Prenatal Parental Exposure to Metals and Birth Defects: A Prospective Birth Cohort Study.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Environmental Signals.

Environmental factors have long been known to play a role in the pathogenesis of congenital heart disease (CHD), but this has not been a major focus of research in the modern era. Studies of human exposures and animal models demonstrate that demographics (age, race, socioeconomic status), diseases (e.g., diabetes, hypertension, obesity, stress, infection, high altitude), recreational and therapeutic drug use, and chemical exposures are associated with an increased risk for CHD. Unfortunately, although studies suggest that exposures to these factors may cause CHD, in most cases, the data are not strong, are inconclusive, or are contradictory. Although most studies concentrate on the effects of maternal exposure, paternal exposure to some agents can also modify this risk. From a mechanistic standpoint, recent delineation of signaling and genetic controls of cardiac development has revealed molecular pathways that may explain the effects of environmental signals on cardiac morphogenesis and may provide further tools to study the effects of environmental stimuli on cardiac development. For example, environmental factors likely regulate cellular signaling pathways, transcriptional and epigenetic regulation, proliferation, and physiologic processes that can control the development of the heart and other organs. However, understanding of the epidemiology and risk of these exposures and the mechanistic basis for any effects on cardiac development remains incomplete. Further studies defining the relationship between environmental exposures and human CHD and the mechanisms involved should reveal strategies to prevent, diagnose, and treat CHD induced by environmental signals.

Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

Birth defects associated with paternal firefighting in the National Birth Defects Prevention Study.

BACKGROUND: Few studies have evaluated birth defects among children of firefighters. We investigated associations between birth defects and paternal work as a firefighter compared to work in non-firefighting and police officer occupations. METHODS: We analyzed 1997-2011 data from the multi-site case-control National Birth Defects Prevention Study. Cases included fetuses or infants with major structural birth defects and controls included a random sample of live-born infants without major birth defects. Mothers of infants self-reported information about parents' occupations held during pregnancy. We investigated associations between paternal firefighting and birth defect groups using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Referent groups included families reporting fathers working non-firefighting and police officer jobs. RESULTS: Occupational groups included 227 firefighters, 36,285 non-firefighters, and 433 police officers. Twenty-nine birth defects were analyzed. In adjusted analyses, fathers of children with total anomalous pulmonary venous return (TAPVR; OR = 3.1; 95% CI = 1.1-8.7), cleft palate (OR = 1.8; 95% CI = 1.0-3.3), cleft lip (OR = 2.2; 95% CI = 1.2-4.2), and transverse limb deficiency (OR = 2.2; 95% CI = 1.1-4.7) were more likely than fathers of controls to be firefighters, versus non-firefighters. In police-referent analyses, fathers of children with cleft palate were 2.4 times more likely to be firefighters than fathers of controls (95% CI = 1.1-5.4). CONCLUSIONS: Paternal firefighting may be associated with an elevated risk of birth defects in offspring. Additional studies are warranted to replicate these findings. Further research may contribute to a greater understanding of the reproductive health of firefighters and their families for guiding workplace practices.

Multigenerational genetic effects of paternal cadmium exposure on ovarian granulosa cell apoptosis.

To explore whether paternal cadmium (Cd) exposure causes ovarian granulosa cell (GC) apoptosis in offspring and the multigenerational genetic effects. From postnatal day 28 (PND28) until adulthood (PND56), SPF male Sprague-Dawley (SD) rats were gavaged daily with varying concentrations of CdCl2. (0, 0.5, 2, and 8 mg/kg). After treatment, the F1 generation was produced by mating with untreated female rats, and the F1 generation male rats were mated with untreated female rats to produce the F2 generation. Apoptotic bodies (electron microscopy) and significantly higher apoptotic rates (flow cytometry) were observed in both F1 and F2 ovarian GCs following paternal Cd exposure. Moreover, the mRNA (qRTPCR) or protein (Western blotting) levels of bax, bcl2, bcl-xl, caspase 3, caspase 8, and caspase 9 were changed to varying degrees. Apoptosis-related miRNAs (qRTPCR) and methylation modifications of apoptosis-related genes (bisulfite-sequencing PCR) in ovarian GCs were further detected. Compared with those of controls, the expression patterns of miRNAs in F1 and F2 offspring were different after paternal Cd exposure, while the average methylation level of apoptosis-related genes did not change significantly (except for individual loci). In summary, there are paternal genetic intergenerational and transgenerational effects on ovarian GC apoptosis induced by paternal Cd exposure. These genetic effects were related to the upregulation of BAX, BCL-XL, Cle-CASPASE 3, and Cle-CASPASE 9 in F1 and the upregulation of Cle-CASPASE 3 in F2 progeny. Important changes in apoptosis-related miRNAs were also observed.

