TNF Inhibitors During Pregnancy Linked to Greater Risk of Birth Problems, Study Finds

Women with ankylosing spondylitis (AS) and other inflammatory conditions who take TNF inhibitors during pregnancy may be at higher risk for preterm birth, cesarean section, and smaller babies, according to a study from Denmark, Finland, and Sweden.

Yet the findings varied by type of inflammatory disease, which may indicate that the risks are more related to underlying disease activity than to direct effects from anti-TNF therapy, the researchers said.

The study, “Anti‐TNF treatment during pregnancy and birth outcomes: A population‐based study from Denmark, Finland, and Sweden,” was published in the journal Pharmacoepidemiology and Drug Safety.

TNF inhibitors — such as Enbrel (etanercept), Humira (adalimumab), infliximab (brand names Remsima, Remicade), Simponi (golimumab) and Cimzia (certolizumab pegol) — are a therapeutic mainstay for AS and other chronic inflammatory conditions.

They reduce inflammation and may stop disease progression by blocking the effects of tumor necrosis factor (TNF), a key inflammatory mediator.

TNF inhibitors have been increasingly used by women during pregnancy. However, due to lack of data, recommendations differ on whether to continue or stop treatment during pregnancy — knowing that stopping is likely to increase the risk for disease recurrence.

While previous guidelines favored ceasing anti-TNF therapy before or early in pregnancy, more recent guidance suggests continuing treatment until the third trimester. On the heels of those recommendations, Humira and Cimzia labels have been extended to cover use during pregnancy.

One concern with their use is that the potent immunosuppressive effects of TNF inhibitors may increase the risk of infections leading to preterm birth or stunted fetal growth. Blocking TNF could also affect embryo implantation, placenta development, and delivery.

However, anti-TNF effects may go both ways. On one hand, they may cause birth problems; on the other, they control disease activity, which in turn may lower the risk of birth problems.

Researchers looked at women with chronic inflammatory diseases — including AS, inflammatory bowel disease (IBD), rheumatoid arthritis, psoriatic arthritis, and psoriasis — who gave birth to single children between 2006 to 2013.

They compared the birth outcomes for women using TNF inhibitors with those of women using non-biologic treatments — mostly azathioprine, corticosteroids, sulfasalazine, anti-malarials, and methotrexate — and to births for women in the general population.

Among a total of 1.63 million births, 1,027 infants were born to women treated with TNF inhibitors, and 9,399 to women receiving non-biologic treatment during pregnancy.

Of those on anti-TNF therapy, 27.9% stayed on treatment throughout pregnancy. A higher percentage (70.2%) stayed on non-biologic treatments during pregnancy.

Patients had a higher prevalence of adverse birth outcomes — including preterm birth (before 37 weeks of gestation), spontaneous preterm birth, and cesarean delivery — than women in the general population.

Compared with patients taking non‐biologic medications, women on anti‐TNF therapy were at greater risk of preterm birth — a prevalence of 12.5%, compared with 8.4%, meaning a 61% greater likelihood. 

They were 57% more likely to have a cesarean delivery (37.7%, compared with 27.4% of women taking non-biologics).

Comparisons among the most commonly used anti-TNF agents — infliximab, Enbrel and Humira — showed that women taking infliximab were at greater risk for having babies small for their gestational ages. This was true for all diseases except IBD.

While continuing anti-TNF treatment through the first trimester was beneficial for women with IBD, the opposite was true for women with AS or other inflammatory diseases. 

For these women — 52.7% of whom continued on anti-TNF therapy through the first trimester, and 11.9% through the second — staying on anti-TNF therapy over the first trimester increased by 89% the chances of having a preterm delivery, compared with stopping treatment.

There were no stillbirths among women on anti-TNF treatment.

“Anti‐TNF agents were associated with increased risks of preterm birth, cesarean section, and [babies who were] small for gestational age,” the researchers wrote. “However, the diverse findings across disease groups may indicate an association related to the underlying disease activity, rather than to agent‐specific effects.”

As the study lacks detailed information on disease activity, the findings could “imply that discontinuers in the ARTPSO group [rheumatoid arthritis, AS, psoriatic arthritis or psoriasis] may represent women with less active disease,” they said. “In contrast, IBD patients who discontinue may be vulnerable to disease exacerbation, in turn leading to an increased risk of preterm birth.”

The research was conducted from a study commissioned by the U.S. Food and Drug Administration and the European Medicines Agency to Janssen, which makes Remicade. It was independent of the company, the investigators said.