AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders that affect women during their childbearing years. Typical clinical symptoms of SLE include fatigue, fever, arthralgias, arthritis, a photosensitive rash, serositis, Raynaud phenomenon, glomerulonephritis, vasculitis, and hematologic abnormalities. Flares of SLE are uncommon during pregnancy and are often easily treated. The most common symptoms of these flares include arthritis, rashes, and fatigue.

SLE increases the risk of spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth. Prognoses for both mother and child are 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.

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.

Pathophysiology

The pathophysiology of 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 in the last 30 years. Possible causes for flare-ups during the postpartum period include decreased levels of anti-inflammatory steroid, elevated levels of prolactin (ie, proinflammatory hormone), and changes in the neuroendocrine axis.

Frequency

United States

The prevalence of SLE is 14.6-50.8 cases per 100,000 general population.

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.

In the United States, the overall average incidence of SLE between 1950 and 1990 was estimated to be 1.8-7.6 cases per 100,000 person-years.

International

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.

Mortality/Morbidity

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, in the 1990s, the 10-year survival rate approached or exceeded 90%, and the 20-year survival rate approached 70%. Factors contributing to this improvement include early diagnosis, increased potency of pharmaceutical agents, and improved treatments (eg, dialysis, kidney transplantation).

Race

• Evidence suggests that SLE is more common in African American groups than in white populations. In general, prognoses are worse in African American or Hispanic patients with SLE than in white patients.
• 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.
• 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.

Sex

The incidence of lupus is dramatically higher in women than in men. The race- and sex-specific incidence rates of definite SLE per 100,000 persons were 0.4 (95% CI, 0.2-0.7) in white males, 3.5 (95% CI, 2.9-4.2) in white females, 0.7 (95% CI, 0-2) in African American males, and 9.2 (95% CI, 6.8-12.5) in African American females.

Age

SLE in pregnancy affects female adolescents and women of reproductive age.

• The incidence peaks between ages 15 and 45 years, ie, the childbearing years, when the female-to-male ratio is about 12:1.
• In patients with SLE that begins during childhood or later, the female-to-male ratio is approximately 2:1.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

History taking is targeted at identifying disease activity, complications related to pregnancy, and adverse effects of various medications.

• General considerations
• • 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 less than 20% of cases.
• Symptoms due to pregnancy
• • Nausea, vomiting, and morning sickness can occur during the first trimester.
  • The aforementioned symptoms may prevent absorption of medications.
• Symptoms suggestive of lupus disease activity
• • Constitutional symptoms 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 was in remission at the time of conception.
• Differentiation of signs and symptoms of normal pregnancy from those of exacerbations of lupus
• • Differentiate malar rash from chloasma.
  • Differentiate proteinuria secondary to preeclampsia from proteinuria due to lupus nephritis.
  • Differentiate thrombocytopenia in pregnancy (ie, hemolysis, elevated liver enzyme levels, and low platelet counts [HELLP] syndrome) from thrombocytopenia of lupus exacerbation (ie, thrombocytopenic purpura [TTP] or idiopathic TTP [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 systemic lupus erythematosus (SLE).

Physical

• Flares
• • In general, pregnancy does not cause flares.
  • Flares that do develop often occur during the first or second trimester or during the first few months after delivery.
  • Most flares are mild and easily treated with small doses of corticosteroids.
• 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. 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.
• Other comorbidities
• • 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.¹
• Preeclampsia
• • Preeclampsia is a frequent complication of pregnancy in SLE, occurring in approximately 13% of patients.
  • Preeclampsia is often difficult to distinguish from lupus nephritis. Laboratory testing is occasionally useful in distinguishing preeclampsia from nephritis.
  • 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 (either unfractionated or low molecular weight 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 (81 mg) 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 (81 mg), with or without hydroxychloroquine.
• Other causes of morbidity
• • 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 urinary tract infections, diabetes mellitus, hypertension, preterm premature rupture of membranes, and preeclampsia are all increased in SLE.
• Risk assessment: Risk assessment in terms of checking for antiphospholipid antibodies (for a risk of fetal loss) and for anti-Ro and anti-La antibodies (for a risk of neonatal lupus) should be performed before pregnancy.
• Neonatal lupus
• • Neonatal lupus manifests as congenital heart block or as lupus rash. It is rare in SLE pregnancies, occurring in 3.5% of cases in one series. Neonatal lupus is highly associated with maternal anti-Ro (usually also with anti-La) antibodies, although the rash may occur with anti-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.
  • 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.
  • In rare cases, neonatal lupus manifests as hepatic or hematologic involvement.
  • 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.
• Fetal loss
• • Rates of pregnancy loss are substantially increased in patients with SLE compared with 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.
• Breastfeeding
• • Breastfeeding is feasible for most women with SLE. However, some medications may enter breast milk. Therefore, immunosuppressive agents are contraindicated, and long-acting NSAIDs are inadvisable. Short-acting NSAIDs, antimalarials, low-dose prednisone (<15-20 mg/d), warfarin, and heparin seem to be safe.
  • 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.
• Fertility: SLE is not associated with infertility unless the woman has been treated with cyclophosphamide, which leads to premature ovarian failure.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lupus disease activity should be distinguished from other complications seen during pregnancy.

