Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente Northern California, Oakland, CA.
Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente Northern California, Oakland, CA.
Am J Obstet Gynecol. 2018 Sep;219(3):275.e1-275.e8. doi: 10.1016/j.ajog.2018.06.002. Epub 2018 Jun 8.
Nonsteroidal antiinflammatory drugs are among the medications most widely used by pregnant women, and previous studies have reported an increased risk of miscarriage that is associated with nonsteroidal antiinflammatory drug use during pregnancy. Although the findings have not always been consistent, there is a well-established mechanism for the association: nonsteroidal antiinflammatory drugs inhibit the production of prostaglandin, which is essential for successful embryonic implantation. Abnormal implantation increases the risk of miscarriage.
The purpose of this study was to examine the impact of nonsteroidal antiinflammatory drug use in early pregnancy on the risk of miscarriage, especially regarding the timing and duration of use.
We conducted a cohort study among pregnant members of Kaiser Permanente Northern California, an integrated healthcare delivery system. Pregnant Kaiser Permanente Northern California members (N=1097) were recruited very early in pregnancy (median gestational age at enrollment, 39 days) to achieve optimal ascertainment of miscarriage, including early miscarriages, which are often missed in studies of miscarriages. Based on the use of nonsteroidal antiinflammatory drugs and acetaminophen, which has similar indication as nonsteroidal antiinflammatory drugs, 3 cohorts were formed: (1) women who used nonsteroidal antiinflammatory drugs only, (2) women who used acetaminophen only (to control for indication), and (3) women who used neither nonsteroidal antiinflammatory drugs nor acetaminophen (unexposed control subjects). Among all eligible women contacted, 63% participated in the study. Miscarriages were ascertained from both electronic medical record data and directly from interviews with participants. The Cox proportional hazards model with accommodation for left truncation was used to examine the risk of miscarriage associated with the use of nonsteroidal antiinflammatory drugs and acetaminophen during pregnancy; we controlled for potential confounders.
After an adjustment for multiple confounders that included maternal age, previous miscarriage, multivitamin use, caffeine drinking, and smoking during pregnancy, we found that nonsteroidal antiinflammatory drug use during pregnancy was associated with a statistically significant increased risk of miscarriage compared with both unexposed control subjects (adjusted hazard ratio, 1.59; 95% confidence interval, 1.13-2.24) and acetaminophen users (indication control subjects; adjusted hazard ratio, 1.45; 95% confidence interval, 1.01-2.08). The risk was largely due to nonsteroidal antiinflammatory drug use around conception (adjusted hazard ratio, 1.89; 95% confidence interval, 1.31-2.71) with a statistically significant dose-response relationship: adjusted hazard ratio, 1.37 (95% confidence interval, 0.70-2.71) for nonsteroidal antiinflammatory drug use of ≤14 days; adjusted hazard ratio, 1.85 (95% confidence interval, 1.24-2.78) for nonsteroidal antiinflammatory drug use of ≥15 days. The association was stronger for early miscarriage (<8 weeks gestational age): adjusted hazard ratio, 4.08 (95% confidence interval, 2.25-7.41). Women with lower body mass index (<25 kg/m) appeared to be more susceptible to the effect of nonsteroidal antiinflammatory drug use around conception (adjusted hazard ratio, 3.78; 95% confidence interval, 2.04-6.99) than women with high body mass index (≥25 kg/m; adjusted hazard ratio, 1.03; 95% confidence interval, 0.61-1.72).
After we controlled for confounding by indication, nonsteroidal antiinflammatory drug use around conception was associated with an increased risk of miscarriage with a dose-response relationship. In addition, women with lower body mass index could be especially vulnerable to the effects of nonsteroidal antiinflammatory drug use around the time of embryonic implantation, although this new observation must be confirmed in future studies.
非甾体抗炎药是孕妇最常使用的药物之一，先前的研究报告称，非甾体抗炎药的使用与流产风险增加有关。尽管这些发现并不总是一致的，但已经确立了一种与该关联相关的机制：非甾体抗炎药抑制前列腺素的产生，而前列腺素对胚胎着床的成功至关重要。异常着床会增加流产的风险。
本研究旨在检查早孕时非甾体抗炎药的使用对流产风险的影响，特别是使用的时间和持续时间。
我们对 Kaiser Permanente Northern California 的孕妇进行了队列研究，这是一个综合医疗服务系统。Kaiser Permanente Northern California 的孕妇（N=1097）在妊娠早期（登记时的中位妊娠龄为 39 天）招募，以实现对包括早期流产在内的流产的最佳确定，因为早期流产在流产研究中经常被遗漏。根据非甾体抗炎药和具有与非甾体抗炎药相似适应症的对乙酰氨基酚的使用情况，形成了 3 个队列：（1）仅使用非甾体抗炎药的女性，（2）仅使用对乙酰氨基酚（以控制适应症）的女性，和（3）既不使用非甾体抗炎药也不使用对乙酰氨基酚的女性（未暴露的对照组）。在所有符合条件的联系到的女性中，有 63%参与了研究。流产情况通过电子病历数据和直接与参与者面谈来确定。使用 Cox 比例风险模型并考虑到左截断来检查怀孕期间使用非甾体抗炎药和对乙酰氨基酚与流产风险的关联；我们控制了潜在的混杂因素。
在调整了包括母亲年龄、既往流产、多种维生素使用、咖啡因摄入和怀孕期间吸烟等多种混杂因素后，我们发现与未暴露的对照组相比，怀孕期间使用非甾体抗炎药与流产风险显著增加相关（调整后的危险比，1.59；95%置信区间，1.13-2.24），与使用对乙酰氨基酚的患者（适应症对照）也相关（调整后的危险比，1.45；95%置信区间，1.01-2.08）。这种风险主要归因于妊娠早期（调整后的危险比，1.89；95%置信区间，1.31-2.71）的非甾体抗炎药使用，且存在统计学显著的剂量-反应关系：非甾体抗炎药使用≤14 天的调整后危险比为 1.37（95%置信区间，0.70-2.71），非甾体抗炎药使用≥15 天的调整后危险比为 1.85（95%置信区间，1.24-2.78）。对于早期流产（<8 周妊娠龄），这种关联更强：调整后的危险比为 4.08（95%置信区间，2.25-7.41）。较低的身体质量指数（<25 kg/m）的女性似乎比高身体质量指数（≥25 kg/m）的女性更容易受到妊娠早期非甾体抗炎药使用的影响（调整后的危险比，3.78；95%置信区间，2.04-6.99）。（调整后的危险比，1.03；95%置信区间，0.61-1.72）。
在我们通过适应症进行混杂因素控制后，妊娠早期非甾体抗炎药的使用与流产风险增加相关，且存在剂量-反应关系。此外，身体质量指数较低的女性可能特别容易受到妊娠早期胚胎着床时非甾体抗炎药使用的影响，尽管这一新发现必须在未来的研究中得到证实。
