Department of Epidemiology, Biostatistics and Biodemography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Odense C, Denmark (M.J.W., R.L.).
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California (Y.L., L.T.).
Ann Intern Med. 2022 May;175(5):665-673. doi: 10.7326/M21-4389. Epub 2022 Mar 29.
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 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring ( = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring ( = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring ( = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before ( = 1751) or after ( = 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%, = 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.
糖尿病会降低精液质量，且在生育期内发病率逐渐升高。二甲双胍等糖尿病药物对男性生殖系统具有葡萄糖以外的作用。但其对子代出生缺陷的相关性尚不清楚。
评估父亲在糖尿病前期接受药物治疗是否会影响后代出现出生缺陷的风险。
基于全国前瞻性登记的队列研究。
丹麦，1997 年至 2016 年。
母亲无糖尿病或原发性高血压史的所有活产单胎儿。
如果父亲在精子发育过程中使用 1 种或多种糖尿病药物处方，即认为后代暴露。比较不同药物、不同暴露时间及同胞间的性别和主要出生缺陷频率。
共纳入 1 116 779 例活产儿，其中 3.3%存在 1 种或多种重大出生缺陷（参照）。胰岛素暴露组（n=5298）的出生缺陷参照频率（校正比值比[aOR]，0.98[95% CI，0.85 至 1.14]）。二甲双胍暴露组（n=1451）的出生缺陷频率升高（aOR，1.40[CI，1.08 至 1.82]）。磺酰脲类药物暴露组（n=647）的 aOR 为 1.34（CI，0.94 至 1.92）。父亲在精子发育前一年（n=1751）或后一年（n=2484）服用二甲双胍的后代，出生缺陷参照频率（aORs，0.88[CI，0.59 至 1.31]和 0.92[CI，0.68 至 1.26]），暴露后代的未暴露同胞（3.2%）也呈现相同结果（暴露与未暴露比值比[aOR]，1.54[CI，0.94 至 2.53]）。在二甲双胍暴露组中，男孩更常见生殖器畸形（aOR，3.39[CI，1.82 至 6.30]），且男婴比例较低（49.4% vs. 51.4%， = 0.073）。
潜在疾病状况信息有限。
父亲在糖尿病前期接受二甲双胍治疗与主要出生缺陷相关，尤其是男孩的生殖器缺陷。进一步的研究应复制这些发现并阐明病因。
美国国立卫生研究院。
