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    The association between season, day length, and temperature on clinical outcomes after cryopreserved embryo transfer. Correia Katharine F B,Farland Leslie V,Missmer Stacey A,Racowsky Catherine Fertility and sterility OBJECTIVE:To investigate whether there is an association between season, temperature, and day length at oocyte retrieval and/or embryo transfer (ET) and clinical outcomes in frozen ET cycles. DESIGN:Retrospective cohort study. SETTING:Large academically affiliated research hospital. PATIENT(S):A total of 3,004 frozen ET cycles from 1,937 different women with oocyte retrieval and transfer between 2012 and 2017. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Implantation, clinical pregnancy, spontaneous abortion, and live birth. RESULT(S):Frozen ETs with oocyte retrieval dates in summer had 45% greater odds of clinical pregnancy (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.15-1.82) and 42% greater odds of live birth (OR, 1.42; 95% CI, 1.13-1.79) compared with those with oocyte retrieval dates in winter. A 41% greater odds of clinical pregnancy (OR, 1.41; 95% CI, 1.16-1.71) and 34% greater odds of live birth (OR, 1.34; 95% CI, 1.10-1.62) were observed among transfers with an average temperature at oocyte retrieval in the highest tertile (17.2-33.3 °C) compared with those in the lowest tertile (-17.2-6.7 °C). There were no consistent associations between clinical outcomes and day length at oocyte retrieval or between season, day length, or temperature at transfer of thawed embryos. CONCLUSION(S):Warmer temperatures at oocyte retrieval are associated with higher odds of clinical pregnancy and live birth among frozen ET cycles. The consistent associations seen with oocyte retrieval dates and the lack of associations observed with ET dates suggest that any seasonality effects on in vitro fertilization success are related to ovarian function and not uterine receptivity. 10.1016/j.fertnstert.2021.11.014
    Impact of the COVID-19 pandemic on the incidence of prematurity: critical role of gestational age and environment. Weinberger Barry,Divers Jasmin,Campbell Deborah,Ham Steven,Juliano Courtney,Kurepa Dalibor,Lagamma Edmund,Mally Pradeep,Nafday Suhas,Nemerofsky Sheri,Sridhar Shanthy,Williams Kim,Hanna Nazeeh American journal of obstetrics and gynecology 10.1016/j.ajog.2022.02.028
    Pesticides and Human Reproduction. Landrigan Philip J JAMA internal medicine 10.1001/jamainternmed.2017.5092
    Exposure to non-persistent chemicals in consumer products and fecundability: a systematic review. Hipwell Alison E,Kahn Linda G,Factor-Litvak Pam,Porucznik Christina A,Siegel Eva L,Fichorova Raina N,Hamman Richard F,Klein-Fedyshin Michele,Harley Kim G, Human reproduction update BACKGROUND:Exposure to non-persistent chemicals in consumer products is ubiquitous and associated with endocrine-disrupting effects. These effects have been linked to infertility and adverse pregnancy outcomes in some studies and could affect couple fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). OBJECTIVE AND RATIONALE:Few epidemiologic studies have examined the impact of non-persistent chemicals specifically on TTP, and the results of these studies have not been synthesized. We undertook a systematic review to summarize the strength of evidence for associations of common non-persistent chemicals with couple fecundability and to identify gaps and limitations in the literature, with the aim of informing policy decisions and future research. SEARCH METHODS:We performed an electronic search of English language literature published between 1 January 2007 and 25 August 2017 in MEDLINE, EMBASE.com, Global Health, DART/TOXLINE, POPLINE and DESTAF. We included human retrospective and prospective cohort, cross-sectional and case-control studies that examined phthalates, bisphenol A, triclosan, triclocarban, benzophenones, parabens and glycol ethers in consumer products, and considered TTP or fecundability as an outcome among women, men and couples conceiving without medical assistance. We excluded editorials, opinion pieces, introductions to special sections, articles that described only lifestyle (e.g. caffeine, stress) or clinical factors (e.g. semen parameters, IVF success). Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. OUTCOMES:The search returned 3456 articles. There were 15 papers from 12 studies which met inclusion criteria, of which eight included biomarkers of chemical exposure. Studies varied widely in terms of exposure characterization, precluding a meta-analytic approach. Among the studies that measured exposure using biospecimens, results were equivocal for associations between either male or female phthalate exposure and TTP. There was preliminary support for associations of female exposure to some parabens and glycol ethers and of male exposure to benzophenone with longer TTP, but further research and replication of these results are needed. The results provided little to no indication that bisphenol A, triclocarban or triclosan exposure was associated with TTP. WIDER IMPLICATIONS:Despite a growing literature on couple exposure to non-persistent endocrine-disrupting chemicals and fecundability, evidence for associations between biologically measured exposures and TTP is limited. Equivocal results with different non-persistent chemical compounds and metabolites complicate the interpretation of our findings with respect to TTP, but do not preclude action, given the documented endocrine disrupting effects on other reproductive outcomes as well as fetal development. We therefore advocate for common-sense lifestyle changes in which both females and males seeking to conceive minimize their exposure to non-persistent chemicals. SYSTEMATIC REVIEW REGISTRATION NUMBER:CRD42018084304. 10.1093/humupd/dmy032
    Outdoor air pollution and human infertility: a systematic review. Checa Vizcaíno Miguel A,González-Comadran Mireia,Jacquemin Benedicte Fertility and sterility Air pollution is a current research priority because of its adverse effects on human health, including on fertility. However, the mechanisms through which air pollution impairs fertility remain unclear. In this article, we perform a systematic review to evaluate currently available evidence on the impact of air pollution on fertility in humans. Several studies have assessed the impact of air pollutants on the general population, and have found reduced fertility rates and increased risk of miscarriage. In subfertile patients, women exposed to higher concentrations of air pollutants while undergoing IVF showed lower live birth rates and higher rates of miscarriage. After exposure to similar levels of air pollutants, comparable results have been found regardless of the mode of conception (IVF versus spontaneous conception), suggesting that infertile women are not more susceptible to the effects of pollutants than the general population. In addition, previous studies have not observed impaired embryo quality after exposure to air pollution, although evidence for this question is sparse. 10.1016/j.fertnstert.2016.07.1110
    Persistent organic pollutants and couple fecundability: a systematic review. Human reproduction update BACKGROUND:Despite increasing regulation, exposure to persistent organic pollutants (POPs) remains a serious public health concern due to their accumulation in the environment and ability to biomagnify up the food chain. POPs are associated with endocrine-disrupting effects including adverse reproductive outcomes that could affect fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). OBJECTIVE AND RATIONALE:Results of epidemiologic studies that examine the impact of various chemical classes of POPs on TTP have not been synthesised. We undertook a systematic review to summarise the strength of evidence for associations of four common groups of POPs with couple fecundability and to identify gaps and limitations in the literature in order to inform policy decisions and future research. SEARCH METHODS:We performed an electronic search of literature published between 1 January 2007 and 6 August 2019 in MEDLINE, EMBASE.com, Global Health, DART/TOXLINE and POPLINE. We included empirical research papers that examined human exposure to organochlorine (OC) pesticides, brominated flame retardants, polychlorinated organic compounds and/or per- and polyfluoroalkyl substances (PFAS) and considered TTP or fecundability as an outcome. Standardised forms for screening, data extraction and study quality were developed using DistillerSR software, and all reviews were completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. OUTCOMES:The search