Risk Factors For Hypospadias Research Articles

Association between maternal peri-conceptional exposures and risk of hypospadias and cryptorchidism in offspring

Objective: To investigate the relationship between maternal exposures to peri-conceptional risk factors and the risk of hypospadias and cryptorchidism in offspring. Methods: Pregnant women who delivered male newborns and participated in the China birth cohort study between February 2018 and December 2020 at the research center of Beijing Obstetrics and Gynecology Hospital, Capital Medical University were selected for the study. All were enrolled at 6-13+6 weeks of their gestation. Baseline risk factor information was collected by questionnaire survey. Information on the outcome of hypospadias and cryptorchidism was obtained by clinical examination at birth and ultrasonography. Logistic regression was used to analyze the Odds Ratio (OR) and 95% Confidence Interval (95%CI) of each factor with respect to the onset of the outcome. Results: A total of 15, 833 pregnant women with an average age of (31.81±3.84) years were included. Among their offsprings, 113 were diagnosed as hypospadias or cryptorchidism (42 hypospadias, 69 cryptorchidism, and 2 both hypospadias and crypterchidism), with an incidence of 7.14‰. The results of multivariate logistic regression analysis showed that mothers with pregnancy history of birth defects (OR=3.01, 95%CI: 1.09-8.35), with preconception Hepatitis B infection (OR=4.74, 95%CI: 1.10-20.42), fetal growth restriction (OR=4.02, 95%CI: 2.10-7.68), multivitamin use since preconception (OR=1.98, 95%CI: 1.12-3.52), and never cook and eat at home (OR=2.17, 95%CI: 1.23-3.82) were risk factors for hypospadias and cryptorchidism (all P<0.05). Conclusions: Obesity in early pregnancy, preconception Hepatitis B infection, pregnancy history of birth defects, fetal growth restriction, multivitamin use before pregnancy, and rarely cook and eat at home were associated with an increased risk of hypospadias or cryptorchidism in their offsprings.

Potential risk factors for hypospadias and negative correlation with DICER1 (rs3742330) A>G variant in Algerian population: A case-control study.

Hypospadias continues to be a prevalent congenital anomaly affecting the male external genitalia, characterized by an unclear origin and complex treatment approaches. This study aimed to investigate the risk factors associated with hypospadias and explore its genetic link with the DICER1 rs3742330 variant. The study involved two groups: 105 male children with hypospadias and 111 healthy male children as matched controls. Detailed history and physical examinations were conducted for all patients and controls. PCR-restriction fragment length polymorphism was utilized to identify the DICER1 rs3742330 variant, analyzing genotype distribution and allele frequency. Logistic regression analysis estimated the risk factors for hypospadias. The mean age in the hypospadias group was 4.56 ± 2.50 years. The most prevalent type of hypospadias observed was the anterior type in 60 children (57.14%). Intrauterine growth restriction, advanced maternal age, and gestational hypertension were identified as significant risk factors for hypospadias (p = .011, p = .016, and p = .041, respectively). Regarding the genetic study, no significant difference was found in both genotype and allele frequencies of the DICER1 rs3742330 variant between case and control groups. The rs3742330 variant in the DICER1 gene showed no association with hypospadias cases in the Algerian population. However, multivariate logistic regression analysis identified preterm birth, low birth weight, intrauterine growth restriction, advanced maternal age, gestational diabetes, and rural residence as the most significant independent predictors for hypospadias.

Genetic and other epidemiological risk factors of infants and children with hypospadias: a case control study

BackgroundTo study hypospadias as regard epidemiological risk factors and genetic association with mutations in Steroid 5 alpha reductase type 2 genes.MaterialsThis study was conducted on two groups; the first group included 50 male children with hypospadias and the other group included 50 male healthy children as a matched control. All patients and controls were subjected to detailed history, physical examination and molecular study of 5-alpha-reductase gene polymorphisms (V89L and G34R).ResultsMean age in hypospadias group was 3.28 ± 2.87 years. The most common type of hypospadias was the glanular type in 19 children (38%). Higher maternal and paternal age, consanguinity, rural residence and preterm labor carry significant epidemiological risk factors for hypospadias. According to genetic study, all healthy children carried the wild valine residue (VV) genotype, while only 44% of hypospadias cases carried the wild VV genotype and 56% carried the mutant L allele (homozygote for leucine residue and heterozygote for both valine and leucine (VL)) with high significant p value (p < 0.001). For Allele Specific—polymerase chain reaction for glycine to arginine (G34R) mutation detection in the 5 alpha reductase type 2 gene, hypospadias children had significantly higher frequency of heterozygous GR genotype than healthy controls. Binary logistic regression analysis showed that mother age and rural residence were the most independent predictors for hypospadias.ConclusionsV89L and G34R Steroid 5 alpha reductase type 2 gene polymorphisms, higher maternal and paternal age, consanguinity, rural residence and preterm labor carry significant risk factors for hypospadias. On multivariate logistic regression, mother age and rural residence are the most independent predictors for hypospadias.

