Exposure to immunosuppressive monotherapies in utero did not increase serious infection risks in young children born to mothers with inflammatory bowel disease (IBD), but the same could not be said for exposures to combination therapies, a French population-based study found.
Children up to 1 year of age who were exposed to tumor necrosis factor (TNF) inhibitor or thiopurine monotherapy were not at higher risk of serious infection, with adjusted hazard ratios (aHRs) of 1.10 (95% CI 0.95-1.27) and 0.94 (95% CI 0.83-1.07), respectively, compared to unexposed children, reported Antoine Meyer, MD, of Hopital Bicetre in Le Kremlin Bicetre, France, and colleagues.
However, infants experienced a higher serious infection risk after exposure to combination therapy (aHR 1.36, 95% CI 1.04-1.79), the group wrote in Clinical Gastroenterology and Hepatology.
IBD treatments were not associated with risk of serious infections in children ages 2 to 5, they noted.
“We treat a lot of [IBD] patients in our hospital and many women with IBD become pregnant,” Meyer told MedPage Today. “Indeed the onset of IBD is frequent between 20 and 30 years of age. Safety of IBD drugs is an important question for these women.”
Studies have found that fetuses develop higher levels of anti-TNF serum in utero, since anti-TNF’s half-life is about four times longer for infants. Prior research that found an increased risk of serious infection after in-utero anti-TNF exposure came with limitations, the authors said.
Current guidelines support the use of anti-TNF monotherapies and thiopurine during pregnancy for mothers with IBD.
“As the excess risk [of combination therapy] is no longer observed after the first year of life, we believe that these drugs do not permanently alter the immune system,” the researchers said.
Meyer and colleagues studied 26,561 children, up to age 5, from the French national health database. Children born from 2010 to 2018 to mothers ages 15 to 49 with IBD and taking anti-TNF agents or thiopurines were included. Median follow-up was 5 years. The primary outcome evaluated any serious infection in children requiring hospitalization.
Median age of mothers was 30. Children were divided into four groups: no drug exposure, anti-TNF monotherapy (certolizumab [Cimzia], adalimumab [Humira], infliximab [Remicade], golimumab [Cimzia]), thiopurine monotherapy (mercaptopurine, azathioprine), or combination therapy (anti-TNF and thiopurines). There were 3,399 children exposed to anti-TNF therapy, 3,992 exposed to thiopurine therapy, 816 exposed to combination therapy and nearly 19,000 unexposed children.
Overall serious infection incidence in children up to age 1 year was 121.1 per 1,000 person-years (95% CI 116.7-125.4), which dropped by age 2 to 44.5 per 1,000 person-years (95% CI 41.9-47.2), and to 18.1 per 1,000 (95% CI 17-19.3) for children ages 3 to 5.
More preterm births occurred in women taking thiopurines or combination therapy (12.7% and 12.5%, respectively) than anti-TNF monotherapy or no drug exposure (8.5% and 7.4%, P<0.0001). Those taking combination therapy had the highest rate of cesarean sections (40.7%). Low birth weights in exposed infants were similarly associated.
There were 5,991 serious infections that occurred among 4,562 children up to age 5. Infants exposed to combination therapy had a threefold higher risk of neurological infections (aHR 3.23, 95% CI 1.12-9.32) and a higher risk for viral infections (aHR 1.52, 95% CI 1.06-2.20). However, there was no significant increased risk for skin and subcutaneous infections or gastrointestinal infections, the authors said.
Researchers encouraged physicians to consider the higher risk for serious infections prescribing combination therapy to pregnant patients, weighing the risk of IBD relapse after deescalating combination therapy.
However, they acknowledged limitations of this study included the possibility for a small percentage of misclassified infections in reported reasons for hospitalization, and that there is no clear association between active IBD cases in mothers and infections in children.
Last Updated July 28, 2021
The authors reported conflicts of interest with Janssen, Ferring, Pfizer, Takeda, Roche, Tillotts, PiLeJe, Takeda, AbbVie, Bristol Myers Squibb, Enterome, Mayoly Spindler, and Merck Sharp & Dohme. The French National Health Service provided study funding.