Systemic Lupus Erythematosus and Pregnancy 

Updated: Oct 17, 2017
  • Author: Ritu Khurana, MD; Chief Editor: Christine Isaacs, MD  more...
  • Print

Practice Essentials

Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders that affect women during their childbearing years. SLE increases the risk of spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth. The presence of SSA and SSB antibodies can lead to fetal heart block and neonatal lupus.

The prognosis for both mother and child is best when SLE is quiescent for at least 6 months before the pregnancy and when the mother’s underlying renal function is stable and normal or near normal. Lupus nephritis can worsen during pregnancy. [1, 2, 3, 4, 5]

The mother’s health and fetal development should be monitored frequently during pregnancy. In addition, an obstetrician with experience in high-risk care should conduct the follow-up of pregnant women with SLE.

Flares of SLE are uncommon during pregnancy and are often easily treated with steroids. The most common signs and symptoms of these flares include arthritis, rashes (see the image below), and fatigue.

Signs and symptoms

Typical clinical signs and symptoms of SLE include the following:

  • Fatigue
  • Fever
  • Arthritis
  • Photosensitive rash
  • Serositis
  • Raynaud phenomenon
  • Glomerulonephritis
  • Vasculitis
  • Hematologic abnormalities

In general, pregnancy does not cause flares of SLE. When flares do develop, they often occur during the first or second trimester or during the first few months after delivery. 

Signs and symptoms of normal pregnancy that must be differentiated from those of SLE exacerbations include the following:

  • Chloasma versus malar rash
  • Proteinuria secondary to preeclampsia versus proteinuria due to lupus nephritis
  • Preeclampsia versus renal disease due to an exacerbation of lupus (may be difficult to differentiate)
  • Thrombocytopenia in pregnancy HELLP syndrome (ie, hemolysis, elevated liver enzyme levels, and low platelet counts syndrome) versus thrombocytopenia of lupus exacerbationITP or TTP (ie, idiopathic thrombocytopenic purpura or Thrombotic thrombocytopenic purpura)
  • Pedal edema and fluid accumulation in joints (especially the knees) in the late stages of pregnancy versus the arthritis of SLE

Diagnostic evaluation

Laboratory testing

The following laboratory studies are recommended with the first visit after or when pregnancy is confirmed:

  • Renal function tests, including determination of the glomerular filtration rate (GFR), urinalysis, and tests of the urinary protein-to-creatinine (P/C) ratio
  • Complete blood count
  • Test for anti-Ro/SSA and anti-La/SSB antibodies
  • Lupus anticoagulant and anticardiolipin antibody studies
  • Anti–double-stranded DNA (anti-dsDNA) test
  • Complement studies (CH50 or C3 and C4)

During the first 2 trimesters, a monthly platelet count or CBC is recommended. In addition, the following studies are recommended at the end of each trimester of pregnancy:

  • Determination of the GFR and measurement of the urinary P/C ratio
  • Anticardiolipin antibody measurement
  • Complement studies (CH50 or C3 and C4)
  • Anti-dsDNA study

In pregnant patients with renal disease, renal biopsy may need to be performed to differentiate preeclampsia from active lupus nephritis when differentiation on clinical grounds is not possible.

Imaging studies

  • Ultrasonography: At first prenatal visit to accurately estimate the gestational age
  • Serial fetal echocardiography: To detect fetal heart block at an early stage

Management

In general, an integrated team consisting of a rheumatologist, an obstetrician experienced with high-risk care, a pediatric cardiologist in cases of fetal heart block in patients with positive SSA and SSB Antibodies and a nephrologist (if renal disease is present or if it develops later) are needed to manage care of a pregnant patient with SLE.

Nonpharmacotherapy

Before initiating therapy, perform preconception counseling, including discussions of teratogenicity and adverse effects of SLE medications as well as contraception once therapy is begun.

Pharmacotherapy

None of the medications used in the treatment of SLE is absolutely safe during pregnancy. Although in studies, hydroxychloroquine and low-dose steroids have been safely used for flares of SLE during pregnancy,  most of those drugs should be avoided during the first trimester. Therefore, the decision to use medications should be made after careful assessment of the risks and benefits in consultation with the patient.

Next:

Pathophysiology

The pathophysiology of systemic lupus erythematosus (SLE) disease activity during pregnancy remains unknown. Increased SLE disease activity is expected during pregnancy because of increased levels of estrogen, prolactin, and T–helper cell 2 cytokines. The incidence of exacerbations during pregnancy and the postpartum period, especially in women in remission at the beginning of pregnancy, has been progressively diminishing over the past few decades.

