SAN FRANCISCO (FRONTLINE MEDICAL NEWS) Etanercept during pregnancy more than doubled the risk of major congenital malformations in a study by the Organization of Teratology Information Specialists.

The group keeps a prospective registry on exposures to biologics during pregnancy. It is finishing up its adalimumab (Humira) investigation and hasn’t found much to worry about, and continues to gather data on abatacept (Orencia), tocilizumab (Actemra), tofacitinib (Xeljanz), apremilast (Otezla), and certolizumab pegol (Cimzia).

Etanercept (Enbrel), however, seems to be a different story; major malformations turned up in the group’s recently completed investigation. Even so, Organization of Teratology Information Specialists (OTIS) investigator Dr. Christina D. Chambers, Ph.D. , of the University of California, San Diego, was careful to note at the annual meeting of the American College of Rheumatology that “etanercept is not meeting the criteria for causality. There’s no pattern” in major defects and “no biological plausibility” because the drug doesn’t seem to cross the placenta when the fetus is most vulnerable to adverse outcomes.

“It is difficult to draw the conclusion that this drug is causing harm. With true teratogens, you tend to see reduced birth weights and an increased risk of spontaneous abortion, which is not the case with etanercept. We are seeing only this one finding that kind of stands alone, and everything else looks pretty good,” she said.

The etanercept study investigated pregnancy outcomes in 370 women exposed to the drug while pregnant, mostly women with rheumatoid arthritis, but also women with psoriasis and ankylosing spondylitis. Their outcomes were compared with 164 pregnant women with the same diseases but no etanercept exposure – the disease control group – and 296 healthy pregnant women.

Women in all three groups were about 33 years old on average, and about 80% were white. The women were enrolled toward the end of their first trimester. Disease severity, comorbidities, and use of vitamins, alcohol, and tobacco were similar between etanercept and disease control women. About 40% of the etanercept and disease control women, but just one in the healthy pregnancy group, were exposed to systemic corticosteroids while pregnant.

There were 33 major structural defects in children born to women taking etanercept versus 7 in the disease control group. That translated to a more than doubling of risk with etanercept (odds ratio, 2.37; 95% confidence interval, 1.02-5.52), and a more than doubling of risk versus the 10 major structural defects in children born to healthy control women (OR, 2.91; 95% CI, 1.37-6.76).

A subanalysis excluded chromosomal anomalies, but “did not [change] our conclusions,” Dr. Chambers said.

Major structural defects generally refer to problems that need a surgical fix, including spina bifida, atrial septal defects, cleft palates, hypospadias, polydactyly, and craniosynostosis.

Minor defects that don’t need surgery, like a missing earlobe, occurred in six children exposed to etanercept and showed two different patterns that involved “three specific minor malformations” not seen in either of the control groups, Dr. Chambers said. She did not elaborate on what those patterns were, but noted that the parents usually had them, too, “suggesting a genetic component as opposed to a drug effect.”

Children in the three study groups had no statistically significant differences in 1-year malignancy rates, serious infections, and hospitalizations, even when exposed to etanercept in the third trimester.

Children exposed to etanercept, however, were more likely to be born preterm and more likely to be small for gestational age in weight, length, and head circumference. They were also more likely than disease control children to screen positive for developmental issues at 1 year, but none of those differences were statistically significant.

Dr. Chambers disclosed funding from 14 companies, including Amgen, the maker of etanercept, and Janssen, Pfizer, Roche, Sanofi/Genzyme, GlaxoSmithKline, and AbbVie, the maker of adalimumab.


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