Association of Parental Preconception Exposure to Phthalates and Phthalate Substitutes With Preterm Birth.

Importance: Although phthalate exposure during pregnancy has been associated with preterm birth, the association of preconception exposure in either parent with preterm birth constitutes a knowledge gap. Objective: To examine the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth. Design, Setting, and Participants: This study, conducted at an academic fertility center in Boston, Massachusetts, included a prospective preconception cohort of subfertile couples comprising 419 mothers and 229 fathers and their 420 live-born singleton offspring born between January 1, 2005, and December 31, 2018. Statistical analysis was performed from August 1 to October 31, 2019. Exposures: Urinary concentrations of metabolites of phthalates and phthalate substitutes obtained before conception. Main Outcomes and Measures: Gestational age was abstracted from delivery records and validated using the American College of Obstetricians and Gynecologists guidelines for births after medically assisted reproduction. The risk ratio (RR) of preterm birth (live birth before 37 completed weeks' gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of 4 di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites, and 2 metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH, a nonphthalate plasticizer substitute) using modified Poisson regression models adjusted for covariates. Results: The mean (SD) age of the 419 mothers was 34.7 (4.0) years, the mean (SD) age of the 229 fathers was 36.0 (4.5) years, and the mean (SD) gestational age of the 420 singleton children (217 boys) was 39.3 (1.7) weeks, with 34 (8%) born preterm. In adjusted models, maternal preconception ΣDEHP concentrations (RR, 1.50; 95% CI, 1.09-2.06; P = .01) and cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH, a metabolite of DINCH) concentrations (RR, 1.70; 95% CI, 0.89-3.24; P = .11) were associated with an increased risk of preterm birth. After additional adjustment for prenatal ΣDEHP or MHiNCH concentrations, the association of maternal preconception exposure to ΣDEHP and preterm birth remained robust (RR, 1.69; 95% CI, 1.17-2.44; P = .006), while the association of maternal preconception exposure to MHiNCH and preterm birth was attenuated (RR, 1.17; 95% CI, 0.49-2.81; P = .72). The remaining urinary metabolites examined in either parent showed no association with preterm birth. Conclusions and Relevance: In this prospective cohort of subfertile couples, maternal preconception exposure to ΣDEHP metabolites was associated with an increased risk of preterm birth. The results suggest that female exposure to select phthalate plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes, which may need to be considered in preconception care strategies.

Simulations and directed acyclic graphs explained why assortative mating biases the prenatal negative control design.

OBJECTIVE: The negative control design can be used to provide evidence for whether a prenatal exposure-outcome association occurs by in utero mechanisms. Assortative mating has been suggested to influence results from negative control designs, although how and why has not yet been adequately explained. We aimed to explain why mutual adjustment of maternal and paternal exposure in regression models can account for assortative mating. STUDY DESIGN AND SETTING: We used directed acyclic graphs to show how bias can occur when modeling maternal and paternal effects separately. We empirically tested our claims using a simulation study. We investigated how increasing assortative mating influences the bias of effect estimates obtained from models that do and do not use a mutual adjustment strategy. RESULTS: In models without mutual adjustment, increasing assortative mating led to increased bias in effect estimates. The maternal and paternal effect estimates were biased by each other, making the difference between them smaller than the true difference. Mutually adjusted models did not suffer from such bias. CONCLUSIONS: Mutual adjustment for maternal and paternal exposure prevents bias from assortative mating influencing the conclusions of a negative control design. We further discuss issues that mutual adjustment may not be able to resolve.

Parental occupational exposure to low-frequency magnetic fields and risk of leukaemia in the offspring: findings from the Childhood Leukaemia International Consortium (CLIC).

OBJECTIVES: Previously published studies on parental occupational exposure to extremely low-frequency magnetic fields (ELF-MF) and risk of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring were inconsistent. We therefore evaluated this question within the Childhood Leukemia International Consortium. METHODS: We pooled 11 case-control studies including 9723 childhood leukaemia cases and 17 099 controls. Parental occupational ELF-MF exposure was estimated by linking jobs to an ELF-MF job-exposure matrix (JEM). Logistic regression models were used to estimate ORs and 95% CIs in pooled analyses and meta-analyses. RESULTS: ORs from pooled analyses for paternal ELF-MF exposure >0.2 microtesla (µT) at conception were 1.04 (95% CI 0.95 to 1.13) for ALL and 1.06 (95% CI 0.87 to 1.29) for AML, compared with ≤0.2 µT. Corresponding ORs for maternal ELF-MF exposure during pregnancy were 1.00 (95% CI 0.89 to 1.12) for ALL and 0.85 (95% CI 0.61 to 1.16) for AML. No trends of increasing ORs with increasing exposure level were evident. Furthermore, no associations were observed in the meta-analyses. CONCLUSIONS: In this large international dataset applying a comprehensive quantitative JEM, we did not find any associations between parental occupational ELF-MF exposure and childhood leukaemia.

