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Drug induced adverse pregnancy outcomes: innovative event history analysis for non-continuously exposed pregnancies in the national German Embryotox patient database

药物引起的不良妊娠结局：德国国家 Embryotox 患者数据库中非持续暴露妊娠的创新事件历史分析

基本信息

批准号：
288952608
负责人：
Professor Dr. Jan Beyersmann
金额：
--
依托单位：
Fachbereich II: Mathematik, Physik, Chemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/288952608?language=en
关键词：
Drug induced adverse pregnancy outcomes

项目摘要

Prenatal development is the most vulnerable phase in human life. Drug toxicity may result in congenital anatomical and functional defects with life-long impacts. With a prevalence of 15-20%, miscarriages are the most frequent adverse events in pregnancy apart from birth defects. Teratogenic agents are the only causes being primarily preventable by avoiding exposure.A major determinant of teratogenic effects is the exposure interval within the first trimester. Exposure before or after the sensitive time period is not expected to cause birth defects. This principle of vulnerable periods for distinct malformations has been precisely characterised in humans only for thalidomide. The rationale of vulnerable periods not only applies to birth defects but also to spontaneous abortions.Empirical evidence on adverse effects of medication in pregnancy is based on observational data. National Teratology Information Services (TIS) like the German Embryotox project provide unique sources to study pregnancy outcome in association with suspicious drug exposure. Embryotox is the largest European Drug in Pregnancy Database with detailed prospectively ascertained information on maternal medication during pregnancy and neonatal outcome.One key characteristic of pregnancy outcome data is its time scale gestational age. However, a pregnancy can only be studied after it has been recognised. The data are, therefore, left-truncated. Drug intake is in general a time-dependent process associated with possibly time-dependent risks. Finally, pregnancy outcome is characterized by competing risks, as a pregnancy may end in a spontaneous abortion but also in an induced abortion or a live-birth. To prevent biased estimates, left-truncation, medication dynamics, and competing risks must be accounted for when analyzing pregnancy outcome data.Statistical event history methodology is both theoretically and practically established and is started to be used with success on pregnancy outcome data. Analyzing time-dependent and time-specific effects in pregnancy outcome data and in the context of left truncation and competing risks, however, raises practical and methodological issues, still to be solved.Managing the risk of adverse drug reactions in pregnancy has a great impact on society. In Germany, around 900000 pregnancies are recognised annually, resulting in approximately 130000 miscarriages, more than 100000 elective terminations, and 660000 live births. A better estimation of teratogenic effects of medication would allow reducing both the number of elective terminations based on irrational overestimation of drug risks as well as the individual and societal burden of preventable congenital anomalies.

产前发育是人类一生中最脆弱的阶段。药物毒性可能导致先天性解剖和功能缺陷，并产生终生影响。流产的患病率为 15-20%，是除出生缺陷之外最常见的妊娠不良事件。致畸剂是唯一可以通过避免接触来预防的原因。致畸效应的一个主要决定因素是妊娠早期的接触时间间隔。敏感时间段之前或之后的暴露预计不会导致出生缺陷。这种明显畸形的易感期原理仅针对沙利度胺在人类中得到了精确表征。脆弱期的基本原理不仅适用于出生缺陷，也适用于自然流产。妊娠期药物不良反应的经验证据基于观察数据。德国 Embryotox 项目等国家畸形学信息服务 (TIS) 提供了独特的来源来研究与可疑药物暴露相关的妊娠结局。 Embryotox 是欧洲最大的妊娠期药物数据库，包含有关妊娠期间孕产妇用药和新生儿结局的详细前瞻性确定信息。妊娠结局数据的一个关键特征是其时间尺度胎龄。然而，只有在确认怀孕后才能对其进行研究。因此，数据被左截断。药物摄入通常是一个与时间相关的过程，并且可能存在与时间相关的风险。最后，妊娠结局的特点是风险相互竞争，因为妊娠可能以自然流产告终，但也可能以人工流产或活产告终。为了防止估计出现偏差，在分析妊娠结局数据时必须考虑左截断、药物动态和竞争风险。统计事件历史方法在理论上和实践上均已建立，并开始成功地应用于妊娠结局数据。然而，在左截断和竞争风险的背景下分析妊娠结局数据中的时间依赖性和时间特异性效应，提出了仍有待解决的实际和方法学问题。管理妊娠期药物不良反应的风险对社会产生巨大影响。在德国，每年确认约 90 万例怀孕，导致约 13 万例流产、超过 10 万例选择性终止妊娠和 66 万例活产。更好地估计药物的致畸作用将有助于减少基于对药物风险的非理性高估而选择性终止妊娠的数量，以及可预防的先天性异常给个人和社会带来的负担。