returned 4573 articles, and 28 papers from 19 different studies met inclusion criteria. Among them, four studies measured TTP prospectively, three had data on participants' prenatal exposure, three examined associations in both male and female partners and one focused exclusively on males. Analyses varied widely in terms of exposure characterisation, precluding a meta-analytic approach. Evidence was strongest for adverse associations of female exposure to polychlorinated biphenyls with TTP, with some additional support for associations of female exposure to polybrominated diphenyl ethers and PFAS with longer TTP. Our review provided little or no support for associations between female exposure to OC pesticides or male exposure to any of the POP groups and TTP. WIDER IMPLICATIONS:Evidence suggests that female exposure to at least some POPs may reduce fecundability. Although many of these chemicals are no longer in production, they are still detectable in human biosamples because of their persistence in the environment. Replacement chemicals that are being introduced as older ones are restricted may have similar reproductive consequences. Future studies should examine these newer POPs, assess interactions between POPs and other chemical and non-chemical exposures, investigate how POPs are distributed in and metabolised by the human body and focus on populations that may be disproportionately exposed. 10.1093/humupd/dmaa037
    Air pollution exposure disparities across US population and income groups. Jbaily Abdulrahman,Zhou Xiaodan,Liu Jie,Lee Ting-Hwan,Kamareddine Leila,Verguet Stéphane,Dominici Francesca Nature Air pollution contributes to the global burden of disease, with ambient exposure to fine particulate matter of diameters smaller than 2.5 μm (PM) being identified as the fifth-ranking risk factor for mortality globally. Racial/ethnic minorities and lower-income groups in the USA are at a higher risk of death from exposure to PM than are other population/income groups. Moreover, disparities in exposure to air pollution among population and income groups are known to exist. Here we develop a data platform that links demographic data (from the US Census Bureau and American Community Survey) and PM data across the USA. We analyse the data at the tabulation area level of US zip codes (N is approximately 32,000) between 2000 and 2016. We show that areas with higher-than-average white and Native American populations have been consistently exposed to average PM levels that are lower than areas with higher-than-average Black, Asian and Hispanic or Latino populations. Moreover, areas with low-income populations have been consistently exposed to higher average PM levels than areas with high-income groups for the years 2004-2016. Furthermore, disparities in exposure relative to safety standards set by the US Environmental Protection Agency and the World Health Organization have been increasing over time. Our findings suggest that more-targeted PM reductions are necessary to provide all people with a similar degree of protection from environmental hazards. Our study is observational and cannot provide insight into the drivers of the identified disparities. 10.1038/s41586-021-04190-y
    The Association of Falling Insulin Requirements With Maternal Biomarkers and Placental Dysfunction: A Prospective Study of Women With Preexisting Diabetes in Pregnancy. Padmanabhan Suja,Lee Vincent W,Mclean Mark,Athayde Neil,Lanzarone Valeria,Khoshnow Qemer,Peek Michael J,Cheung N Wah Diabetes care OBJECTIVE:To investigate the association of falling insulin requirements (FIR) among women with preexisting diabetes with adverse obstetric outcomes and maternal biomarkers longitudinally in pregnancy. RESEARCH DESIGN AND METHODS:A multicenter prospective cohort study of 158 women (41 with type 1 diabetes and 117 with type 2 diabetes) was conducted. Women with FIR of ≥15% from the peak total daily dose after 20 weeks' gestation were considered case subjects ( = 32). The primary outcome was a composite of clinical markers of placental dysfunction (preeclampsia, small for gestational age [≤5th centile], stillbirth, premature delivery [<30 weeks], and placental abruption). Maternal circulating angiogenic markers (placental growth factor [PlGF] and soluble fms-like tyrosine kinase 1 [sFlt-1]), placental hormones (human placental lactogen, progesterone, and tumor necrosis factor-α), HbA, and creatinine were studied serially during pregnancy. RESULTS:FIR ≥15% were associated with an increased risk of the composite primary outcome (odds ratio [OR] 4.38 [95% CI 1.9-10.3]; < 0.001), preeclampsia (OR 6.76 [95% CI 2.7-16.7]; < 0.001), and was more common among women with type 1 diabetes (36.6 vs. 14.5%; = 0.002). Creatinine was modestly elevated among women with FIR ≥15%; however, there was no difference in HbA. The ratio of sFlt-1 to PlGF was significantly higher among women with FIR at 25, 30, and 36 weeks, with differences maintained in the subgroup that developed preeclampsia. There was no difference in placental hormones between the groups. CONCLUSIONS:This is the first prospective study to associate FIR with altered expression of placental antiangiogenic factors and preeclampsia. FIR are an important clinical sign, among women with preexisting diabetes, that should alert the clinician to investigate underlying placental dysfunction. 10.2337/dc17-0391
    Pregnancy complications in women with polycystic ovary syndrome. Palomba Stefano,de Wilde Marlieke A,Falbo Angela,Koster Maria P H,La Sala Giovanni Battista,Fauser Bart C J M Human reproduction update BACKGROUND:The great majority of studies performed so far concerning women diagnosed with polycystic ovary syndrome (PCOS) have focused on diagnosis, menstrual cycle abnormalities, hirsutism and infertility. Although progress has been made in developing methods for achieving a pregnancy and reducing multiple gestations in women with PCOS, little attention has been paid to pregnancy complications and subsequent child outcomes. This review aims to summarize current knowledge regarding the clinical and pathophysiological features of pregnancy and children in women with PCOS. METHODS:A literature search up to April 2015 was performed in PubMed, Medline, the Cochrane Library and Web of Science without language restriction. All articles were initially screened for title and abstract and full texts of eligible articles were subsequently selected. Systematic reviews with meta-analysis were initially included for each specific subject. Recent randomised controlled trials (RCTs), which were not included in the systematic reviews, were also included. In addition to evidence from meta-analyses or RCTs, we used non-randomized prospective, uncontrolled prospective, retrospective and experimental studies. When specific data for patients with PCOS were lacking, results from general population studies were reported. RESULTS:Women with PCOS exhibit a clinically significant increased risk of pregnancy complications compared with controls. Data which were not adjusted for BMI or other confounders demonstrated in PCOS a 3-4-fold increased risk of pregnancy-induced hypertension and pre-eclampsia, a 3-fold increased risk of gestational diabetes and 2-fold higher chance for premature delivery. Features characteristic of PCOS, such as hyperandrogenism, obesity, insulin resistance and metabolic abnormalities, may contribute to the increased risk of obstetric and neonatal complications. Limited available data suggest that offspring of women with PCOS have an increased risk for future metabolic and reproductive dysfunction. Underlying pathophysiological mechanisms of pregnancy complications along with its association with health of offspring remain uncertain. To date, the strategies for prevention and management of pregnancy complications in women with PCOS, and whether long-term health of these women is influenced, and to what extent, by pregnancy and/or pregnancy complications, remain to be elucidated. CONCLUSIONS:Women with PCOS show an increased risk of pregnancy complications. Heterogeneous aetiological factors involved in PCOS and associated co-morbidities may all be involved in compromised pregnancy and child outcomes. In women with PCOS, a possible relationship with genetic, environmental, clinical and biochemical factors involved in this complex condition, as well as with pregnancy complications and long-term health for both mother and child, remains to be established. 10.1093/humupd/dmv029
    Defining the Human Envirome: An Omics Approach for Assessing the Environmental Risk of Cardiovascular Disease. Riggs Daniel W,Yeager Ray A,Bhatnagar Aruni Circulation research Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility. 10.1161/CIRCRESAHA.117.311230
