Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case-control study in Spain.

BACKGROUND: Hypospadias is one of the most frequently occurring genital anomalies described in infants prenatally exposed to valproic acid (VA). However, to our knowledge, only one publication has studied a potential causal relationship between VA and hypospadias, only estimating the unadjusted global risk. Here we present the results of a multivariate case-control study aimed at analysing and quantifying the specific risk of hypospadias in newborn infants exposed to VA during the first trimester of pregnancy. METHODS: The data analysed here were derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC), an ongoing, hospital-based, case-control study and surveillance system in which collaborating paediatricians identify case and control infants. The paediatricians collect the same data for both case and control infants, blinded to information on any prenatal exposure. The information includes 312 items related to many prenatal exposures, including drug exposure, reproductive and family history, and other characteristics. The sample analysed included 2,393 infants with hypospadias and 12,465 male controls. RESULTS: The results showed that the unadjusted risk of hypospadias in infants prenatally exposed to VA was 5.23 (95% CI 2.31, 11.86; p < 0.00001). Once adjusted for 13 potential confounding factors using conditional logistic regression analyses, the value of the risk was of a similar magnitude (odds ratio = 5.71; 95% CI 1.78, 18.36; p = 0.003). In addition, the frequency of hypospadias in the study population was approximately 1.8/1000 births. This allowed us to calculate the specific risk for an infant with hypospadias to be born to an exposed mother, which was 1 child in 97 births to mothers using VA during the first trimester of pregnancy. We consider this information much more useful for risk assessment than the risk value itself. CONCLUSIONS: An alteration of placental gonadotrophic stimulation caused by changes in gonadotropin-releasing hormone release produced by the effects of VA on GABA is a possible pathogenic mechanism. Our results support the relationship between prenatal exposure to VA and hypospadias.     

Dose-related effect by maternal exposure to di-(2-ethylhexyl) phthalate plasticizer on inducing hypospadiac male rats

The aim of this study was to evaluate dose-related effects on external genitalia of adult male offspring rats by maternal exposure to di-(2-ethylhexyl) phthalate (DEHP) plasticizer. Timed-pregnant rats were given DEHP by gastric intubation at doses of 0, 500, 750 or 1000 mg/kg body weight/day from gestation day 12–19 to establish a hypospadiac rat model. The hypospadias was observed and the incidence in three DEHP dosage levels was 10.7%, 30.6% and 37.0%, respectively. With exposed dose increased, mild, moderate and severe hypospadiac rats were distinguished and an increased incidence of severe hypospadias was observed. The other reproductive lesions like reduced penile length and anogenital distance/body weight were observed. The results indicated the dose-related external genitalia teratogenic toxicity, and graded hypospadias on male offspring was resulted from high dosage DEHP maternal exposure.     

Infant mortality among women on a methadone program during pregnancy

INTRODUCTION AND AIMS: The rate and correlates of infant death in those born to opioid-dependent women are unclear. This study aims to determine the infant mortality rate of infants born to women on a methadone program during pregnancy and to identify any modifiable risk factors. DESIGN AND METHODS: A retrospective study of live births to all women in New South Wales, Australia during the period 1995-2002. Using record linkage four groups were compared: (i) live births to women on a methadone program during pregnancy who subsequently died during infancy; (ii) live births to women not on a methadone program who subsequently died during infancy; (iii) live births to women on a methadone program during pregnancy who did not die during infancy; and (iv) live births to women not on a methadone program who did not die during infancy. RESULTS, DISCUSSION AND CONCLUSION: The infant mortality rate was higher among infants whose mothers were on methadone during pregnancy (24.3 per 1000 live born infants in group 1 and 4.0 per 1000 live born infants in group 2) compared with infants of all other mothers. The single main cause of death for all infants was Sudden Infant Death Syndrome. There was a higher rate of smoking among women on methadone. The findings suggest that methadone and non-methadone infant-mother pairs have different symptom profiles, diagnostic procedures and/or different patterns of access to care.     

