Maternal and gestational risk factors for hypospadias

BACKGROUND: An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown. OBJECTIVES: Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors. METHODS: We conducted a case-control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls. RESULTS: A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6-13.3]. Boys born to obese [body mass index (BMI) > or = 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2-5.7) compared with boys born to mothers with a normal weight (BMI = 20-24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1-3.7) and 1.8-fold (95% CI, 1.2-2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1-53). CONCLUSIONS: A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.     

Maternal pregnancy levels of trans-nonachlor and oxychlordane and prevalence of cryptorchidism and hypospadias in boys

Background: The etiologies of the male urogenital anomalies—cryptorchidism and hypospadias—are poorly understood. Given positive associations between chlordane isomers and testicular germ cell tumors, it is reasonable to assume that chlordanes might also be associated with other testicular dysgenesis syndrome disorders, namely cryptorchidism and hypospadias.Objective: To examine whether exposure to in utero chlordane is related to cryptorchidism and hypospadias, we evaluated levels of chlordane derivatives, trans-nonachlor and oxychlordane, among pregnant women enrolled in the Collaborative Perinatal Project (CPP).Methods: From 1959 to 1965, the CPP enrolled pregnant women at 12 U.S. medical centers. We analyzed serum trans-nonachlor and oxychlordane levels measured in third-trimester serum from the mothers of 217 sons with cryptorchidism, 197 sons with hypospadias, and 557 sons with neither condition. Adjusted odds ratios (ORs) and 95% confidence intervals were calculated using conditional logistic regression.Results: The quartile-specific ORs for cryptorchidism or hypospadias show no notable associations with trans-nonachlor or oxychlordane. Further, there were no significant trends with increasing quartile of maternal trans-nonachlor or oxychlordane level in either cryptorchidism or hypospadias (p-trend all > 0.45).Conclusions: The results do not support an association between chlordane levels and cryptorchidism or hypospadias. It is unlikely that current chlordane exposure is related to the development of either anomaly, given that serum chlordane levels at the time of sample collection, the early 1960s, were considerably higher than levels at present.     

Maternal reproductive and demographic characteristics as risk factors for hypospadias

This study examined the association of hypospadias risk with several maternal reproductive and demographic characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy (NVP), multiple pregnancy, fertility treatments and procedures, education and race-ethnicity. The study included data on deliveries with estimated due dates from October 1997 to December 2000 that were part of the National Birth Defects Prevention Study, a multi-state case-control study of many birth defects. The analysis included 502 cases with second or third degree hypospadias (i.e. the urethra opened at the penile shaft, scrotum or perineum) and 1286 male, liveborn, non-malformed controls. Risks were estimated from a multivariable logistic regression model that included all exposures of interest. Results indicated particularly elevated risks among births to women who were primiparae, aged >or=35 years and had a BMI of >26, compared with women who were multiparae, aged <30 years and had a BMI of 相似文献   

Maternal pregnancy serum level of heptachlor epoxide, hexachlorobenzene, and beta-hexachlorocyclohexane and risk of cryptorchidism in offspring

Prenatal exposure to environmental endocrine disrupters has been postulated to cause adverse effects on male reproductive health. Exposure to organochlorine pesticides with anti-androgenic and estrogenic potency has been shown to interfere with the sex-hormone-dependent process of testicular descent in animal models. We examined the relation between serum levels of the pesticides heptachlor epoxide (HCE), hexachlorobenzene (HCB), and beta-hexachlorocyclohexane (beta-HCCH) in pregnant women, and the occurrence of cryptorchidism in their sons. These three pesticides were previously suggested as risk factors for cryptorchidism. In a nested case-control design, we compared serum levels between mothers of cases (n = 219) and controls (n = 564), selected from the Collaborative Perinatal Project, a US birth cohort study of pregnancies in 1959-1966. The offspring of mothers with HCE levels above the 90th percentile compared to those below the 10th percentile had an adjusted odds ratio of cryptorchidism of 1.2 (95% confidence interval 0.6-2.6); for beta-HCCH the odds ratio was 1.6 (0.7-3.6). For HCB the adjusted odds ratio was near one. These results provide little support for an association of cryptorchidism with exposure to low levels of HCE or HCB. For beta-HCCH the findings were somewhat suggestive of an association but were inconclusive.     

Maternal Pregnancy Levels of Polychlorinated Biphenyls and Risk of Hypospadias and Cryptorchidism in Male Offspring

Background

The etiologies of the male urogenital anomalies cryptorchidism and hypospadias are poorly understood. It has been suggested, however, that in utero hormone levels may be related to risk. Endocrine-disrupting chemicals, including polychlorinated biphenyl (PCB) compounds, may alter hormone levels and thereby affect the fetus.

