INTRODUCTION

As systemic lupus erythematosus (SLE) treatment has improved, more women with lupus are able to become pregnant. Whereas pregnancy used to be discouraged in these women, it is now a frequent issue raised by patients to their physicians. The majority of women with lupus can successfully carry a pregnancy and deliver a healthy infant. The chances for this are improved if the lupus is well controlled and the woman is followed carefully by both a rheumatologist and an obstetrician trained in high-risk pregnancies.

There are some women, however, who should carefully consider the risks of pregnancy prior to conception. These include women taking immunosuppressant medications (especially cyclophosphamide, mycophenolate mofetil, and methotrexate) and women with a prior history of arterial thrombosis from antiphospholipid syndrome (APS). Cyclophosphamide, mycophenolate mofetil, and methotrexate are contraindicated during pregnancy (particularly in the first trimester), as they frequently lead to fetal anomalies. Women with prior arterial thrombosis are at high risk for repeated (sometimes catastrophic) arterial thrombosis during pregnancy despite adequate anticoagulation. This chapter discusses the risks of pregnancy to lupus, the risks of lupus to pregnancy, and recommended methods of monitoring and treating these women in order to decrease these risks.

EPIDEMIOLOGY

The Effect of Lupus on Fertility

The majority of women with SLE maintain their fertility and can even conceive during a time of severe lupus activity. The number of pregnancies that occur in a woman with lupus is similar to that seen in healthy women of the same age.^1,² However, the majority of the pregnancies occurred prior to the onset of lupus in the studies that compare fertility rates. It is not clear if the reason for fewer pregnancies after diagnosis is because of the increased age of the mother, the personal choice of a woman with a serious illness, the warnings of physicians, or ovarian failure due to cyclophosphamide treatment.

The Effect of Lupus on Pregnancy

Women with lupus have an increased rate of pregnancy loss over women without lupus (Table 40.1). In a comparison study of women with lupus compared with their friends and relatives, 60% of pregnancies that occurred after the onset of lupus ended in a live birth versus 80% of those in healthy friends and 87% in relatives (p<0.01).¹ A population study in the United Kingdom confirmed this increase in pregnancy loss, with 23% of pregnancies after the onset of lupus ending in loss compared to 8% of those in controls (p<0.01).² Similarly, a Greek case-control study demonstrated a fourfold increase in pregnancy loss in women with lupus versus healthy women.³

TABLE 40.1 THE EFFECT OF LUPUS ON PREGNANCY

Fertility rate	Similar to women without lupus
Pregnancy loss rate	Increased over women without lupus Between 15 and 30% of pregnancies end with a loss	Increased risk for loss: High activity lupus Antiphospholipid syndrome Hypertension Lupus nephritis Prior pregnancy losses
Preterm birth rate	Increased over women without lupus At least a third of lupus pregnancies deliver before 37 weeks gestation	Increased risk for preterm delivery: High activity lupus Antiphospholipid syndrome Hypertension Prednisone use Immunosuppressive medications

The rate of pregnancy loss varies between the reported cohorts of lupus pregnancies, ranging from 13 to 59% and averaging about 20%.⁴^–⁶ The few studies with loss rates over 30% had an unusually high rate of elective abortions, perhaps inflating these rates beyond that physiologically associated with lupus.^5,⁷ The timing for each woman’s entry into the cohort, whether it is prior to conception or in the midst of pregnancy, may also impact this rate. A woman who presents to a tertiary center for care in the second or third trimester is not at the same risk for pregnancy loss as a woman who is seen in her first trimester. The standard of care of lupus, high-risk pregnancies, and premature infants has improved over the decades in which the cohorts of lupus pregnancies have been collected. A comparison of lupus pregnancy loss rates from the 1960s (43%) to the twenty-first century (17%) demonstrates the benefits of these improvements.^8,⁹

Miscarriage, defined as a pregnancy loss prior to 20 weeks of gestation, is the most common form of pregnancy loss in all pregnancies, including those affected by lupus. However, the rate of stillbirths (defined as a pregnancy loss after 20 weeks gestation) is particularly elevated in lupus pregnancies. In developed countries, the stillbirth rate is generally under 1.5%. However, in pregnancies affected by lupus this rate can be as high as 11%.¹⁰^–¹²

The strongest risk factors for pregnancy loss in lupus are increased lupus activity at conception or during pregnancy, and secondary antiphospholipid syndrome (APS).^10,¹³^–¹⁵ Other risk factors include hypertension, hypocomplementemia, and renal disease.^10,¹⁶ Women who have the onset of lupus during pregnancy (“gestational lupus”) are also at high risk for pregnancy loss.¹⁴