    Forensics: Identical twins don't share fingerprints. Vanderkolk John R Nature 10.1038/499029d
    Genetic and environmental continuity in personality development: a meta-analysis. Briley Daniel A,Tucker-Drob Elliot M Psychological bulletin The longitudinal stability of personality is low in childhood but increases substantially into adulthood. Theoretical explanations for this trend differ in the emphasis placed on intrinsic maturation and socializing influences. To what extent does the increasing stability of personality result from the continuity and crystallization of genetically influenced individual differences, and to what extent does the increasing stability of life experiences explain increases in personality trait stability? Behavioral genetic studies, which decompose longitudinal stability into sources associated with genetic and environmental variation, can help to address this question. We aggregated effect sizes from 24 longitudinal behavioral genetic studies containing information on a total of 21,057 sibling pairs from 6 types that varied in terms of genetic relatedness and ranged in age from infancy to old age. A combination of linear and nonlinear meta-analytic regression models were used to evaluate age trends in levels of heritability and environmentality, stabilities of genetic and environmental effects, and the contributions of genetic and environmental effects to overall phenotypic stability. Both the genetic and environmental influences on personality increase in stability with age. The contribution of genetic effects to phenotypic stability is moderate in magnitude and relatively constant with age, in part because of small-to-moderate decreases in the heritability of personality over child development that offset increases in genetic stability. In contrast, the contribution of environmental effects to phenotypic stability increases from near zero in early childhood to moderate in adulthood. The life-span trend of increasing phenotypic stability, therefore, predominantly results from environmental mechanisms. 10.1037/a0037091
    Ultrahigh strain hardening in thin palladium films with nanoscale twins. Idrissi Hosni,Wang Binjie,Colla Marie Stéphane,Raskin Jean Pierre,Schryvers Dominique,Pardoen Thomas Advanced materials (Deerfield Beach, Fla.) 10.1002/adma.201004160
    Delivering twins. Greene Michael F The New England journal of medicine 10.1056/NEJMe1310744
    Genotype-covariate interaction effects and the heritability of adult body mass index. Robinson Matthew R,English Geoffrey,Moser Gerhard,Lloyd-Jones Luke R,Triplett Marcus A,Zhu Zhihong,Nolte Ilja M,van Vliet-Ostaptchouk Jana V,Snieder Harold, ,Esko Tonu,Milani Lili,Mägi Reedik,Metspalu Andres,Magnusson Patrik K E,Pedersen Nancy L,Ingelsson Erik,Johannesson Magnus,Yang Jian,Cesarini David,Visscher Peter M Nature genetics Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 × 10 and LRT = 30.80, P = 1.42 × 10), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI. 10.1038/ng.3912
    Make more digital twins. Tao Fei,Qi Qinglin Nature 10.1038/d41586-019-02849-1
    Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hansen Michèle,Kurinczuk Jennifer J,Milne Elizabeth,de Klerk Nicholas,Bower Carol Human reproduction update BACKGROUND:It has been 10 years since we carried out a systematic search of the literature on birth defect risk in infants born following assisted reproductive technology (ART) compared with non-ART infants. Because of changes to ART practice since that review and the publication of more studies the objective of this review was to include these more recent studies to estimate birth defect risk after ART and to examine birth defect risk separately in ART singletons and multiples. METHODS:We searched Medline, Embase and Current Contents databases (1978-2012). We used the same data extraction sheet and questionnaire we had used previously with the addition of a quality score to the questionnaire. Pooled relative risk (RR) estimates were calculated using a random effects model. All data were analysed using Comprehensive Meta-Analysis V2. RESULTS:There were 45 cohort studies included in this review. ART infants (n = 92 671) had a higher risk of birth defects [RR 1.32, 95% confidence interval (CI) 1.24-1.42] compared with naturally conceived infants (n = 3 870 760). The risk further increased when data were restricted to major birth defects (RR 1.42, 95% CI 1.29-1.56) or singletons only (RR 1.36, 95% CI 1.30-1.43). The results for ART multiples were less clear. When all data for multiples were pooled the RR estimate was 1.11 (95% CI 0.98-1.26) but this increased to 1.26 (0.99-1.60) when the analysis was restricted to studies of ART twins where some adjustment was made for differences in zygosity distribution between ART and non-ART multiples. CONCLUSIONS:Birth defects remain more common in ART infants. Further research is required to examine risks for important subgroups of ART exposure. 10.1093/humupd/dmt006
    Determinants of monozygotic twinning in ART: a systematic review and a meta-analysis. Hviid Kathrine Vauvert R,Malchau Sara Sofia,Pinborg Anja,Nielsen Henriette Svarre Human reproduction update BACKGROUND:The incidence of monozygotic twins (MZT) after ART appears to be higher than the incidence after spontaneous conceptions contradicting the aim of ART to avoid multiple pregnancies because of the associated risks. OBJECTIVE AND RATIONALE:The aim was to study the frequency of MZT after IVF and ICSI and how it is influenced by the day of embryo transfer, maternal age, zona pellucida manipulation, controlled ovarian stimulation, stimulation protocol, culture media and embryo quality. SEARCH METHODS:Original studies and reviews were identified by searching the PubMed, Embase and Cochrane databases up to March 2017. The inclusion criterion was publications focusing on the five study questions related to MZT in our study. The exclusion criteria were articles that did not include blastocyst transfer, were on non-humans, were not published in peer-reviewed journals, and were based only on case studies. All of the articles were categorized according to the Oxford Centre for Evidence-based Medicine's 'Levels of Evidence', and quality and risk of bias assessment was performed with 'The Cochrane Collaboration's Risk of Bias Tools'. A meta-analysis was performed to study the impact of the day of embryo transfer on the MZT rate. OUTCOMES:The literature search resulted in a total of 42 articles, including 38 original studies, for analysis. The included original studies reported a MZT rate with blastocyst transfer from zero to 13.2%. Our meta-analysis found a higher frequency of MZT after blastocyst transfer compared with cleavage-stage embryos transfer: odds ratio = 2.18, 95% CI: 1.93-2.48 (fixed effect meta-analysis). A younger maternal age may increase the MZT rate, and recent studies regarding the use of zona pellucida manipulating techniques have disagreed with the previous suspicion of a higher MZT rate after the use of these methods. The extended culture to-blastocyst stage is a potential risk factor for MZT, but it is uncertain whether this phenomenon is due to the extended time, culture media or greater likelihood of younger oocytes to reach the blastocyst stage. An increased frequency of MZT following the GnRH-agonist suppression protocol has been suggested, as well as a decreased frequency of MZT with high gonadotrophin doses, which could reflect an age-related effect. Only limited literature has focused on the role of embryo morphology in the MZT rate, therefore, this issue remains unresolved. WIDER IMPLICATIONS:We found blastocyst transfer to be a risk factor for MZT. Hence, the results of this meta-analysis may weaken the previously proposed view that greater experience with blastocyst transfer and improved culture media could decrease the high rate of MZT after blastocyst transfer. To minimize the rate of MZT and the associated complications, the mechanisms underlying blastocyst transfer and MZT pregnancy must be elucidated. 10.1093/humupd/dmy006
