TNF Placental Transfer Makes Little Difference in Offspring Infections

Neil Osterweil

June 03, 2022

COPENHAGEN — Here's reassuring news for pregnant women with rheumatic diseases treated with tumor necrosis factor alpha (TNFα) inhibitors: although the drugs vary widely in their transmissibility across the placenta, there appears to be no excess risk for serious infections in children exposed in utero to TNF inhibitors with high, compared with low, placental transfer.

Leah Flatman

That's according to investigators at McGill University in Montreal, who studied outcomes for nearly 3000 infants who were exposed to TNF inhibitors during gestation.

Our data are reassuring as we saw no strong signal, which suggests that there is no need to switch the mother’s drugs. More studies are needed, but this is a step in the right direction to reduce maternal stress and reassure physicians," said Leah K. Flatman, a PhD candidate in epidemiology at McGill.

Flatman presented the findings in an oral abstract session here at the European Alliance of Associations for Rheumatology 2022 Annual Meeting.

Not Without Risks

Approximately 20% of pregnant women with chronic inflammatory diseases are prescribed a TNF inhibitor, a class of drug that is effective for disease control but also increases risk for infection because of immunosuppressive effects.

"Similarly, offspring exposed in utero to TNF inhibitors may also experience immunosuppression and subsequent serious infections in their first year of life. This is the result of the TNF inhibitor entering the fetal bloodstream at different concentrations," Flatman said.

Anti-TNF monoclonal immunoglobulins, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and golimumab (Simponi) have the highest placental transfer, reaching higher levels in fetal circulation than in maternal circulation, she noted.

In contrast, certolizumab (Cimzia), a pegylated humanized antigen-binding fragment, and etanercept (Enbrel and biosimilars), a fusion protein, have the lowest placental penetration, Flatman said.

Population Study

The investigators conducted a population cohort study using the IBM MarketScan database of commercial claims from employer-provided health insurance plans in the United States.

They looked at data on offspring of mothers with rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis and/or inflammatory bowel diseases (IBD; Crohn's disease and ulcerative colitis). The children were born from January 1, 2011 through December 31, 2019.

The exposure was at least one filled prescription and/or infusion procedure claim for TNF inhibitors in the 6 months before delivery. The exposures were divided into high and low placental-transfer categories.

A total of 26,088 offspring were identified, of whom 2,902 (11.1%) were exposed to a TNF inhibitor in utero. A little more than half of these children were born to mothers treated with TNF inhibitors for IBD.

For the primary outcome of serious infections (based on at least one hospitalization with infection in the first year of life), the investigators plotted Kaplan-Meier curves, which showed that the survival probability of serious infections in the high and low groups overlapped, indicating no large differences.

Of 2105 offspring of mothers treated with a high placental-transfer drug, 38 (1.8%) had serious infections, compared with 10 of 797 offspring (1.3%) of mothers who received low placental-transfer drugs.

In multivariable analysis that controlled for maternal age at delivery, any RA diagnosis without an IBD diagnosis, and IBD diagnosis, gestational or pregestational diabetes, maternal asthma, preterm delivery, corticosteroid use, and disease-modifying antirheumatic drug use, the investigators saw that the hazard ratio for risk for serious infection in the high, compared with the low, placental-transfer group was 1.20, with a confidence interval crossing 1, indicating nonsignificance.

Similar Results Reported

Frauke Förger, MD, professor of rheumatology and immunology at the University of Bern, Switzerland, who comoderated the oral abstract session where the data were presented, told Medscape Medical News that the findings were in line with those of a recent meta-analysis looking at the safety of biologic agents in pregnant women with IBD.

She added, however, that although the meta-analysis also showed little difference in outcomes for the children of women treated with high, compared with low, placental-transfer drugs, "we need more data to be sure about this."

Comoderator Gabriela Riemekasten, MD, director of the clinic for rheumatology and clinical immunology at University Hospital in Lübeck, Germany, told Medscape Medical News that she was surprised to see that more women received high than low placental-transfer drugs.

Although there was a 20% difference between the groups, the numbers were relatively low, and "I would consider this in my practice and give my patients the advice of these data," she said.

The study was supported by an Arthritis Society PhD Salary Award, and a Canadian Institutes of Health Project grant. Flatman, Förger, and Riemekasten reported having no relevant financial disclosures.

European Alliance of Associations for Rheumatology (EULAR) 2022 Annual Meeting: Abstract OP0130. Presented June 2, 2022

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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