Case-control study of paternal occupational exposures and childhood lymphoma in Great Britain, 1962-2010.

BACKGROUND: This nationwide study investigates associations between paternal occupational exposure and childhood lymphoma. METHODS: The UK National Registry of Childhood Tumours provided cases of childhood lymphoma born and diagnosed in Great Britain 1962-2010. Control births, unaffected by childhood cancer, were matched on sex, birth period and birth registration sub-district. Fathers' occupations were assigned to one or more of 33 exposure groups and also coded for occupational social class. RESULTS: We analysed 5033 childhood lymphoma cases and 4990 controls. Total lymphoma and the subgroups Hodgkin, Burkitt and non-Hodgkin lymphoma were considered separately. No one exposure was significantly associated with increased risk within all subgroups and for total lymphoma. However, exposure to "ceramics and glass" was significantly associated with increased risk of total lymphoma, Hodgkin and non-Hodgkin lymphoma. Paternal lead exposure was associated with Burkitt lymphoma and exposure to metal fumes was associated with Hodgkin lymphoma. CONCLUSIONS: This study provides no support for previous suggestions of an association between childhood lymphoma and paternal occupational exposure to pesticides, solvents/hydrocarbons or infections potentially transmitted by father's social contacts. An association with exposure to "ceramics and glass" was noted for the two major lymphoma subtypes together comprising 80% of total lymphoma.

Risk of selected childhood cancers and parental employment in painting and printing industries: A register-based case‒control study in Denmark 1968-2015.

Objectives Parental exposures and offspring's risk of cancer have been studied with inconsistent results. We investigated parental employment in painting and printing industries and risk of childhood leukemia, central nervous system (CNS) cancers, and prenatal cancers (acute lymphoblastic leukemia, Wilms tumor, medulloblastoma, neuroblastoma, retinoblastoma, and hepatoblastoma). Methods Using Danish registries, children aged ≤19 years diagnosed from 1968-2015 with leukemia (N=1999), CNS cancers (N=1111) or prenatal cancers (N=2704) were linked to parents and their employment history one year before birth to birth for fathers, and one year before birth to one year after for mothers. Twenty randomly selected controls per case were matched by age and sex. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Results For fathers, we found increased risks for acute myeloid leukemia (AML) consistent in painting (OR 2.26, 95% CI 1.07-4.80) and printing industries (OR 2.43, 95% CI 0.94-6.23) and these industries combined (OR 2.10, 95% CI 1.14-3.87). For mothers, increased risks of CNS cancers were found for painting industries (OR 2.34, 95% CI 1.10-4.95) and painting and printing combined (OR 1.97, 95% CI 1.08-3.64). For fathers working in combined industries, the OR for CNS was increased (OR 1.54, 95% CI 1.02-2.31), most prominently in printing industries (OR 2.09, 95% CI 1.17-3.75). Conclusion We observed increased risks of CNS tumors in offspring after parental employment in painting and printing industries. Children of fathers employed in painting and printing industries had a two-fold increase in AML.

Factores sociodemográficos y factores de riesgo preconcepcionales en padres y madres de niños con cardiopatías congénitas / Socio-demographic and preconception risk factors in parents of children suffering from congenital cardiopathy