    Genetic and environmental influences on the familial transmission of externalizing disorders in adoptive and twin offspring. Hicks Brian M,Foster Katherine T,Iacono William G,McGue Matt JAMA psychiatry IMPORTANCE:Twin-family studies have shown that parent-child resemblance on substance use disorders and antisocial behavior can be accounted for by the transmission of a general liability to a spectrum of externalizing disorders. Most studies, however, include only biological parents and offspring, which confound genetic and environmental transmission effects. OBJECTIVE:To examine the familial transmission of externalizing disorders among both adoptive (genetically unrelated) and biological relatives to better distinguish genetic and environmental mechanisms of transmission. DESIGN:Family study design wherein each family included the mother, father, and 2 offspring, including monozygotic twin, dizygotic twin, nontwin biological, and adoptive offspring. Structural equation modeling was used to estimate familial transmission effects and their genetic and environmental influences. SETTING:Participants were recruited from the community and assessed at a university laboratory. PARTICIPANTS:A total of 1590 families with biological offspring and 409 families with adoptive offspring. Offspring participants were young adults (mean age, 26.2 years). MAIN OUTCOMES AND MEASURES:Symptom counts of conduct disorder, adult antisocial behavior, and alcohol, nicotine, and drug dependence. RESULTS There was a medium effect for the transmission of the general externalizing liability for biological parents (r = 0.27-0.30) but not for adoptive parents (r = 0.03-0.07). In contrast, adoptive siblings exhibited significant similarity on the general externalizing liability (r = 0.21). Biometric analyses revealed that the general externalizing liability was highly heritable (a2 = 0.61) but also exhibited significant shared environmental influences (c2 = 0.20). CONCLUSIONS AND RELEVANCE:Parent-child resemblance for substance use disorders and antisocial behavior is primarily due to the genetic transmission of a general liability to a spectrum of externalizing disorders. Including adoptive siblings revealed a greater role of shared environmental influences on the general externalizing liability than previously detected in twin studies and indicates that sibling rather than parent-child similarity indexes important environmental risk factors for externalizing disorders. 10.1001/jamapsychiatry.2013.258
    Continuity of genetic and environmental influences on cognition across the life span: a meta-analysis of longitudinal twin and adoption studies. Tucker-Drob Elliot M,Briley Daniel A Psychological bulletin The longitudinal rank-order stability of cognitive ability increases dramatically over the life span. Theoretical perspectives differ in their emphasis on genetic mechanisms in explaining the longitudinal stability of cognition and how stability changes with development. However, the patterns of stability of genetic and environmental influences on cognition over the life span remain poorly understood. We searched for longitudinal studies of cognition that reported raw genetically informative longitudinal correlations or parameter estimates from longitudinal behavior genetic models. We identified 150 combinations of time points and measures from 15 independent longitudinal samples. In total, longitudinal data came from 4,548 monozygotic twin pairs raised together, 7,777 dizygotic twin pairs raised together, 34 monozygotic twin pairs raised apart, 78 dizygotic twin pairs raised apart, 141 adoptive sibling pairs, and 143 nonadoptive sibling pairs, ranging in age from infancy through late adulthood. At all ages, cross-time genetic correlations and shared environmental correlations were substantially larger than cross-time nonshared environmental correlations. Cross-time correlations for genetic and shared environmental components were, respectively, low and moderate during early childhood, increased sharply over child development, and remained high from adolescence through late adulthood. Cross-time correlations for nonshared environmental components were low across childhood and gradually increased to moderate magnitudes in adulthood. Increasing phenotypic stability over child development was almost entirely mediated by genetic factors. Time-based decay of genetic and shared environmental stability was more pronounced earlier in child development. Results are interpreted in reference to theories of gene-environment correlation and interaction. 10.1037/a0035893
    The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis. Vitthala S,Gelbaya T A,Brison D R,Fitzgerald C T,Nardo L G Human reproduction update BACKGROUND:It is estimated that there is at least a 2-fold rise in the incidence of monozygotic twinning after assisted reproductive technology compared with natural conception. This can result in adverse pregnancy outcomes. METHODS:We searched MEDLINE, EMBASE and SCISEARCH for studies that estimated the risk of monozygotic twinning and its association with any particular assisted reproductive technique. Monozygotic twinning was defined by ultrasound or Weinberg criteria. A meta-analysis of the proportion of monozygotic twins was performed using both fixed and random effects models. RESULTS:The search revealed 37 publications reporting on the incidence of monozygotic twins after assisted reproductive techniques. Twenty-seven studies met the inclusion criteria and were included in the meta-analysis. The summary incidence of monozygotic twins after assisted conception was 0.9% (0.8-0.9%). The incidence of monozygotic twins in natural conception is 0.4%. Blastocyst transfer and intracytoplasmic sperm injection are associated with 4.25 and 2.25 times higher risk of monozygotic twins. CONCLUSIONS:The risk of monozygotic twins in assisted conception is 2.25 times higher than the natural conceptions. Larger studies reporting on monozygotic twinning following single-embryo transfer or after post-natal confirmation of zygosity with DNA analysis are warranted before definitive conclusions can be drawn and guidelines produced. In order to provide adequate pre-conceptional counselling, it is important to monitor the incidence of monozygotic twins in both natural and assisted conceptions. We suggest building a national multiple pregnancy database based on accurate diagnosis of zygosity. 10.1093/humupd/dmn045
    Twins or triplets? Lancet (London, England) 10.1016/S0140-6736(11)61594-8
    What we can learn from twins: congenital heart disease in the danish twin registry. Mahle William T Circulation 10.1161/CIRCULATIONAHA.113.005109
    Heritability of left ventricular and papillary muscle heart size: a twin study with cardiac magnetic resonance imaging. Busjahn Christoph A,Schulz-Menger Jeanette,Abdel-Aty Hassan,Rudolph Andre,Jordan Jens,Luft Friedrich C,Busjahn Andreas European heart journal AIMS:Earlier studies in monozygotic (MZ) and dizygotic (DZ) twins showed genetic variance on echocardiographically determined heart size. However, cardiovascular magnetic resonance (CMR) is more precise and reproducible. We performed a twin study relying on CMR, focusing on left ventricular (LV) mass and papillary muscle, since there are no genetic reports on this structure. METHODS AND RESULTS:We measured left heart dimensions of 25 healthy twin pairs with a 1.5T MR scanner, analysed with the mass, Medis Software. We performed heritability analysis and tests for genetic influences shared between cardiac structures. We found that CMR-based heritability estimates (h(2) = 84%) substantially exceeded estimates based on echocardiography. We also found significant genetic influence on papillary muscle mass (h(2) = 82%). Bivariate analysis of papillary and LV muscle mass revealed significant genetic influences shared by both phenotypes (genetic correlation 0.59) and suggested an additional genetic component specific to papillary muscle. We observed correlations between body mass index, surface area, and systolic blood pressure with cardiac dimensions, even in this small study. Environmental influences were relevant as well, indicating reciprocal influences on papillary vs. LV muscle mass. CONCLUSION:Cardiovascular magnetic resonance, even with few subjects, allows a genetic assessment of cardiac structures that cannot be attained with echocardiography. Hitherto fore unappreciated relationships can be uncovered by this method. 10.1093/eurheartj/ehp142
    Meta-analysis of the heritability of human traits based on fifty years of twin studies. Polderman Tinca J C,Benyamin Beben,de Leeuw Christiaan A,Sullivan Patrick F,van Bochoven Arjen,Visscher Peter M,Posthuma Danielle Nature genetics Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool. 10.1038/ng.3285