Objectives

To examine whether in utero PCB exposure is related to cryptorchidism and hypospadias, we examined PCB levels among pregnant women enrolled in the Collaborative Perinatal Project (CPP).

Methods

The CPP enrolled pregnant women at 12 U.S. medical centers between 1959 and 1965. For the present research, we analyzed third-trimester serum samples from the mothers of 230 sons with cryptorchidism, 201 sons with hypospadias, and 593 sons with neither condition. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression and examined the associations of each anomaly with individual PCB congener levels, sum of PCBs, and several functional groupings of PCBs.

Results

In general, the ORs for cryptorchidism or hypospadias showed no notable associations with individual PCB congener levels or functional groupings of PCBs. However, the ORs and 95% CIs for the sum of PCBs associated with hypospadias were as follows: 0–1.9 μg/L, reference group; 2–2.9 μg/L, OR = 1.57, 95% CI, 1.05–2.34; 3–3.9 μg/L, OR = 1.45, 95% CI, 0.90–2.34; and ≥ 4.0 μg/L, OR = 1.69, 95% CI, 1.06–2.68; p-value for trend = 0.08.

Conclusions

Given the large number of associations examined, these findings do not strongly support the hypothesis that PCBs are associated with cryptorchidism or hypospadias. Because population serum PCB levels at the time of sample collection were considerably higher than levels at present, it is unlikely that current PCB exposure is related to the development of either anomaly.     

Maternal dietary glycaemic intake during pregnancy and the risk of birth defects

High sugar intake has been linked to fetal anomalies in the presence and absence of insulin resistance. Using dietary data collected in the Boston University Slone Epidemiology Birth Defects Study, we examined whether high dietary glycaemic index (dGI) or load (dGL) increased the risk of birth defects. Non-diabetic mothers of 1921 cases and 704 controls were interviewed within 6 months of delivery (1988-98) about pregnancy events and exposures, including a 99-item food frequency questionnaire. Case groups included amniotic bands, craniosynostosis, gastroschisis, hypospadias, small intestinal defects, anorectal defects, limb reductions, omphalocele, cleft lip and/or palate, renal agenesis, and tracheoesophageal fistula. Cubic splines were used to determine cut-point values for high dGI and dGL in relation to the risk of each birth defect. The cut-points were used in logistic regression models to calculate odds ratios (OR) and 95% confidence intervals [CI]. Control mothers in the lowest quartile of glycaemic intake were more likely to be non-Hispanic White, ≥ 30 years of age, have higher family income, have a normal body mass index and reside in Boston. Findings were null for most case groups. The anorectal defect case group was found to have elevated risks for dGL [adjusted OR: 2.4; 95% CI: 1.1, 4.9], while estimates for dGI were elevated for the amniotic band case group [adjusted OR: 3.0; 95% CI: 1.1, 8.1]. Because this is the first paper (to our knowledge) to explore dGI and dGL in relation to a spectrum of birth defects, additional studies are needed.     

Maternal serum level of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 microg/liter, boys with maternal levels greater than or equal to 85.6 microg/liter had adjusted odds ratios of 1.3 (95% confidence interval (CI): 0.7, 2.4) for crypt-orchidism, 1.2 (95% CI: 0.6, 2.4) for hypospadias, and 1.9 (95% CI: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.     

Relationship between maternal dietary patterns and hypospadias

Little is known about the role of maternal nutrition in the development of hypospadias, which is the most common urogenital congenital anomaly. This study investigated the relationship between maternal nutrition and the risk of hypospadias, particularly focusing on maternal food patterns. We compared 471 hypospadias cases with 490 controls in the United Kingdom. A questionnaire including information on life style, occupation, usual maternal diet and dietary supplements was administered using telephone interviews. Cases and controls were compared for individual food item intake and food patterns derived by cluster analysis. Multivariable logistic regression analysis adjusted for income, maternal age, low birthweight, smoking and folic acid supplement use was used to assess the relationship between maternal nutrition and hypospadias. Three food patterns were created with the labels 'health conscious', 'mixed' and 'non-health conscious'. 'Non-health conscious' subjects (low frequency of consumption of yoghurt, cheese, eggs, fruit and vegetables, fish, beans and pulses, olive oil and organic food) had a higher risk of hypospadias (odds ratio 1.54; 95% confidence interval 1.06, 2.26) compared with 'health conscious' subjects (high frequency of consumption of fresh fruit and vegetables, dried fruit, fresh or frozen fish, beans, pulses, soya products, olive oil and organic food), after adjustment for potential confounders. Intakes of individual foods were not strongly associated with hypospadias. We could not exclude the possibility of residual confounding, and this needs to be further investigated. We found an association between food pattern and hypospadias, with those with less health conscious food patterns having a higher risk. Further study is needed to confirm this association.     

