Hypospadias, one of the most common congenital anomalies affecting male infants, occurs when the urethral opening forms on the underside of the penis rather than at the tip. Despite decades of investigation, the causes behind the majority of cases remain stubbornly unclear, and the suspected environmental and maternal contributors have produced a tangle of conflicting findings across the epidemiological literature. A new hospital-based case-control study conducted in Hainan, a tropical island province in southern China, now adds fresh detail to that picture, identifying several maternal conditions and fetal characteristics that appear to be independently associated with the malformation while also clearing some long-suspected factors of any link.
The research, published as an open-access article in BMC Pediatrics, was carried out by a team led by pediatric urology specialists at Hainan Women and Children’s Medical Center in Haikou, with additional participation from the Children’s Hospital of Fudan University in Shanghai. Between 2019 and 2021, the investigators retrospectively enrolled women who had delivered newborns with hypospadias at Hainan Maternal and Child Health Hospital as cases, while randomly selecting mothers of normal newborn male infants as controls. The final analysis included 96 infants with hypospadias and 480 male controls, a one-to-five matching ratio that gives the study reasonable statistical power for a single-center investigation.
Methodologically, the team relied on archived clinical records for maternal demographic and clinical characteristics, with the underlying information originally gathered through face-to-face or telephone communication as part of routine clinical care. Birth outcomes and maternal complications were verified directly from medical records, a step intended to reduce recall bias, a persistent weakness in retrospective case-control designs. Because the study was a secondary analysis of de-identified archived data, the hospital’s ethics committee formally waived the requirement for written informed consent, and the work was conducted in accordance with the principles of the Declaration of Helsinki. The statistical backbone of the analysis was multivariable conditional logistic regression, a technique well suited to matched case-control data because it allows researchers to estimate the independent effect of each exposure while holding other measured variables constant.
The results are striking for what they did not find. Maternal weight before pregnancy, weight gain during pregnancy, body mass index at delivery, maternal age, and infection with hepatitis B virus all showed no association with hypospadias in offspring. This is notable because maternal pre-pregnancy BMI, gestational weight gain, BMI at delivery, and gestational diabetes mellitus have all been proposed as modifiable factors independently linked to the condition, yet previous studies have reported mixed and sometimes contradictory results. The Hainan findings suggest that some of these commonly hypothesized metabolic pathways may not withstand scrutiny, at least in this population, and that the search for modifiable risk factors may need to look elsewhere.
Where associations did emerge, they clustered around maternal pregnancy complications and fetal characteristics. Maternal education showed a strong inverse relationship with hypospadias: compared with the reference group, higher education levels carried adjusted odds ratios of 0.35 (95 percent confidence interval 0.18 to 0.68) and 0.18 (95 percent confidence interval 0.07 to 0.50), meaning that children of more highly educated mothers were substantially less likely to be represented among the cases. Whether this reflects genuine biological protection, differences in health care access, nutritional patterns, or unmeasured confounding remains an open question that the authors themselves frame as hypothesis-generating rather than definitive.
Among the maternal complications, three stood out with particularly large effect sizes. Gestational hypertension was associated with an adjusted odds ratio of 6.27 (95 percent confidence interval 2.44 to 16.13), while intrahepatic cholestasis of pregnancy, a liver disorder characterized by impaired bile flow that typically presents with intense maternal itching, carried an adjusted odds ratio of 13.86 (95 percent confidence interval 3.00 to 64.03). Most dramatic of all was maternal hypothyroidism, with an adjusted odds ratio of 16.63 (95 percent confidence interval 5.01 to 55.20). The thyroid connection is biologically plausible: thyroid hormones play a role in fetal growth and development, and disruptions to the maternal endocrine milieu during the critical window of genital development in the first trimester have long been theorized to interfere with normal urethral fold fusion, the embryological process whose failure produces hypospadias.
On the fetal side, two factors were independently associated with the anomaly. Birth weight showed the largest effect in the entire study, with an adjusted odds ratio of 19.07 (95 percent confidence interval 6.58 to 55.25), and multiple gestation, meaning twin or higher-order pregnancies, carried an adjusted odds ratio of 7.89 (95 percent confidence interval 1.05 to 59.48). Both findings fit with a broader pattern in the hypospadias literature linking altered fetal growth and placental insufficiency to the malformation. Low birth weight and multiple pregnancies are both markers of a stressed intrauterine environment, and some researchers have proposed that compromised placental function may alter hormone signaling, including the production of human chorionic gonadotropin and the fetal testosterone surge that masculinizes the external genitalia in early gestation.
The wide confidence intervals on several of these estimates, particularly for multiple gestation and intrahepatic cholestasis, are a reminder of the study’s limitations. With only 96 cases, rare exposures produce imprecise estimates, and the very large odds ratios should be interpreted with caution. The retrospective design also means that only factors recorded in routine clinical records could be examined; unmeasured variables such as paternal factors, specific environmental endocrine disruptors, medication exposures, and detailed dietary patterns were outside the scope of the analysis. The authors are explicit that their findings may help generate hypotheses regarding maternal and fetal characteristics associated with hypospadias and warrant confirmation in larger prospective studies, a appropriately measured conclusion for a single-center dataset.
Nevertheless, the study’s clinical implications are worth taking seriously. Gestational hypertension, intrahepatic cholestasis, and hypothyroidism are all conditions that are routinely screened for or detectable during standard prenatal care, and hypothyroidism in particular is treatable with levothyroxine supplementation. If the association between maternal hypothyroidism and hypospadias is confirmed prospectively, it would raise the tantalizing possibility that a fraction of cases might be preventable through adequate preconception and first-trimester thyroid screening, especially in regions where iodine status and thyroid disease prevalence vary. Similarly, the strong birth weight signal suggests that clinicians caring for growth-restricted fetuses or multiple pregnancies might reasonably include genital examination in newborn assessment, since hypospadias can be missed in the immediate postpartum period.
For now, the Hainan study takes its place in a growing body of evidence that reframes hypospadias not as a mystery of genetics alone but as a developmental outcome shaped by the maternal and fetal environment. The work was funded by the Hainan Provincial Clinical Medical Center and related Hainan provincial science and health funds, and the authors declare no competing interests. As larger prospective cohorts are assembled, the specific odds ratios reported here will be tested and refined, but the study’s central message, that pregnancy complications and fetal growth parameters deserve a central place in hypospadias research, is likely to endure. For families and clinicians alike, that shift in focus from unmodifiable mystery to potentially actionable maternal health is the most consequential finding of all.
Subject of Research: Maternal and fetal risk factors for hypospadias in a Chinese case-control study
Article Title: Maternal and fetal risk factors for hypospadias: a hospital-based case-control study in Southern China
Article References: Bu, W., Li, X., Xuan, Y., Hu, X., & Zhao, Z. (2026). Maternal and fetal risk factors for hypospadias: a hospital-based case-control study in Southern China. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07724-3
Image Credits: AI Generated
DOI: 10.1186/s12887-026-07724-3
Keywords: hypospadias, congenital anomalies, case-control study, maternal health, hypothyroidism, gestational hypertension, intrahepatic cholestasis of pregnancy, birth weight, multiple gestation, pediatric urology, BMC Pediatrics, China
News Source: Harold Sullivan. (October 10, 2026). Maternal Health Clues Emerge in Study of Hypospadias in Southern China. Scienmag.
