Luteijn Johannes M, Morris Joan K, Garne Ester, Given Joanne, de Jong-van den Berg Lolkje, Addor Marie-Claude, Bakker Marian, Barisic Ingeborg, Gatt Miriam, Klungsoyr Kari, Latos-Bielenska Anna, Lelong Nathalie, Nelen Vera, Neville Amanda, O'Mahony Mary, Pierini Anna, Tucker David, de Walle Hermien, Wiesel Awi, Loane Maria, Dolk Helen
Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Paediatric Department, Hospital Lillebaelt, Kolding, Denmark.
Br J Clin Pharmacol. 2016 Oct;82(4):1110-22. doi: 10.1111/bcp.13056. Epub 2016 Aug 4.
Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries.
EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens.
The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14).
Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity.
关于孕期用药安全性的信息尚不充分。我们旨在开发一种信号检测方法，利用15个欧洲先天性异常登记处收集的数据，常规识别药物与先天性异常之间的异常关联。
对1995 - 2011年期间14950例孕早期有用药暴露的畸形胎儿/婴儿的EUROmediCAT数据库数据进行分析。将数据中40385种药物与异常组合中特定异常的特定药物暴露（根据化学物质或亚组编码）的比值比与所有其他异常的该暴露比值比进行比较。采用错误发现率（FDR）为50%的Simes多重检验程序，识别最不可能由偶然因素导致的关联，并选择暴露和异常均有两例以上病例的关联进行进一步调查。通过考虑对已知致畸剂的检测来评估该方法。
最常见的暴露药物为生殖泌尿系统药物和性激素（35.2%）、神经系统药物（28.0%）以及全身用抗感染药（25.7%）。识别出52种特定的药物与异常关联。剔除10种重叠关联和3种保护性关联后，选择39种关联进行进一步调查。这些关联包括16种涉及已明确的致畸剂，丙戊酸（2种）以及以胰岛素使用代表的母体糖尿病（14种）。
可对EUROmediCAT中央数据库中的用药暴露数据进行系统分析，以确定一组可管理的关联进行验证，然后在独立数据集中进行测试。致畸剂的检测取决于暴露频率、风险水平和致畸特异性。