The prevalence of hypospadias in newborn males in Hangzhou, China from 2011 to 2020: A cross-sectional population-based study

Hypospadias is one of the most common anomalies of the human genitourinary system. The prevalence of hypospadias varies considerably by region, ethnicity, and clinical practice. This research was designed to investigate the prevalence and related influencing factors of neonatal hypospadias in Hangzhou from 2011 to 2020 in order to provide a scientific basis for the clinical prevention and treatment of hypospadias. This study retrospectively analyzed the Hangzhou Maternal Child Information System and Birth Defect Monitoring System and included data from a total of 1,008,754 pregnant women between October 2010 and September 2020. The chi-square test was adopted to compare the prevalence of hypospadias at different maternal ages and different years. The prevalence of neonatal hypospadias in Hangzhou, China, was 2.89 per 10,000, with a total of 292 newborns diagnosed with hypospadias from 2011 to 2020. The prevalence of hypospadias in Hangzhou showed temporal, regional, and age distribution characteristics: from 1.08/10,000 in 2011 to 7.03/10,000 in 2020; the prevalence was higher in suburban areas than that in the urban area and the counties, with statistically significant differences (P<0.001); the prevalence of hypospadias was lowest in maternal age < 25 years (1.20/10,000) and highest in maternal age ≥ 40 years old (14.59/10,000). The difference was statistically significant (P<0.001). The risk factor for hypospadias in the offspring of advanced pregnant women was 3.86 times higher than that of younger pregnant women. The overall prevalence of neonatal hypospadias in Hangzhou from 2011 to 2020 was 2.89/10,000 and showed temporal, regional, and age distribution characteristics.

Association between perinatal factors and hypospadias in newborns: a retrospective case–control study of 42,244 male infants

BackgroundHypospadias is one of the most common male congenital malformations worldwide. It is characterised by the abnormal positioning of the opening of urethra, and may lead to problems with urination and sexual function. Various factors were suggested to contribute to hypospadias pathogen. This study aimed to evaluate the relationship between perinatal factors and neonatal hypospadias based on a large sample of male newborns.MethodsThis retrospective case–control study was conducted at the International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine. Male infants with hypospadias (N = 97) and without any birth defects (N = 42,147) who were born in January 2015 to December 2019 were enrolled in this study. A statistical analysis of perinatal factors, such as maternal age, primiparity, multiple births, hypertensive disorders of pregnancy (HDP), diabetes mellitus (DM), placenta previa, thyroid diseases, hepatitis B, obesity, meconium-stained amniotic fluid, gestational age, low birth weight (LBW), small for gestational age (SGA) and in vitro fertilization (IVF) was used to assess the risk factors for hypospadias.ResultsThe overall incidence of hypospadias in male infants was 0.23% (97/42,244). The univariate analysis of potential risk factors for hypospadias showed that HDP, primiparity, multiple births, hyperthyroidism, preterm delivery, LBW and SGA had a statistical association with hypospadias. After adjusting for potential confounders in a multivariate regression analysis, the odds ratios (OR) and 95% confidence intervals (CI) were calculated for the following risk factors for hypospadias: HDP (OR: 3.965, 95% CI: 2.473–6.359, P < 0.01), multiple births (OR: 2.607, 95% CI: 1.505–4. 514, P < 0.01) and hyperthyroidism (OR:4.792, 95% CI: 1.700–13.506, P < 0.01), which suggested these factors were significant independent risk factors for hypospadias.ConclusionsPerinatal factors, such as HDP, multiple births and hyperthyroidism may be associated with hypospadias in male infants.