Possible causes of flares during the postpartum period include the following:

  • Decreased levels of anti-inflammatory steroid
  • Elevated levels of prolactin (ie, proinflammatory hormone)
  • Changes in the neuroendocrine axis
  • Changes in estrogen and progesterone levels
Previous
Next:

Epidemiology

United States statistics

The prevalence of systemic lupus erythematosus (SLE) is 14.6-50.8 cases per 100,000 population. In the United States, the overall average incidence of SLE from 1950 to 1990 was estimated to be 1.8-7.6 cases per 100,000 person-years. Lupus exacerbation during pregnancy occurs in about 20-30% of women with SLE.

The frequency of exacerbation or persistently active disease varies with disease activity at conception. Rates range from 7-33% in women who have been in remission for at least 6 months to 61-67% in women who have active disease at the time of conception.

Renal disease flare is the most common exacerbation seen. Serositis with pleural and pericardial effusions is noted in up to 10% of these patients.

International statistics

Incidences in 4 European cohorts from Iceland, England, and Sweden were similar to those observed in the United States. Rates in these cohorts were 3.3-4.8 cases per 100,000 person-years. The incidence of renal disease exacerbation in European populations is comparable to that in the United States population. [6]

Age-related demographics

SLE in pregnancy affects female adolescents and women of reproductive age. The incidence peaks between ages 15 and 45 years (ie, the childbearing years). No definite studies are available, but lupus exacerbations are more commonly seen in younger patients during pregnancy.

Sex-related demographics

The incidence of lupus is dramatically higher in women than in men. During the childbearing years, the female-to-male ratio is about 9:1. In patients with SLE that begins during childhood or later, the female-to-male ratio is approximately 2:1. The race- and sex-specific incidence rates of definite SLE per 100,000 persons were 0.4 in white males, 3.5 in white females, 0.7 in African American males, and 9.2 in African American females.

Race-related demographics

Evidence suggests that SLE is more common in African American and Hispanic groups than in whites. When the prevalence of SLE is stratified by race, the prevalence among African Caribbean individuals was approximately 5 times the rate observed in people of white descent. In the United States, the prevalence of SLE in female African Americans ranges from 17.9-283 cases per 100,000. A West Indian study of female patients with SLE reported a prevalence of 83.8 cases per 100,000.

Lupus nephritis is more commonly seen in Hispanics, followed by African Americans and Caucasians. No definite studies are available, but lupus exacerbations are more commonly seen in African American patients during pregnancy.

Previous
Next:

Clinical Presentation

Patient history

History taking is targeted at identifying systemic lupus erythematosus (SLE) disease activity, complications related to pregnancy, and adverse effects of various medications.

Nausea, vomiting, and morning sickness during the first trimester may prevent absorption of medications. Constitutional symptoms suggestive of SLE disease activity may be present. Most patients with lupus report fatigue during pregnancy. The likelihood of developing renal disease during pregnancy is not increased if the patient is in remission at the time of conception.

Disease flares

In general, pregnancy does not cause flares of SLE. Flares that do develop often occur during the first or second trimester or during the first few months after delivery. Complications due to flare of the lupus activity during pregnancy can cause increased morbidity and mortality, especially with renal disease. Most flares are mild and easily treated with small doses of corticosteroids.

In addition to the obvious morbidity from SLE flares and their treatment, other morbidity is also increased in a pregnancy associated with SLE. Rates of the following are all increased in SLE:

  • Urinary tract infections
  • Gestational diabetes mellitus
  • Hypertension
  • Premature rupture of membranes
  • Preeclampsia .

Renal disease

Patients with organ damage at the time of pregnancy may have difficulty because pregnancy adds to the burden on malfunctioning organs. This phenomenon is particularly important in patients with renal disease.

Pregnancy in women with lupus nephritis is associated with an increased risk of fetal loss (up to 75%) and with worsening of the renal and extrarenal manifestations, as shown in most studies. Although the incidence is not high, severe renal exacerbations are possible. [7, 8] Thus, women with lupus nephritis should be encouraged to delay pregnancy until the disease can be rendered inactive for at least 6 months.

Although the risk of adverse effects on the fetus are minimized if conception and pregnancy occur in the absence of glucocorticoids or other immunosuppressive drugs, continuing glucocorticoids at the lowest effective dose and/or cautious use of azathioprine may be preferred in some patients.