Birth outcomes associated with paternal polybrominated and polychlorinated biphenyl exposure.

In 1973-74, a polybrominated biphenyl (PBB) flame retardant mixture was shipped to Michigan livestock feed mills in place of a nutritional supplement and contaminated the food supply. Following the accident, the Michigan PBB Registry was established to study the long-term health effects of halogenated compounds and is now led by a community-academic partnership. PBB exposure is associated with altered DNA methylation in sperm, which may lead to adverse birth outcomes in children whose fathers have increased levels of serum PBB or polychlorinated biphenyl (PCB). Paternal PBB and PCB levels of men enrolled in the Michigan PBB Registry (n = 155) were analyzed against matched offspring birthweight and gestational age (n = 336). Birthweight and gestational age were dichotomized at the 25th percentile and 37 weeks, respectively, and paternal PBB and PCB levels were examined as continuous measures and divided into tertiles. Associations of offspring birthweight and gestational age with paternal PBB and PCB serum concentrations were modeled using multivariable linear spline and log-risk regression, adjusting for family clustering, paternal health and lifestyle factors, maternal PBB, and PCB serum concentrations, sex, and offspring gestational age (for birthweight). Fathers in the middle and upper PBB and PCB tertiles had increased risks for lowest quartile birthweight compared to the first tertile, with adjusted risk ratios (aRR) = 1.67 (95% CI: 0.93, 2.99) and aRR = 2.06 (95% CI: 1.12, 3.79) for PBB, and aRR = 1.47 (95% CI: 0.79, 2.75) and aRR = 1.34 (95% CI: 0.70, 2.54) for PCB, respectively. Elevated paternal PBB levels were not associated with an increased risk for preterm birth, while PCB levels were associated with a small, but not significant, decrease in gestational age, ß = -0.37 (95% CI: -0.76, 0.03) weeks per log unit increase PCB. The findings suggest that increased paternal PBB and PCB levels negatively impact offspring birthweight, and paternal PCB levels may negatively impact gestational age.

Paternal long-term PM2.5 exposure causes hypertension via increased renal AT1R expression and function in male offspring.

Maternal exposure to fine particulate matter (PM2.5) causes hypertension in offspring. However, paternal contribution of PM2.5 exposure to hypertension in offspring remains unknown. In the present study, male Sprague-Dawley rats were treated with PM2.5 suspension (10 mg/ml) for 12 weeks and/or fed with tap water containing an antioxidant tempol (1 mM/L) for 16 weeks. The blood pressure, 24 h-urine volume and sodium excretion were determined in male offspring. The offspring were also administrated with losartan (20 mg/kg/d) for 4 weeks. The expressions of angiotensin II type 1 receptor (AT1R) and G-protein-coupled receptor kinase type 4 (GRK4) were determined by qRT-PCR and immunoblotting. We found that long-term PM2.5 exposure to paternal rats caused hypertension and impaired urine volume and sodium excretion in male offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposed paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased urine volume and sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol in paternal rats restored the increased blood pressure and decreased urine volume and sodium excretion in the offspring of PM2.5-exposed paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring. We suggest that paternal PM2.5 exposure causes hypertension in offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in male offspring.

A systematic overview of the spermatotoxic and genotoxic effects of methotrexate, ganciclovir and mycophenolate mofetil.

