Association of a GATA Binding Protein 4 Polymorphism with the Risk of Hypospadias in the Chinese Children.

PURPOSE: GATA binding protein 4 (GATA4) has been implicated in the etiology of congenital malformation of the urogenital system. The present study investigated the influence of GATA4 polymorphisms on susceptibility to hypospadias. METHODS: We genotyped 4 potentially functional polymorphisms (rs12458, rs12825, rs884662, and rs904018) in GATA4 in the hospital-based case-control study including 410 child patients and 520 nonmalformed individuals by the TaqMan MGB method. Risk associations were assessed using unconditional logistic regression, adjusted for potential confounding factors. RESULTS: A significant association was found between rs12458 (3'-UTR of GATA4) and susceptibility to hypospadias (p = 0.008). Compared with rs12458 AA genotype individuals, those harboring the variant allele (rs12458 AT/TT) were correlated with significantly higher risk of hypospadias (AT/TT vs. AA: OR = 1.42, 95% CI = 1.17-2.35, p = 0.036). Furthermore, the rs12458T allele showed significantly decreased activity in a luciferase reporter assay, indicating a possible role of rs12458 variant in regulating the combination of microRNAs with the GATA4 mRNA. CONCLUSIONS: The present results indicate that the functional GATA4 rs12458 variant confers individuals' susceptibility to hypospadias, possibly through regulating the GATA4 expression level.

Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016.

A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997-2016. Since our initial results showed some surprising findings in the Hutterite Brethren, such as zero cases of spina bifida, cleft lip and palate, gastroschisis, and omphalocele, and a significant excess of cases with hypospadias, we extended the study to prior years (1980-1996) for selected anomalies. For the extended study period (1980-2016), there was a significant increased prevalence of hypospadias, tetralogy of Fallot and tricuspid atresia in the Hutterite population, and although not statistically significant, zero cases of cleft lip with cleft palate, gastroschisis and omphalocele were confirmed. Further research is needed to determine the precise effects of rural environmental exposures, lifestyle factors, and genetic associations for selected multifactorial congenital anomalies.

Placental Weight and Risk of Cryptorchidism and Hypospadias in the Collaborative Perinatal Project.

Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.

Differences in risk factors for second and third degree hypospadias in the national birth defects prevention study.

BACKGROUND: Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias. METHODS: A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center. RESULTS: In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history. CONCLUSION: Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between second and third degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype.

Geographic analysis of individual and environmental risk factors for hypospadias births.

BACKGROUND: Hypospadias is a relatively common birth defect affecting the male urinary tract. We explored the etiology of hypospadias by examining its spatial distribution in North Carolina and the spatial clustering of residuals from individual and environmental risk factors. METHODS: We used data collected by the North Carolina Birth Defects Monitoring Program from 2003 to 2005 to estimate local Moran's I statistics to identify geographic clustering of overall and severe hypospadias, using 995 overall cases and 16,013 controls. We conducted logistic regression and local Moran's I statistics on standardized residuals to consider the contribution of individual variables (maternal age, maternal race/ethnicity, maternal education, smoking, parity, and diabetes) and environmental variables (block group land cover) to this clustering. RESULTS: Local Moran's I statistics indicated significant clustering of overall and severe hypospadias in eastern central North Carolina. Spatial clustering of hypospadias persisted when controlling for individual factors, but diminished somewhat when controlling for environmental factors. In adjusted models, maternal residence in a block group with more than 5% crop cover was associated with overall hypospadias (odds ratio = 1.22; 95% confidence interval = 1.04-1.43); that is living in a block group with greater than 5% crop cover was associated with a 22% increase in the odds of having a baby with hypospadias. Land cover was not associated with severe hypospadias. CONCLUSION: This study illustrates the potential contribution of mapping in generating hypotheses about disease etiology. Results suggest that environmental factors including proximity to agriculture may play some role in the spatial distribution of hypospadias. Birth Defects Research (Part A) 100:887-894, 2014. © 2014 Wiley Periodicals, Inc.

Population based nationwide study of hypospadias in Sweden, 1973 to 2009: incidence and risk factors.

