Gastroenterology

Gastroenterology

Volume 151, Issue 1, July 2016, Pages 110-119
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection

https://doi.org/10.1053/j.gastro.2016.04.002Get rights and content

Background & Aims

Little is known about in utero exposure to and postnatal clearance of anti–tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life.

Methods

We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected.

Results

The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94–1.49) and 1.97 for infliximab (95% CI, 1.50–2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9–5.0) and 7.3 months for infliximab (95% CI, 6.2–8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09–6.78; P = .02).

Conclusions

In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Section snippets

Materials and Methods

Pregnant women with IBD who received treatment with adalimumab (Humira, AbbVie, North Chicago, IL) or infliximab (Remicade, MSD, Kenilworth, NJ) were recruited prospectively from 14 tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 to November 2014. Multiple pregnancies were excluded because they were associated with an increased risk of adverse outcomes.13 If a woman gave birth more than once during the study period (n = 2), both pregnancies were included.

All eligible

Mother–Baby Pairs

Of the 89 pregnant women recruited, 5 (6%) miscarried before GW 10 and 4 (4%) failed blood collection (samples were not correctly prepared or transported), leaving 80 mother–baby pairs for analysis: 42 from Denmark, 29 from Australia, and 9 from New Zealand. Demographic and clinical details are shown in Table 1.

Medical Therapy During Pregnancy

Thirty-six (45%) women received adalimumab and 44 (55%) received infliximab. The majority (90%) received standard-dose treatment (ie, adalimumab 40 mg every other week or infliximab 5

Discussion

This international multicenter study comprehensively examined the outcomes of fetal exposure to the 2 complete IgG1 antibodies, adalimumab and infliximab, in infants born of women with IBD. It provides novel data in a well-characterized prospective cohort representative of clinical practice, showing that postnatal clearance of anti-TNF is prolonged, particularly of infliximab. The study provides a solid evidence-based rationale for the counseling and management of pregnant women and infants

References (37)

  • U. Mahadevan et al.

    Achievement of developmental milestones among offspring of women with inflammatory bowel disease: the PIANO registry (abstr 1)

    Gastroenterology

    (2014)
  • U. Mahadevan et al.

    Exposure to anti-TNF-alpha therapy in the third trimester of pregnancy is not associated with increased adverse outcomes: results from the PIANO registry (abstr 960)

    Gastroenterology

    (2014)
  • Available from: http://www.firstwordpharma.com. Accessed: December...
  • J. Burisch et al.

    Initial disease course and treatment in an inflammatory bowel disease inception cohort in Europe: the ECCO-EpiCom cohort

    Inflamm Bowel Dis

    (2014)
  • M.K. Vester-Andersen et al.

    Disease course and surgery rates in inflammatory bowel disease: a population-based, 7-year follow-up study in the era of immunomodulating therapy

    Am J Gastroenterol

    (2014)
  • J. Burisch et al.

    East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort

    Gut

    (2014)
  • G.C. Nguyen et al.

    The Toronto Consensus Statements for the Management of IBD in Pregnancy

    Gastroenterology

    (2016)
  • C.J. van der Woude et al.

    The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease

    J Crohns Colitis

    (2015)
  • Cited by (240)

    View all citing articles on Scopus

    Conflicts of interest These authors disclose the following: Lisbet Christensen has served on the advisory boards of AbbVie and MSD, and has received speaker’s fee from MSD, Ferring, UCB, Takeda, Tillotts, and AbbVie; Peter Gibson has served on the advisory boards of AbbVie, Ferring, Janssen, Merck, Nestle Health Science, Danone, Allergan, and Takeda, has received consultation fees from AbbVie, Ferring, Janssen, Merck, Nestle Health Science, Danone, Allergan, and Takeda, has received research grants for other investigator-driven studies/clinical trial funding from AbbVie, Janssen, Falk Pharma, Danone, and A2 Milk Company, and has received speaker's fees from Ferring, Takeda, AbbVie, Janssen, Fresenius Kabi, and Pfizer; Richard Gearry has served on the advisory boards of AbbVie, MSD, Janssen, and Baxter, has received research grants for other investigator-driven studies/clinical trial funding from AbbVie and Ferring, and has received speaker's fees from MSD, Ferring, Takeda, AbbVie, and Janssen; Alissa Walsh has served on the advisory boards of AbbVie, Ferring, Janssen, Takeda, and Hospira, and has received speaker's fees from Ferring, Takeda, AbbVie, Janssen, and Hospira; Susan Connor has served on the advisory boards of AbbVie, Janssen, Hospira, and Vifor, and has received speaker's fees from Ferring, AbbVie, Janssen, and Shire; Ian Lawrance has served on the advisory boards of AbbVie, MSD, Ferring, Janssen, Takeda, and Hospira, has received speaker's fees from Ferring, Takeda, AbbVie, Janssen, Hospira, and Shire; Jane Andrews has served on the advisory boards of AbbVie, Ferring, Janssen, Takeda, Hospira, Abbott, Shire, and Pfizer, and has received research grants for other investigator-driven studies/clinical trial funding from AbbVie, Janssen, Ferring, Abbott, Takeda, Shire, Hospira, and Pfizer; Signe Wildt has served on the advisory boards of MSD and Tillotts, and has received speaker’s fees from MSD and Takeda; Miles Sparrow has served on the advisory boards of Janssen, Takeda, and Hospira, and has received speaker’s fees from Ferring, Takeda, AbbVie, Janssen, Hospira, and Shire; Sally Bell has received consultation fees from AbbVie and Janssen, has received research grants for other investigator-driven studies/clinical trial funding from AbbVie, Janssen, and Shire, and has received speaker’s fees from AbbVie and Janssen; Mette Julsgaard has received speaker’s fees from MSD, Ferring, UCB, and Takeda; Christian Hvas has received speaker’s fees from MSD, Takeda, Tillotts, and AbbVie; Jens Kjeldsen has received speaker’s fees from MSD, Takeda, and Bristol-Myers Squibb; William Connell has received speaker’s fees from AbbVie and Janssen; and Steven Brown has received speaker’s fees from AbbVie and Janssen. The remaining authors disclose no conflicts.

    Funding The intra-uterine ExposuRe to Anti-tnf-alpha therapy (ERA) study was supported by unrestricted grants from the Health Research Fund of the Central Denmark Region, Colitis-Crohn Denmark, the A.P. Moeller Foundation of the Advancement of Medical Science, the Department of Gastroenterology at Monash University, and Alfred Hospital (Melbourne, Victoria, Australia). The external funders had no involvement in any aspect of the study or writing of the report.

    Author names in bold designate shared co-first authors.

    View full text