    Sex differences in the pathways to major depression: a study of opposite-sex twin pairs. Kendler Kenneth S,Gardner Charles O The American journal of psychiatry OBJECTIVE:The authors sought to clarify the nature of sex differences in the etiologic pathways to major depression. METHOD:Retrospective and prospective assessments of 20 developmentally organized risk factors and the occurrence of past-year major depression were conducted at two waves of personal interviews at least 12 months apart in 1,057 opposite-sex dizygotic twin pairs from a population-based register. Analyses were conducted by structural modeling, examining within-pair differences. RESULTS:Sixty percent of all paths in the best-fit model exhibited sex differences. Eleven of the 20 risk factors differed across sexes in their impact on liability to major depression. Five had a greater impact in women: parental warmth, neuroticism, divorce, social support, and marital satisfaction. Six had a greater impact in men: childhood sexual abuse, conduct disorder, drug abuse, prior history of major depression, and distal and dependent proximal stressful life events. The life event categories responsible for the stronger effect in males were financial, occupational, and legal in nature. CONCLUSIONS:In a co-twin control design, which matches sisters and brothers on genetic and familial-environmental background, personality and failures in interpersonal relationships played a stronger etiologic role in major depression for women than for men. Externalizing psychopathology, prior depression, and specific "instrumental" classes of acute stressors were more important in the etiologic pathway to major depression for men. The results are consistent with previously proposed typologies of major depression that suggest two subtypes that differ in prevalence in women (deficiencies in caring relationships and interpersonal loss) and men (failures to achieve expected goals, with lowered self-worth). 10.1176/appi.ajp.2013.13101375
    Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes. Lakhani Chirag M,Tierney Braden T,Manrai Arjun K,Yang Jian,Visscher Peter M,Patel Chirag J Nature genetics We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h = 0.311) and shared environmental variance (c = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (var = 0.002), daily air quality (var = 0.0004), and average temperature (var = 0.001) overall, as well as for individual phenotypes. We found significant heritability and shared environment for a number of comorbidities (h = 0.433, c = 0.241) and average monthly cost (h = 0.290, c = 0.302). All results are available using our Claims Analysis of Twin Correlation and Heritability (CaTCH) web application. 10.1038/s41588-018-0313-7
    Is cardiovascular mortality related to the season of birth?: evidence from more than 6 million cardiovascular deaths between 1992 and 2007. Reffelmann Thorsten,Ittermann Till,Empen Klaus,Dörr Marcus,Felix Stephan B Journal of the American College of Cardiology 10.1016/j.jacc.2010.10.021
    Impact of a stepwise introduction of smoke-free legislation on the rate of preterm births: analysis of routinely collected birth data. Cox Bianca,Martens Evelyne,Nemery Benoit,Vangronsveld Jaco,Nawrot Tim S BMJ (Clinical research ed.) OBJECTIVE:To investigate the incidence of preterm delivery in the Belgian population after implementation of smoke-free legislation in three phases (in public places and most workplaces January 2006, in restaurants January 2007, and in bars serving food January 2010). DESIGN:Logistic regression analyses on routinely collected birth data from January 2002 to December 2011. SETTING:Flanders, Belgium. POPULATION:All live born singleton births delivered at 24-44 weeks of gestation (n = 606,877, with n = 448,520 spontaneous deliveries). MAIN OUTCOME MEASURES:Preterm birth (gestational age <37 weeks). RESULTS:We found reductions in the risk of preterm birth after the introduction of each phase of the smoking ban. No decreasing trend was evident in the years or months before the bans. We observed a step change in the risk of spontaneous preterm delivery of -3.13% (95% CI -4.37% to -1.87%; P<0.01) on 1 January 2007 (ban on smoking in restaurants), and an annual slope change of -2.65% (-5.11% to -0.13%; P=0.04) after 1 January 2010 (ban on smoking in bars serving food). The analysis for all births gave similar results: a step change of -3.18% (-5.38% to -0.94%; P<0.01) on 1 January 2007, and an annual slope change of -3.50% (-6.35% to -0.57%; P=0.02) after 1 January 2010. These changes could not be explained by personal factors (infant sex, maternal age, parity, socioeconomic status, national origin, level of urbanisation); time related factors (underlying trends, month of the year, day of the week); or population related factors (public holidays, influenza epidemics, and short term changes in apparent temperature and particulate air pollution). CONCLUSION:Our study shows a consistent pattern of reduction in the risk of preterm delivery with successive population interventions to restrict smoking. This finding is not definitive but it supports the notion that smoking bans have public health benefits from early life. 10.1136/bmj.f441
    Air pollution exposure associates with increased risk of neonatal jaundice. Zhang Liqiang,Liu Weiwei,Hou Kun,Lin Jintai,Song Changqing,Zhou Chenghu,Huang Bo,Tong Xiaohua,Wang Jinfeng,Rhine William,Jiao Ying,Wang Ziwei,Ni Ruijing,Liu Mengyao,Zhang Liang,Wang Ziye,Wang Yuebin,Li Xingang,Liu Suhong,Wang Yanhong Nature communications Clinical experience suggests increased incidences of neonatal jaundice when air quality worsens, yet no studies have quantified this relationship. Here we reports investigations in 25,782 newborns showing an increase in newborn's bilirubin levels, the indicator of neonatal jaundice risk, by 0.076 (95% CI: 0.027-0.125), 0.029 (0.014-0.044) and 0.009 (95% CI: 0.002-0.016) mg/dL per μg/m for PM exposure in the concentration ranges of 10-35, 35-75 and 75-200 μg/m, respectively. The response is 0.094 (0.077-0.111) and 0.161 (0.07-0.252) mg/dL per μg/m for SO exposure at 10-15 and above 15 μg/m, respectively, and 0.351 (0.314-0.388) mg/dL per mg/m for CO exposure. Bilirubin levels increase linearly with exposure time between 0 and 48 h. Positive relationship between maternal exposure and newborn bilirubin level is also quantitated. The jaundice-pollution relationship is not affected by top-of-atmosphere incident solar irradiance and atmospheric visibility. Improving air quality may therefore be key to lowering the neonatal jaundice risk. 10.1038/s41467-019-11387-3
    Risk factors and outcomes associated with first-trimester fetal growth restriction. Mook-Kanamori Dennis O,Steegers Eric A P,Eilers Paul H,Raat Hein,Hofman Albert,Jaddoe Vincent W V JAMA CONTEXT:Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. OBJECTIVE:To determine the risk factors and outcomes associated with first-trimester growth restriction. DESIGN, SETTING, AND PARTICIPANTS:Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of first-trimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, The Netherlands. Mothers were enrolled between 2001 and 2005. MAIN OUTCOME MEASURES:First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age <37 weeks), low birth weight (<2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. RESULTS:In the multivariate analysis, maternal age was positively associated with first-trimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, -0.40 mm; 95% CI, -0.74 to -0.06 and -0.52 mm; 95% CI, -0.90 to -0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, -3.84 mm; 95% CI, -5.71 to -1.98). Compared with normal first-trimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in first-trimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). CONCLUSIONS:Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood. 10.1001/jama.2010.78
    Lower perinatal exposure to Proteobacteria is an independent predictor of early childhood wheezing. The Journal of allergy and clinical immunology 10.1016/j.jaci.2018.06.051
    Effect modification of perinatal exposure to air pollution and childhood asthma incidence. Lavigne Éric,Bélair Marc-André,Rodriguez Duque Daniel,Do Minh T,Stieb David M,Hystad Perry,van Donkelaar Aaron,Martin Randall V,Crouse Daniel L,Crighton Eric,Chen Hong,Burnett Richard T,Weichenthal Scott,Villeneuve Paul J,To Teresa,Brook Jeffrey R,Johnson Markey,Cakmak Sabit,Yasseen Abdool S,Walker Mark The European respiratory journal Perinatal exposure to ambient air pollution has been associated with childhood asthma incidence, however, less is known regarding the potential effect modifiers in this association. We examined whether maternal and infant characteristics modified the association between perinatal exposure to air pollution and development of childhood asthma.761 172 births occurring between 2006 and 2012 were identified in the province of Ontario, Canada. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6) were estimated using Cox regression models.110,981 children with asthma were identified. In models adjusted for postnatal exposures, second trimester exposures to particulate matter with a diameter ≤2.5 μm (PM) (Hazard Ratio (HR) per interquartile (IQR) increase=1.07, 95% CI: 1.06-1.09) and nitrogen dioxide (NO) (HR per IQR increase=1.06, 95% CI: 1.03-1.08) were associated with childhood asthma development. Enhanced impacts were found among children born to mothers with asthma, those who smoked during pregnancy, boys, those born preterm, of low birth weight and among those born to mothers living in urban areas during pregnancy.Prenatal exposure to air pollution may have a differential impact on the risk of asthma development according to maternal and infant characteristics. 10.1183/13993003.01884-2017
