Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.

For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

Liu Z ，Julsgaard M ，Zhu X ，Martin J ，Barclay ML ，Cranswick N ，Gibson PR ，Gearry RB ，van der Giessen J ，Connor SJ ，Rosella O ，Grosen A ，Toong C ，Flanagan E ，Wieringa JW ，Janneke van der Woude C ，Bell SJ ，CARINA Study Group ... -  《-》

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

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.

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 ... -  《-》

Validation of the Pharmacokinetic Model for Anti-TNFα Clearance in Infants Exposed to Anti-TNFα During Pregnancy.

The ECCO guideline recommends postponing live attenuated vaccines in infants exposed to anti-tumour necrosis factor alpha [anti-TNFα] in utero until drug clearance. The aim was to validate the predictive performance of the anti-TNFα clearance model. Newborns and data for anti-TNFα concentrations from the prospective PETIT cohort were included. The anti-TNFα clearance model was used to predict all measured concentrations in the PETIT cohort, based on the measured cord blood concentration and the mean population clearance described in the model. Bayesian maximum a posteriori optimization was used to estimate the use of drug monitoring. Predictive capability and drug monitoring were assessed through mean absolute error [MAE], root mean squared prediction error, and limits of agreement according to Bland and Altman. Observed drug concentrations after birth were within the 80% prediction interval in 94% of adalimumab samples and 93% of infliximab samples. The anti-TNFα clearance model accurately predicted the concentration at 6 months after birth with an MAE of 0.03 µg/mL [SD 0.03] for adalimumab and 0.11 µg/mL [SD 0.18] for infliximab based on cord blood concentrations. Addition of an additional sample between 1 and 4 months after birth improved the predictive accuracy for infliximab (MAE 0.05 [SD 0.09]) but not for adalimumab. Guidance for use in clinical practice was formulated. The validity of the anti-TNFα clearance model is high, and hence can be used to guide clinicians regarding the timing of live vaccines in infants exposed to adalimumab or infliximab in utero.

Wieringa JW ，Kruizinga MD ，Driessen GJA ，van der Woude CJ ，Julsgaard M ... -  《-》

Vaccines in Children Exposed to Biological Agents In Utero and/or During Breastfeeding: Are They Effective and Safe?

Biological agents cross the placenta, resulting in detectable blood levels in the neonate. Neonatal vaccinations are essential to prevent serious infections. To review the effectiveness and safety of vaccines in children exposed to biological drugs in utero and/or those whose mothers received biological agents during lactation. A systematic bibliographic search was performed. Infants exposed in utero to anti-tumour necrosis factor drugs [anti-TNFs], vedolizumab or ustekinumab mount adequate serological responses to vaccines. No relevant adverse events for non-live inactivated vaccines have been reported in newborns exposed in utero to biologics. Studies assessing the safety of live-attenuated vaccines administered to infants exposed to biologics in utero have not observed, in general, serious adverse events. However, although no severe complications have been reported with rotavirus live vaccination, several fatal disseminated tuberculosis infections after administration of the BCG live vaccine in infants exposed to anti-TNFs in utero have been reported. Infliximab, adalimumab, and probably also vedolizumab and ustekinumab treatments are considered compatible with breastfeeding, although minuscule amounts of these biologics have been detected in breast milk of treated nursing mothers. Based on the literature available, the benefits from breastfeeding while receiving infliximab [or any other anti-TNF] and at the same time adhering to national infant immunization programmes probably outweigh any hypothetical risk for the infant. Vaccines appear to be effective in infants exposed to biologics in utero. Inactivated vaccines are probably safe, whereas live-attenuated vaccines should be avoided while the children have detectable levels of biological drugs. Vaccines [non-live and live] are probably safe in children breastfed by mothers treated with biologics.

Gisbert JP ，Chaparro M 《-》

Physiologically-Based Pharmacokinetic Modeling of Anti-Tumor Necrosis Factor Agents for Inflammatory Bowel Disease Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.

Chen J ，Lin R ，Guo G ，Wu W ，Ke M ，Ke C ，Huang P ，Lin C ... -  《-》