INTRODUCTION: Immunosuppressant drugs are increasingly being used in the reproductive years. Theoretically, such medications could affect fetal health either through changes in the sperm DNA or through fetal exposure caused by a presence in the seminal fluid. This systematic overview summarizes existing literature on the spermatotoxic and genotoxic potentials of methotrexate (MTX), a drug widely used to treat rheumatic and dermatologic diseases, and mycophenolate mofetil (MMF), which alone or supplemented with ganciclovir (GCV) may be crucial for the survival of organ transplants. MATERIAL AND METHODS: The systematic overview was performed in accordance with the PRISMA guidelines: A systematic literature search of the MEDLINE and Embase databases was done using a combination of relevant terms to search for studies on spermatotoxic or genotoxic changes related to treatment with MTX, GCV or MMF. The search was restricted to English language literature, and to in vivo animal studies (mammalian species) and clinical human studies. RESULTS: A total of 102 studies were identified, hereof 25 human and 77 animal studies. For MTX, human studies of immunosuppressive dosages show transient effect on sperm quality parameters, which return to reference values within 3 months. No human studies have investigated the sperm DNA damaging effect of MTX, but in other organs the genotoxic effects of immunosuppressive doses of MTX are fluctuating. In animals, immunosuppressive and cytotoxic doses of MTX adversely affect sperm quality parameters and show widespread genotoxic damages in various organs. Cytotoxic doses transiently change the DNA material in all cell stages of spermatogenesis in rodents. For GCV and MMF, data are limited and the results are indeterminate, for which reason spermatotoxic and genotoxic potentials cannot be excluded. CONCLUSIONS: Data from human and animal studies indicate transient spermatotoxic and genotoxic potentials of immunosuppressive and cytotoxic doses of MTX. There are a limited number of studies investigating GCV and MMF.

Parental occupational exposure and congenital heart diseases in a Hungarian case-control study.

PURPOSE: Our study aimed to explore the effect of parental occupational exposure to endocrine disrupting chemicals (EDCs) on the development of congenital heart diseases (CHDs) in the offspring, and to compare job-exposure matrix (JEM)-assessed and self-reported occupational exposures with each other. METHODS: Live-born infants born in 2007-2008 were selected from the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities Study. 577 cases with any CHDs were compared to 1731 matched controls. Parental periconceptional occupational exposure to EDCs was assessed by a JEM and by questionnaire-based self-reporting of parents. Multivariate conditional logistic regression analyses were conducted to explore associations between parental occupational exposure to EDCs and the entire spectrum of CHDs and by CHD subtypes in the offspring. Kappa statistics were also performed to determine the consistency among JEM-assessed and self-reported occupational exposure of parents. RESULTS: JEM-assessed paternal exposure to polychlorinated organic substances, phthalates, biphenolic compounds, and solvents were significantly associated with the entire spectrum of CHDs. Ventricular septal defects were significantly associated with paternal self-reported exposure to pesticides, while atrial septal defects were significantly associated to paternal JEM-assessed phthalate exposure. Paternal solvent exposure was significantly associated with atrial septal defects and right ventricle outflow tract obstructions. JEM-assessed and self-reported exposures to pesticides, heavy metals, and solvents exhibited poor agreement for mothers and slight agreement for fathers. CONCLUSION: Even though parental occupational exposure to EDCs seems to have a minor impact on the occurrence of CHDs, the results of biological and environmental monitoring should be taken into consideration as well.

Paternal Inheritance of Bisphenol A Cardiotoxic Effects: The Implications of Sperm Epigenome.

Parental exposure to bisphenol A (BPA) has been linked to a greater incidence of congenital diseases. We have demonstrated that BPA induces in zebrafish males an increase in the acetylation of sperm histones that is transmitted to the blastomeres of the unexposed progeny. This work is aimed to determine whether histone hyperacetylation promoted by paternal exposure to BPA is the molecular mechanism underlying the cardiogenesis impairment in the descendants. Zebrafish males were exposed to 100 and 2000 µg/L BPA during early spermatogenesis and mated with non-exposed females. We analyzed in the progeny the expression of genes involved in cardiogenesis and the epigenetic profile. Once the histone hyperacetylation was confirmed, treatment with epigallocatechin gallate (EGCG), an inhibitor of histone acetyltransferases, was assayed on F1 embryos. Embryos from males exposed to 2000 µg/L BPA overexpressed the transcription factor hand2 and the receptor esr2b, showing their own promoters-as well as that of kat6a-an enrichment in H3K9ac. In embryos treated with EGCG, both gene expression and histone acetylation (global and specific) returned to basal levels, and the phenotype was recovered. As shown by the results, the histone hyperacetylated landscape promoted by BPA in the sperm alters the chromatin structure of the progeny, leading to the overexpression of the histone acetyltransferase and genes involved in cardiogenesis.