OBJETIVO: Caracterizar los factores de riesgo preconcepcionales en padres y madres de niños con cardiopatías congénitas. MÉTODO: Estudio descriptivo de corte transversal que incluyó a padres y madres de niños con cardiopatías atendidos en consulta en una organización sin ánimo de lucro, para ser diagnosticados y direccionados a cirugía cardiaca o para ser valorados en control postoperatorio de cardiología. La muestra estuvo constituida por 500 personas, a quienes se aplicó un cuestionario para la identificación de los factores sociodemográficos y los factores de riesgo preconcepcionales. RESULTADOS: Se encontraron parejas hasta con 3 niños cardiópatas. Los padres que tenían 2 o más hijos con cardiopatías se caracterizaban por pertenecer mayormente al estrato socioeconómico medio y no poseer vivienda propia. Se encontró asociación entre el número de hijos con cardiopatías y el nivel educativo de los progenitores (p = 0,013), la zona de residencia (p = 0,041) y el tipo de vivienda (p = 0,045). En cuanto a los factores de riesgo preconcepcionales, se evidenciaron asociaciones estadísticamente significativas entre el número de hijos con cardiopatías y la exposición a fertilizantes (p = 0,024), la exposición a combustibles (p = 0,025), el consumo de medicamentos antihipertensivos (p = 0,037), el consumo de alcohol (p = 0,042) y el consumo de cocaína (p = 0,039). CONCLUSIONES: La población de padres que poseían un mayor número de hijos con cardiopatías se caracterizaba por presentar limitaciones socioeconómicas y educativas. Los factores preconcepcionales que muestran asociación con el número de hijos con cardiopatías se caracterizaban por ser factores de riesgo ambientales de tipo físico y químico, además del consumo de algunas sustancias psicoactivas y medicamentos. Es necesario estudiar cada factor de riesgo teniendo en cuenta los diferentes tipos de cardiopatías por separado

OBJECTIVE: To identify the preconception risk factors in parents of children suffering from congenital cardiopathy. METHOD: A cross-sectional descriptive study, which included parents of children suffering from cardiopathy, attended at consultations in a not-for-profit organization, in order to be diagnosed and referred for heart surgery or to be assessed in postoperative cardiac monitoring. The sample population included 500 people who responded to a survey for the identification of socio-demographic and preconception risk factors. RESULTS: Couples were found with up to 3 cardiac children. Parents with 2 or more children suffering from cardiopathy were classified in the majority as belonging to the middle socioeconomic level and not owning their own house. An association with the number of children with cardiopathy, the educational level of their parents (P=.013), their home area (P=.041) and type of accommodation (P=.045) was found. Regarding the preconception risk factors, there was evidence of statistically significant associations among the number of children with cardiopathy and their exposure to fertilizers (P=.024), their exposure to fuels (P=.025), the use of antihypertensive medication (P=.37), and alcohol consumption (P=.042) and cocaine use (P=.039) by their parents. CONCLUSIONS: The population of parents with a greater number of children suffering from cardiopathy were characterized as having socioeconomic and educational constraints. The preconception risk factors which show an association with the number of children suffering from cardiopathy were characterized as physical and/or chemical environmental risk factors and the consumption of certain psychoactive substances and medication by their parents. It is necessary to analyze each risk factor separately, taking into account the different types of cardiopathy

Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report.

OBJECTIVES: We described pregnancy outcomes in Crohn's disease (CD) patients enrolled in the TREAT Registry who received infliximab before, or during pregnancy and those not treated with infliximab or any biologic agent. METHODS: In the TREAT Registry (1999-2012), pregnancy outcomes were analyzed from maternal and paternal patients exposed to infliximab ≤365 days (gestational exposure), >365 days (pre-gestational exposure) of pregnancy outcome or without infliximab exposure (non-biologic exposed). "Healthy infants" were defined as those with no congenital abnormalities, neonatal complications (e.g., jaundice, prematurity, heart murmur, cortical vision/fine motor delay, cardiac failure, hemophilia, or torticollis), prolonged hospitalization, or those who received no special treatment. Disease activity and concomitant medications were also evaluated. RESULTS: Overall, 92.3% (324/351) of pregnancies had known outcomes. The majority of both maternal pregnancies (92.6, 91.2, and 87.8%) and partner outcomes (92.7, 93.8, and 91.7%) resulted in live births of healthy infants across gestational, pre-gestational, and non-biologic exposure groups, respectively. Among these, rates of neonatal complications were low for both maternal (6.2, 7.0, and 8.5%), and partner outcomes (4.9, 0, and 0%) in gestational, pre-gestational, and non-biologic exposure groups, respectively. Among maternal pregnancies, numerically higher rates of spontaneous abortions were observed for the gestational exposure group than for the pre-gestational or non-biologic exposed groups. CONCLUSIONS: The clinical condition of infants born to women with gestational infliximab exposure was similar to those without exposure. Although a lower live birth rate was reported among infliximab-exposed women, these patients had more severe CD and were more likely to have been exposed to immunosuppressives.