A preterm birth is usually defined as a live birth before 37 weeks of gestation, which occurs in about 12% of all pregnancies in the United States.¹⁷ A third of lupus pregnancies, however, end with a preterm birth.⁶ Some of the increase in prematurity is iatrogenic: the physician decides to deliver a pregnancy early because of the presence of lupus. There is, however, also an increased risk of preterm premature rupture of membranes in women with lupus.¹⁸ Risk factors for preterm delivery are similar to those that cause pregnancy loss. These include increased lupus activity, secondary antiphospholipid syndrome (APS) and the presence of antiphospholipid antibodies, and prednisone use during pregnancy.^6,^10,¹³

The long-term effects of maternal lupus on offspring have not been systematically studied. There does not appear to be an increase in the rate of congenital abnormalities in these offspring.¹⁹ Several reports, however, demonstrate an increase in learning disabilities in the sons of lupus patients, particularly women with Ro or La antibodies.²⁰^–²³

APS is associated with repeated pregnancy failure, preterm birth, and preeclampsia. This syndrome is further discussed in Chapter 36. The presence of Ro and/or La antibodies puts an infant at risk for congenital lupus, which is discussed in Chapter 42.

The Effect of Pregnancy on Lupus

There is considerable debate as to whether pregnancy increases lupus activity or not. Some studies show that the rate of lupus flare in women who become pregnant increases several-fold over that of lupus patients who are not pregnant.^12,²⁴ Other studies have not found an increased risk for lupus flare during pregnancy.²⁵^–²⁸ Fortunately, most lupus flares during pregnancy are mild to moderate and involve the skin and joints.^3,^4,²⁴ There are a few women, however, who will develop a severe lupus flare during pregnancy. The risk for lupus flare exists in each trimester, and also in the weeks following delivery.

The risk of flare during pregnancy is increased by the presence of lupus activity at the time of conception.^14,¹⁵ In the Hopkins Lupus cohort, women with increased activity in the six months prior to conception had a fourfold risk for increased lupus activity during pregnancy.¹³ Other risks for increased lupus activity in pregnancy include cessation of anti-malarial medication, prior history of lupus nephritis, and a history of three or more lupus flares.^10,^29,³⁰

Proteinuria is common during lupus pregnancy and can be related to chronic renal disease, preeclampsia, or increased lupus activity. In the Hopkins Lupus cohort, 25% of women had over 500 mg/24 hour of protein in their urine at some point during pregnancy. This rate is similar to that reported in other cohorts, with rates ranging between 5 and 20%.^3,^10,²⁶ The rate of renal failure after pregnancy is low. There are isolated reports of dialysis dependence after a lupus nephritis flare during pregnancy. However, the vast majority of women regain renal function with aggressive medical therapy after delivery.^3,^10,^24,^31,³²

The risk of maternal death after pregnancy, although low, may be higher than in the general population. A population-based study of all lupus-related births in California in a two-year period revealed 555 births and no maternal deaths.³³ In the Hopkins Lupus cohort, 3 out of 265 pregnancies ended with a maternal death within six weeks of delivery. Few other cohorts report any maternal deaths.^3,¹¹ The causes of death include HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, thrombosis associated with APS, pulmonary hypertention, and infection following severe lupus flare.³⁴

PATHOGENESIS

Placental damage from inflammation and ischemia are likely the main pathogenic mechanisms for complications in lupus pregnancy. Placentas from pregnancies affected by lupus are smaller than those resulting from healthy pregnancy, with over 25% of them weighing less than 2 standard deviations below normal size.³⁵ Placentas in pregnancies affected by active lupus may show signs of chronic inflammation. With immunofluorescence, deposits of immunoglobulins and complement may be found in uterine blood vessels and within the placenta.^36,³⁷ Inflammation in the uterus may damage the placenta, leading to poor delivery of blood, nutrients, and oxygen to the fetus—resulting in intrauterine growth retardation. Inflammation may also mimic the cytokine cascade found in infectious chorioamniitis, which can prompt premature rupture of membranes and preterm labor.³⁸

The placental damage caused by secondary APS may be more related to complement activation by antiphospholipid antibodies than by thrombosis. A murine model has demonstrated that an intact complement cascade is required for pregnancy loss from exposure to antiphospholipid antibodies.³⁹ This model also demonstrates that the main function of heparin may be to decrease complement activation, rather than to serve as an anticoagulatant.⁴⁰

Ischemia can also lead to poor placental function. This may occur because of poor spiral artery recruitment early in pregnancy, leading to decreased blood flow as the demands of the fetus increase later in pregnancy.³⁶ Ischemia may also occur from artery occlusion by thrombosis, particularly in patients with secondary APS. Up to a third of placentas from women with lupus and antiphospholipid antibodies have greater than 20% of their volume consumed by infarction, and almost half have diffuse ischemia.³⁵ As the placenta ages, the degree of atherosis increases, which can lead to placental insufficiency. In lupus pregnancies, however, there is a much greater increase in atherosis, contributing to diffuse ischemia within the placenta.³⁶

Monitoring Pregnancy

The combined skills of a high-risk obstetrician and rheumatologist are best suited to following a woman with lupus during pregnancy. The patient must be monitored for increased lupus activity, preeclampsia, and preterm labor. The fetus must be closely watched to ensure adequate growth and development, particularly in the third trimester.