Renal disease secondary to an exacerbation of lupus may be difficult to differentiate from preeclampsia.

Lupus nephritis is often associated with proteinuria and/or an active urine sediment (RBCs, 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.

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.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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
  • CBC count
  • Test for anti-Ro/SSA and anti-La/SSB antibodies
  • Lupus anticoagulant and anticardiolipin antibody studies
  • Anti-dsDNA test
  • Complement (CH50 or C3 and C4) tests
• During the first 2 trimesters, a monthly platelet count or CBC count 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

Imaging Studies

• 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.

Other Tests

• Fetal monitoring: 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Preconception counseling is recommended.
• Counsel patients about the teratogenicity and adverse effects of the medications used to treat systemic lupus erythematosus (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.
• 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.
• Women with lupus and the antiphospholipid antibody syndrome require more frequent monitoring than those with SLE alone.
• In 2007, the European League Against Rheumatism (EULAR) released new recommendations for the treatment of SLE.

Surgical Care

Patients with SLE may have increased rates of emergency or cesarean delivery secondary to flares of renal disease or preeclampsia.

Consultations

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 lupus.

Diet

• A low-salt diet is recommended in pregnancy to prevent weight increase and hypertension.
• An exercise program may help prevent bone loss and depression.
• Calcium and vitamin D supplementation may be advised to prevent osteoporosis.

Activity

Strenuous activity is best avoided when patients have flare-ups.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 listed should be avoided.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

These agents have analgesic, antipyretic, and anti-inflammatory activity. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist. These may include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Drug Category: Disease modifying agents

These agents modify immune responses to diverse stimuli.

Drug Category: Immunosuppressive drugs

These agents may suppress mechanisms responsible for autoimmune reactions.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

These drugs are used to treat the fetus in mothers with positive anti-SSA antibodies.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients may require admission for management of the complications of labor and delivery.

Further Outpatient Care

• All patients should be screened for postpartum depression.
• Patients must be monitored closely after delivery because some are likely to have flare-ups during the postpartum period.

In/Out Patient Meds

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

Transfer

• Transfer to intensive care unit may be required for emergency intervention or monitoring during flares.

Deterrence/Prevention

• Patients should avoid pregnancy when lupus is active, especially in the presence of renal disease.
• Patients should use contraception while they are taking immunosuppressive disease-modifying drugs.

Complications

• Complications due to flare of the disease during pregnancy or the adverse effects of drugs on the fetus are possible.

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.

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to inform patients of the teratogenic effects of certain immunosuppressive drugs
• Failure to inform patients about the potential adverse maternal and fetal effects of the drugs recommended during pregnancy
• Failure to diagnose pregnancy before teratogenic disease-modifying agents are started
• Failure to inform patients to not breastfeed while they are taking certain drugs (eg, azathioprine, mycophenolate, cyclophosphamide)

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. McGrory CH, McCloskey LJ, DeHoratius RJ, et al. Pregnancy outcomes in female renal recipients: a comparison of systemic lupus erythematosus with other diagnoses. Am J Transplant. Jan 2003;3(1):35-42. [Medline].
2. Bermas BL, Hill JA. Effects of immunosuppressive drugs during pregnancy. Arthritis Rheum. Dec 1995;38(12):1722-32. [Medline].
3. Chakravarty EF, Colón I, Langen ES, et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol. Jun 2005;192(6):1897-904. [Medline].
4. Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol. Sep 2005;32(9):1709-12. [Medline].
5. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. Nov 2003;48(11):3207-11. [Medline].
6. Erkan D, Sammaritano L. New insights into pregnancy-related complications in systemic lupus erythematosus. Curr Rheumatol Rep. Oct 2003;5(5):357-63. [Medline].
7. Mintz G, Niz J, Gutierrez G, et al. Prospective study of pregnancy in systemic lupus erythematosus. Results of a multidisciplinary approach. J Rheumatol. Aug 1986;13(4):732-9. [Medline].
8. Moroni G, Quaglini S, Banfi G, et al. Pregnancy in lupus nephritis. Am J Kidney Dis. Oct 2002;40(4):713-20. [Medline].
9. Repke JT. Hypertensive disorders of pregnancy. Differentiating preeclampsia from active systemic lupus erythematosus. J Reprod Med. Apr 1998;43(4):350-4. [Medline].
10. Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol. Feb 1996;35(2):133-8. [Medline].
11. Tandon A, Ibañez D, Gladman DD, Urowitz MB. The effect of pregnancy on lupus nephritis. Arthritis Rheum. Dec 2004;50(12):3941-6. [Medline].
12. Urowitz MB, Gladman DD, Farewell VT, et al. Lupus and pregnancy studies. Arthritis Rheum. Oct 1993;36(10):1392-7. [Medline].

Article Last Updated: Feb 14, 2008