Socio-demographic and preconception risk factors in parents of children suffering from congenital cardiopathy. / Factores sociodemográficos y factores de riesgo preconcepcionales en padres y madres de niños con cardiopatías congénitas.

OBJECTIVE: To identify the preconception risk factors in parents of children suffering from congenital cardiopathy. METHOD: A cross-sectional descriptive study, which included parents of children suffering from cardiopathy, attended at consultations in a not-for-profit organization, in order to be diagnosed and referred for heart surgery or to be assessed in postoperative cardiac monitoring. The sample population included 500 people who responded to a survey for the identification of socio-demographic and preconception risk factors. RESULTS: Couples were found with up to 3 cardiac children. Parents with 2 or more children suffering from cardiopathy were classified in the majority as belonging to the middle socioeconomic level and not owning their own house. An association with the number of children with cardiopathy, the educational level of their parents (P=.013), their home area (P=.041) and type of accommodation (P=.045) was found. Regarding the preconception risk factors, there was evidence of statistically significant associations among the number of children with cardiopathy and their exposure to fertilizers (P=.024), their exposure to fuels (P=.025), the use of antihypertensive medication (P=.37), and alcohol consumption (P=.042) and cocaine use (P=.039) by their parents. CONCLUSIONS: The population of parents with a greater number of children suffering from cardiopathy were characterized as having socioeconomic and educational constraints. The preconception risk factors which show an association with the number of children suffering from cardiopathy were characterized as physical and/or chemical environmental risk factors and the consumption of certain psychoactive substances and medication by their parents. It is necessary to analyze each risk factor separately, taking into account the different types of cardiopathy.

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.

Parental Occupational Exposure to Organic Solvents and Testicular Germ Cell Tumors in their Offspring: NORD-TEST Study.

BACKGROUND: Testicular germ cell tumors (TGCT) were suggested to have a prenatal environmentally related origin. The potential endocrine disrupting properties of certain solvents may interfere with the male genital development in utero. OBJECTIVES: We aimed to assess the association between maternal and paternal occupational exposures to organic solvents during the prenatal period and TGCT risk in their offspring. METHODS: This registry-based case control study included TGCT cases aged 14­49 y (n=8,112) diagnosed from 1978 to 2012 in Finland, Norway, and Sweden. Controls (n=26,264) were randomly selected from the central population registries and were individually matched to cases on year and country of birth. Occupational histories of parents prior to the child's birth were extracted from the national censuses. Job codes were converted into solvent exposure using the Nordic job-Nordic Occupational Cancer Study Job-Exposure Matrix. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Overall, no association was found between prenatal maternal exposure to solvents and TGCT risk. In subset analyses using only mothers for whom occupational information was available in the year of or in the year prior to the child's birth, there was an association with maternal exposure to aromatic hydrocarbon solvents (ARHC) (OR=1.53; CI: 1.08, 2.17), driven by exposure to toluene (OR=1.67; CI: 1.02, 2.73). No association was seen for any paternal occupational exposure to solvents with the exception of exposure to perchloroethylene in Finland (OR=2.42; CI: 1.32, 4.41). CONCLUSIONS: This study suggests a modest increase in TGCT risk associated with maternal prenatal exposure to ARHC. https://doi.org/10.1289/EHP864.

Exposure to toxics during pregnancy and childhood and asthma in children: A pilot study.

Environmental factors, pesticides, alcohol and smoking are linked to asthma in children. The association of toxic substances exposure with asthma has not been evaluated. Our objective is to assess such associations among children aged less than 16years old. This is a cross-sectional study, conducted between January and May 2015, using a sample of Lebanese students from private schools in Beirut and Mount Lebanon. Out of 700 distributed questionnaires, 527 (75.2%) were returned to us. Verbal informed consent was also obtained from all parents prior to participating in the study. A significant association was found between waterpipe smoking and diagnosed asthma (p=0.003; ORa=13.25; 95% CI 2.472-71.026). Alcohol during pregnancy, waterpipe smoking during pregnancy and parents respiratory problems significantly increased the risk of respiratory problems by approximately 5 times, 6 times and 2 times respectively (p=0.016; ORa=4.889; 95% CI 1.339-17.844, p=0.021; ORa=6.083; 95% CI 1.314-28.172, p=0.004; ORa=1.748; 95% CI 1.197-2.554 respectively). Waterpipe smoking, alcohol during pregnancy, recurrent otitis and humidity at home seem to be significantly correlated with asthma in children. Spreading awareness by health care professionals is needed to permit a reduction of the prevalence of these allergic diseases, especially asthma, in children.

