are typically avoided as they are more likely to cross the placenta compared with nonfluorinated formulations (eg, prednisone) and may be associated with harm [44,65-67].

The use of glucocorticoids during pregnancy and adverse effects and monitoring of glucocorticoids are discussed in detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids' and "Major adverse effects of systemic glucocorticoids".)

Additional immunosuppression with azathioprine may be added for some patients with mild disease flares (eg, skin rashes, joint swelling); sulfasalazine is an alternative for patients with arthritis. Other types of immunosuppressive therapies should not be used during pregnancy due to potential adverse effects (eg, mycophenolate mofetil, methotrexate). The dosing, contraindications, adverse effects, and monitoring of azathioprine and sulfasalazine, as well as their use during pregnancy, are described in detail elsewhere:

●(See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

●(See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine'.)

Moderate flares — For pregnant patients with a moderate SLE disease flare, we start nonfluorinated oral glucocorticoids as is done for mild flares. (See 'Mild flares' above.)

In addition, for most patients with a moderate flare of SLE during pregnancy, we add azathioprine rather than giving glucocorticoids alone. Sulfasalazine is an alternative for patients with arthritis. The dosing, adverse effects, and monitoring of these agents are similar in pregnant and nonpregnant patients and are discussed in detail elsewhere. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

Certain biologics are also sometimes used for patients with moderate SLE flares who do not respond to initial therapy with glucocorticoids and azathioprine. The optimal type of biologic depends on the specific disease manifestations, but possibilities in pregnant patients include abatacept, anifrolumab, belimumab, and rituximab. While data on all of the biologics safety during pregnancy are limited, these medications can likely be used safely through conception and the first trimester since they do not cross the placenta significantly until the second trimester. Drug selection, dosing, and monitoring are similar when these agents are used in pregnant or nonpregnant patients and is described in detail elsewhere. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Approach to drug therapy'.)

The use of these medications during pregnancy is summarized in the table (table 1) and described in detail elsewhere:

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine'.)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Biologics with limited data'.)

Severe flares — Pregnant patients with a severe SLE disease flare often require therapy with nonfluorinated glucocorticoids, azathioprine, and additional immunosuppressive and/or immunomodulatory therapy. The specific disease manifestations will guide the selection of biologic therapy and potential need for additional therapies.

●Glucocorticoids – The dose of glucocorticoids is often higher for patients with severe flares (ie, >20 mg/day of prednisone or its equivalent); pulse-dose steroids (ie, methylprednisolone 1 g/day for three days) may be required if the flare poses a serious risk to the patient's health. As with other types of flares, the specific glucocorticoid regimen depends on the variety and severity of disease manifestations, and the goal is to give the lowest dose for the shortest time possible to control disease. The adverse effects and monitoring of glucocorticoids and their use in pregnancy are discussed in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

●Azathioprine – Azathioprine is added unless there is a contraindication. The dosing, adverse effects, and monitoring of azathioprine are typically the same in pregnant and nonpregnant patients and are discussed in detail elsewhere. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

●Additional therapies – Patients with severe disease need immunosuppressive and/or immunomodulatory therapy beyond glucocorticoids and azathioprine. The optimal type of therapy to add depends on the specific disease manifestations. The approach to choosing a therapy in pregnant patients is similar to that in nonpregnant patients, which is described separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Approach to drug therapy'.)

Additional therapies that can be safely or selectively used during pregnancy include the following:

•Cyclosporine or tacrolimus (eg, tacrolimus for lupus nephritis)

•Intravenous immunoglobulin (IVIG; eg, for autoimmune hemolytic anemia, thrombocytopenia, and/or rash)

•Biologic therapies – As noted above, data on the safety of biologic use during pregnancy are limited, but they can likely be used safely through conception and the first trimester (see 'Moderate flares' above). In severe, life-threatening disease, consideration can be given to continuing biologics throughout pregnancy. Examples of biologics that might be used include the following:

-Belimumab (eg, for lupus nephritis)

-Rituximab (eg, for severe cytopenias)

-Anakinra, rilonacept, or canakinumab (eg, for pericarditis)

-Eculizumab (eg, for TMA)

The use of these medications during pregnancy is also described in detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Biologics with limited data'.)

●Additional therapy for specific disease manifestations – Certain types of flares will also require therapy beyond immunosuppression (eg, anticoagulation for patients with CAPS, pericardiocentesis for pericarditis with evidence of hemodynamic compromise). A detailed discussion of treatment for specific clinical manifestations seen in severe SLE flares is provided separately (see appropriate disease manifestation topics).