Preeclampsia (toxemia of pregnancy)

Preeclampsia is a frequent complication of pregnancy in SLE, occurring in approximately 13% of patients. It is often difficult to distinguish from lupus nephritis. Laboratory testing is occasionally useful in distinguishing the 2 conditions. Preeclampsia is most likely in patients with antiphospholipid antibodies, diabetes mellitus, or a previous episode of preeclampsia. Pre-existing thrombocytopenia may also be a risk factor.

Thrombosis

Pregnancy, and especially the postpartum period, represents an additional thrombotic risk in patients with SLE who have antiphospholipid antibodies.

Patients who are already taking warfarin because of a past venous or arterial thrombotic event should be switched to therapeutic doses of heparin as soon as the pregnancy is recognized. Patients who have had only fetal losses or other pregnancy morbidity due to antiphospholipid antibody syndrome are treated with prophylactic doses of heparin and low-dose aspirin during subsequent pregnancies.

Currently, no accepted prophylaxis is available for women with SLE who have antiphospholipid antibodies and no past morbidity, although many consider the use of low-dose aspirin, with or without hydroxychloroquine. In a retrospective, single-center cohort study, hydroxychloroquine treatment was associated with a higher rate of live births (67% vs 57%) and a lower prevalence of antiphospholipid antibody–related pregnancy morbidity (47% vs 63%). Fetal losses at >10 weeks of gestation and placenta-mediated complications were also less frequent in hydroxychloroquine-treated women.

Fetal loss

Rates of pregnancy loss are substantially higher in patients with SLE than in control groups. Fetal loss is possible in any trimester. First-trimester losses are associated with antiphospholipid antibodies and with markers of lupus activity (eg, low complement concentrations and increased anti–double-stranded DNA [anti-dsDNA] antibodies) and renal disease. Late losses are associated with antiphospholipid antibodies. Hypercoagulable states other than antiphospholipid antibody syndrome are also associated with increased fetal loss.

Women with SLE with fetal losses who are negative for antiphospholipid antibodies (including lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein 1) should be screened for genetic causes of hypercoagulability, such as factor V Leiden, prothrombin mutation, and hyperhomocysteinemia.

Women with anti-Ro/SSA and anti-La/SSB antibodies may have detectable amounts of these antibodies in breast milk, but no evidence suggests that neonatal lupus results from breastfeeding.

Infertility

SLE is not associated with infertility perse. Use of  mycophenolate and cyclophosphamide can lead to premature ovarian failure. Egg banking should be discussed with all young patients before starting these medications.

Neonatal lupus

Neonatal lupus typically manifests as congenital heart block or as lupus rash. In rare cases, it may manifest as hepatic or hematologic involvement.

Neonatal lupus is rare in SLE pregnancies, occurring in 3.5% of cases in one series. Neonatal lupus is highly associated with maternal anti-Ro/SSA (usually also with anti-La/SSB) antibodies, although the rash may occur with anti-ribonucleoprotein (RNP) antibodies. Because not all pregnancies in the setting of anti-Ro/La antibodies are associated with congenital heart block, prophylactic treatment is not appropriate. Instead, fetal 4-chamber cardiac echocardiography performed at 16-28 weeks’ gestation is recommended (see Other Studies).

Most babies with congenital heart block can be delivered at term; if severe hydrops is present, early cesarean delivery is necessary. Pacing is occasionally required in the neonate. Rare children with congenital heart block develop a connective tissue disease in adolescence.

Previous
Next:

Diagnosis

Signs and symptoms of normal pregnancy must be differentiated from those of exacerbations of systemic lupus erythematosus (SLE). Differentiate malar rash from chloasma. Differentiate proteinuria secondary to preeclampsia from proteinuria due to lupus nephritis. Renal disease secondary to an exacerbation of lupus may be difficult to differentiate from preeclampsia.

Differentiate thrombocytopenia in pregnancy (ie, hemolysis, elevated liver enzyme levels, and low platelet counts [HELLP] syndrome) from thrombocytopenia of lupus exacerbation (ie, thrombotic thrombocytopenic purpura [TTP] or idiopathic thrombocytopenic purpura [ITP]).

Pedal edema and fluid accumulation in joints, especially the knees, can occur in the late stages of pregnancy and should be differentiated from the arthritis of SLE.