CORRELATION BETWEEN MATERNAL AGE, LOW BIRTH WEIGHT, PREMATURITY AND HORMONAL DRUGS USING WITH THE OCCURRENCE OF HYPOSPADIAS (CASE STUDY AT BINA SEHAT JEMBER HOSPITAL, PARU JEMBER HOSPITAL, AND BHAYANGKARA BONDOWOSO HOSPITAL)

Objective: This research aims to determine the correlation between maternal age during pregnancy, low birth weight (LBW), prematurity, and history of hormonal drugs used in the first trimester of pregnancy with the occurrence of hypospadias. Material &amp; Methods: This research is an observational analytic research with case control design. The sample in this study were 50 samples that consisting of 25 patients with hypospadias and 25 patients without hypospadias at Bina Sehat Jember Hospital, Paru Jember Hospital, and Bhayangkara Bondowoso Hospital. After determined every case and control group, data acquired retrospectively by traced the hypospadias risk factors (maternal age at pregnancy, LBW, prematurity, and history of hormonal drugs using in the first trimester of pregnancy) by interviewing the patient's mother. The data of this research were analyzed by bivariate and multivariate using SPSS 16.0. Bivariate analysis in this study used chi-square Yates correction (chi-square with continuity correction) and fisher's exact test, whereas multivariate analysis used logistic regression techniques with significance p-value&lt;0.05. Results: The result of bivariate analysis in this study showed that variable maternal age during pregnancy more than 35 years (p = 0.667) has no correlation with occurrence of hypospadias, while variable of LBW (p = 0.027), prematurity (p = 0.041), and the history of hormonal drug use in the first trimester of pregnancy (p = 0.049) have a correlation with the occurrence of hypospadias. Conclusion: In this study, there was a significant correlation between LBW, prematurity, and history of hormonal drugs using in the first trimester of pregnancy with the occurrence of hypospadias. This study did not show a significant correlation between maternal age during pregnancy with the occurrence of hypospadias.&#x0D;

Risk Factors for hypospadias in Northwest Russia: A Murmansk County Birth Registry Study.

BackgroundHypospadias is the most common congenital anomaly of the penis, but its causes are mainly unknown. Of the risk factors identified, the most plausible are hormonal and genetic. The aim of this study was to identify risk factors for hypospadias in Northwest Russia based on registry data.MethodsThe study population included male infants registered in the Murmansk County Birth Registry between 1 January 2006 and 31 December 2011 (n = 25 475). These infants were followed-up for 2 years using the Murmansk Regional Congenital Defects Registry to identify cases of hypospadias not diagnosed at birth. We used logistic regression analysis to examine the contributions of hypospadias risk factors.ResultsOut of 25 475 male infants born during the study period, 148 had isolated hypospadias. The overall prevalence rate was 54.2 (95% CI 53.6–54.8) per 10 000 male infants. Those born to mothers with preeclampsia (OR = 1.65; 95% CI 1.03–2.66) or infant birthweight < 2500 g (OR = 2.06; 95% CI 1.18–3.60) exhibited increased risk for hypospadias. Maternal age, smoking during pregnancy, folic acid intake during pregnancy or hepatitis B surface antigen positivity did not associate with increased risk of hypospadias.ConclusionsCombining data from a birth registry with those from a congenital defects registry provided optimal information about the prevalence of hypospadias and its association with low infant birthweight and preeclampsia. These factors have in common changes in hormone levels during pregnancy, which in turn may have contributed to hypospadias development.

Maternal and fetal risk factors associated with hypospadias in a sample of Iraqi boys