Pregnancy outcomes in DMARD-exposed patients with juvenile idiopathic arthritis-results from a JIA biologic registry.

OBJECTIVES: To investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs. METHODS: In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis. RESULTS: The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively. CONCLUSION: Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes.

Pregnancy outcomes in partners of male ankylosing spondylitis patients treated with anti-tumour necrosis factor-α biologics: real-life results from a single-centre cross-sectional study.

Most patients with inflammatory arthritis are at their reproductive ages. Use of anti-tumour necrosis factor alpha (anti-TNF-α) agents, one of the important treatment options for inflammatory arthritis, can cause foetal morbidity and mortality. While most studies on the effects of anti-TNF-α agents on pregnancy outcomes are about maternal exposure, the number of studies on the risks related to paternal exposure is insufficient. This study aimed to assess pregnancy periods and outcomes of the partners of male ankylosing spondylitis (AS) patients receiving anti-TNF-α treatment during the preconception period. Totally, 163 male AS patients using anti-TNF-α agents were identified from the Hacettepe University Biological Registry. Of these patients, 45 (27.6%) who declared that their partners got pregnant after initiation on anti-TNF-α agents were included. Data regarding demographics and drug exposure and pregnancy and infant outcomes were evaluated. Of 45 pregnancies, 39 (86.7%) resulted in healthy live births, 3 (6.7%) resulted in spontaneous abortion, and 3 (6.7%) were terminated with curettage. Of 39 live births, 34 (87.2%) were term and 5 (12.8%) were preterm, 30 (76.9%) had normal birth weight, 6 (15.4%) had low birth weight, and 3 (7.7%) had fetal macrosomia. No congenital malformations related to paternal exposure were observed. This study is valuable as being one of the studies providing pregnancy outcomes of partners of male AS patients receiving anti-TNF-α agents with its relatively high number of patients. The results suggested that paternal exposure to anti-TNF-α agents during preconception period could be safe on pregnancy outcomes.

Aging Induces Profound Changes in sncRNA in Rat Sperm and These Changes Are Modified by Perinatal Exposure to Environmental Flame Retardant.

Advanced paternal age at fertilization is a risk factor for multiple disorders in offspring and may be linked to age-related epigenetic changes in the father's sperm. An understanding of aging-related epigenetic changes in sperm and environmental factors that modify such changes is needed. Here, we characterize changes in sperm small non-coding RNA (sncRNA) between young pubertal and mature rats. We also analyze the modification of these changes by exposure to environmental xenobiotic 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). sncRNA libraries prepared from epididymal spermatozoa were sequenced and analyzed using DESeq 2. The distribution of small RNA fractions changed with age, with fractions mapping to rRNA and lncRNA decreasing and fractions mapping to tRNA and miRNA increasing. In total, 249 miRNA, 908 piRNA and 227 tRNA-derived RNA were differentially expressed (twofold change, false discovery rate (FDR) p ≤ 0.05) between age groups in control animals. Differentially expressed miRNA and piRNA were enriched for protein-coding targets involved in development and metabolism, while piRNA were enriched for long terminal repeat (LTR) targets. BDE-47 accelerated age-dependent changes in sncRNA in younger animals, decelerated these changes in older animals and increased the variance in expression of all sncRNA. Our results indicate that the natural aging process has profound effects on sperm sncRNA profiles and this effect may be modified by environmental exposure.

Infertility and teratogenicity after paternal exposure to systemic dermatologic medications: A systematic review.

BACKGROUND: This systematic review assesses effects of paternal exposure to dermatologic medications by using the former US Food and Drug Administration (FDA) pregnancy categories as a benchmark. OBJECTIVE: To assess whether systemic dermatologic medications can cause infertility and teratogenicity when taken by men. METHODS: Categories D and X dermatologic medications were identified; a systematic review of the literature and reviews of the FDA Adverse Events Reporting System and prescribing information were performed to identify the effects of these medications on male fertility and teratogenicity. A secondary search was performed to assess for other systemic dermatologic medications causing teratogenicity or infertility following paternal exposure. RESULTS: A total of 13 medications met the inclusion criteria. Of 1,032 studies identified, 19 were included after a systematic review of the literature. Studies evaluating medication effects with paternal exposure were identified for 10 of the 13 evaluated medications, and evidence of a negative effect was identified for 6 medications. LIMITATIONS: We did not encounter any studies for 3 medications that met the inclusion criteria. Information submitted to the FDA Adverse Events Reporting System may not reflect the incidence of side effects. CONCLUSIONS: Many former pregnancy category D and X systemic dermatologic medications also have effects on male fertility. More research and better-quality studies are required in this area, particularly studies assessing potential teratogenicity.

