Are We Overcautious With TNF Inhibitors in Pregnancy? Save

What may seem like a prudent approach to treatment of inflammatory bowel disease (IBD) in pregnant women actually represents an overabundance of caution, suggested researchers who found no increased risk from tumor necrosis factor (TNF) inhibitors.

French women with IBD who received TNF inhibitors from weeks 24 to 32 of pregnancy experienced adverse birth outcomes at the same or lower rates than among those who -- in accord with some published recommendations -- stopped anti-TNF treatment before week 24, according to Antoine Meyer, MD, PhD, of Hôpital Bicêtre & Université Paris-Saclay, Le Kremlin Bicêtre, France, and colleagues.

Moreover, those who continued TNF inhibitors past week 24 were significantly less likely to experience an IBD flare during the remainder of their pregnancy and the 6-month postpartum period (adjusted RR 0.93, 95% CI 0.86-0.99), the researchers reported in Annals of Internal Medicine.

"[C]ontinuation of anti-TNF after 24 weeks of pregnancy seems beneficial regarding IBD activity and prematurity, while not affecting neonatal outcomes and susceptibility to serious infections in the offspring," Meyer's group concluded.

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 However, recent European consensus guidelines called for these treatments to be withdrawn at around gestational week 24 in pregnant patients in stable remission, because the drugs cross the placental barrier and their effects on fetal development aren't known.

At the same time, stillbirth, preterm delivery, and other adverse pregnancy outcomes are known to be more common when IBD flares develop, and hard evidence that TNF inhibitors cause fetal harm is lacking. "For these reasons, North American guidelines recommend the continuation of anti-TNF throughout pregnancy," Meyer and colleagues noted. (Even so, they added, a study last year indicated that 20% of pregnant U.S. IBD patients had anti-TNFs withdrawn during the third trimester.)

Hence, the researchers sought to resolve this disparity by examining records of female IBD patients in France's national health system from 2010 to 2020. They identified 2,403 patients who appeared to be in stable remission with anti-TNF therapy and who continued on it beyond week 24; their outcomes were compared to those of 2,890 similar patients who stopped by week 24.

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

Renewed IBD activity recorded from week 32 to 6 months post-delivery occurred in 39.0% of the "anti-TNF stop" group versus 35.8% of those who continued on the drugs. These disease flares were more common both during pregnancy and after delivery.

Meanwhile, adverse pregnancy outcomes were very similar in the two groups. Rates of pregnancy-related hospitalization and low birthweight hardly differed at all; there were a few more stillbirths in the "continue" group (nine vs five) and a numerically higher rate of caesarean section (35.7% vs 33.1%) but these did not approach statistical significance. Rates of preterm birth were 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 leave the children more vulnerable to infections in infancy and beyond. Meyer and colleagues tracked records for children born to women in the study up to age 5 and found no significant difference in serious infection rates (54.2 "continue" vs 50.2 "stop" per 1,000 child-years; adjusted HR 1.09, 95% CI 0.94-1.25). There was, however, a significantly higher rate of ear-nose-throat infections among children born in the "continue" group (aHR 1.44, 95% CI 1.01-2.05).

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

Source Reference: Meyer A, et al "Benefits and risks associated with continuation of anti–tumor necrosis factor after 24 weeks of pregnancy in women with inflammatory bowel disease: a nationwide emulation trial" Ann Intern Med 2022; DOI: 10.7326/M22-0819.