Background: Hypospadias is one of the most common congenital anomalies among boys. The exact causes of this anomaly are not clearly defined yet. However, many of the risk factors have been identified in different ethnic groups. Objective: The objectives of this study are to evaluate the maternal- and fetal-related risk factors for hypospadias in a sample of Iraqi patients. Materials and Methods: This case–control study included 42 boys with hypospadias cases and other 42 age-matched boys free from any genital anomalies as a control group. Maternal data, including age, parity, body mass index, hypertension, diabetes mellitus (DM), the use of assisted reproduction techniques (ART), level of education, consanguinity, and residence; and infant-related factors. Logistic regression analysis was used to predict the risk of each variable through the calculation of odds ratio (OR) and its corresponding 95% of confidence interval (CI). Results: Three maternal factors were found to be associated significantly with increased risk of hypospadias. These were maternal age >33 years (OR = 3.08, 95% CI = 1.02–9.26, P = 0.045), consanguineous marriage (OR = 3.0, 95% CI = 1.02–8.8, P = 0.045), and rural residence (OR = 2.64, 95% CI = 1.04–6.73, P = 0.041). Hypertension, DM, and using ART were more frequent among mothers of cases than controls; however, the differences were not significant. For fetal-related factors, infants with low-birth weight (LBW) were more frequent among cases than controls (40.48% vs. 19.05%), with a statistically significant difference (OR = 2.89, 95% CI = 1.08–7.75, P =0.035). Of note, twins were more frequent among cases than controls; however, this difference was not statistically significant (P = 0.074). Conclusions: These results highly suggest the critical role of advanced maternal age, consanguinity, rural residence, and infant LBW, as predisposing factors for the occurrence of hypospadias among Iraqi boys.

Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias: a Review.

Endocrine disrupting chemicals (EDCs) potentially have a role in causing hypospadias malformation through modifiable in-utero exposure. Considering the emerging literature on the role of potential endocrine disrupting substances on the occurrence of hypospadias and the potential to inform public health efforts to prevent the occurrence of these malformations, we have summarized the current literature, identified areas of consensus, and highlighted areas that warrant further investigation. Pharmaceuticals, such as diethylstilbestrol, progestin fertility treatments, corticosteroids, and valproic acid, have all been associated with hypospadias risk. Data on exposure to dichlorodiphenyltrichloroethane and hexachlorobenzene pesticides, as well as non-persistent pollutants, particularly phthalates, is less consistent but still compelling. Improving exposure assessment, standardizing sample timing to relevant developmental windows, using clear case identification and classification schemes, and elucidating dose-response relationships with EDCs will help to provide clearer evidence. Promising directions for future research include identification of subgroups with genetic hypospadias risk factors, measurement of intermediate outcomes, and study of EDC mixtures that will more accurately represent the total fetal environment.

Editorial comment: Birth prevalence of hypospadias and hypospadias risk factors in newborn males in the United States from 1997 to 2012

Editorial comment: Birth prevalence of hypospadias and hypospadias risk factors in newborn males in the United States from 1997 to 2012

Birth prevalence of hypospadias and hypospadias risk factors in newborn males in the United States from 1997 to 2012

Hypospadias is a common genitourinary malformation and there are conflicting data on whether its prevalence is increasing. Previous studies have described associations with risk factors including small for gestational age (SGA), multiple gestation birth, environmental influences, and maternal factors. The objective of this study was to examine birth prevalence of hypospadias and hypospadias risk factors in a large national dataset and to evaluate for changes from 1997 to 2012. We hypothesized that any increase in the birth prevalence of hypospadias would be associated with an increase in risk factors such as SGA, prematurity, or multiple gestation birth. The Kids' Inpatient Database was used to generate national estimates for prevalence of males born with hypospadias, SGA, prematurity, or to a multiple gestation and then prevalences were evaluated for association with time. Multivariable logistic regression was used to evaluate whether birth prevalence of hypospadias was associated with increasing year, SGA, prematurity, and multiple gestation birth. The estimated birth prevalence of hypospadias increased from 6.1 per 1000 births (95% confidence interval [CI] 5.9 to 6.3) to 6.8 per 1000 births (95% CI 6.7 to 7.0), an 11.5% increase from 1997-2012 (P = 0.014). Among male births, the prevalence of SGA increased 74%, multiple gestation increased 25%, and prematurity increased 20% (P < 0.001 for all) (Summary Figure). A risk factor was seen in around 20% of males born with hypospadias. Hypospadias birth prevalence also increased in males without risk factors but was not statistically significant (9.1% increase, P = 0.5). On multivariable logistic regression, being born SGA (odds ratio [OR] = 3.3), to a multiple gestation (OR = 1.1), or premature (OR 1.9) were associated with increased odds of hypospadias (P < 0.01 for all), whereas increasing year was not (P = 0.3). The estimated birth prevalence of hypospadias in the United States increased from 6.1 to 6.8 per 1000 births from 1997 to 2012. Known hypospadias risk factors of SGA birth, multiple gestation birth, and premature birth also increased over this time to a higher degree. About 20% of males born with hypospadias had one of these risk factors. The birth prevalence of hypospadias in males without any studied risk factors also increased, but this was not statistically significant. More studies are needed to evaluate whether this increase in hypospadias prevalence is due to increases in known hypospadias risk factors, new environmental exposures, improved diagnosis at birth, some combination, or unrelated causes.

