Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection

Mette Julsgaard, Lisbet A Christensen, Peter R Gibson, Richard B Gearry, Jan Fallingborg, Christian L Hvas, Bo M Bibby, Niels Uldbjerg, William R Connell, Ourania Rosella, Anne Grosen, Steven J Brown, Jens Kjeldsen, Signe Wildt, Lise Svenningsen, Miles P Sparrow, Alissa Walsh, Susan J Connor, Graham Radford-Smith, Ian C Lawrance & 3 others Jane M Andrews, Kathrine Ellard, Sally J Bell

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalGastroenterology
Volume151
Issue number1
Pages (from-to)110-119
ISSN0016-5085
DOIs
Publication statusPublished - 8. Apr 2016

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Tumor Necrosis Factor-alpha
Mothers
Pharmaceutical Preparations
Confidence Intervals
Umbilical Cord
Pregnant Women
Newborn Infant
Prospective Studies
Adalimumab
Virus Diseases
Denmark
Fetal Blood
New Zealand
Inflammatory Bowel Diseases
Tertiary Care Centers
Medical Records

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Julsgaard, M., Christensen, L. A., Gibson, P. R., Gearry, R. B., Fallingborg, J., Hvas, C. L., ... Bell, S. J. (2016). Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology, 151(1), 110-119. https://doi.org/10.1053/j.gastro.2016.04.002
Julsgaard, Mette ; Christensen, Lisbet A ; Gibson, Peter R ; Gearry, Richard B ; Fallingborg, Jan ; Hvas, Christian L ; Bibby, Bo M ; Uldbjerg, Niels ; Connell, William R ; Rosella, Ourania ; Grosen, Anne ; Brown, Steven J ; Kjeldsen, Jens ; Wildt, Signe ; Svenningsen, Lise ; Sparrow, Miles P ; Walsh, Alissa ; Connor, Susan J ; Radford-Smith, Graham ; Lawrance, Ian C ; Andrews, Jane M ; Ellard, Kathrine ; Bell, Sally J. / Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. In: Gastroenterology. 2016 ; Vol. 151, No. 1. pp. 110-119.
@article{b119ecfe0d0c45148b672aaeb91648f1,
title = "Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection",
abstract = "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.",
author = "Mette Julsgaard and Christensen, {Lisbet A} and Gibson, {Peter R} and Gearry, {Richard B} and Jan Fallingborg and Hvas, {Christian L} and Bibby, {Bo M} and Niels Uldbjerg and Connell, {William R} and Ourania Rosella and Anne Grosen and Brown, {Steven J} and Jens Kjeldsen and Signe Wildt and Lise Svenningsen and Sparrow, {Miles P} and Alissa Walsh and Connor, {Susan J} and Graham Radford-Smith and Lawrance, {Ian C} and Andrews, {Jane M} and Kathrine Ellard and Bell, {Sally J}",
note = "Copyright {\circledC} 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2016",
month = "4",
day = "8",
doi = "10.1053/j.gastro.2016.04.002",
language = "English",
volume = "151",
pages = "110--119",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Heinemann",
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Julsgaard, M, Christensen, LA, Gibson, PR, Gearry, RB, Fallingborg, J, Hvas, CL, Bibby, BM, Uldbjerg, N, Connell, WR, Rosella, O, Grosen, A, Brown, SJ, Kjeldsen, J, Wildt, S, Svenningsen, L, Sparrow, MP, Walsh, A, Connor, SJ, Radford-Smith, G, Lawrance, IC, Andrews, JM, Ellard, K & Bell, SJ 2016, 'Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection', Gastroenterology, vol. 151, no. 1, pp. 110-119. https://doi.org/10.1053/j.gastro.2016.04.002

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. / Julsgaard, Mette; Christensen, Lisbet A; Gibson, Peter R; Gearry, Richard B; Fallingborg, Jan; Hvas, Christian L; Bibby, Bo M; Uldbjerg, Niels; Connell, William R; Rosella, Ourania; Grosen, Anne; Brown, Steven J; Kjeldsen, Jens; Wildt, Signe; Svenningsen, Lise; Sparrow, Miles P; Walsh, Alissa; Connor, Susan J; Radford-Smith, Graham; Lawrance, Ian C; Andrews, Jane M; Ellard, Kathrine; Bell, Sally J.

In: Gastroenterology, Vol. 151, No. 1, 08.04.2016, p. 110-119.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection

AU - Julsgaard, Mette

AU - Christensen, Lisbet A

AU - Gibson, Peter R

AU - Gearry, Richard B

AU - Fallingborg, Jan

AU - Hvas, Christian L

AU - Bibby, Bo M

AU - Uldbjerg, Niels

AU - Connell, William R

AU - Rosella, Ourania

AU - Grosen, Anne

AU - Brown, Steven J

AU - Kjeldsen, Jens

AU - Wildt, Signe

AU - Svenningsen, Lise

AU - Sparrow, Miles P

AU - Walsh, Alissa

AU - Connor, Susan J

AU - Radford-Smith, Graham

AU - Lawrance, Ian C

AU - Andrews, Jane M

AU - Ellard, Kathrine

AU - Bell, Sally J

N1 - Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2016/4/8

Y1 - 2016/4/8

N2 - 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.

AB - 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.

U2 - 10.1053/j.gastro.2016.04.002

DO - 10.1053/j.gastro.2016.04.002

M3 - Journal article

VL - 151

SP - 110

EP - 119

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -

Julsgaard M, Christensen LA, Gibson PR, Gearry RB, Fallingborg J, Hvas CL et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology. 2016 Apr 8;151(1):110-119. https://doi.org/10.1053/j.gastro.2016.04.002