PURPOSE: We studied the incidence of hypospadias in Sweden during a 40-year period to determine if changes were associated with known risk factors. MATERIALS AND METHODS: We analyzed prospective data from nationwide health care and demographic registers collected for all males (1,948,591 total) born in Sweden between 1973 and 2009. The incidence of hypospadias per 1,000 live-born boys was calculated as number of cases divided by total number of births yearly. The association between hypospadias and risk factors was estimated using logistic regression, expressed as odds ratios. RESULTS: The nationwide incidence of boys diagnosed with hypospadias was approximately 4.5 per 1,000 live-born boys until 1990, increasing to 8 per 1,000 boys during the following decade. Mild and severe phenotypes comprised the increase. Boys born small for gestational age (OR 4.34), as a twin (OR 1.8), as a result of in vitro fertilization (OR 1.15), or with parents from Asia (OR 1.45) or continental Europe (OR 1.41) were at increased risk for hypospadias. Multivariate analyses revealed that changes in risk factors did not explain the increased incidence. However, a systematic change in the classification of the diagnosis in registers could not be ruled out. CONCLUSIONS: This nationwide study demonstrates an increased incidence of hypospadias diagnoses in Sweden from 1990 to 1999 that is not attributable to previously known risk factors. The increase includes mild and severe phenotypes, suggesting that shifts in the diagnostic criteria are not the underlying cause.

Epidemiologic trends in penile anomalies and hypospadias in the state of California, 1985-2006.

PURPOSE: Using statewide data, we evaluated whether the changing incidence of penile anomalies and hypospadias is reflected in the diverse California population of newborn males over the past 20 years. METHODS: Discharge data from all California hospitals, prepared by the OSHPD (Sacramento, CA) was reviewed for the years 1985-2006 for male infant births with an ICD-9 code (752.6) for hypospadias, epispadias or other penile anomalies. Trends were examined by Generalized Estimation Equations for Poisson regression. RESULTS: From 1985 to 2006, the birth incidence of newborn penile anomalies increased in California from 47 to 57 cases per 10,000 newborn discharges, yet the trend for hypospadias alone appears stable from 1997. The rates for penile anomalies in newborns increased 1.4% annually (p < 0.001). All racial/ethnic groups analyzed showed this increase (p < 0.001 for each). During the study period there was a 2% increase per year in plural births (p < 0.001). Interestingly, the rate of change in penile anomaly incidence was greater in males of plural births compared to their singleton cohorts (2% vs 1% annually) (p < 0.001). The birth incidence of cleft palate, another congenital anomaly known to be stable over time, remained unchanged over this period. CONCLUSIONS: From 1985 to 2006 in California the incidence of penile anomalies increased in a statistically significant manner, but the incidence of hypospadias appears stable for the last decade. Our data support the notion that different racial/ethnic groups have distinct incidences of penile anomaly formation and that an association with plural births appears to be present.

Hypospadias and maternal exposures to cigarette smoke.

The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

Hypospadias: a contemporary epidemiologic assessment.

OBJECTIVES: To determine whether the incidence of hypospadias is increasing and whether racial differences among patients are significant, we evaluated the current incidence of hypospadias and patient race in an equal-access healthcare system. METHODS: We undertook a retrospective review of discharge records between 1990 and 1998 from 15 military treatment facilities to determine the total number of male live births and the number of male live births with hypospadias reported by race (categorized as white, black, Asian, Native American, and unknown). RESULTS: Among 99,210 male live births, 709 cases of hypospadias were identified (0.7%). Of the total male live births, 68,444 were white, 18,984 were black, 1761 were Asian, 175 were Native American, and 9846 were unknown, with an incidence of hypospadias of 0.8%, 0.6%, 0.5%, 0.6%, and 0.6%, respectively. Racial differences were not statistically significant (P = 0.2). CONCLUSIONS: The 0.7% incidence of hypospadias detected is near the upper limit of what has been historically reported. No significant difference between races was found, but the incidence of hypospadias in minorities is higher than previously reported.