by Michelle Petri, M.D., M.P.H
Introduction
Because lupus is a disease that strikes predominantly young women in the reproductive years, pregnancy is both a practical and a research issue. For most women with lupus, a successful pregnancy is possible. This is an immense change from the 1970’s, when most women with lupus were counseled not to become pregnant. Studies of the immune system in pregnancy are of interest for what they have taught us about the effect of hormones on lupus flares.
Risk of Miscarriage
First, the risks of pregnancy in lupus patients are real and involve both the mother and the fetus. About ten percent of pregnancies currently end in miscarriage. The first trimester losses appear either to have no known cause or to associate with signs of active lupus. Later losses occur primarily due to the antiphospholipid antibody syndrome, inspite of treatment with heparin and aspirin. All women with lupus, even if they do not have a previous history of miscarriage, should be screened for antiphospholipid antibodies, both the lupus anticoagulant (the RVVT and sensitive PTT are the best screening battery) and anticardiolipin antibody.
The classification criteria for the antiphospholipid antibody syndrome were revised last year. There are now two major criteria–vascular thrombosis and pregnancy morbidity. A woman who has had a past venous or arterial thrombosis should be therapeutically anticoagulated during the next pregnancy. A woman who has pregnancy morbidity–one or more late losses, three or more first trimester losses, or severe pre-eclampsia or placental insufficiency–should be treated with prophylactic doses of heparin and a baby aspirin during the next pregnancy. Several clinical trials have indicated that the combination of heparin and aspirin is likely preferable to aspirin alone, although some women do have successful pregnancies on aspirin alone. These pregnancies should be considered high risk, with appropriate fetal monitoring, including ultrasounds to monitor growth and placental development, and biophysical profiles, usually from the 26th week onwards. Many of these babies can be rescued by early C-section when there are signs of severe placental insufficiency. There is no consensus on whether treatment is indicated for the woman with lupus who has antiphospholipid antibodies in her first pregnancy. Many authorities in the field would use a baby aspirin in this situation.
Risk of Preterm Birth and Intrauterine Growth Retardation
An equal, if not more important risk is the risk of preterm birth. Preterm birth in lupus is usually not due to antiphospholipid antibodies, but due to pre-eclampsia and premature rupture of membranes. Risk factors for preterm birth in general include active lupus, high dose prednisone, and renal disease. Maternal hypertension in the second trimester is a good predictor. Overzealous treatment of maternal blood pressure could reduce placental blood flow, and is not recommended. We have not found any risk factors that predict premature rupture of membranes. In addition to being preterm, the baby is also at risk for intrauterine growth retardation (IUGR). We have not found a clinical variable that is predictive of IUGR. In fact, lupus activity, prednisone, and antiphospholipid antibodies are not predictive of IUGR. The best predictor using ultrasound monitoring is an abdominal circumference below the 10th percentile and an estimated fetal weight below the 50th percentile.
Maternal Risks
The most important maternal risk, that of a lupus flare, is actually the most controversial. In prospective studies at both Hopkins and in London, the risk of flare is greater in a pregnant than a non-pregnant woman. However, other centers have not confirmed this. There may be differences in patient selection that account for the different findings. We have found that the hormone prolactin, which rises during pregnancy, is associated with lupus activity during pregnancy. Likely other hormonal influences, especially estrogen, changes in cytokines are involved as well, although these have not been studied. We have found that the type of organ system involvement is different in pregnant vs. non-pregnant patients. In pregnancy we have found an excess of renal and hematologic flares, and fewer arthritis flares.
Some of the risk to the mother is not directly due to lupus. In a case-control study we found that women with lupus were more likely to have multiple complications of pregnancy, including diabetes, urinary tract infections, and pre-eclampsia. For this reason, referral to a high-risk obstetrician is always appropriate. Women on prednisone were more likely to have hypertension and diabetes, as would be expected. The physician caring for a woman with lupus who wishes to become pregnant must review her medications. Prednisone is largely metabolized by the placenta, and is unlikely to cause any fetal malformations, but will increase the risk of diabetes and hypertension in the mother. Some immunosuppressives, such as imuran (azathioprine) have been continued during lupus pregnancy when necessary to control maternal lupus. Cyclophosphamide should never be used during pregnancy because of the high risk of important birth defects. Because of potential teratogenicity, Coumadin should be switched to heparin as soon as the woman knows she is pregnant. ACE-inhibitors, because of effects on fetal kidney development, should be stopped as soon as the woman knows she is pregnant. NSAIDs are usually allowed during the first trimester only, because of potential adverse effects on the fetal ductus arteriosus. Plaquenil (hydroxychloroquine) has a good safety record in lupus pregnancy, and is usually continued if needed to control maternal lupus.
Management and Monitoring
Lupus pregnancy should be timed to coincide with a period of good disease control if at all possible. It does not make sense to taper medication simply because a woman desires pregnancy, because of the likelihood of inducing a flare if medications are reduced too low. General screening tests should include the antiphospholipid antibodies, and also anti-Ro and anti-La. A woman who is positive for these antibodies is at increased risk of congenital heart block in the baby, and monitoring of the fetal cardiac conduction system by 4-chamber fetal cardiac echo should be instituted. We generally monitor the mother monthly during pregnancy and obviously more often if disease activity warrants it. Laboratory monitoring done monthly includes the complete blood count, creatinine, liver function tests, urinalysis, and a 24 hour urine for creatinine clearance and total protein. It is controversial whether serologic tests are helpful during pregnancy. In normal pregnancy the C3 and C4 should rise.
Summary
We are lucky to have a long-term collaboration between our high-risk obstetricians and the Lupus Center at Hopkins that has allowed not only for superb clinical care of the mothers and babies, but also for the prospective database that has led to the studies summarized above. For nearly all mothers, a happy outcome is possible, but we must not forget that we have had one maternal death in our 150 pregnancies and that 7% of the pregnancies are characterized by a severe maternal complication. This is our impetus to continue our research into lupus and its interactions with pregnancy.
Selected Reference
Petri M. Systemic lupus erythematosus and pregnancy. Rheum Dis Clin North America 20:87117, 1994.
Fine LG, Barnett EV, Danovitch GM, et al. Systemic lupus erythematosus in pregnancy. Ann Intern Med 94:667-677, 1981.
Cowchock FS, Reece EA, Balaban D, et al. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low dose heparin treatment. Am J Obstet Gynecon 166:1318-23, 1992.