Single nucleotide polymorphisms of HAAO and IRX 6 genes as risk factors for hypospadias

PurposeWe evaluated the association of hypospadias with 17 susceptibility loci previously identified by a European genome-wide association study (GWAS) in Japanese patients. We also examined the expression of candidate genes in male mouse embryos to discuss the possible underlying mechanisms of this disease. Materials and MethodsWe enrolled 169 Japanese patients (mean age at surgery: 3.7 years) who underwent repair of hypospadias. Genotyping of 17 SNPs was performed by using a multiplex-polymerase chain reaction (PCR) invader assay. We also performed in situ hybridization to determine whether candidate genes were expressed in the male genital tubercle during embryonic development of the external genitalia in mice. ResultsSNP rs3816183 of HAAO was significantly associated with susceptibility to hypospadias in general (p=0.0019) and both anterior/middle hypospadias (p=0.0283) and posterior hypospadias (p=0.0226), while SNP rs6499755 of IRX6 showed an association with susceptibility to anterior/middle hypospadias (p=0.0472). In mouse embryos, there was no significant upregulation of Haao expression in the developing male external genitalia. Irx3 and Irx5, which are linked to Irx6 within the IrxB cluster, were expressed in the mesenchyme remote from the urethral plate epithelium during the critical embryonic period for masculinization. Irx6 was expressed in the ectodermal epithelium, showing prominent dorsal ectodermal expression without expression in ventral ectoderm adjacent to the urethral plate during the same period. ConclusionsGenetic variations of HAAO and IRX6 influence susceptibility to hypospadias in Japanese population, although further study will be needed to clarify the mechanism by which contributes to the pathogenesis of hypospadias.

Hypospadias and environment: A registry-based case-control study

Introduction Monitoring carried out by Remera (“Registre des Malformations en Rhone-Alpes”) since 2009 shows a significantly increasing prevalence of hypospadias. As endocrine disruptors are suspected risk factors for hypospadias and could explain the observed trend, we analyzed the registry data to determine whether factors such as pesticide exposure are involved, using multivariate statistical methods, machine learning and spatial data mining. Materials and methods Cases and controls were identified in the registry. Cases (n = 479) were male children born in Rhone, Isere, or Loire between 2009 and 2015 with an isolated hypospadias (CIM 10 code Q54). Controls (n = 1142) were male children born in the same period and region, with a unique and isolated malformation. Malformations were selected as controls if and only if no correlation with endocrine disruptors exposure is known and if they are independent from genital abnormalities. Multivariate generalized linear models (binomial regressions) were used to estimate adjusted odds ratios (OR) and P-values (P) after univariate regressions and backward selection of variables of interest. Cross-validation, c-statistic and Hosmer–Lemeshow test were used for model validation. Spatial interpolations were computed with inverse distance weighting and k nearest neighbours methods. A statistic was introduced to test the null hypothesis H0: “Hypospadias prevalence is constant on all the region”. Two clustering algorithms were performed either to survey high-risk (e.g., polluted) zones or as post hoc analysis after rejecting H0. Algorithms were based on Kulldorff or hierarchical clustering approach. Results Mothers living in a rural municipality (with more than 40% of utilized agricultural area) at the beginning of their pregnancy had an increased risk to bear boys with hypospadias (OR = 1.42, P = 0.02). The risk also increased if the baby was conceived between May and October (OR = 1.35, P = 0.01). In that case, the first months of pregnancy matched with agricultural spreading of insecticides, fungicides and several herbicides. Moreover, prevalence increased each year (OR = 1.09, P = 0.005) from 2009 to 2015. Risk decreased with parity (OR = 0.79, P = 0.0002). No correlation was shown between assisted reproductive technology and hypospadias (P = 0.4). Hypospadias risk was higher when the boy was born before 32 weeks after last menstrual period (severe prematurity: OR = 2.4, P = 0.002). Neither maternal/paternal age nor medically assisted procreation appeared as risk factors (P > 0.2), which could exclude subfertility as a risk factor. Conclusion Our study based on more than 1500 cases and controls, with a good statistical power and without identified selection bias, confirms the previous observation of a link between the risk of hypospadias and exposure to agricultural pollutants in early pregnancy. As prevalence was not homogeneous across the studied region (P

Associations of TGFBR1 and TGFBR2 gene polymorphisms with the risk of hypospadias: a case-control study in a Chinese population.

