Risk Summary

Available observational studies in pregnant women exposed to infliximab products showed no increased risk of major malformations among live births as compared to those exposed to non-biologics. However, findings on other birth and maternal outcomes were not consistent across studies of different study design and conduct [see Data].

Monoclonal antibodies such as infliximab products are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. In a developmental study conducted in mice using an analogous antibody, no evidence of maternal toxicity or fetal harm was observed [see Data].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that there is an increased risk of adverse pregnancy outcomes in women with inflammatory bowel disease or rheumatoid arthritis associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2.5 kg) and small for gestational age at birth.

Fetal/Neonatal adverse reactions

As with other IgG antibodies, infliximab products cross the placenta. Infliximab products have been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.13)]. Cases of agranulocytosis in infants exposed in utero have also been reported [see Adverse Reactions (6.2)].

Data

Human Data

Two prospective cohort studies were conducted assessing birth outcomes as well as the health status of infants up to the age of one year in women exposed to infliximab compared to non-biologic comparators including methotrexate, azathioprine, 6-mercaptopurine and systemic corticosteroids used for the treatment of similar diseases. The first study was conducted in an IBD pregnancy registry in the United States and assessed pregnancy outcomes in 294 women with inflammatory bowel disease exposed to infliximab during pregnancy compared with 515 women on a non-biologic treatment. Infliximab exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life. The second study among IBD and non-IBD patients in Sweden, Finland, and Denmark compared 97, 7, and 166 women exposed to infliximab to 2,693, 2,499 and 1,268 women on non-biologic systemic therapy, respectively. In this study, comparing pooled data across the three countries, exposure to infliximab was not associated with increased rates of congenital anomalies or infant death. Infliximab in combination with immunosuppressants (mainly systemic corticosteroids and azathioprine) was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared with non-biologic systemic treatment. Although the study did not show any associations with infliximab monotherapy, the analyses could have been underpowered to detect an association.

There were additional methodological limitations with these studies that may account for the study findings in both studies: the concomitant use of other medications or treatments was not controlled and disease severity was not assessed; in the U.S. study, patient reported outcomes were collected without clinical validation. These methodological limitations hinder interpretation of the study results.

Animal Data

Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. An embryofetal development study was conducted in pregnant mice using cV1q anti-mouse TNFα, an analogous antibody that selectively inhibits the functional activity of mouse TNFα. This antibody administered in mice, during the period of organogenesis on gestation days (GDs) 6 and 12, at IV doses up to 40 mg/kg produced no evidence of maternal toxicity, fetal mortality, or structural abnormalities. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Analyses of fetal samples on GD 14 indicated placental transfer of the antibody and exposure of the fetuses during organogenesis. In a peri- and post-natal development study in mice, no maternal toxicity or adverse developmental effects in offspring were observed when dams were administered IV doses of 10 or 40 mg/kg of the analogous antibody on GDs 6, 12 and 18 and lactation days 3, 9 and 15.