    Association of Gestational Weight Gain With Adverse Maternal and Infant Outcomes. ,Voerman Ellis,Santos Susana,Inskip Hazel,Amiano Pilar,Barros Henrique,Charles Marie-Aline,Chatzi Leda,Chrousos George P,Corpeleijn Eva,Crozier Sarah,Doyon Myriam,Eggesbø Merete,Fantini Maria Pia,Farchi Sara,Forastiere Francesco,Georgiu Vagelis,Gori Davide,Hanke Wojciech,Hertz-Picciotto Irva,Heude Barbara,Hivert Marie-France,Hryhorczuk Daniel,Iñiguez Carmen,Karvonen Anne M,Küpers Leanne K,Lagström Hanna,Lawlor Debbie A,Lehmann Irina,Magnus Per,Majewska Renata,Mäkelä Johanna,Manios Yannis,Mommers Monique,Morgen Camilla S,Moschonis George,Nohr Ellen A,Nybo Andersen Anne-Marie,Oken Emily,Pac Agnieszka,Papadopoulou Eleni,Pekkanen Juha,Pizzi Costanza,Polanska Kinga,Porta Daniela,Richiardi Lorenzo,Rifas-Shiman Sheryl L,Roeleveld Nel,Ronfani Luca,Santos Ana C,Standl Marie,Stigum Hein,Stoltenberg Camilla,Thiering Elisabeth,Thijs Carel,Torrent Maties,Trnovec Tomas,van Gelder Marleen M H J,van Rossem Lenie,von Berg Andrea,Vrijheid Martine,Wijga Alet,Zvinchuk Oleksandr,Sørensen Thorkild I A,Godfrey Keith,Jaddoe Vincent W V,Gaillard Romy JAMA Importance:Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. Objectives:To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. Design, Setting, and Participants:Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. Exposures:Gestational weight gain. Main Outcomes and Measures:The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. Results:Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79). Conclusions and Relevance:In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed. 10.1001/jama.2019.3820
    CC16 Levels into Adult Life Are Associated with Nitrogen Dioxide Exposure at Birth. Beamer Paloma I,Furlong Melissa,Lothrop Nathan,Guerra Stefano,Billheimer Dean,Stern Debra A,Zhai Jing,Halonen Marilyn,Wright Anne L,Martinez Fernando D American journal of respiratory and critical care medicine Lung function and growth are adversely associated with nitrogen dioxide (NO) exposure. Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function. NO exposure may induce epithelial damage in lungs and alter club cell proliferation and morphology. To determine if increased ambient NO levels at participants' home addresses in early life were associated with decreased levels of CC16 from age 6 to 32 years. Participants were enrolled at birth in the Tucson Children's Respiratory Study and had circulating CC16 measured at least once between age 6 and 32. Linear mixed models were used to determine the association between estimated ambient NO exposure at participants' home address at birth or age 6 with CC16 levels from age 6 to 32. NO exposures at birth or age 6 were available for 777 children with one or more CC16 measurement. We found a negative association between NO exposure and CC16 levels, with a 4.7% (95% confidence interval, -8.6 to -0.7) decrease in CC16 levels from age 6 to 32 per interquartile range increase in NO exposure (6.0 ppb) at the participants' birth address. We observed modification by race (p interaction = 0.04), with stronger associations among participants with at least one black parent (-29.6% [95% confidence interval, -42.9% to -13.2%] per interquartile range). NO at participant's age 6 address was not significantly associated with CC16 levels (-1.9%; 95% confidence interval, -6.3 to 2.6). Higher exposure to NO at birth is associated with persistently low levels of CC16 from 6 to 32 years. 10.1164/rccm.201808-1488OC
    A life exposed (and better for it). Aagaard Kjersti Nature medicine 10.1038/s41591-019-0341-6
    Prenatal Household Air Pollution Is Associated with Impaired Infant Lung Function with Sex-Specific Effects. Evidence from GRAPHS, a Cluster Randomized Cookstove Intervention Trial. Lee Alison G,Kaali Seyram,Quinn Ashlinn,Delimini Rupert,Burkart Katrin,Opoku-Mensah Jones,Wylie Blair J,Yawson Abena Konadu,Kinney Patrick L,Ae-Ngibise Kenneth A,Chillrud Steven,Jack Darby,Asante Kwaku Poku American journal of respiratory and critical care medicine RATIONALE:Approximately 2.8 billion people are exposed daily to household air pollution from polluting cookstoves. The effects of prenatal household air pollution on lung development are unknown. OBJECTIVES:To prospectively examine associations between prenatal household air pollution and infant lung function and pneumonia in rural Ghana. METHODS:Prenatal household air pollution exposure was indexed by serial maternal carbon monoxide personal exposure measurements. Using linear regression, we examined associations between average prenatal carbon monoxide and infant lung function at age 30 days, first in the entire cohort (n = 384) and then stratified by sex. Quasi-Poisson generalized additive models explored associations between infant lung function and pneumonia. MEASUREMENTS AND MAIN RESULTS:Multivariable linear regression models showed that average prenatal carbon monoxide exposure was associated with reduced time to peak tidal expiratory flow to expiratory time (β = -0.004; P = 0.01), increased respiratory rate (β = 0.28; P = 0.01), and increased minute ventilation (β = 7.21; P = 0.05), considered separately, per 1 ppm increase in average prenatal carbon monoxide. Sex-stratified analyses suggested that girls were particularly vulnerable (time to peak tidal expiratory flow to expiratory time: β = -0.003, P = 0.05; respiratory rate: β = 0.36, P = 0.01; minute ventilation: β = 11.25, P = 0.01; passive respiratory compliance normalized for body weight: β = 0.005, P = 0.01). Increased respiratory rate at age 30 days was associated with increased risk for physician-assessed pneumonia (relative risk, 1.02; 95% confidence interval, 1.00-1.04) and severe pneumonia (relative risk, 1.04; 95% confidence interval, 1.00-1.08) in the first year of life. CONCLUSIONS:Increased prenatal household air pollution exposure is associated with impaired infant lung function. Altered infant lung function may increase risk for pneumonia in the first year of life. These findings have implications for future respiratory health. Clinical trial registered with www.clinicaltrials.gov (NCT 01335490). 10.1164/rccm.201804-0694OC
    Use of antibiotics to reduce preterm birth. McClure Elizabeth M,Goldenberg Robert L The Lancet. Global health 10.1016/S2214-109X(18)30543-6
    Prevention: Air of danger. Kessler Rebecca Nature 10.1038/509S62a
    Current tobacco use and secondhand smoke exposure among women of reproductive age--14 countries, 2008-2010. MMWR. Morbidity and mortality weekly report Tobacco use and secondhand smoke (SHS) exposure in reproductive-aged women can cause adverse reproductive health outcomes, such as pregnancy complications, fetal growth restriction, preterm delivery, stillbirths, and infant death. Data on tobacco use and SHS exposure among reproductive-aged women in low- and middle-income countries are scarce. To examine current tobacco use and SHS exposure in women aged 15-49 years, data were analyzed from the 2008-2010 Global Adult Tobacco Survey (GATS) from 14 low- and middle-income countries: Bangladesh, Brazil, China, Egypt, India, Mexico, Philippines, Poland, Russia, Thailand, Turkey, Ukraine, Uruguay, and Vietnam. The results of this analysis indicated that, among reproductive-aged women, current tobacco smoking ranged from 0.4% in Egypt to 30.8% in Russia, current smokeless tobacco use was <1% in most countries, but common in Bangladesh (20.1%) and India (14.9%), and SHS exposure at home was common in all countries, ranging from 17.8% in Mexico to 72.3% in Vietnam. High tobacco smoking prevalence in some countries suggests that strategies promoting cessation should be a priority, whereas low prevalence in other countries suggests that strategies should focus on preventing smoking initiation. Promoting cessation and preventing initiation among both men and women would help to reduce the exposure of reproductive-aged women to SHS.
