Pregnancy in Women With Lupus: We Have Come So Far and Have So Far to Go

Abstract

Substantial progress has been made during the past 20 years in pregnancy management and outcomes in women with systemic lupus erythematosus (SLE), as Mehta and colleagues show in their current article in Annals (1). Thirty years ago, most women with SLE were advised to avoid pregnancy because of high risks for maternal and fetal morbidity and mortality. Now, this advice has shifted entirely, and most women with SLE, with careful management, can safely build a family thanks to several developments. Many prospective cohorts of pregnant women with SLE have demonstrated that disease activity in the months before and during pregnancy is the prime predictor of adverse events (2). For this reason, women are encouraged to use effective contraception to avoid becoming pregnant while their lupus is active. Historically, the prevailing approach to SLE management in pregnancy was to hold all medicationsfor fear these agents might cause fetal harmand hope for the best. Now, however, hydroxychloroquine (HCQ) is considered standard of care for pregnant women with SLE. The first and only randomized trial of HCQ was published in 2001, a few years after several major academic centers started to routinely prescribe it to women with SLE during pregnancy (3). The primary benefit seems to be lupus disease control: Continuing the drug during pregnancy eliminates the increased risk for a pregnancy-related flare (4). However, use by pregnant women with SLE remains suboptimal: Its frequency of use increased from 12.4% in 2001 to only 37.7% in 2015 (5). In recent decades, study of large cohorts of pregnant women with inflammatory bowel disease and solid organ transplants found that several key immunosuppressant medications are compatible with pregnancy (2). Azathioprine, 6-mercaptopurine, tacrolimus, and cyclosporine are now prescribed routinely during pregnancy, without increasing risk for fetal anomalies. Several randomized trials showed that daily low-dose aspirin decreases the risk for preeclampsia by about 20% in high-risk pregnancies. In 2014, the U.S. Preventive Services Task Forceand subsequently the American College of Obstetrics and Gynecology (ACOG) in 2018recommended daily low-dose aspirin for all pregnant women with SLE (6, 7). Yet, few pregnant women with SLE are currently managed with aspirin. A recent analysis of data from academic centers across the globe found that only 25% of these women receive aspirin (8). Antiphospholipid syndrome was first reported in 1983 by Dr. Graham Hughes and colleagues, who linked recurrent pregnancy loss, early preeclampsia, and thrombotic events to false-positive syphilis test results, antiphospholipid antibodies, and lupus anticoagulant (9). The syndrome is diagnosed in up to about 20% of SLE pregnancies in some cohorts, placing these women at high risk for fetal loss and maternal thrombosis. The benefits of treatment with heparin and aspirin to decrease pregnancy loss were clear in the late 1990s and early 2000s, and therapy with low-molecular-weight heparin plus low-dose aspirin is now routine during pregnancy and 6 weeks after delivery for women with antiphospholipid syndrome. In 1999, ACOG published a practice bulletin recommending routine prepartum testing for women at high risk for stillbirth, including those with SLE or antiphospholipid syndrome (10). This evaluation includes repeated fetal ultrasonography, starting at around 32 weeks of gestation, to identify fetuses at high risk for death, allowing for early delivery. Within the context of these great advances in the management of pregnant women with SLE, Mehta and colleagues (1) used the National Inpatient Sample (NIS) database to identify improvements over 18 years in both maternal and fetal mortality among pregnant women with SLE (1). Fetal mortality dropped from more than 250 deaths per 10000 deliveries to just over 150 deaths per 10000 deliveries, with most of the decline seen in the first half of the study period. Maternal mortality declined progressively, with a decrease in the final period, suggesting that the risk for maternal death during SLE pregnancy has been nearly eliminated. Although a progressive reduction in maternal mortality seems very likely, the final decrease from 140 maternal deaths per 100000 births in 2010 to 2012 to fewer than 50 per 100000 in 2013 to 2015 warrants some reflection for 3 reasons. First, SLE pregnancy management has not advanced within the past 5 years to an extent great enough to explain such a large drop in mortality. Second, because the NIS reports about 20% of all hospital deliveries, very rare events, such as maternal deaths in women with SLE, may take on an outsized meaning. The NIS data use agreement warns against using data for very rare events in an analysis, requesting that researchers avoid publishing data points with fewer than 10 events to avoid revealing patient identity. Very few deaths seem to have occurred in the final 3 years of the study period. The accuracy of estimates based on a small number of maternal deaths might be altered dramatically by a shift in the women sampled. Third, the SLE diagnosis in the NIS might include pregnancies in women who do not have SLE, but perhaps have an elevated level of antinuclear antibody or lupus anticoagulant. Including these pregnancies might dilute the frequency of poor outcomes, perhaps explaining the lower rate of preeclampsia in this study (approximately 9%) than in prospective SLE pregnancy cohorts (approximately 20%). For these reasons, I am concerned that the observed decline in maternal mortality may be an artifact, underestimating the ongoing risk of pregnancy for women with SLE. Mehta and colleagues have demonstrated important improvements in maternal and fetal mortality by using one of the few data sets large enough to study these rare events. Work still must be done, however, regarding preeclampsia and fetal and maternal mortality, each of which is several times more common in women with SLE than in those without the disease. Although great advances have been made in therapy, recent analyses demonstrate that use of HCQ and aspirin in SLE pregnancy is not widespread. The inaugural reproductive health guidelines soon to be published by the American College of Rheumatology will have the potential to help expand state-of-the-art approaches to the management of pregnant women with SLE seen in everyday practice.