The CHARGE study: an assessment of parental occupational exposures and autism spectrum disorder.

OBJECTIVES: The aim of this study is to determine if parental occupational exposure to 16 agents is associated with autism spectrum disorder (ASD). METHODS: Demographic, health and parental occupational data were collected as part of the CHildhood Autism Risks from Genetics and Environment study. The workplace exposure assessment was conducted by two experienced industrial hygienists for the parents of 537 children with ASD and 414 typically developing (TD) children. For each job, frequency and intensity of 16 agents were assessed and both binary and semi-quantitative cumulative exposure variables were derived. Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) to assess associations between parental occupational exposures 3 months pre-pregnancy until birth. RESULTS: The OR of ASD in the children of mothers exposed to any solvents was 1.5 times higher than the mothers of TD children (95% CI=1.01-2.23). Cumulative exposure indicated that the OR associated with a moderate level of solvent exposure in mothers was 1.85 (95% CI=1.09, 3.15) for children with ASD compared with TD children. No other exposures were associated with ASD in mothers, fathers or the parents combined. CONCLUSION: Maternal occupational exposure to solvents may increase the risk for ASD. These results are consistent with a growing body of evidence indicating that environmental and occupational exposures may be associated with ASD. Future research should consider specific types of solvents, larger samples and/or different study designs to evaluate other exposures for potential associations with ASD.

Boron-exposed male workers in Turkey: no change in sperm Y:X chromosome ratio and in offspring's sex ratio.

Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 ± 18.32 mg B/day, 1643.23 ± 965.44 ng B/g semen and 553.83 ± 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions.

Prenatal exposure to maternal and paternal depressive symptoms and white matter microstructure in children.

BACKGROUND: Prenatal maternal depression has been associated with multiple problems in offspring involving affect, cognition, and neuroendocrine functioning. This suggests that prenatal depression influences neurodevelopment. However, the underlying neurodevelopmental mechanism remains unclear. We prospectively assessed whether maternal depressive symptoms during pregnancy and at the child's age 3 years are related to white matter microstructure in 690 children. The association of paternal depressive symptoms with childhood white matter microstructure was assessed to evaluate genetic or familial confounding. METHODS: Parental depressive symptoms were measured using the Brief Symptom Inventory. In children aged 6-9 years, we used diffusion tensor imaging to assess white matter microstructure characteristics including fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Exposure to maternal depressive symptoms during pregnancy was associated with higher MD in the uncinate fasciculus and to lower FA and higher MD in the cingulum bundle. No associations of maternal depressive symptoms at the child's age of 3 years with white matter characteristics were observed. Paternal depressive symptoms also showed a trend toward significance for a lower FA in the cingulum bundle. CONCLUSIONS: Prenatal maternal depressive symptoms were associated with higher MD in the uncinate fasciculus and the cingulum bundle. These structures are part of the limbic system, which is involved in motivation, emotion, learning, and memory. As paternal depressive symptoms were also related to lower FA in the cingulum, the observed effect may partly reflect a genetic predisposition and shared environmental family factors and to a lesser extent a specific intrauterine effect.

Agreement between paternal self-reported medication use and records from a national prescription database.

