title: Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark; Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: mjn@clin.au.dk.
authors.forename: Mette
authors.initials: M
authors.lastname: Julsgaard
authors.affiliation: Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.
authors.forename: Lisbet A
authors.initials: LA
authors.lastname: Christensen
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Gibson
authors.affiliation: Department of Medicine, Christchurch Hospital, University of Otago, Christchurch, New Zealand.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.affiliation: Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Fallingborg
authors.affiliation: Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Hvas
authors.affiliation: Department of Biostatistics, University of Aarhus, Aarhus, Denmark.
authors.forename: Bo M
authors.initials: BM
authors.lastname: Bibby
authors.affiliation: Department of Obstetrics and Gynaecology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Uldbjerg
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: William R
authors.initials: WR
authors.lastname: Connell
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
authors.forename: Ourania
authors.initials: O
authors.lastname: Rosella
authors.affiliation: Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Grosen
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Department of Gastroenterology, Odense University Hospital, University of Odense, Odense, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Kjeldsen
authors.affiliation: Department of Medicine, Køge Hospital, University of Copenhagen, Køge, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Wildt
authors.affiliation: Department of Medicine, Herning Hospital, Herning, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Svenningsen
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Sparrow
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Alissa
authors.initials: A
authors.lastname: Walsh
authors.affiliation: Department of Gastroenterology, Liverpool Hospital, Sydney, New South Wales, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Connor
authors.affiliation: Inflammatory Bowel Diseases Unit, Royal Brisbane and Women's Hospital, University of Queensland School of Medicine, Brisbane, Queensland, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Radford-Smith
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, Western Australia, Australia; Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia, Australia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Lawrance
authors.affiliation: Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Andrews
authors.affiliation: Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Ellard
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Bell
mesh_terms: D000068879:Adalimumab / Q000097:blood*; D000328:Adult; D001315:Australia; D003718:Denmark; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000097:blood*; D006801:Humans; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000188:drug therapy; D000069285:Infliximab / Q000097:blood*; D008431:Maternal-Fetal Exchange; D009035:Mothers; D009520:New Zealand; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood* / Q000188:drug therapy; D011446:Prospective Studies
chemical_list: D005765:Gastrointestinal Agents; D000069285:Infliximab; D000068879:Adalimumab
keywords: ERA Study; Inflammatory Bowel Diseases; Safety; Vaccination