Evidence that a maternal “junk food” diet during pregnancy and lactation can reduce muscle force in offspring

Background  Obesity is a multi-factorial condition generally attributed to an unbalanced diet and lack of exercise. Recent evidence suggests that maternal malnutrition during pregnancy and lactation can also contribute to the development of obesity in offspring. We have developed an animal model in rats to examine the effects of maternal overeating on a westernised “junk food” diet using palatable processed foods rich in fat, sugar and salt designed for human consumption. Using this model, we have shown that such a maternal diet can promote overeating and a greater preference for junk food in offspring at the end of adolescence. The maternal junk food diet also promoted adiposity and muscle atrophy at weaning. Impaired muscle development may permanently affect the function of this tissue including its ability to generate force. Aims  The aim of this study is to determine whether a maternal junk food diet can impair muscle force generation in offspring. Methods  Twitch and tetanic tensions were measured in offspring fed either chow alone (C) or with a junk food diet (J) during gestation, lactation and/or post-weaning up to the end of adolescence such that three groups of offspring were used, namely the CCC, JJC and JJJ groups. Results  We show that adult offspring from mothers fed the junk food diet in pregnancy and lactation display reduced muscle force (both specific twitch and tetanic tensions) regardless of the post-weaning diet compared with offspring from mothers fed a balanced diet. Conclusions  Maternal malnutrition can influence muscle force production in offspring which may affect an individual’s ability to exercise and thereby combat obesity.     

Maternal serum alpha-fetoprotein level during pregnancy and isolated cryptorchidism in male offspring

Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.     

Maternal occupational exposure and congenital heart defects in offspring

Objectives:Congenital heart defects (CHD) are the most prevalent congenital anomalies. This study aims to examine the association between maternal occupational exposures to organic and mineral dust, solvents, pesticides, and metal dust and fumes and CHD in the offspring, assessing several subgroups of CHD.Methods:For this case–control study, we examined 1174 cases with CHD from EUROCAT Northern Netherlands and 5602 controls without congenital anomalies from the Lifelines cohort study. Information on maternal jobs held early in pregnancy was collected via self-administered questionnaires, and job titles were linked to occupational exposures using a job exposure matrix.Results:An association was found between organic dust exposure and coarctation of aorta [adjusted odds ratio (OR_adj) 1.90, 95% confidence interval (CI) 1.01–3.59] and pulmonary (valve) stenosis in combination with ventricular septal defect (OR_adj 2.68, 95% CI 1.07–6.73). Mineral dust exposure was associated with increased risk of coarctation of aorta (OR_adj 2.94, 95% CI 1.21–7.13) and pulmonary valve stenosis (OR_adj 1.99, 95% CI 1.10–3.62). Exposure to metal dust and fumes was infrequent but was associated with CHD in general (OR_adj 2.40, 95% CI 1.09–5.30). Exposure to both mineral dust and metal dust and fumes was associated with septal defects (OR_adj 3.23, 95% CI 1.14–9.11). Any maternal occupational exposure was associated with a lower risk of aortic stenosis (OR_adj 0.32, 95% CI 0.11–0.94).Conclusions:Women should take preventive measures or avoid exposure to mineral and organic dust as well as metal dust and fumes early in pregnancy as this could possibly affect foetal heart development.     

Maternal investment,life-history strategy of the offspring and adult chronic disease risk in South Asian women in the UK

Background and objectives: Patterns of development predict cardiovascular disease (CVD) risk, and ethnic differences therein, but it remains unclear why apparently ‘adaptive plasticity’ in early life should generate health costs in later life. We hypothesized that offspring receiving low maternal investment during fetal life, the primary period of organogenesis, should predict a shorter reproductive career and develop a fast life-history strategy, prioritizing reproduction over growth and homeostatic maintenance.Methodology: We studied 58 young adult South Asian women living in the UK, a group with high susceptibility to CVD. We obtained gestational age, birth weight (BW) and menarcheal age by recall and measured anthropometry, body composition, resting metabolic rate (RMR) and blood pressure (BP).Results: BW and gestational age were inversely associated with menarcheal age, indicating that lower maternal investment is associated with faster maturation. Menarcheal age was positively associated with height but inversely with adiposity, indicating that rapid maturation prioritizes lipid stores over somatic growth. BW was inversely associated with BP, whereas adiposity was positively associated, indicating that lower maternal investment reduces BP homeostasis. BW was positively associated with RMR, whereas menarche was inversely associated, indicating that maternal investment influences adult metabolism.Conclusions and implications: Supporting our hypothesis, low maternal investment promoted faster life histories, demonstrated by earlier menarche, reduced growth and elevated adiposity. These traits were associated with poorer BP regulation. This is the first study demonstrating strategic adjustment of the balance between reproduction and metabolic health in response to the level of maternal investment during fetal life.     