Previous
Next:

Laboratory Studies

At the first visit after or when pregnancy is confirmed, the following assessments are recommended:

  • Physical examination, including blood pressure evaluation
  • Renal function tests, including determination of the glomerular filtration rate, urinalysis, and tests of the urine protein–to–urine creatinine ratio
  • Complete blood count (CBC)
  • Test for anti-Ro/SSA and anti-La/SSB antibodies
  • Lupus anticoagulant and anticardiolipin antibody studies
  • Anti–double-stranded DNA (anti-dsDNA) test
  • Complement (CH50 or C3 and C4) tests

During the first 2 trimesters, a monthly platelet count or CBC is recommended. The following evaluations are recommended at the end of each trimester of pregnancy:

  • Determination of the glomerular filtration rate and measurement of the urine protein–to–urine creatinine ratio
  • Anticardiolipin antibody measurement
  • Complement (CH50 or C3 and C4) test
  • Anti-dsDNA antibody study

Lupus nephritis is often associated with proteinuria and/or an active urine sediment (red blood cells [RBCs], white blood cells [WBCs], and cellular casts), whereas only proteinuria is seen in patients with preeclampsia.

Flares of systemic lupus erythematosus (SLE) are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies; in comparison, complement levels are usually (but not always) increased in patients with preeclampsia.

Thrombocytopenia, elevated serum levels of liver enzymes and uric acid, and decreased urinary excretion of calcium are more prominent in patients with preeclampsia than in those with lupus nephritis. However, thrombocytopenia may also be associated with antiphospholipid antibodies, thrombotic thrombocytopenic purpura, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.

In the PROMISSE Study (redictors of pegnancy utcome: Bioarkers n antiphospholipid antibody yndrome and ystemic upus Erythematosus), Circulating angiogenic factors measured during early gestation proved to have a high negative predictive value for ruling out the development of severe adverse outcomes among patients with SLE and/or antiphospholipid (APL) syndrome.  

At 12-15 weeks’ gestation, elevated levels of fms-like tyrosine kinase 1 (sFlt1) were the strongest predictor of severe adverse pregnancy outcomes. At 16-19 weeks, the combination of sFlt1 and placental growth factor (PlGF) was most predictive of severe adverse pregnancy outcome, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL). When the sFlt1/PlGF ratio at 16-19 weeks was used as a screening test with a cutoff of more than 3.45, the positive predictive value was 41% and the negative predictive value was 97%.

 

Previous
Next:

Other Studies

Fetal echocardiography

Women who have antibodies to Ro/SSA and/or La/SSB are at increased risk of pregnancies complicated by fetal heart block and may benefit from serial fetal echocardiographic monitoring. The goal is to detect fetal heart block at an early stage, when therapeutic interventions may prevent its progression. If heart block of any degree is found, dexamethasone 4 mg/day is given to the mother because it crosses the placenta. Third-degree heart block is rarely reversible.

Ultrasonography

Women with systemic lupus erythematosus (SLE) are at increased risk for intrauterine growth restriction and preterm birth. Therefore, menstrual dating should be confirmed with ultrasonography at the first prenatal visit to accurately estimate the gestational age.

Renal biopsy

In pregnant patients with renal disease, renal biopsy should be performed to differentiate preeclampsia from active lupus nephritis when differentiation on clinical grounds is not possible.

Previous
Next:

Treatment & Management

A rheumatologist, an obstetrician experienced with high-risk care, and a nephrologist (if renal disease present or if it develops later) should work as a team to care for a pregnant patient with systemic lupus erythematosus (SLE).

Preconception counseling

Preconception counseling is recommended. Counsel patients about the teratogenicity and adverse effects of the medications used to treat SLE before therapy is initiated. Patients may need to be reminded about the importance of using contraception while they are taking methotrexate, leflunomide, cyclophosphamide, and mycophenolate.

Educate patients that, because of prolonged half-lives, some medications may need to be discontinued several months before the planned conception. In addition, measures may need to be undertaken to enhance elimination of some medications as soon as pregnancy is detected.

Women with lupus and the antiphospholipid antibody syndrome will require more frequent monitoring than those with SLE alone.

Pharmacologic therapy

None of the medications used in the treatment of systemic lupus erythematosus (SLE) is absolutely safe during pregnancy. Hence, whether to use medications should be decided after careful assessment of the risks and benefits in consultation with the patient. During the first trimester, most of the drugs should be avoided.

In the absence of any historical features of antiphospholipid syndrome (recurrent pregnancy loss, venous or arterial thromboembolism), patients with lupus anticoagulant and/or high levels of anticardiolipin antibodies should receive low-dose aspirin. Some suggest the use of low-dose heparin and aspirin for such patients, even in the absence of previous pregnancy complications.

Although, breastfeeding is feasible for most women with SLE, some medications may enter breast milk. Therefore, immunosuppressive agents are contraindicated, and long-acting NSAIDs are inadvisable. Short-acting NSAIDs, antimalarials, low-dose prednisone, warfarin, and heparin seem to be safe.

