Women with well-controlled rheumatoid arthritis (RA) who used a tumor necrosis factor (TNF) inhibitor during pregnancy gave birth to infants with higher birth weight than did other patients, without an increased risk of adverse outcomes, according to findings from a Dutch prospective cohort study published online July 11 in Annals of the Rheumatic Diseases.
The study involved 188 patients drawn from the ongoing Preconceptional Counseling in Active RA (PreCARA) study, which followed patients with inflammatory rheumatic diseases before and during pregnancy. Women enrolled in PreCARA were closely monitored and treated with a therapeutic approach that aimed to achieve minimal disease activity, which included the use of TNF inhibitors.
Much research on TNF inhibitors during pregnancy has been limited to the first trimester and focused primarily on congenital malformations. In addition, most previous studies evaluating TNF inhibitors during pregnancy involved patients with different underlying diseases, making it difficult to interpret the results.
Hieronymus T. W. Smeele, MD, and colleagues at Erasmus University Medical Center, Rotterdam, Netherlands, evaluated participants every 3 months before pregnancy; then again in the first, second, and third trimesters; and at 6, 12, and 26 weeks postpartum. At these visits, in addition to undergoing an examination of their joints, patients completed questionnaires and gave blood samples. Disease activity was determined using the Disease Activity Score in 28 joints (DAS28). Twin births and diagnoses other than RA were excluded.
The study found that use of TNF inhibitors during pregnancy (n = 92 women) did not increase the risk of birth defects or emergency caesarean sections. While RA is typically associated with small-for-gestational-age (SGA) birth weights, TNF inhibitors were associated with a significant increase in birth weight and fewer infants born SGA, even when the comparison was adjusted for confounders, such as disease activity. At the same time, TNF inhibitors were not associated with high birth weight or with infants who were large for gestational age (LGA).
The results showed that the effects were greatest when TNF inhibitors were used in the third trimester. However, teasing out the effects based on trimester is difficult because participants who used TNF inhibitors during the third trimester were likely to use them in the first and second trimester as well. The study’s authors point out that these results need to be replicated.
“The immune system is not only important in the pathogenesis of RA,” the study’s authors write, “but also for ensuring and maintaining a normal pregnancy.” They point out that many adverse outcomes of pregnancy that are thought to arise from inadequate development of the placenta, such as intrauterine growth restriction, SGA, and hypertensive disorders of pregnancy, can involve an increase in pro-inflammatory cytokines, such as TNF. “It is tempting to speculate that treatment with [TNF inhibitors] during pregnancy promotes placentation and thereby fetal growth and birth weight by changing the balance between pro-inflammatory and anti-inflammatory cytokines and by increasing the number and function of [regulatory T cells],” the authors write. They also hypothesize that treatment with TNF inhibitors induces epigenetic changes in the fetus, which positively influence fetal growth.
This is a well done, interesting study that will add to the still slim body of research on pregnancy in rheumatic diseases, Kevin Byram, MD, assistant professor of medicine in the division of rheumatology and immunology and associate director of the rheumatology training program at Vanderbilt University, Nashville, Tennessee, told Medscape Medical News. “Historically, pregnant women have been excluded from clinical trials, not just in rheumatoid arthritis, but in other rheumatic diseases, so we don't have a lot of great data,” he said, adding that the more interesting part of the study was that it showed there was no increased risk of adverse outcomes. “I’m not sure what to make of the increased birth weight. It will be interesting to see if the hypothesis that there might be a role for this molecule in preventing low birth weight goes anywhere.”
The work was supported by the Dutch Arthritis Foundation. PreCARA is an investigator-initiated study that was financially supported by UCB. The authors declared no competing interests.
Ann Rheum Dis. Published online July 11, 2022. Full text.
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