Maternal protein malnutrition induces autism-like symptoms in rat offspring

Objective: We tested the correlation between maternal protein malnutrition and autistic-like symptoms using behavioral tests in rodents that measure main behavioral characteristics observed in humans with autism spectrum disorder (ASD).

Methods: Pregnant female rats were fed a normal diet or a hypoproteic diet during gestation and lactation periods. The litters were weighed every 3 days during lactation, and the offspring were tested in behavioral tasks during infancy (postnatal day (PND) 5: quantification of ultrasonic vocalizations; PND 13: homing behavior test) and adolescence (PND 30–32: open field, hole-board, play social behavior, and object recognition tests) in order to capture the prevalence of some of the core and associated symptoms of ASD.

Results: Litters of the hypoproteic diet group had a lesser weight gain during lactation. In addition, pups of dams fed with a hypoproteic diet vocalized less compared to those fed with a normal diet, and they showed impaired social discrimination abilities in the homing behavior test. In adolescence, both male and female offspring of the hypoproteic diet group showed no impairment in locomotor activity; however, they exhibited stereotypic behavior in the hole-board test and a decrease in social play behaviors. Male offspring showed increased interest in exploring a familiar object rather than a novel object.

Conclusion: Our results show that maternal protein malnutrition in rats causes offspring behaviors that resemble core and associated ASD symptoms.     

Maternal and gestational factors affecting the risk of cryptorchidism and inguinal hernia

Case-control studies of cryptorchidism and inguinal hernia were undertaken on white males born within the cohort of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Significantly elevated risks of cryptorchidism were found for low birthweight, for a high maternal Quetelet's index and for oestrogens administered during gestation (R = 2.8). Similarly, in the case of inguinal hernia, significantly increased risk ratios were observed for low birthweight, for gestational use of progestins (RR = 2.1), and for breech labour (RR = 2.3). Because these malformations and testis cancer share many of the same risk factors, a common mechanism for production of these diseases is proposed which is mediated by testicular hypoplasia induced by excess exogenous or endogenous oestrogen in the mother.     

Maternal Exposure to a Brominated Flame Retardant and Genitourinary Conditions in Male Offspring

Background

The upward trend in industrial nations in the incidence of male genitourinary (GU) conditions may be attributed to increased exposure to endocrine disruptors. Polybrominated biphenyl (PBB), a brominated flame retardant, is one such suspected endocrine disruptor.

Objective

We investigated the relationship between maternal serum levels of PBBs and GU conditions among male offspring exposed in utero.

Methods

In this cohort study of sons born to women accidentally exposed to PBBs during 1973–1974, we examined self-reported data on GU conditions among male offspring in relation to maternal serum PBB levels. We used generalized estimating equations to calculate odds ratios (ORs), controlling for gestational age at birth.

Results

Of 464 sons, 33 reported any GU condition (13 hernias, 10 hydroceles, 9 cryptorchidism, 5 hypospadias, and 1 varicocele). Four reported both hernia and hydrocele, and one both hernia and cryptorchidism. After adjustment for gestational age at birth, sons of highly exposed women (> 5 ppb) were twice as likely to report any GU condition compared with sons of the least exposed women [≤1 ppb; OR = 2.0; 95% confidence interval (CI), 0.8–5.1]. This risk was increased when we excluded sons born after the exposure but before the mother’s serum PBB measurement (OR = 3.1; 95% CI, 1.0–9.1). We found evidence of a 3-fold increase in reported hernia or hydrocele among sons with higher PBB exposure (test of trend p-value = 0.04). Neither hypospadias nor cryptorchidism was individually associated with PBB exposure.

Conclusions

Although cryptorchidism and hypospadias were not associated with in utero PBB exposure, this study suggests that other GU conditions may be associated with exposure to endocrine-disrupting chemicals during development.     

International trends in rates of hypospadias and cryptorchidism

Researchers from seven European nations and the United States have published reports of increasing rates of hypospadias during the 1960s, 1970s, and 1980s. Reports of increasing rates of cryptorchidism have come primarily from England. In recent years, these reports have become one focus of the debate over endocrine disruption. This study examines more recent data from a larger number of countries participating in the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) to address the questions of whether such increases are worldwide and continuing and whether there are geographic patterns to any observed increases. The ICBDMS headquarters and individual systems provided the data. Systems were categorized into five groups based on gross domestic product in 1984. Hypospadias increases were most marked in two American systems and in Scandinavia and Japan. The increases leveled off in many systems after 1985. Increases were not seen in less affluent nations. Cryptorchidism rates were available for 10 systems. Clear increases in this anomaly were seen in two U.S. systems and in the South American system, but not elsewhere. Since 1985, rates declined in most systems. Numerous artifacts may contribute to or cause upward trends in hypospadias. Possible "real" causes include demographic changes and endocrine disruption, among others.