Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.
Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.
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DOI：
10.7326/m21-4389
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发表时间：
2022-05
影响因子：
39.2
通讯作者：
Eisenberg ML
中科院分区：
文献类型：
--
作者：
Wensink MJ;Lu Y;Tian L;Shaw GM;Rizzi S;Jensen TK;Mathiesen ER;Skakkebæk NE;Lindahl-Jacobsen R;Eisenberg ML
糖尿病会降低精液质量，并越来越多地发生在生育年龄。糖尿病药物，如二甲双胍，对男性生殖系统有不依赖葡萄糖的作用。与后代出生缺陷的关系尚不清楚。评估对患有糖尿病的父亲进行孕前药物治疗是否会改变其后代出生缺陷的风险。全国前瞻性登记队列研究。从1997年到2016年。所有母亲没有糖尿病或原发性高血压病史的活产单胎。如果父亲在受精精子发育过程中服用了1种或1种以上的糖尿病药物，子女就会被认为是暴露在糖尿病环境中。主要出生缺陷的性别和频率在药物、暴露时间和兄弟姐妹之间进行了比较。在纳入的1116779名后代中，3.3%有1种或1种以上的重大出生缺陷（参考）。胰岛素暴露的后代（n = 5298）有参考出生缺陷频率（校正优势比[aOR]， 0.98 [95% CI, 0.85 ~ 1.14]）。二甲双胍暴露的后代（n = 1451）出生缺陷发生率升高（aOR, 1.40 [CI, 1.08 ~ 1.82]）。磺脲暴露子代（n = 647）的aOR为1.34 （CI为0.94 ~ 1.92）。父亲在精子发育前（n = 1751）或后（n = 2484）一年服用二甲双胍处方的后代有参考出生缺陷频率（aor分别为0.88 [CI， 0.59至1.31]和0.92 [CI， 0.68至1.26]），暴露后代的未暴露的兄弟姐妹也有参考出生缺陷频率（3.2%；暴露vs.未暴露or， 1.54 [CI， 0.94至2.53]）。二甲双胍暴露子代中，生殖器官出生缺陷的发生率均为男孩（aOR, 3.39 [CI, 1.82 ~ 6.30]），而男性子代的比例较低（49.4%比51.4%,P = 0.073）。关于潜在疾病状况的信息有限。孕前父亲二甲双胍治疗与主要出生缺陷有关，特别是男孩的生殖器出生缺陷。进一步的研究应该重复这些发现并澄清因果关系。国立卫生研究院。
Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown. To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. Nationwide prospective registry-based cohort study. Denmark from 1997 to 2016. All liveborn singletons from mothers without histories of diabetes or essential hypertension. Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. Of 1116779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073). Information on underlying disease status was limited. Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation. National Institutes of Health.