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring.

Importance: Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective: To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants: This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures: Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures: Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results: Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance: Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy.

OBJECTIVE: To study the association between paternal exposure to methotrexate within the 90-day period before pregnancy and congenital malformations and stillbirth in the offspring. METHODS: We conducted a nationwide register study. Our cohort consisted of all live births in Denmark between 1997 and 2011 identified from the Medical Birth Registry. Methotrexate-exposed fathers were identified from the National Prescription Registry. From the national Hospital Registry we identified paternity, live births, and stillbirths as well as discharge diagnoses on congenital malformations. RESULTS: We identified 849,676 live births with known paternity. There were 127 live births of methotrexate-exposed fathers. Of these, four (3.2%) had major malformations compared with 28,814 (3.4%) of the unexposed. The odds ratio (OR) for major congenital malformation among exposed fathers compared with unexposed was 0.93 (95% confidence interval [CI] 0.34-2.51) and when adjusted for year of birth, maternal age, educational length, household income, and parity, the adjusted OR was 1.01 (95% CI 0.37-2.74). There were no stillbirths in the methotrexate-exposed group compared with 2,541 (0.3%) in the unexposed group and no increased risk of preterm birth (adjusted OR 1.31, 95% CI 0.66-2.59) among the children from exposed fathers. CONCLUSION: We found no association between paternal exposure to methotrexate within 90 days before pregnancy and congenital malformations, stillbirths, or preterm birth. Available data suggest that prepregnancy paternal methotrexate exposure should not be of major concern. Multinational recommendations should be changed accordingly.

Impact of maternal and paternal smoking on birth outcomes.

Background: The adverse effects of maternal and paternal smoking on child health have been studied. However, few studies demonstrate the interaction effects of maternal/paternal smoking, and birth outcomes other than birth weight have not been evaluated. The present study examined individual effects of maternal/paternal smoking and their interactions on birth outcomes. Methods: A follow-up hospital-based study from pregnancy to delivery was conducted from 1997 to 2010 with parents and newborn infants who delivered at a large hospital in Hamamatsu, Japan. The relationships between smoking and growth were evaluated with logistic regression. Results: The individual effects of maternal smoking are related to low birth weight (LBW), short birth length and small head circumference. The individual effects of paternal smoking are related to short birth length and small head circumference. In the adjusted model, both parents' smoking showed clear associations with LBW (odds ratio [OR] = 1.64, 95% confidence interval [CI] 1.18-2.27) and short birth length (-1 standard deviation [SD] OR = 1.38, 95% CI 1.07-1.79; -2 SD OR = 2.75, 95% CI 1.84-4.10). Conclusions: Maternal smoking was significantly associated with birth weight and length, but paternal smoking was not. However, if both parents smoked, the risk of shorter birth length increased.

Spontaneous adverse drug reaction reports for neonates and infants in the UK 2001-2010: content and utility analysis.

AIMS: The UK Medicines and Healthcare products Regulatory Agency (MHRA) runs a national spontaneous reporting system (Yellow Card [YC] Scheme) to collect 'suspected' adverse drug reaction (ADR) data. We aim to describe the content and utility of YC reports received for patients aged <2 years. METHODS: Data on all ADRs reported using YC in infants aged <2 years from the years 2001-10 were supplied by the MHRA. RESULTS: For infants age <2 years, 3496 suspected ADRs were reported using YC (paternal medication pre-conception n = 3, transplacental n = 246, transmammary n = 30, neonates n = 97, infant n = 477, and vaccinations n = 2673), averaging 0.96 YC per day. There was a male preponderance (male 49.1%, female 44.4%, unknown 6.5%), and only 34 (1.0%) of YC reports stated a gestational age. The medications most frequently reported were: transplacental and transmammary (fluoxetine, n = 21 and n = 4 respectively), neonate (swine flu vaccine, n = 8) infant (oseltamivir, n = 37) and vaccines (meningococcal vaccine, n = 693). Paternal, transmammary, neonatal and infant YC did not reflect clinical concerns raised by the UK regulator. Transplacental and vaccination reports did correlate with some of the changes in practice and clinical alerts received. CONCLUSIONS: The frequency of YC reports for those <2 years is low, neonates are poorly represented, and recording of gestational age is poor. With the exception of vaccinations, spontaneous reports alone are not currently generating the data required, and important safety messages from the regulator do not match reporting patterns. Additional reporting strategies are required to improve the quantity and quality of suspected ADR data in young children.

