Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study
Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study
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DOI：
10.1371/journal.pone.0131130
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发表时间：
2015-07-06
期刊：
影响因子：
3.7
通讯作者：
Tata, Laila J.
中科院分区：
文献类型：
--
作者：
Ban, Lu;Fleming, Kate M.;Tata, Laila J.
研究背景：产前抗癫痫药物（AED）的使用与主要先天性异常（CA）风险增加有关。然而，这种AED相关的风险是否根据围受孕期高剂量（每日5 mg）叶酸补充剂而不同，目前尚不清楚。方法我们纳入了1990-2013年来自英国大型初级保健数据库健康改善网络的258，591名15-44岁母亲的单胎活产儿童。我们根据欧洲先天性畸形监测分类确定了所有主要CA。计算绝对风险和调整后的比值比（aOR），比较母亲服用抗癫痫药物与未服用抗癫痫药物的儿童，并按怀孕前后的叶酸处方进行分层结果妊娠早期使用抗癫痫药物的母亲所生的孩子患CA的风险为476/10，000，而妊娠早期使用抗癫痫药物的母亲所生的孩子患CA的风险为269/10，000，相当于aOR为1.82，95%置信区间为1.30-2.56。最高的系统特异性风险是心脏异常（分别为198/10，000和79/10，000，aOR 2.49，1.47 -4.21）。丙戊酸钠和拉莫三嗪均与任何CA的风险增加（aOR分别为2.63，1.46 -4.74和aOR 2.01，1.12 -3.59）和系统特异性风险增加相关。补充叶酸的分层并未显示AED相关风险的显著降低（例如，对于CA，高剂量叶酸组的总体aOR为1.75，1.01-3.03，低剂量或无叶酸组为1.94，95% CI 1.21-3.13）;但是，在此情况下，大多数服用抗癫痫药物的母亲仅从妊娠第二个月开始服用高剂量叶酸。与未暴露者相比，主要CA的风险增加10倍。我们发现没有证据表明处方的高剂量叶酸补充剂可以降低这种AED相关风险。虽然统计能力是有限的，处方叶酸太晚，它是有效的器官期或选择性处方那些更严重的发病率可能解释这些结果。
BackgroundAntenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear.MethodsWe included 258,591 singleton live-born children ofmothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception).ResultsCA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95% CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy.ConclusionsChildren of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.