    Polluting Developing Brains - EPA Failure on Chlorpyrifos. Rauh Virginia A The New England journal of medicine 10.1056/NEJMp1716809
    Prenatal Particulate Air Pollution and Asthma Onset in Urban Children. Identifying Sensitive Windows and Sex Differences. Hsu Hsiao-Hsien Leon,Chiu Yueh-Hsiu Mathilda,Coull Brent A,Kloog Itai,Schwartz Joel,Lee Alison,Wright Robert O,Wright Rosalind J American journal of respiratory and critical care medicine RATIONALE:The influence of particulate air pollution on respiratory health starts in utero. Fetal lung growth and structural development occurs in stages; thus, effects on postnatal respiratory disorders may differ based on timing of exposure. OBJECTIVES:We implemented an innovative method to identify sensitive windows for effects of prenatal exposure to particulate matter with a diameter less than or equal to 2.5 μm (PM2.5) on children's asthma development in an urban pregnancy cohort. METHODS:Analyses included 736 full-term (≥37 wk) children. Each mother's daily PM2.5 exposure was estimated over gestation using a validated satellite-based spatiotemporal resolved model. Using distributed lag models, we examined associations between weekly averaged PM2.5 levels over pregnancy and physician-diagnosed asthma in children by age 6 years. Effect modification by sex was also examined. MEASUREMENTS AND MAIN RESULTS:Most mothers were ethnic minorities (54% Hispanic, 30% black), had 12 or fewer years of education (66%), and did not smoke in pregnancy (80%). In the sample as a whole, distributed lag models adjusting for child age, sex, and maternal factors (education, race and ethnicity, smoking, stress, atopy, prepregnancy obesity) showed that increased PM2.5 exposure levels at 16-25 weeks gestation were significantly associated with early childhood asthma development. An interaction between PM2.5 and sex was significant (P = 0.01) with sex-stratified analyses showing that the association exists only for boys. CONCLUSIONS:Higher prenatal PM2.5 exposure at midgestation was associated with asthma development by age 6 years in boys. Methods to better characterize vulnerable windows may provide insight into underlying mechanisms. 10.1164/rccm.201504-0658OC
    Spatiotemporal Variations in Ambient Ultrafine Particles and the Incidence of Childhood Asthma. Lavigne Eric,Donelle Jessy,Hatzopoulou Marianne,Van Ryswyk Keith,van Donkelaar Aaron,Martin Randall V,Chen Hong,Stieb David M,Gasparrini Antonio,Crighton Eric,Yasseen Abdool S,Burnett Richard T,Walker Mark,Weichenthal Scott American journal of respiratory and critical care medicine Little is known regarding the impact of ambient ultrafine particles (UFPs; <0.1 μm) on childhood asthma development. To examine the association between prenatal and early postnatal life exposure to UFPs and development of childhood asthma. A total of 160,641 singleton live births occurring in the City of Toronto, Canada between April 1, 2006, and March 31, 2012, were identified from a birth registry. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6) were estimated using random effects Cox proportional hazards models, adjusting for personal- and neighborhood-level covariates. We investigated both single-pollutant and multipollutant models accounting for coexposures to particulate matter ≤2.5 μm in aerodynamic diameter (PM) and NO. We identified 27,062 children with incident asthma diagnosis during the follow-up. In adjusted models, second-trimester exposure to UFPs (hazard ratio per interquartile range increase, 1.09; 95% confidence interval, 1.06-1.12) was associated with asthma incidence. In models additionally adjusted for PM and nitrogen dioxide, UFPs exposure during the second trimester of pregnancy remained positively associated with childhood asthma incidence (hazard ratio per interquartile range increase, 1.05; 95% confidence interval, 1.01-1.09). This is the first study to evaluate the association between perinatal exposure to UFPs and the incidence of childhood asthma. Exposure to UFPs during a critical period of lung development was linked to the onset of asthma in children, independent of PM and NO. 10.1164/rccm.201810-1976OC
    Origins of lifetime health around the time of conception: causes and consequences. Fleming Tom P,Watkins Adam J,Velazquez Miguel A,Mathers John C,Prentice Andrew M,Stephenson Judith,Barker Mary,Saffery Richard,Yajnik Chittaranjan S,Eckert Judith J,Hanson Mark A,Forrester Terrence,Gluckman Peter D,Godfrey Keith M Lancet (London, England) Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring. 10.1016/S0140-6736(18)30312-X
    Prevention of preterm birth: harnessing science to address the global epidemic. Rubens Craig E,Sadovsky Yoel,Muglia Louis,Gravett Michael G,Lackritz Eve,Gravett Courtney Science translational medicine Preterm birth is a leading cause of infant morbidity and mortality worldwide, but current interventions to prevent prematurity are largely ineffective. Preterm birth is increasingly recognized as an outcome that can result from a variety of pathological processes. Despite current research efforts, the mechanisms underlying these processes remain poorly understood and are influenced by a range of biological and environmental factors. Research with modern techniques is needed to understand the mechanisms responsible for preterm labor and birth and identify targets for diagnostic and therapeutic solutions. This review evaluates the state of reproductive science relevant to understanding the causes of preterm birth, identifies potential targets for prevention, and outlines challenges and opportunities for translating research findings into effective interventions. 10.1126/scitranslmed.3009871
    Effects of air pollution on fetal development-more than low birthweight? Grigg Jonathan The Lancet. Respiratory medicine 10.1016/S2213-2600(13)70219-4
    Seasonal Changes in the Prevalence of Gestational Diabetes Mellitus. Moses Robert G,Wong Veronica C K,Lambert Kelly,Morris Gary J,San Gil Fernando Diabetes care OBJECTIVE:To determine the effect of different seasons on the prevalence of gestational diabetes mellitus (GDM) by using World Health Organization criteria. RESEARCH DESIGN AND METHODS:The results of all pregnancy glucose tolerance tests (GTTs) were prospectively collected over a 3-year period in a temperate climate, and the results were grouped by season. RESULTS:The results of 7,369 pregnancy GTTs were available for consideration. In winter, the median 1-h and 2-h glucose results after GTT were significantly (P < 0.0001) lower than the overall 1-h and 2-h results. The prevalence of GDM at the 1-h diagnostic level was 29% higher in summer and 27% lower in winter than the overall prevalence (P = 0.02). The prevalence of GDM at the 2-h diagnostic level was 28% higher in summer and 31% lower in winter than the overall prevalence (P = 0.01). CONCLUSIONS:The prevalence of GDM varies according to seasons, which leads to the possible overdiagnosis of GDM in summer and/or underdiagnosis in winter. Further research into standardization of the GTT or seasonal adjustment of the results may need to be considered. 10.2337/dc16-0451