Birth Outcomes in Children Fathered by Men Treated with Anti-TNF-α Agents Before Conception.

OBJECTIVES: The safety of paternal use of anti-tumor necrosis factor-α (TNF-α) agents immediately prior to conception is practically unknown. On the basis of nationwide data from Danish health registries, we examined the association between paternal use of anti-TNF-α agents within 3 months before conception and adverse birth outcomes. METHODS: This nationwide cohort study is based on data from all women who had a live born singleton child in Denmark from 1 January 2007 through 2013. Children fathered by men treated with anti-TNF-α agents within three months before conception constituted the exposed cohort (N=372), and children fathered by men not treated before conception constituted the unexposed cohort (N=399,498). The outcomes were congenital abnormalities (CAs), preterm birth, and small for gestational age (SGA). We adjusted for multiple covariates, and considered paternal underlying disease and concomitant medication. RESULTS: The adjusted risks of CAs and preterm birth were close to unity, and the adjusted odds ratio (OR) for SGA was 1.70 (95% confidence interval (CI): 0.94-3.09). Restricting our analysis to fathers with inflammatory bowel disease, we found no increased risk of CAs or SGA, and the adjusted OR for pretem birth was 1.42 (95% CI: 0.52-3.86). Restricting our analysis to fathers with rheumatologic/dermatological diseases, we found no increased risk of CAs or preterm birth, and the adjusted OR for SGA was 1.70 (95% CI: 0.74-3.89). CONCLUSIONS: Our results are overall reassuring regarding the safety of paternal preconceptional use of anti-TNF-α agents. The result regarding SGA should, however, be interpreted with caution as we found an increased risk, although not significantly increased.

Enhanced anxiety in the male offspring of sires that self-administered cocaine.

We previously showed that paternal cocaine exposure reduced the reinforcing efficacy of cocaine in male offspring. Here, we sought to determine whether paternal cocaine experience could also influence anxiety levels in offspring. Male rats were allowed to self-administer cocaine (controls received saline passively) for 60 days and then were bred with naïve females. Measures of anxiety and cocaine-induced anxiogenic effects were assessed in the adult offspring. Cocaine-sired male offspring exhibited increased anxiety-like behaviors, as measured using the novelty-induced hypophagia and defensive burying tasks, relative to saline-sired males. In contrast, sire cocaine experience had no effect on anxiety-like behaviors in female offspring. When challenged with an anxiogenic (but not anorectic) dose of cocaine (2.5 mg/kg, i.p.), anxiety-like behavior was enhanced in all animals to an equal degree regardless of sire drug experience. Since anxiety and depression are often co-morbid, we also assessed measures of depressive-like behavior. Sire cocaine experience had no effect on depression-like behaviors, as measured by the forced swim task, among male offspring. In a separate group of naïve littermates, select neuronal correlates of anxiety were measured. Male offspring of cocaine-experienced sires showed increased mRNA and protein expression of corticotropin-releasing factor receptor 2 in the hippocampus. Together, these results indicate that cocaine-experienced sires produce male progeny that have increased baseline anxiety, which is unaltered by subsequent cocaine exposure.

Multigenerational effects of parental prenatal exposure to famine on adult offspring cognitive function.

The effects of prenatal nutrition on adult cognitive function have been reported for one generation. However, human evidence for multigenerational effects is lacking. We examined whether prenatal exposure to the Chinese famine of 1959-61 affects adult cognitive function in two consecutive generations. In this retrospective family cohort study, we investigated 1062 families consisting of 2124 parents and 1215 offspring. We assessed parental and offspring cognitive performance by means of a comprehensive test battery. Generalized linear regression model analysis in the parental generation showed that prenatal exposure to famine was associated with a 8.1 (95% CI 5.8 to 10.4) second increase in trail making test part A, a 7.0 (1.5 to 12.5) second increase in trail making test part B, and a 5.5 (-7.3 to -3.7) score decrease in the Stroop color-word test in adulthood, after adjustment for potential confounders. In the offspring generation, linear mixed model analysis found no significant association between parental prenatal exposure to famine and offspring cognitive function in adulthood after adjustment for potential confounders. In conclusion, prenatal exposure to severe malnutrition is negatively associated with visual- motor skill, mental flexibility, and selective attention in adulthood. However, these associations are limited to only one generation.