Clinical

Many symptoms of normal pregnancy can mimic symptoms of active lupus, and vice versa. In normal pregnancy, many women suffer significant fatigue. Pregnancy can also lead to skin changes such as palmar erythema, facial blushing, and melasma. Melasma (or the “mask of pregnancy”) results in a macular, photosensitive, hyperpigmented area over the cheeks and forehead. Hair loss is very common in the months after delivery, as is hair regrowth that can be most obvious in the temples. A pregnant woman may develop mild shortness of breath early in pregnancy from increased progesterone and late in pregnancy because of the enlarging uterus, although they are generally not hypoxic. Many pregnant women will develop back pain as their gravid uterus increases their lumbar lordosis. They may also develop noninflammatory knee effusions. Finally, pregnancy complications such as hypertension and preeclampsia may cause seizures or headaches.

Signs and symptoms of active lupus in pregnancy are similar to those of non-pregnant lupus patients. In the Hopkins Lupus Pregnancy cohort of 265 pregnancies, 26% of lupus patients had cutaneous findings during pregnancy—including malar rash, discoid lesions, and photosensitivity. Arthritic complaints were also common, occurring in 20% of pregnancies, with findings of joint swelling and morning stiffness. Serositis, manifesting as pleuritic chest pain (pain that increases with inspiration) and shortness of breath, is also an indication of increased lupus activity and occurred in 9% of pregnancies in the Hopkins cohort. Less common lupus findings included neurologic changes in 3% and pulmonary disease in 1%.

Laboratory

Laboratory data can be helpful in predicting pregnancy complications, assessing lupus activity, and distinguishing between lupus activity and preeclampsia.

Predicting Complications

There are several autoantibodies and laboratory changes that can either precede pregnancy or develop in the course of pregnancy. These should be assessed as early in pregnancy (or prior to pregnancy if possible) and repeated as needed.

Ro and La Antibodies

SSA/Ro antibodies are found in 35% and SSB/La antibodies are found in 15% of SLE patients.⁴¹ They can also be clinically associated with Sjogren’s syndrome. The presence of Ro and La antibodies places a fetus at risk for neonatal lupus; namely, congenital heart block or neonatal lupus rash (see Chapter 42). These autoantibodies should be assessed early in pregnancy. If they are positive in pregnancy or at any point prior to pregnancy, the women will need to undergo weekly fetal four-chamber echocardiography between weeks 16 and 28 of gestation.

Antiphospholipid Antibodies

APS is associated with a significant increase in pregnancy loss and preterm birth. (See Chapter 36.) At the onset of pregnancy, anticardiolipin antibodies and the lupus anticoagulant should be tested. If either of these is positive, they should be confirmed six weeks later.

Double-stranded DNA Antibodies

These antibodies are positive in 40% of patients with lupus.⁴¹ Antibodies to double-stranded DNA (dsDNA) vary over time, and their ability to predict lupus flare is debated.^42,⁴³ In the Hopkins Lupus Pregnancy cohort, the presence of the dsDNA antibody increased the risk for preterm birth whether or not there was increased clinical lupus activity (44% without dsDNA versus 60% with dsDNA). In women with both highly active lupus clinically and dsDNA antibodies, the risk for perinatal mortality increased more than fivefold.⁴⁴

Complement

Complement activation is an important component of lupus pathophysiology, and a decrease in complement levels may signal an increase in lupus activity. Complement is best measured with C3 and C4 levels, both of which may fall during a lupus flare.^45,⁴⁶ During pregnancy in healthy patients, complement can increase by 10 to 50%, and there may be an increase in the degree of complement activation.⁴⁷ Half of the pregnancies in the Hopkins Lupus Pregnancy cohort were hypocomplementemic. Hypocomplementemia during pregnancy led to a small increase in the risk for pregnancy loss. However, women with both increased lupus activity clinically and low complement had a fivefold increase in risk for stillbirth. Only 16% of pregnancies with increased lupus activity clinically and low complement resulted in a full-term birth.⁴⁴ C3 and C4 levels should be monitored monthly during pregnancy.