{"doi":"10.7326/m21-4389","title":"Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring","abstract":"Background: 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. Objective: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. Design: Nationwide prospective registry-based cohort study. Setting: Denmark from 1997 to 2016. Participants: All liveborn singletons from mothers without histories of diabetes or essential hypertension. Measurements: 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. Results: Of 1 116 779 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). Limitation: Information on underlying disease status was limited. Conclusion: 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. Primary Funding Source: National Institutes of Health.","journal":"Annals of Internal Medicine","year":2022,"id":235814,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":75,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":50832,"name":"Ying Lü","orcid":"0000-0002-7698-8962","position":1,"is_corresponding":false},{"id":51246,"name":"Lü Tian","orcid":"0000-0002-5893-0169","position":2,"is_corresponding":false},{"id":17736,"name":"Gary M. Shaw","orcid":"0000-0001-7438-4914","position":3,"is_corresponding":false},{"id":325107,"name":"Silvia Rizzi","orcid":"0000-0002-3512-2361","position":4,"is_corresponding":false},{"id":318538,"name":"Tina Kold Jensen","orcid":"0000-0003-2311-5778","position":5,"is_corresponding":false},{"id":854812,"name":"Elisabeth R. Mathiesen","orcid":"0000-0003-3279-0863","position":6,"is_corresponding":false},{"id":637874,"name":"Niels E. Skakkebæk","orcid":"0000-0002-4282-8020","position":7,"is_corresponding":false},{"id":325109,"name":"Rune Lindahl‐Jacobsen","orcid":"0000-0002-4622-9826","position":8,"is_corresponding":false},{"id":232339,"name":"Michael L. Eisenberg","orcid":"0000-0001-5482-0141","position":9,"is_corresponding":false},{"id":325105,"name":"Maarten Jan Wensink","orcid":"0000-0001-6518-1015","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T00:21:53.333008Z","pmid":"35344380","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}