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PurposeRisk factors for congenital upper limb differences (CoULDs) are often studied at the general population level. The CoULD registry provides a unique opportunity to study prenatal risk factors within a large patient sample.MethodsAll patients enrolled between June 2014 and March 2020 in the prospective CoULD registry, a national multicenter database of patients diagnosed with a CoULD, were included in the analysis. We analyzed self-reported, prenatal risk factors, including maternal smoking, alcohol use, recreational drug use, prescription drug use, gestational diabetes mellitus (GDM), and gestational hypertension. The outcome measures included comorbid medical conditions, proximal involvement of limb difference, bilateral involvement, and additional orthopedic conditions. Multivariable logistic regression was used to analyze the effect of the risk factors, controlling for sex and the presence of a named syndrome.ResultsIn total, 2,410 patients were analyzed, of whom 72% (1,734) did not have a self-reported risk factor. Among the 29% (676) who did have at least 1 risk factor, prenatal maternal prescription drug use was the most frequent (376/2,410; 16%). Maternal prescription drug use was associated with increased odds of patient medical comorbidities (odds ratio [OR] = 1.43, P = .02). Gestational diabetes mellitus was associated with increased odds of comorbid medical conditions (OR = 1.58, P = .04), additional orthopedic conditions (OR = 1.51, P = .04), and proximal involvement (OR = 1.52, P = .04). Overall, reporting 1 or more risk factors increased the odds of patient comorbid medical conditions (OR = 1.42, P < .001) and additional orthopedic conditions (OR = 1.25, P = .03).ConclusionsMost caregivers (72%) did not report a risk factor during enrollment. However, reporting a risk factor was associated with patient medical and orthopedic comorbidities. Of note, GDM alone significantly increased the odds of both these outcome measures along with proximal limb differences. These findings highlight the ill-defined etiology of CoULDs but suggest that prenatal risk factors, especially GDM, are associated with a higher degree of morbidity.Type of study/level of evidencePrognostic III.