Modifying therapy in the postpartum period — For patients who experienced a SLE flare during pregnancy that prompted medication adjustment, modification of immunosuppressive therapy in the postpartum period depends on multiple factors, such as the extent of disease control on the new regimen, the severity of any residual disease activity, the presence of any adverse medication effects, and the patient's breastfeeding preferences. As an example, a postpartum patient who is not breastfeeding and who has an ongoing flare of lupus nephritis despite treatment with glucocorticoids, azathioprine, and tacrolimus may benefit from switching to medications that are contraindicated during pregnancy (eg, mycophenolate mofetil, voclosporin, cyclophosphamide). By contrast, a patient with a moderate flare of arthritis who is now in remission off of glucocorticoids after starting azathioprine would likely continue azathioprine during the postpartum period and consider tapering therapy after a sustained period of remission (eg, six months).

POSTPARTUM MANAGEMENT — 

Postpartum patients with systemic lupus erythematosus (SLE) require ongoing monitoring for disease flare and may need medication adjustments if they are breastfeeding. More information on postpartum management in all patients is provided separately. (See "Overview of the postpartum period: Normal physiology and routine maternal care".)

Detailed information about contraception in the postpartum period and contraception in patients with SLE is also provided separately. (See "Contraception: Postpartum counseling and methods" and "Approach to contraception in women with systemic lupus erythematosus".)

Monitoring SLE activity in the early postpartum period — There is an increased risk of SLE flare in the postpartum period, especially for patients with active disease at conception and/or significant end-organ damage [68]. Patients therefore require close monitoring in the postpartum period.

While the intensity of monitoring should be individualized to the patient's disease activity, we typically reassess disease activity four to six weeks following an uncomplicated delivery. After this period, we resume the typical monitoring schedule for nonpregnant patients (eg, every three to six months). The components of monitoring SLE disease activity are described in detail elsewhere and briefly summarized below (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Assessment of disease activity'):

●Detailed history and comprehensive physical examination

●Laboratory testing

•Complete blood count (CBC)

•Kidney function

•Urinalysis, urine protein/creatinine ratio

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)

Breastfeeding — Breastfeeding carries short- and long-term health benefits to mothers and babies and should be supported when possible for most patients with SLE [69]. 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. 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.

A detailed discussion on the use of immunosuppressive drugs during lactation can be found elsewhere and is summarized below (see "Safety of rheumatic disease medication use during pregnancy and lactation"):

●Compatible with breastfeeding – Hydroxychloroquine (HCQ), prednisone, azathioprine, sulfasalazine, cyclosporine, and tacrolimus are considered compatible with breastfeeding. Most injectable and/or intravenous biologics (eg, rituximab, belimumab, anifrolumab) are unlikely to be transferred into breast milk in significant concentrations due to their large size and are therefore compatible with breastfeeding.

●Not compatible with breastfeeding – Mycophenolate mofetil, cyclophosphamide, voclosporin, and leflunomide are not compatible with breastfeeding. Low-dose methotrexate may be allowable for breastfeeding, although this should be discussed first with a pediatrician [70].

Detailed information regarding compatibility of medications with lactation is also provided by the United States National Library of Medicine (LactMed drug and lactation database).

SPECIAL POPULATIONS

Conception while taking teratogenic medications — When a patient becomes pregnant while taking teratogenic medications (eg, methotrexate, leflunomide, mycophenolate mofetil), we urgently refer them to an obstetrician experienced in caring for high-risk mothers, such as a maternal fetal medicine specialist, and order an obstetrical ultrasound to confirm the viability of the pregnancy to allow pregnancy decision-making, including the option for abortion. We also adjust medications as needed. (See 'Medication management' above.)

Patients with antiphospholipid antibodies — Antiphospholipid antibodies (aPLs) are present in approximately a quarter to a half of patients with SLE; however, few patients develop thrombotic or obstetric complications related to antiphospholipid syndrome (APS). For patients with aPLs, the potential for complications during pregnancy, and therefore the monitoring and management, depends on whether the patient has a formal diagnosis of APS:

●Patients with APS – The management of patients with APS who are contemplating pregnancy or who are pregnant is discussed in more detail separately, with key points highlighted in the table and below (table 2) (see "Antiphospholipid syndrome: Obstetric implications and management in pregnancy"):

•Patients with APS may need to start prophylactic anticoagulation (eg, prophylactically-dosed low molecular weight heparin [LMWH] for patients with obstetrical APS), or change certain types of anticoagulation (eg, transition from coumadin to therapeutically-dosed LMWH). (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Pregnancy management'.)

•The duration of low-dose aspirin during pregnancy may be extended for patients with certain types of complications related to APS (eg, stroke, myocardial infarction). (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Pregnancy management'.)

•Fetal testing in the third trimester may begin sooner (ie, at 32 weeks) than for patients with SLE who do not have APS (typically at 32 to 36 weeks). (See 'Maternal-fetal monitoring' above.)