Patients can breastfeed if they are not taking azathioprine, methotrexate, cyclophosphamide, or mycophenolate. Hydroxychloroquine is also secreted in breast milk; therefore, this drug should be used with caution. Hydroxychloroquine may displace bilirubin, resulting in kernicterus.

Prednisone (<15-20 mg/d) can be used safely during breastfeeding because small amounts (5% of the glucocorticoid dose) are secreted in breast milk. At doses of prednisone higher than 20 mg once or twice daily, breast milk should be pumped and discarded 4 hours after the dose to minimize drug exposure to the infant.

NSAIDs should be used with caution in newborns without jaundice because NSAIDs can displace bilirubin and predispose the fetus to kernicterus.

Diet and activity

A low-salt diet is recommended in pregnancy to prevent weight increase and hypertension. Calcium and vitamin D supplementation may be advised to prevent osteoporosis.

An exercise program may help prevent bone loss and depression. Strenuous activity is best avoided when patients have flareups.

Deterrence/prevention

Risk assessment in terms of checking for antiphospholipid antibodies (for a risk of fetal loss) and for anti-Ro/SSA and anti-La/SSB antibodies (for a risk of neonatal lupus) should be performed before pregnancy.

Patients should avoid pregnancy when lupus is active, especially in the presence of active renal disease, which can be exacerbated during pregnancy and difficult to control.

Patients should use contraception while they are taking immunosuppressive disease-modifying drugs, such as mycophenolate and, in particular, cyclophosphamide. Malformations of the fetus from these drugs are possible. Cyclophosphamide is absolutely contraindicated during pregnancy.

Previous
Next:

Prognosis

The long-term effect of pregnancy in patients with systemic lupus erythematosus (SLE) is unknown. Data from retrospective studies suggest no clinically significant adverse or positive effect of pregnancy on the course of SLE.

Currently, more than 50% of all pregnancies in women with lupus have a normal outcome. About 25% of women with lupus deliver healthy babies prematurely. Fetal loss due to spontaneous abortion occurs in fewer than 20% of cases. Patients with SLE may have increased rates of emergency or cesarean delivery secondary to flares of renal disease or preeclampsia.

Over the past 50 years, the survival rate in patients with SLE has improved dramatically. In 1955, the 5-year survival rate was only 50%, whereas by the 1990s, the 10-year survival rate was approaching or exceeding 90%, and the 20-year survival rate was approaching 70%. Factors contributing to this improvement include early diagnosis, increased potency of pharmaceutical agents, and improved treatments (eg, dialysis, kidney transplantation).

Nonetheless, despite improved survival rates, mortalities among patients with SLE remain 3-5 times greater than those in the general population. As with studies of incidence and prevalence, research about factors predictive of mortality in patients with SLE has focused on the patient’s sex, race or ethnicity, socioeconomic status, or age at disease onset.

In a prospective study, hypertension during pregnancy, preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism were more common in women with SLE than in women without SLE. In addition, fetal growth restriction/ retardation and neonatal deaths were most often seen in association with SLE.

An increase in fetal mortality rates is seen in women who have Ro/SSA or La/SSB antibodies present, secondary to fetal heart block. This increase can be reduced by collaborating with high-risk obstetricians during follow-up, frequent fetal echocardiograms, and aggressive interventions. [9]

A population-based cohort of children born to 509 women who had ≥1 hospitalization for a delivery(stillbirth or live birth) after SLE diagnosis were compared to a randomly selected group of over 8,000 children born to women without SLE who were matched by maternal age and year of deliver. The children born to mothers with SLE had an increased risk of autism spectrum disorder (ASD) and  congenital heart defects (CHDs) in comparison with children born to women without SLE.. The frequency of recorded ASDs was 1.4% versus 0.6%. [10]  The frequency of CHD was 5.2% versus 1.9%. [11]

Patients with preexisting hypertension, proteinuria, and azotemia are at an increased risk. Pregnancy outcomes in women with SLE who receive renal transplants are remarkably similar to those of other transplant recipients. [12]

Overall, in North America and Europe, prognoses are worse in patients with SLE who are of Asian, Indian, African Caribbean, or Hispanic race than in white patients.

Previous
Next:

Patient Education

Patients should be aware of the potential teratogenic effects of the drugs they are taking. Preconception counseling must be stressed. Use of contraception must be stressed frequently while patients are taking teratogenic medications.

When treatment is recommended during pregnancy, patients must be informed of the potential adverse effects of the drugs on the fetus.

Previous
Next: