Lupus Affects Pregnancy Outcome Even Before Diagnosis

Janis C. Kelly

February 16, 2016

Pregnancy complications and poor fetal outcomes are known to be more common among women with systemic lupus erythematosus (SLE) during pregnancy. Now researchers report that the risk is also elevated among women who had subclinical SLE during pregnancy but were diagnosed within 5 years postpartum.

"Our study supports the idea that the underlying immunologic profile of subclinical SLE may be associated with higher likelihood of adverse maternal and fetal outcomes," write Elizabeth V. Arkema, PhD, and colleagues in an article published online February 1 in Arthritis Care & Research.

The data from the prospective cohort study confirm what was already known about pregnancy with SLE: increased risk for preeclampsia, preterm birth, and small-for-gestational-weight infants, says Sara K. Tedeschi, MD, rheumatology fellow at Brigham and Women's Hospital, Boston, Massachusetts.

"What is new is that prior studies have not specifically evaluated pregnancy outcomes among women who were later diagnosed with SLE compared to outcomes among healthy women," Dr Tedeschi told Medscape Medical News. "In this study, women who were diagnosed with SLE within 2 years after delivery had a higher proportion of adverse pregnancy outcomes compared to women with prevalent SLE and women without SLE, although whether these differences were statistically significant was not reported."

The researchers identified women with first singleton pregnancies registered in the Swedish Lupus Linkage database and in the Swedish Medical Birth Register, including 551 women with prevalent SLE, 65 with pre-SLE diagnosed within 0 to 2 years after pregnancy, and 133 with pre-SLE diagnosed within 2 to 5 years. Maternal and fetal outcomes in these women were compared with those of a randomly selected matched sample from the general population in the Swedish Medical Birth Register (n = 12,847).

The authors found that diagnosed SLE or pre-SLE was associated with an increased risk for Cesarean delivery, preterm birth, preeclampsia, serious infection during pregnancy, hypothyroidism, and postpartum stroke. Risk was highest in women with prevalent SLE and in those diagnosed with SLE 0 to 2 years after their first pregnancy. Risk was lower for women diagnosed with SLE 2 to 5 years postpartum but was still higher than in the general population.

Specifically, cesarean delivery rates were 35.4% for women with prevalent SLE, 33.9% for pre-SLE diagnosed at 0 to 2 years postpartum, 28.6% for pre-SLE diagnosed at 2 to 5 years, and 16.1% in women without SLE. Preterm delivery rates were 23.4%, 30.8%, 16.5%, and 6.5%, respectively. Preeclampsia rates were 16.2%, 26.2%, 12.8%, and 4.7%, respectively. Hypothyroidism rates were 7.8%, 4.6%, 3%, and 0.7%. Rates for postpartum stroke were 2.5%, 3.1%, 1.5%, and 0.4%.

For infant outcomes, small-for-gestational-age birth rates were 14.7% for infants of mothers with prevalent SLE, 18.5% for infants of women with pre-SLE diagnosed at 0 to 2 years after birth, 14.3% for infants of women with pre-SLE diagnosed at 2 to 5 years, and 3.7% for infants of non-SLE mothers. Rates for 1-minute APGAR scores of 7 or less were18%, 26.2%, 17.3%, and 10.9%. Serious infections in the first year of life occurred in 21.1% 29.2%, 24.8%, and 14% of infants, respectively.

Dr Tedeschi said, "These findings spark further questions about SLE pathogenesis, particularly in the setting of pregnancy. During pregnancy, hormonal changes (including shifts in estrogen/progesterone balance) and immunologic changes (including alterations in natural killer cell activity and T helper cell responses), both of which have been implicated in SLE pathogenesis and activity, could potentially trigger the onset of SLE in women with increased susceptibility due to genetic, environmental, or other factors. This study also raises the question of whether preeclampsia and other adverse pregnancy outcomes could themselves trigger the development of SLE in susceptible women."

Among the study limitations Dr Tedeschi noted were that SLE diagnosis was based on insurance codes and that subclinical SLE was characterized by the future development of SLE within 5 years after delivery. "It is possible that patients in the subclinical SLE group actually had signs and symptoms of SLE that could not be captured in these claims data and were undiagnosed at the time of delivery. As women without a diagnosis of SLE are less likely to be under the care of maternal-fetal medicine specialists during pregnancy, undiagnosed SLE could negatively impact pregnancy outcomes. Furthermore, for women with subclinical SLE, we do not have information about the type or duration of SLE symptoms prior to SLE diagnosis, which are important areas for investigation," she said.

The authors also note that the lack of a diagnosis may affect a woman's care during pregnancy. Whereas average disease activity may be highest in patients with pre-SLE, subclinical pre-SLE pregnancies are unlikely to be labeled as "high risk," and therefore receive ordinary maternal care, often from midwives, rather than the special maternal care appropriate for patients with known SLE. They suggest that in this group of women, unrecognized and untreated SLE may increase disease-related inflammation and autoimmunity during pregnancy.

Dr Tedeschi said this is not an indication for ramping up screening such as antinuclear antibody (ANA) testing, as at least 5% of healthy women have a positive ANA test, but only a small percentage will develop SLE, and an isolated positive ANA test during pregnancy does not predict poor pregnancy outcome.

"On the other hand, given that the pathophysiology of SLE is still not fully understood, identifying biomarkers of preclinical SLE and identifying populations at risk are important areas for further research. Prior work suggests that among patients evaluated by a rheumatologist as having "possible SLE," meaning a combination of positive serologies and clinical symptoms, but not sufficient to be diagnosed with SLE, factors predicting future development of SLE include oral ulcers, dsDNA antibody, and proteinuria or cellular casts. During the course of routine prenatal care, complete blood counts and urinalysis are routinely performed; unexpected cytopenias, proteinuria (beyond the physiologic increase seen in normal pregnancy), or cellular casts should prompt an evaluation for SLE. The sooner the diagnosis of SLE is made, the sooner a woman can start treatment for SLE, which will hopefully improve pregnancy outcomes for both the mother and fetus," Dr Tedeschi said.

According to Dr Tedeschi, since the mid-2000s, use of hydroxychloroquine during SLE pregnancies has been standard of care, and women who enter into pregnancy with quiescent SLE tend to have favorable outcomes. She said, "We still advise women with active SLE, in particular lupus nephritis, to delay conception until their SLE has stabilized and their SLE medications have been switched to nonteratogenic medications when applicable. We recently reported that specific lupus manifestations (lupus nephritis, cytopenias, serositis, arthritis, skin disease), if active in the 6 months before conception, each increased the risk of continued SLE activity of the same type during pregnancy."

The authors and Dr Tedeschi have disclosed no relevant financial relationships.

Arthritis Care Res. Published online February 1, 2016. Abstract

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