PURPOSE: Father's medication use is of interest in fertility studies and as negative control exposures in pregnancy medication safety studies. We sought to compare self-report to prescription records to understand how reliably each of these sources of information may be used. METHODS: We compared self-reported medication use in the 6 months prior to pregnancy from fathers participating in the Norwegian Mother and Child Cohort Study to records of dispensed prescriptions from the Norwegian Prescription Database that overlapped in time. Medications from 3 main categories were assessed: prescription medications used chronically, prescription medications used episodically, and over-the-counter/prescription medications (predominantly obtained without prescription). We calculated agreement between self-report and dispensing records using Cohen's kappa statistic. RESULTS: We included 42 848 pregnancies with the father's prescription data available for the 9 months before pregnancy. Prescription medications used chronically including antiepileptics, antipsychotics, and antidepressants showed substantial agreement between self-report and prescription records: kappa statistics 0.87, 0.63, and 0.74, respectively. Prescription medications used episodically like anti-infectives, opioids, anxiolytics, and hypnotics and sedatives showed worse agreement: kappa 0.19, 0.32, 0.40, 0.32. Over-the-counter/prescription medications like paracetamol and nonsteroidal anti-inflammatory drugs had slight agreement: kappa 0.02 and 0.20. CONCLUSIONS: There is good agreement between paternal self-report and prescription data for prescribed medications used chronically and substantially less for medications used episodically. Suboptimal agreement for episodic medications suggests poor recall (for questionnaires) or false positives due to noncompliance (prescription data). Not surprisingly, use of medications available both with and without a prescription is not well captured using prescription databases alone.

Counselling regarding paternal exposures: Can we do better?

BACKGROUND: MotherSafe is a free telephone-based counselling service for the general public and healthcare providers concerned about exposures during pregnancy and breastfeeding. Calls relating to paternal exposures are less common, but can cause distress to the person concerned. This review seeks to identify the key concerns and what information is available to address these concerns. AIMS: To review calls made to MotherSafe about paternal exposures to teratogens during the 16 year period, 2000-2015, and to document any patterns or changes in calls over the period. MATERIALS AND METHODS: A retrospective descriptive assessment of a prospectively collected database (2000-2015) was undertaken. Telephone counselling records identified the drugs of concern regarding paternal exposures. The information about paternal exposures provided in consumer and production information was also reviewed. RESULTS: Of a total of 253 103 calls received at MotherSafe between 2000 and 2015, 1072 calls (0.4%) were regarding paternal exposures. The majority of these calls related to immunomodifiers (19%), hair loss products (11%) and antidepressant medications. CONCLUSIONS: Paternal exposures represent a small proportion of all the counselling calls made to MotherSafe. The study highlighted the deficient and often misleading information about paternal exposures found in most consumer and product information sheets or via the internet. The study indicates the important role of Teratogen Information Services like Mothersafe in providing evidence-based information to both consumers and healthcare providers.

Birth defects in infants born to employees of a microelectronics and business machine manufacturing facility.

BACKGROUND: Concerns about solvent releases from a microelectronics/business machine manufacturing facility in upstate New York led to interest in the health of former workers, including this investigation of birth defects in children of male and female employees. METHODS: Children born 1983 to 2001 to facility employees were enumerated and matched to New York State's Congenital Malformations Registry. Reported structural birth defects were compared with numbers expected from state rates (excluding New York City), generating standardized prevalence ratios (SPRs). Exposure assessors classified employees as ever/never potentially exposed at the facility to metals, chlorinated hydrocarbons, and other hydrocarbons during windows critical to organogenesis (female workers) or spermatogenesis (male workers). Among workers, adjusted prevalence ratios were generated to evaluate associations between potential exposures and specific birth defects. RESULTS: External comparisons for structural defects were at expectation for infants of male workers (SPR = 1.01; 95% confidence interval [CI], 0.77-1.29; n = 60) and lower for births to female workers (SPR = 0.84; 95% CI, 0.50-1.33; n = 18). Among full-term infants of male workers, ventricular septal defects (VSDs) were somewhat elevated compared with the general population (SPR = 1.58; 95% CI, 0.99-2.39; n = 22). Within the cohort, potential paternal metal exposure was associated with increased VSD risk (adjusted prevalence ratio = 2.70; 95% CI, = 1.09-6.67; n = 7). CONCLUSION: While overall SPRs were near expectation, paternal exposure to metals (primarily lead) appeared to be associated with increased VSD risk in infants. Take-home of occupational exposures, nonoccupational exposures, and chance could not be ruled out as causes. Case numbers for many defects were small, limiting assessment of the role of occupational exposures. Birth Defects Research (Part A) 106:696-707, 2016. © 2016 Wiley Periodicals, Inc.