Drug-induced pulmonary hypertension in newborns: a review

Persistent pulmonary hypertension (PPHN) is a disease characterised by the disruption of the transition from fetal to neonatal circulation with the persistence of high pulmonary vascular resistances and right-to left shunting. This condition, occurring in about 1-2 newborns per 1000 live births, causes severe hypoxemia. Despite significant improvements in treatment, the mortality of PPHN varies from 10 to 20 % of affected newborns. Pulmonary hypertension is frequently observed in some cardiac malformation and in congenital diaphragmatic hernia, in meconium aspiration syndrome, neonatal sepsis, podalic presentation and male sex. Maternal risk factors are tobacco smoking, cesarean section, low socio-economic conditions, diabetes and urinary infections. Another predisposing condition is antenatal or postnatal exposure to some drugs. The medications involved in drug-induced pulmonary hypertension and the mechanisms involved are reviewed.     

Risk of Hypospadias in Offspring of Women Using Loratadine during Pregnancy : A Systematic Review and Meta-Analysis

BACKGROUND: Loratadine, a second-generation antihistamine, is commonly used to treat seasonal allergies. Some studies have suggested that use of loratadine by pregnant women increases the risk of hypospadias in male offspring. OBJECTIVE: This meta-analysis was designed to assess the strength of the association between loratadine and hypospadias. METHODS: To locate pertinent articles published in any language from January 1989 until August 2007, we searched electronic databases (MEDLINE, OVID, EMBASE, SCOPUS, TOXLINE Special, ReproTox, TERIS, CINAHL and others), conference proceedings and bibliographies. Studies were eligible for this analysis if they were cohort, case-control or case series studies that reported the incidence of hypospadias in the offspring of women who were or were not exposed to loratadine during pregnancy. Two authors independently extracted information on study design, participant characteristics, measures of outcome, control for potential confounding factors and risk estimates using a standardized data collection form. The Newcastle-Ottawa Scale was then used to assess the quality of each study. We used a random-effects meta-analysis model to combine the risk data. RESULTS: In 1402 potentially relevant titles, we found three case-control studies and seven cohort studies that reported the incidence of hypospadias or other congenital malformations in offspring of women who did or did not use loratadine during pregnancy. Together the studies in our meta-analysis provided information about 453 053 male births in Brazil, Canada, Denmark, Israel, Italy, Sweden, the UK and the US.Of 2694 male infants born to women using loratadine, 39 (1.4%) had hypospadias. Of 450 413 male infants born to women not using loratadine, 4231 (0.9%) had hypospadias. Women who used loratadine during pregnancy were not significantly more likely to have a son with hypospadias (unadjusted odds ratio [OR] 1.27, 95% CI 0.73, 2.23; adjusted OR 1.28, 95% CI 0.69, 2.39). CONCLUSION: The results of our systematic review and meta-analysis of controlled observational studies indicate that the use of loratadine during pregnancy does not significantly increase the risk of hypospadias in male offspring.     

Remarkably low incidence of hypospadias in Greenland despite high exposure to endocrine disrupters; possible protective effect of androgen receptor genotype

Endocrine disrupters, such as persistent organohalogen pollutants (POPs) may cause hypospadias, which is a common congenital anomaly in males, affecting 0.2-0.7%. We hypothesized that hypospadias incidence would be high among Greenlanders, who are one of the most POP exposed populations on earth through consumption of contaminated sea mammals. Interestingly, among the 11 076 boys born in Greenland 1982-2002, only two cases of hypospadias were noted (incidence 0.02%; 95% CI: 0.002-0.06). Normal male sexual differentiation is dependent on the androgen receptor (AR). AR function is regulated by polymorphic repeats of CAG and GGN trinucleotide bases. In Greenland 85% were carriers of GGN=23, which in a previous report was less frequent in patients with hypospadias than in the general population. This finding indicates that AR genotype could contribute to a genetic predisposition in Greenlanders, who despite one of the worlds highest body burden of POPs, seem to be protected from hypospadias.     

Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy

The objective of this study was to determine the effects of maternal exposure to butyl benzyl phthalate (BBP) on the development of the reproductive system in male offspring. Pregnant rats were given BBP by gastric intubation at 250, 500, or 1000 mg/kg on days 15 to 17 of pregnancy. A significant decrease in maternal body weight gain and food consumption was found in rats given BBP at 500 and 1000 mg/kg. A significant decrease in the number of live fetuses per litter was found at 1000 mg/kg. The weights of male and female fetuses were significantly decreased in the groups given BBP at 1000 mg/kg. A significant increase in the incidence of fetuses with undescended testes was found at 500 and 1000 mg/kg. A significant decrease in the anogenital distance (AGD) of male fetuses was observed at 500 and 1000 mg/kg. The AGD/cube root of body weight ratio in male fetuses was also significantly reduced at 500 mg/kg and higher. The AGD and AGD/cube root of body weight ratio of female fetuses in the BBP-treated groups were comparable to those in the control group. It was concluded that BBP on days 15 to 17 of pregnancy produced adverse effects on the development of the reproductive system in male offspring.     

First trimester exposure to cefuroxime: a prospective cohort study

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.     

Occurrence of neural tube defects in pregnancy: an excess of cases in a 2773-km2 area in Central Italy

Neural tube defects (NTDs) have a complex and imperfectly understood etiology, in which both genetic and environmental factors might be involved. The aim of the study was to describe an excess of cases of NTDs in a small area in central Italy. Over a 2-wk period in autumn 2002, three diagnoses of anencephaly were made in a 2773-km(2) area. As a consequence of these events, information on known risk factors as well as data on environmental changes, or epidemics of infectious diseases, in 2002-2004, were collected. The NTD rate was estimated for 10,000 births (live and stillborn) in this area. The 95% confidence intervals of rates were estimated assuming Poisson distribution of cases. Six cases of NTD were observed, with an NTD prevalence rate of 18.5 per 10,000 births (95% CI 17.0, 20.12). No evidence of known risk factors was reported. During summer 2002, the local service for environmental surveillance observed that the threshold level of drinking-water bacterial contamination had been exceeded, which probably resulted in an adjustment in the amount of chlorine added. The major difficulty in making hypotheses regarding the causes of birth defects is linking environmental risk factors exposure to fetal outcome. The prompt gathering of data may be essential. Thus, we emphasize the need for the activation of a population-based congenital malformation registry in order to achieve a deeper understanding of these events etiology.     

Lethal malformations and perinatal mortality: a 10 year review with comparison of ethnic differences.

During 1976 to 1985 perinatal mortality in Leicestershire decreased from 21 to 9.5 per 1000 births. Throughout this period the incidence of lethal malformations, excluding neural tube defects, remained relatively constant at around 1.8 per 1000 births. Analysis of the malformations present in 201 lethally malformed babies showed that 147 (73%) had a disorder carrying a recurrence risk of 1% or greater. Only 7% of these malformations might have been predicted from the family history or advanced maternal age. The incidence of lethal malformations was significantly increased in the Asian population, largely because of an excess of autosomal recessive disorders. The contribution of lethal malformations to perinatal mortality has almost doubled over the past 10 years and is likely to increase despite prenatal diagnosis and improvements in obstetric and paediatric services.     

Incidence of fetal alcohol syndrome and economic impact of FAS-related anomalies

The world-wide incidence of the fetal alcohol syndrome (FAS) is 1.9 per 1000 live births. Incidence rates vary considerably, however, depending on study site. Mental retardation is a cardinal feature of FAS and is now recognized as the leading known cause of mental retardation in the Western world. Conservatively estimated for the United States, the economic cost associated with FAS-related growth retardation, surgical repair of organic anomalies (e.g. cleft palate, Tetralogy of Fallot), treatment of sensorineural problems, and mental retardation, is +321 million per year. FAS-related mental retardation alone may account for as much as 11% of the annual cost for all mentally retarded institutionalized residents in the United States. Current treatment costs for FAS-related problems are about 100 times federal funding for FAS research necessary to develop cost-effective early identification and prevention strategies.     

镇江市2003～2008年流动儿童新生儿破伤风监测分析

目的:分析镇江市流动儿童新生儿破伤风(neonatal tetanus,NNT)流行病学特征,为消除NNT提供科学依据.方法:利用描述流行病学方法分析镇江市2003～2008年流动儿童NNT监测资料.结果:镇江市2003～2008年NNT平均发病率0.19‰,其中流动儿童中NNT发病率1.50‰,病死率36.36％;NNT发病率总体呈下降趋势,但相隔4年有一个相对高峰期;病例散在分布,无明显地区聚集性,其患儿主要来自于四川,云南,贵州;男女性别比为1.44:l;在家分娩占86.36％;母亲均无破伤风类毒素(tetanus toxoid,TT)接种史.结论:非住院分娩与未进行TT免疫是流动儿童发生NNT的主要危险因素;加大对流动儿童传染病监测、干预的力度,才能彻底消除非高危地区NNT疫情.     

Ethnic differences in the incidence of cleft lip and/or cleft palate in Auckland, 1960-1976

The incidence of facial clefts among live births in the Auckland urban area has been studied for the years 1960-1976. After correction for ascertainment, the live-born incidence of non-syndromal cleft palate among Maoris was 1.867/1000, and among Europeans it was 0.643/1000. The incidences for non-syndromal cleft lip, with or without cleft palate, were 0.397/1000 for Maoris, and 1.195/1000 for Europeans. The sex ratio for cleft palate showed the usual female preponderance, although there was evidence of heterogeneity between the races. Cleft lip occurred more commonly among males. Birth rank, maternal age, and paternal age had no apparent effect on the incidences, and there were no significant secular or seasonal changes in incidence.     

Per- and polyfluoroalkyl substances and male reproductive health: a systematic review of the epidemiological evidence

ABSTRACT

Exposure to environmental pollutants may produce impairment of male reproductive health. The epidemiological literature evaluating potential consequences of human exposure to per- and polyfluoroalkyl substances (PFAS) has grown in recent years with concerns for both pre- and postnatal influences. The aim of this systematic review was to assess available evidence on associations between PFAS exposures in different stages of life and semen quality, reproductive hormones, cryptorchidism, hypospadias, and testicular cancer. A systematic search of literature published prior to March 9th, 2020, was performed in the databases PubMed and Embase®. Predefined criteria for eligibility were applied by two authors screening study records independently. Among the 242 study records retrieved in the literature search, 26 studies were eligible for qualitative assessment. While several investigations suggested weak associations for single compounds and specific outcomes, a lack of consistency across studies limited conclusions of overall evidence. The current gap in knowledge is particularly obvious regarding exposures prior to adulthood, exposure to combinations of both PFAS and other types of environmental chemicals, and outcomes such as cryptorchidism, hypospadias, and testicular cancer. Continued efforts to clarify associations between PFAS exposure and male reproductive health through high-quality epidemiological studies are needed.     

Risk factors for low birthweight in New Zealand, 1981-83

This paper describes the patterns of risk factors for low birthweight in a cohort of New Zealand births. The trend of low birthweight with maternal age and parity was U-shaped. Maori mothers had the highest (79.38/1000 livebirths) and Pacific Island mothers the lowest (39.88/1000), rates of low birthweight infants. There was an indication that the risk for Pacific Island mothers was modified by the mother's place of birth. Compared to nonMaori nonPacific Island New Zealand born women, the risk was high for Pacific Island New Zealand born women (RR = 1.27, 95% CI 1.04-1.56), but low for nonNew Zealand born Pacific Island mothers (RR = 0.70, 95% CI 0.61-0.79). The risk for Maori mothers increased if the father was also of Maori ethnic origin. The risk of a low birthweight infant increased (p less than 0.001) with social class, and the rate was high among exnuptial births (75.25/1000 live births). The rates of low birthweight for nonMaori and Pacific Island births in the South Island were similar to those in the North Island, but among Maori births the rate in the South Island (RR = 0.64, 95% CI 0.51-0.82) was lower than in the North Island.     

Some factors associated with birth weight in Jima, southwestern Ethiopia

A retrospective analysis of factors associated with the birth weights of 1707 singleton live births in Jima Hospital, Southwestern Ethiopia was carried out from Sept. 30, 1986 to August 31, 1988. The mean birth weight was 3183.0 grams (+/- 25.0 grams with 95% confidence); and the incidence of low birth weight was 12.3%. The use of multiple linear regression analysis determined significant independent effects of residence, parity, and sex of the baby on birth weight, while maternal age alone was not significantly (P greater than 0.05) related to birth weight. It is suggested that proper recording and analysis of birth weights be practised, as they are useful in monitoring maternal and child health.     

Study on developmental abnormalities in hypospadiac male rats induced by maternal exposure to di-n-butyl phthalate (DBP)

The objective of this study was to establish a hypospadiac rat model by maternal exposure to di-n-butyl phthalate (DBP) and to evaluate the developmental abnormalities of hypospadiac male rats. Timed-pregnant rats were given DBP by gastric intubation at doses of 0, 250, 500, 750 or 1000 mg/kg body weight (bw)/day from gestation day (GD) 14 to 18 to establish a hypospadiac rat model. The hypospadias was observed in the 500 and 750 mg/kg bw/day groups, the incidence of which was 6.8 and 41.3%, respectively. Transverse serial histological analysis of genitalia of hypospadiac male rats confirmed the malformation. With exposed dose increasing, the serum testosterone (T) levels of male rats inversely decreased, and in the same dosage group the serum T levels of hypospadiac rats were significantly lower than the levels of nonhypospadiac counterparts. The other reproductive lesions such as cryptorchidism and decreased ratio of anogenital distance/body weight (AGD/bw) were also observed. Autopsy analysis revealed the development of reproductive organs (prostate, testes, epididymis, pituitary gland) and nonreproductive organs (adrenal gland, liver, kidney, heart, spleen) of hypospadiac rats and nonhypospadiac counterparts. The results indicated that the reproductive system and developmental condition of hypospadiac male offspring were damaged severely by DBP.     

男性儿童尿道下裂与先天性直肠肛门畸形相关性分析

目的 探究男性儿童尿道下裂患者与先天性直肠肛门畸形的相关性,以获得可靠数据为后续研究提供重要的生物学材料.方法 选取来本院接受治疗的男性儿童尿道下裂患儿300例进行回顾性分析,采用病例对照研究,观察尿道下裂与先天性儿童尿道下裂与先天性直肠肛门畸形的关联性.结果 尿道下裂与先天性直肠肛门畸形存在关联性(P＜0.05),且男性儿童尿道下裂导致先天性直肠肛门畸形的危险性是无尿道下裂儿童的9.89倍,二者呈正相关,是导致先天性直肠肛门畸形的危险因素(OR=9.00,95％CI:4.49～18.03);阴茎头型尿道口下裂构成比最大,占47.33％,最低为会阴型,占15.33％.所有类型尿道下裂中会阴型先天性直肠肛门畸形发生率最高68.75％,其次为阴囊型(21.05％)、阴茎型(14.42％)以及阴茎头型(7.75％),相关系数(φ)=0.353,相关性较好,呈正相关.结论 男性儿童尿道下裂与先天性直肠肛门畸形具有一定相关性,且会阴型以及阴囊型尿道下裂患儿发生先天性直肠肛门畸形几率大,故应加大产前诊断力度,保证优生优育.     

Exposure to firework chemicals from production factories in pregnant women and risk of preterm birth occurrence in Liuyang,China

In the production of fireworks, various pollutants including particles of metals and organic compounds are released into the environment. Although the adverse effects of these air pollutants are known, the impact on pregnant women residing in this area remains to be determined. The aim of this study was to examine the association between maternal exposure to fireworks production chemicals and frequency of preterm birth in Liuyang, China. Maternal exposure to fireworks production was estimated at the residential district level and assessed using factory density, which was defined as the number of fireworks factories per 1000 residents in each district. The association of maternal exposure to particulates released from fireworks production plants with frequency of preterm birth was determined using data obtained from a cohort study conducted in Liuyang, China. Data were analyzed utilizing linear regression and logistic regression. There was no significant association between factory density and spontaneous preterm or medically induced preterm birth. Unexpectedly, pregnant women residing in areas with higher density of fireworks factories were at a reduced risk of preterm premature rupture of membranes (PPROM). Data demonstrated that residential density of fireworks factories appeared to be negatively correlated with preterm birth rate as evidenced by PPROM. At present, it is difficult to reconcile the inverse relationship between firework chemical exposure and frequency of preterm births as ambient particulate inhalation is known to adversely affect preterm birth occurrence.