Thomsen Anne Marie L, Liew Zeyan, Riis Anders Hammerich, Stayner Leslie Thomas, Ramlau-Hansen Cecilia Høst, Sigsgaard Torben, Olsen Jørn
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
Pharmacoepidemiol Drug Saf. 2019 Sep;28(9):1204-1210. doi: 10.1002/pds.4867. Epub 2019 Jul 26.
Nitrosatable drugs can react with nitrite in the stomach and form N-nitroso compounds. Exposure to nitrosatable drugs has been associated with congenital malformations and preterm birth, but use during pregnancy as a cause of fetal death is not well-known. We examined if prenatally nitrosatable drug use is associated with risk of stillbirth.
A nationwide cohort was conducted using 554 844 women with singleton and first recorded pregnancies regardless of previous pregnancy history from the Danish Medical Birth Register from 1996 to 2015. Exposure was recorded by use of the Danish National Prescription Register and defined as women who had redeemed a prescribed nitrosatable drug in the first 22 weeks of pregnancy. The reference group was women with no redeemed prescribed nitrosatable drug in this time period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for stillbirth.
Among the 84 720 exposed women, 348 had a stillbirth compared with 1690 stillbirths among the 470 124 unexposed women. Women who used any prescribed nitrosatable drug were more likely to have a stillbirth compared with unexposed women (aHRs 1.24; 95% CI, 1.03-1.49).
Nitrosatable drug use during the first 22 weeks of pregnancy might increase risk of stillbirth. The findings should be interpreted cautiously because of important unmeasured factors that might influence the observed association, including maternal vitamin C intake, dietary, and other sources of nitrate/nitrite intake.
可亚硝化的药物能与胃中的亚硝酸盐发生反应并形成N-亚硝基化合物。接触可亚硝化的药物与先天性畸形和早产有关，但孕期使用此类药物导致胎儿死亡的情况尚鲜为人知。我们研究了产前使用可亚硝化的药物是否与死产风险相关。
利用丹麦医疗出生登记处1996年至2015年的554844名单胎且首次有记录妊娠的女性（无论既往妊娠史如何）进行了一项全国性队列研究。通过丹麦国家处方登记处记录暴露情况，将其定义为在妊娠前22周内领取过处方可亚硝化药物的女性。参照组为在此期间未领取过处方可亚硝化药物的女性。我们将可亚硝化药物分为仲胺、叔胺和酰胺。采用Cox风险回归分析来估计死产的粗风险比和调整后风险比（aHRs）及95%置信区间（CIs）。
在84720名暴露女性中，有348例死产，而在470124名未暴露女性中有1690例死产。与未暴露女性相比，使用过任何处方可亚硝化药物的女性死产的可能性更高（aHRs为1.24；95%CI为1.03 - 1.49）。
妊娠前22周使用可亚硝化药物可能会增加死产风险。由于可能影响所观察到的关联的重要未测量因素，包括母体维生素C摄入量、饮食以及硝酸盐/亚硝酸盐摄入的其他来源，这些研究结果应谨慎解读。
