First trimester exposure to paroxetine and risk of cardiac malformations in infants:: The importance of dosage
First trimester exposure to paroxetine and risk of cardiac malformations in infants:: The importance of dosage
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DOI：
10.1002/bdrb.20099
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发表时间：
2007-02-01
影响因子：
--
通讯作者：
Oraichi, Driss
中科院分区：
文献类型：
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作者：
Berard, Anick;Ramos, Elodie;Oraichi, Driss
背景：关于妊娠早期使用帕罗西汀的致畸风险的相互矛盾的发现促使FDA、加拿大卫生部和该药物的制造商发出警告，反对在妊娠期间使用该药物。鉴于怀孕期间未经治疗的抑郁症可能对母亲和未出生的胎儿造成有害影响，因此有关剂量与畸形范围之间关系的数据是有必要的。本研究试图量化妊娠早期接触帕罗西汀与先天性心脏畸形之间的关系，调整可能的混杂因素，并量化帕罗西汀使用与心脏缺陷之间的剂量-反应关系。方法：采用药物和妊娠登记。这个以人口为基础的登记处是通过连接三个管理数据库（RAMQ、Med-Echo和ISQ）建立的，包括1997年1月1日至2003年6月30日期间魁北克的所有怀孕情况。登记日期为最后一次月经的第一天。为了有资格参加这项研究，女性必须：1)进入研究时年龄在15-45岁；2)纳入RAMQ药物计划：怀孕前和怀孕期间的12个月；3)在妊娠早期只使用一种抗抑郁药；4)活产。进行了两项嵌套病例对照研究，比较了妊娠前三个月使用帕罗西汀的患病率与同期使用其他抗抑郁药的患病率。病例定义为：1)有重大畸形；或2)出生后第一年被诊断出心脏畸形；对照组被定义为没有重大或轻微畸形。采用多元逻辑回归技术对数据进行分析。结果：在1403名符合纳入标准的女性中，有101名婴儿存在严重先天性畸形；24例有心脏畸形。调整可能的混杂因素后，妊娠早期使用帕罗西汀（优势比[OR] = 1.38, 95%可信区间[CI] = 0.49-3.92）和使用其他ssri类抗抑郁药（OR = 0.89, 95% Cl = 0.28-2.84）与使用非ssri类抗抑郁药相比，不会增加先天性心脏畸形的风险。然而，当考虑剂量时，观察到剂量-反应关系，因此在妊娠前三个月暴露于bbb25 mg/天的帕罗西汀的妇女，其婴儿患有严重先天性畸形（调整[adj] OR = 2.23, 95% CI = 1.19, 4.17）或严重心脏畸形（adj OR = 3.07, 95% CI = 1.00, 9.42）的风险增加。结论：妊娠期暴露于帕罗西汀与主要先天性畸形和主要心脏畸形有关，仅在妊娠早期暴露于25mg /天以上。
BACKGROUND: Conflicting findings with regard to the teratogenic risks of first trimester use of paroxetine have prompted the FDA, Health Canada, and the manufacturer of the drug to issue warnings against its use during pregnancy. Given that untreated depression during pregnancy can lead to deleterious effect on the mother and her unborn fetus, data on the relationship between the dose and the range of malformations is warranted. This study attempts to quantify the association between first trimester exposure to paroxetine and congenital cardiac malformations, adjusting for possible confounders, and to quantify the dose-response relationship between paroxetine use and cardiac defects. METHODS: The Medication and Pregnancy registry was used. This population-based registry was built by linking three administrative databases (RAMQ, Med-Echo, and ISQ), and includes all pregnancies in Quebec between 01/01/1997 and 06/30/2003. Date of entry in the registry is the date of the first day of the last menstrual period. To be eligible for this study, women had to: 1) be 15-45 years of age at entry; 2) be covered by the RAMQ drug plan : 12 months before and during pregnancy; 3) be using only one type of antidepressant during the first trimester; and 4) have a live birth. Two nested case-control studies were carried out comparing the prevalence of paroxetine use in the first trimester of pregnancy to the prevalence of other antidepressant exposures during the same time period. Cases were defined as: 1) any major malformations; or 2) any cardiac malformations diagnosed in the first year of life; controls were defined as no major or minor malformations. Multivariate logistic regression techniques were used to analyze data. RESULTS: Among the 1,403 women meeting inclusion criteria, 101 infants with major congenital malformations were identified; 24 had cardiac malformations. Adjusting for possible confounders, the use of paroxetine (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 0.49-3.92), and the use of other SSRIs (OR = 0.89, 95% Cl = 0.28-2.84) during the first trimester of pregnancy did not increase the risk of congenital cardiac malformations compared with the use of non-SSRI antidepressants. When considering the dose, however, a dose-response relationship was observed, thus women exposed to > 25 mg/ day of paroxetine during the first trimester of pregnancy were at increased risk of having an infant with major congenital malformations (adjusted [adj] OR = 2.23, 95% CI = 1.19, 4.17), or major cardiac malformations (adj OR = 3.07, 95% CI = 1.00, 9.42). CONCLUSIONS: Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day.