Sato Ryosuke, Ikuma Mutsuhiro, Takagi Kazunori, Yamagishi Yoshiaki, Asano Junichi, Matsunaga Yusuke, Watanabe Hiroshi
From the Pharmaceuticals and Medical Devices Agency, Chiyoda-ku, Tokyo (RS, MI, KT, YY, JA, YM); and Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Japan (RS, HW).
Medicine (Baltimore). 2015 Jan;94(1):e386. doi: 10.1097/MD.0000000000000386.
Assessment of perinatal effects of drug exposure during pregnancy after approval is an important issue for regulatory agencies. The study aimed to explore associations between perinatal outcomes and maternal exposure to drugs for chronic diseases, including hypertension, diabetes, and autoimmune disease.We reviewed 521 cases of adverse reactions due to drug exposure during pregnancy who were reported to the Pharmaceuticals and Medical Devices Agency, a regulatory authority in Japan. The primary outcomes were fetal and neonatal death and malformation of infants. Associations between perinatal outcomes and exposure to each drug category for hypertension, diabetes, and autoimmune disease were evaluated using logistic regression analysis.Of the 521 cases (maternal age: 15-47 years; mean 32.3 ± 5.5), fetal and neonatal deaths were reported in 159 cases (130 miscarriage; 12 stillbirth; 4, neonatal death; and 13 abortion due to medical reasons), and malformations of infants were observed in 124 cases. In contrast to the trend of association between diabetes with or without medication and fetal and neonatal death (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.17-1.36), exposure to oral antidiabetics tended to be associated with fetal and neonatal death (OR, 4.86; 95% CI, 0.81-29.2). Malformation tended to be correlated with exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (OR, 2.98; 95% CI, 0.76-11.7). This association showed trends opposite to that of the association with hypertension itself (OR, 0.42; 95% CI, 0.18-1.02) or overall antihypertensives (OR, 0.42; 95% CI, 0.15-1.13). Occurrence of multiple malformations was associated with exposure to biologics (OR, 8.46; 95% CI, 1.40-51.1), whereas there was no significant association between multiple malformations and autoimmune disease with or without medication (OR 1.07; 95% CI, 0.37-3.06).These findings suggest that drugs of different categories may have undesirable effects when used during pregnancy. However, the regulatory database was not originally designed to evaluate the causal associations between drug exposure and adverse drug reactions. The limitations of spontaneous reporting systems should be carefully taken into account. Further studies are needed to elucidate the effects of individual drugs in each category on perinatal outcomes.
药品获批后评估孕期药物暴露的围产期影响是监管机构面临的一个重要问题。本研究旨在探讨围产期结局与母亲暴露于治疗慢性病的药物（包括高血压、糖尿病和自身免疫性疾病用药）之间的关联。
我们回顾了向日本监管机构药品和医疗器械局报告的521例孕期药物暴露不良反应病例。主要结局是胎儿和新生儿死亡以及婴儿畸形。使用逻辑回归分析评估围产期结局与高血压、糖尿病和自身免疫性疾病各类药物暴露之间的关联。
在这521例病例中（母亲年龄15 - 47岁；平均32.3 ± 5.5岁），159例报告有胎儿和新生儿死亡（130例流产；12例死产；4例新生儿死亡；13例因医学原因流产），124例观察到婴儿畸形。与糖尿病用药与否和胎儿及新生儿死亡之间的关联趋势相反（比值比[OR]，0.49；95%置信区间[CI]，0.17 - 1.36），口服降糖药暴露往往与胎儿和新生儿死亡相关（OR，4.86；95% CI，0.81 - 29.2）。畸形往往与血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂暴露相关（OR，2.98；95% CI，0.76 - 11.7）。这种关联呈现出与高血压本身（OR，0.42；95% CI，0.18 - 1.02）或总体抗高血压药物（OR，0.42；95% CI，0.15 - 1.13）的关联相反的趋势。多种畸形的发生与生物制剂暴露相关（OR，8.46；95% CI，1.40 - 51.1），而多种畸形与自身免疫性疾病用药与否之间无显著关联（OR 1.07；95% CI，0.37 - 3.06）。
这些发现表明，不同类别的药物在孕期使用时可能产生不良影响。然而，监管数据库最初并非设计用于评估药物暴露与药物不良反应之间的因果关联。应谨慎考虑自发报告系统的局限性。需要进一步研究以阐明各类别中个别药物对围产期结局的影响。