This case–control study investigated the association of transforming growth factor-β (TGF-β) receptor type I and II (TGFBR1 and TGFBR2) gene polymorphisms with the risk of hypospadias in a Chinese population. One hundred and sixty two patients suffering from hypospadias were enrolled as case group and 165 children who underwent circumcision were recruited as control group. Single nucleotide polymorphisms (SNPs) in TGFBR1 and TGFBR2 genes were selected on the basis of genetic data obtained from HapMap. PCR-restriction fragment length polymorphism (PCR-RFLP) was performed to identify TGFBR1 and TGFBR2 gene polymorphisms and analyze genotype distribution and allele frequency. Logistic regression analysis was conducted to estimate the risk factors for hypospadias. No significant difference was found concerning the genotype and allele frequencies of TGFBR1 rs4743325 polymorphism between the case and control groups. However, genotype and allele frequencies of TGFBR2 rs6785358 in the case group were significantly different in contrast with those in the control group. Patients carrying the G allele of TGFBR2 rs6785358 polymorphism exhibited a higher risk of hypospadias compared with the patients carrying the A allele (P<0.05). The TGFBR2 rs6785358 genotype was found to be significantly related to abnormal pregnancy and preterm birth (both P<0.05). The frequency of TGFBR2 rs6785358 GG genotype exhibited significant differences amongst patients suffering from four different pathological types of hypospadias. Logistic regression analysis revealed that preterm birth, abnormal pregnancy, and TGFBR2 rs6785358 were the independent risk factors for hypospadias. Our study provides evidence that TGFBR2 rs6785358 polymorphism might be associated with the risk of hypospadias.

Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring.

Pregnant women are exposed to various chemical products at home and at work. Some of these products contain endocrine-disrupting chemicals (EDCs) such as cosmetics, pesticides, industrial chemicals, heavy metals, plastics or medications that could alter sexual differentiation and increase the risk of hypospadias. We evaluated maternal occupational and household exposures that could constitute risk factors for hypospadias. From 2011 to 2014, we enrolled 57 full-term newborns with hypospadias and three randomly selected controls per case (162 control newborns), matched for gestational age, from 11 maternity units in Picardy, France. Neonatal and parental data were collected at birth (personal characteristics, maternal lifestyle, and medical history). Maternal occupational exposure was assessed by a job-exposure matrix for EDCs from a job history questionnaire completed by mothers. Odds ratios (OR) and 95% confidence intervals (CI) were calculated with univariate and multivariable logistic regression, and adjusted for relevant covariates. Multivariate analysis showed a strong association between hypospadias and potential maternal occupational exposure to EDCs and maternal household use of hair cosmetics (OR 6.1, 95% CI: 1.1–34.9; OR: 9.6, 95% CI: 1.4–66.1, respectively). Our results suggest that maternal occupational exposure to EDCs is a risk factor for hypospadias and suggests a possible influence of household use of hair cosmetics during early pregnancy on the incidence of hypospadias in the offspring. A larger study with more accurate exposure assessment should evaluate the impact of EDCs in hair cosmetics on the incidence of hypospadias.

Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect

BackgroundNumerous studies have focused on the association between endocrine-disrupting chemicals (EDCs) and hypospadias. Phenotype variability, the absence of representative comparison groups and concomitant genetic testing prevent any definitive conclusions. ObjectiveTo identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias. Design, setting, and participantsA total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009–2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery. Outcome measurements and statistical analysisIn patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs. Environmental exposure was estimated using the zip code, the type of surrounding hazards, and distance from these hazards. Multivariate analysis was performed. ResultsFetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias (40.00% vs 17.55%, odds ratio 3.13, 95% confidence interval 2.11–4.65). The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys (19.73% vs 10.26%, p=0.0019), especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias (40.13% vs 27.48%, p=0.02). Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys (13.29% vs. 6.64%, p<0.00005). Association of occupational and environmental exposures increases this risk. ConclusionsThis multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk. Patient summaryOur multi-institutional study showed that parental professional, occupational, and environmental exposures to chemical products increase the risk of hypospadias in children.