●Patients without APS – It is unlikely that most patients with aPLs without an APS diagnosis are at increased risk of pregnancy loss [71]. We prescribe low-dose aspirin through pregnancy for these patients, as we do for most patients with SLE to prevent preeclampsia. 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 'aPL-positive patients without APS'.)

Patients with anti-Ro/La antibodies — A fetus exposed to anti-Ro/SSA and/or anti-La/SSB antibodies has an increased risk of developing neonatal lupus (NL), including congenital complete heart block; this risk may be mitigated by maternal use of hydroxychloroquine (HCQ) [53,72,73]. There is no evidence that NL results from breastfeeding, despite detectable amounts of anti-Ro/SSA and anti-La/SSB in breastmilk [74]. Monitoring for fetal heart block in pregnancies exposed to anti-Ro/SSA antibodies is controversial. These issues are discussed in more detail separately:

●(See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Neonatal lupus'.)

●(See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●(See "Neonatal lupus: Management and outcomes".)

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 5^th to 6^th 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 10^th to 12^th 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

●Risks of pregnancy – Most patients with systemic lupus erythematosus (SLE) have uncomplicated pregnancies; however, there are a variety of risks during pregnancy, including worsening SLE disease activity and adverse pregnancy outcomes. Active SLE at the time of conception is a strong predictor of adverse outcomes. (See 'Risks of pregnancy' above.)

●Pregnancy planning – Planning for pregnancy in patients with SLE allows time to determine whether pregnancy may pose an unacceptably high maternal or fetal risk, minimize factors that may adversely impact pregnancy outcomes (eg, active disease, use of certain medications), and ensure that protective factors are in place (eg, use of hydroxychloroquine [HCQ]) (algorithm 1). (See 'Pregnancy planning' above.)

•Preconception counseling – Patients with SLE who are considering pregnancy should be counseled about the common issues that arise during pregnancy, the morbidity and mortality risks to both mother and fetus associated with pregnancy, and their individual risk profiles. (See 'Preconception counseling' above.)

•Medication management – Although some medications used to treat SLE are potentially harmful or contraindicated during pregnancy, many are safe (table 1). Patients considering conception should ideally be maintained on treatment that is compatible with pregnancy, including HCQ, and continue this treatment during pregnancy. (See 'Medication management' above and 'Hydroxychloroquine' above.)

●Management during pregnancy – An overview of management of pregnant people with SLE, including those with comorbid antiphospholipid syndrome (APS), is provided in the table (table 2). Optimal care for patients with SLE during pregnancy requires coordination and collaboration across the patient's entire medical team, including a rheumatologist and an obstetrician experienced in caring for high-risk mothers (eg, a maternal fetal medicine specialist). (See 'Management during pregnancy' above.)

•Monitoring SLE activity – Once pregnancy is confirmed, patients with SLE should be regularly monitored for disease activity with regular clinical assessments and laboratory testing. (See 'Monitoring SLE activity' above.)

•Preeclampsia

-Aspirin for primary prevention – 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 'Aspirin for primary prevention' above and "Preeclampsia: Prevention", section on 'Candidates'.)

-Differentiating preeclampsia from SLE flares – Lupus nephritis flares during pregnancy may mimic preeclampsia (eg, increasing proteinuria, deterioration in kidney function, hypertension, and thrombocytopenia); clinical features can often help differentiate these diagnoses. (See 'Differentiating preeclampsia from SLE flares' above.)

•Management of SLE flares – The treatment of active SLE in pregnant patients is guided by the severity and degree of organ involvement (algorithm 2), as it is for nonpregnant patients. However, the therapeutic options are more limited because certain immunosuppressive therapies can cross the placenta and potentially cause fetal harm. Thus, the risks of treatment must be weighed against the risks of uncontrolled SLE negatively impacting the mother and/or fetus. (See 'Approach to treatment' above.)

-Mild flares – For patients with mild flares, we start nonfluorinated oral glucocorticoids rather than fluorinated ones (Grade 2C). The exact dose and duration will depend on the type and severity of disease flare but is typically less than 20 mg/day of prednisone or its equivalent. (See 'Mild flares' above.)

-Moderate flares – For patients with moderate flares, we start nonfluorinated oral glucocorticoids and azathioprine rather than giving glucocorticoids alone (Grade 2C). Patients with persistent disease despite initial treatment may require the addition of certain biologic therapies. (See 'Moderate flares' above.)

-Severe flares – Pregnant patients with a severe SLE disease flare often require therapy with nonfluorinated glucocorticoids, azathioprine, and additional immunosuppressive and/or immunomodulatory therapy. (See 'Severe flares' above.)

●Postpartum management – Postpartum patients with SLE require ongoing monitoring for disease flare and may need medication adjustments, especially if they are breastfeeding. (See 'Postpartum management' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.