Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark; Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.
Gastroenterology. 2016 Jul;151(1):110-9. doi: 10.1053/j.gastro.2016.04.002. Epub 2016 Apr 8.
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.
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.
对于新生儿在子宫内接触和产后清除抗肿瘤坏死因子（anti-TNF）药物的情况，人们知之甚少。我们研究了阿达木单抗和英夫利昔单抗在新生儿脐血中的浓度以及出生后清除的速度，以及这些与母亲出生时的药物浓度和婴儿出生后第一年感染的风险之间的关系。
我们对 2012 年 3 月至 2014 年 11 月在丹麦、澳大利亚和新西兰的三家三级医院的 80 名患有炎症性肠病的孕妇进行了前瞻性研究：36 名孕妇接受阿达木单抗治疗，44 名孕妇接受英夫利昔单抗治疗；39 名孕妇在怀孕期间同时接受硫唑嘌呤治疗。数据来自孕妇在怀孕前后的疾病活动和治疗记录。在母亲分娩时和脐带中以及婴儿出生后每 3 个月采集一次血液样本，以检测抗 TNF 药物的浓度。
孕妇在怀孕期间最后一次接触抗 TNF 药物与药物在脐带中的浓度呈负相关（阿达木单抗：r=-0.64，P=0.0003；英夫利昔单抗：r=-0.77，P<.0001）和母亲在分娩时的药物浓度（阿达木单抗，r=-0.80；英夫利昔单抗，r=-0.80；P<.0001）。婴儿与母亲在出生时的药物浓度比值中位数为阿达木单抗 1.21（95%置信区间 [CI]，0.94-1.49），英夫利昔单抗 1.97（95%CI，1.50-2.43）。阿达木单抗和英夫利昔单抗的婴儿药物清除平均时间分别为 4.0 个月（95%CI，2.9-5.0）和 7.3 个月（95%CI，6.2-8.3；P<.0001）。12 个月后，婴儿体内未检测到药物。4 名婴儿（5%）出现细菌感染，16 名婴儿（20%）出现病毒感染，均为良性。与 TNF 单药治疗相比，母亲接受 TNF 药物联合硫唑嘌呤治疗的婴儿感染的相对风险为 2.7（95%CI，1.09-6.78；P=0.02）。
在对接受 TNF 药物治疗的孕妇所生婴儿的前瞻性研究中，我们检测到婴儿体内的药物直至 12 个月大。孕妇在怀孕期间最后一次接触药物与脐带中药物浓度呈负相关。英夫利昔单抗从婴儿体内清除的速度比阿达木单抗慢。与 TNF 单药治疗相比，母亲在怀孕期间接受 TNF 药物联合硫唑嘌呤治疗，婴儿感染的相对风险增加近 3 倍。因此，除非药物清除得到证实，否则应避免在 1 年内接种活疫苗，并且应向孕妇宣传使用 TNF 药物的风险。
