背景:大多数致畸药物的风险缓解依赖于通过药物标签的风险沟通,产前暴露仍然很常见。有关产前暴露于具有致畸风险的药物的类型和风险因素的信息可以指导减少暴露的策略。
目的:确定在怀孕期间通常使用的已知或潜在致畸风险的药物。
方法:我们使用MarketScan®商业索赔和遭遇数据来识别活体或非活体妊娠发作(异位妊娠,自然流产和选择性流产,2011-2018年12至55岁人群的死产)结局。通过基于验证研究的适应性算法确定药物暴露的开始/结束日期和妊娠结局。我们要求从怀孕前90天到怀孕结束后30天连续进行健康计划登记。根据风险水平和证据质量(已知138种,潜在风险60种),从Teratogen信息系统(TERIS)和药物专著中选择具有已知或潜在致畸风险的药物。我们根据≥1次门诊药房索赔或在目标妊娠期间考虑药物风险状况的药物管理的医疗遭遇定义了产前暴露(例如,风险仅在妊娠早期或在一定剂量阈值)。性激素和激素类似物,流产和产后/流产出血治疗不被认为是致畸药物,因为不同妊娠相关适应症的挑战,如果阿片类药物的唯一致畸机制是体重减轻,则阿片类药物(由于复杂的风险-获益)或抗肥胖药物也不是。
结果:在所有怀孕中,已知致畸风险和最高产前暴露的10种药物是磺胺甲恶唑/甲氧苄啶(SMX/TMP)(每100,000个妊娠年1,988),大剂量氟康唑(1248),托吡酯(351),赖诺普利(144),华法林(57),氯沙坦(56),卡马西平(50),丙戊酸盐(49),维多珠单抗(自2015年以来28个),缬沙坦(25)。在2011年至2018年期间,SMX/TMP的暴露率从每100,000个妊娠年2,346降至1,453,但自2015年批准以来,vedolizumab的暴露率增加了六倍。与活产妊娠相比,非活产妊娠的头三个月的产前暴露量较高,华法林的差异最大(非直播370与活产78),其次是丙戊酸盐(258vs.86)和托吡酯(1,728vs.674).产前暴露于具有潜在致畸风险的药物是低剂量氟康唑最普遍的(6,495),美托洛尔(1,325)和阿替洛尔(448)。非活产和活产妊娠之间最大的孕早期暴露差异是结石(242与89),加巴喷丁(1,639vs.653),和度洛西汀(1,914vs.860).在研究期间,观察到肼屈嗪和加巴喷丁暴露的稳定增长,而阿替洛尔暴露减少(561至280)。
结论:在怀孕期间继续使用几种具有致畸风险的药物,这些药物有可能更安全的替代品。在某些致畸药物中观察到的产前暴露率的波动表明,需要定期重新评估风险缓解策略。未来的研究集中在了解药物使用的临床背景是必要的,以制定有效的策略来减少怀孕期间对具有致畸风险的药物的暴露。
Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure.
This
study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons.
We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss.
Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the
study years, whereas atenolol exposure decreased (561 to 280).
Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.