Hypospadias: One Defect, Multiple Causes, Acting Through Shared Pathways

Hypospadias is one of the most common birth defects among males. Although the birth prevalence of hypospadias has been reported as increasing in some geographic regions, inconsistencies in ascertainment of mild cases and variability in reporting standards are likely contributing to these apparent trends. While hypospadias is highly heritable, there is limited knowledge about the specific genetic and epigenetic factors that play a role in its etiology. Risk factors for hypospadias include family history, older maternal age, nulliparity, high maternal prepregnancy body mass index, hypertension or preeclampsia, multiple gestations, reduced birth weight, and small for gestational age. Of the various prenatal exposures to medications that have been studied, the strongest evidence supports valproic acid as a contributor to hypospadias. Studies evaluating the impact of assisted reproductive technologies (ART) on hypospadias are inconclusive because of potential confounding by subfertility. Many causes of hypospadias may act through a few shared pathways, such as placental dysfunction.

Genetic and environmental origins of hypospadias.

The purpose of this study was to review and comment on recent original presentations dealing with genetic and environmental factors in the cause of hypospadias. The heritability is definitely high and having an affected family member is the highest identified risk factor so far. Many candidate genes and polymorphisms have been suggested for hypospadias. Some associations with hypospadias were found, and many of these were replicated inconsistently as would be expected in a complex disorder affected by both genes and environment. The consistent association of hypospadias with low birth weight, maternal hypertension, and preeclampsia suggests that placental insufficiency is a major risk factor. Maternal exposure to chemical pollutants or endocrine disruptors in high concentrations related to selected occupations or geographic areas may be additional risk factors for hypospadias, especially in genetically predisposed individuals. So far, however, no environmental chemical pollutants or endocrine disruptor with a general common impact on the risk for hypospadias in most societies has been demonstrated. A major point that should be considered regarding the action of environmental toxicants in inducing hypospadias is the cumulative effects of multiple low-dose exposures. Furthermore, interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.

Risk factors for hypospadias in China.

This case-controlled study was designed to evaluate the association between various baseline parental factors and the risk of hypospadias in China. Patients were selected from tertiary referral hospitals in Anhui, a province in mid-eastern China. A questionnaire was given to the parents of each patient. The final database included 193 cases and 835 controls. The incidence of additional coexistent anomalies was 13.0%, primarily cryptorchidism (9.8%). Ten patients (5.1%) were from families with genital anomaly, including five families (2.6%) with hypospadias. The risks of hypospadias was higher for children of mothers > 35 (odds ratio [OR] =1.47) and < 18 (OR = 2.95) years of age, and in mothers who had consumed alcohol (OR = 2.67), used drugs (OR = 1.53) and had an infection (OR = 1.87) during pregnancy. The risk of hypospadias was also higher when mothers (OR = 1.68) and fathers (OR = 1.74) were engaged in agriculture. Other factors assessed were not associated with the risk of hypospadias.

Hypospadias Risk among North-Indian Children

Objective: The objective of the study was to determine the incidence of hypospadias in Northern Indian region and to identify the various risk factors involved. Materials and Methods: 101 boys with hypospadias of age 4–10 years old were prospectively entered in the study along with 110 age-, geography-, ethnicity- and language-matched controls. Demographic and clinical data pertaining to reproductive profile of the mother, occupation of the parents and family history of genital abnormalities in male blood relatives were recorded for cases and controls. Frequency of hypospadias cases and birth defects registered with the AIIMS Paediatric Surgery outpatient department from the years 2003–2011 was also scrutinised. Results: An increase trend in the incidence of hypospadias from the year 2003 (7.66%) to the year 2011 (9.33%) was observed. Analysis of the demographic data of cases on the basis of parental occupational status depicted a major group of children (72.27%) affected with hypospadias had their parents from rural background having agriculture as their primary occupation. Conclusion: Although the causes of male genital malformations are multifactorial, our data support the hypothesis that prenatal contamination of pesticides or exposure to endocrine- disrupting chemicals may be a potential risk factor for hypospadias in India.