Have We Been Overcautious With TNF Inhibitors in Pregnancy?

What may seem like a prudent approach to treating inflammatory bowel disease (IBD) in pregnant women is in fact over-caution, suggested researchers who found no increased risk from tumor necrosis factor (TNF) inhibitors.

French women with IBD who received TNF inhibitors from 24 to 32 weeks of gestation experienced adverse birth outcomes with the same or less frequency than those who, consistent with some published recommendations, started anti-TNF treatment before 24 weeks Week ended Antoine Meyer, MD, PhD, Hôpital Bicêtre & Université Paris-Saclay, Le Kremlin Bicêtre, France, and colleagues.

In addition, those who continued TNF inhibitors after 24 weeks were more likely to experience an IBD flare-up during the remainder of pregnancy and 6 months postpartum (adjusted RR 0.93, 95% CI 0, 86-0.99), the researchers reported in Annals of Internal Medicine.

“[C]”continuation of anti-TNF beyond 24 weeks’ gestation appears to be beneficial in terms of IBD activity and prematurity without compromising neonatal outcomes and susceptibility to serious infections in the offspring,” concluded Meyer’s group.

TNF inhibitors such as infliximab (Remicade) and adalimumab (Humira) are common second-line therapies for IBD, including Crohn’s disease and ulcerative colitis. However, recent European consensus guidelines have required these treatments to be discontinued around 24 weeks gestation in pregnant patients in stable remission because the drugs cross the placenta and their effects on fetal development are unknown.

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At the same time, stillbirth, preterm birth, and other adverse pregnancy outcomes are known to be more common when IBD flares develop, and clear evidence that TNF inhibitors harm the fetus is lacking. “For these reasons, North American guidelines recommend continued anti-TNF therapy throughout pregnancy,” Meyer and colleagues noted. (Nevertheless, they added, a study last year showed that 20% of pregnant IBD patients in the US stopped anti-TNFs by the third trimester.)

Therefore, the researchers sought to resolve this discrepancy by examining the records of female IBD patients in the French national healthcare system from 2010 to 2020. They identified 2,403 patients who appeared to be in stable remission on anti-TNF therapy and continued beyond week 24; Their results were compared to those of 2,890 similar patients who stopped by week 24.

The median patient age was 29 years in both groups, with similar socioeconomic profiles. About 80% had Crohn’s disease, with a median duration of IBD of 6 years. The risk factors for adverse pregnancy outcomes were similar in both groups. For about half of the patients, the pregnancy examined was their first.

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Recurrence of IBD activity, recorded from week 32 to 6 months after delivery, occurred in 39.0% of the “stop anti-TNF” group versus 35.8% of those who remained on medication. These flare-ups were more common both during pregnancy and after delivery.

Meanwhile, the adverse pregnancy outcomes were very similar in the two groups. The rates for pregnancy-related hospitalizations and low birth weight did not differ much; there were a few more stillbirths in the continue group (nine versus five) and a numerically higher cesarean rate (35.7% versus 33.1%), but these did not reach statistical significance. The rate of preterm births was actually higher in the “stop” group (8.9% vs. 7.6%; aRR 0.82, 95% CI 0.68-0.99).

One concern about fetal exposure to TNF inhibitors has been that they may make children more susceptible to infection in infancy and beyond. Meyer and colleagues followed records for children born to women in the study up to age 5 and found no significant difference in severe infection rates (54.2 “go ahead” vs. 50.2 “stop” per 1,000 child-years ; adjusted HR 1.09, 95% CI 0.94 -1.25). However, there was a significantly higher rate of ear, nose and throat infections in children born in the “Continue” group (aHR 1.44, 95% CI 1.01-2.05).

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Meyer and colleagues cited a number of limitations of the study, principally the possibility of gaps and errors in the national database. For example, some biomarker data that could have made the identification of IBD flares more accurate were not included in the records, and the database only recorded the delivery, not the actual administration, of subcutaneous TNF inhibitors.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

disclosure

The study had no external funding. A co-author reported relationships with Arena, Enterome, Janssen, MaaT Pharma, Nordic Pharma, Takeda, Tillotts, Ferring, and Nestlé. Meyer and other authors stated that they had no relevant financial interests.