    Is Season of Birth Important for Multiple Sclerosis Risk? Graves Jennifer S JAMA neurology 10.1001/jamaneurol.2016.1763
    Mysteries of development. How does fetal environment influence later health? Couzin-Frankel Jennifer Science (New York, N.Y.) 10.1126/science.340.6137.1160
    Preterm birth and air pollution: Critical windows of exposure for women with asthma. Mendola Pauline,Wallace Maeve,Hwang Beom Seuk,Liu Danping,Robledo Candace,Männistö Tuija,Sundaram Rajeshwari,Sherman Seth,Ying Qi,Grantz Katherine L The Journal of allergy and clinical immunology BACKGROUND:Ambient air pollutants may increase preterm birth (PTB) risk, but critical exposure windows are uncertain. The interaction of asthma and pollutant exposure is rarely studied. OBJECTIVE:We sought to assess the interaction of maternal asthma and air pollutant exposures in relation to PTB risk. METHODS:Electronic medical records for 223,502 US deliveries were linked with modified Community Multiscale Air Quality model outputs. Logistic regression with generalized estimating equations estimated the odds ratio and 95% CIs for PTB on the basis of the interaction of maternal asthma and particulate matter with aerodynamic diameter of less than 2.5 microns and particulate matter with aerodynamic diameter of less than 10 microns, ozone (O3), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO) per interquartile range. For each gestational week 23 to 36, exposures among women who delivered were compared with those remaining pregnant. Three-month preconception, whole pregnancy, weeks 1 to 28, and the last 6 weeks of gestation averages were also evaluated. RESULTS:On assessing PTB by gestational week, we found that significant asthma interactions were sporadic before 30 weeks but more common during weeks 34 to 36, with higher risk among mothers with asthma for NOx, CO, and SO2 exposure and an inverse association with O3 in week 34. Odds of PTB were significantly higher among women with asthma for CO and NOx exposure preconception and early in pregnancy. In the last 6 weeks of pregnancy, PTB risk associated with particulate matter with aerodynamic diameter of less than 10 microns was higher among women with asthma. CONCLUSIONS:Mothers with asthma may experience a higher risk for PTB after exposure to traffic-related pollutants such as CO and NOx, particularly for exposures 3-months preconception and in the early weeks of pregnancy. 10.1016/j.jaci.2015.12.1309
    The Urban Environment and Childhood Asthma study. Gern James E The Journal of allergy and clinical immunology Childhood asthma is not distributed evenly throughout the population, and children who grow up in crowded urban neighborhoods have higher rates of asthma and experience greater morbidity because of asthma. There are several environmental and lifestyle factors associated with urban living that are suspected to promote the development of asthma, particularly in the first few years of life. Collectively, this information suggests the hypothesis that exposure in early life to adverse environmental and lifestyle factors associated with disadvantaged urban environments modifies immune development to increase the risk for allergic diseases and asthma. The Urban Environment and Childhood Asthma (URECA) birth cohort study was initiated in 2004 to test this hypothesis. The study population was recruited prenatally and consisted of 560 families from 4 urban areas who were at high risk for allergies and/or asthma on the basis of parental histories, along with an additional 49 families without atopic parents. Immune development, respiratory illnesses, and exposure to stress, indoor pollutants, microbial products, and allergens were measured prospectively, and the major study outcomes are recurrent wheeze at 3 years of age and asthma at age 7 years. This review summarizes the study design, methods, and early findings of the URECA study. 10.1016/j.jaci.2010.01.037
    The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. Bonde Jens Peter,Flachs Esben Meulengracht,Rimborg Susie,Glazer Clara Helene,Giwercman Aleksander,Ramlau-Hansen Cecilia Høst,Hougaard Karin Sørig,Høyer Birgit Bjerre,Hærvig Katia Keglberg,Petersen Sesilje Bondo,Rylander Lars,Specht Ina Olmer,Toft Gunnar,Bräuner Elvira Vaclavik Human reproduction update BACKGROUND:More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE:The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS:A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES:The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS:The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. 10.1093/humupd/dmw036
    Ambient air pollution and low birthweight: a European cohort study (ESCAPE). Pedersen Marie,Giorgis-Allemand Lise,Bernard Claire,Aguilera Inmaculada,Andersen Anne-Marie Nybo,Ballester Ferran,Beelen Rob M J,Chatzi Leda,Cirach Marta,Danileviciute Asta,Dedele Audrius,Eijsden Manon van,Estarlich Marisa,Fernández-Somoano Ana,Fernández Mariana F,Forastiere Francesco,Gehring Ulrike,Grazuleviciene Regina,Gruzieva Olena,Heude Barbara,Hoek Gerard,de Hoogh Kees,van den Hooven Edith H,Håberg Siri E,Jaddoe Vincent W V,Klümper Claudia,Korek Michal,Krämer Ursula,Lerchundi Aitana,Lepeule Johanna,Nafstad Per,Nystad Wenche,Patelarou Evridiki,Porta Daniela,Postma Dirkje,Raaschou-Nielsen Ole,Rudnai Peter,Sunyer Jordi,Stephanou Euripides,Sørensen Mette,Thiering Elisabeth,Tuffnell Derek,Varró Mihály J,Vrijkotte Tanja G M,Wijga Alet,Wilhelm Michael,Wright John,Nieuwenhuijsen Mark J,Pershagen Göran,Brunekreef Bert,Kogevinas Manolis,Slama Rémy The Lancet. Respiratory medicine BACKGROUND:Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations of ambient air pollution on birthweight. METHODS:We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74 178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2·5 absorbance and concentrations of nitrogen dioxide (NO2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models. FINDINGS:A 5 μg/m(3) increase in concentration of PM2·5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio [OR] 1·18, 95% CI 1·06-1·33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2·5 limit of 25 μg/m(3) (OR for 5 μg/m(3) increase in participants exposed to concentrations of less than 20 μg/m(3) 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m(3) increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/m(3) increase 1·09, 1·00-1·19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1·06, 1·01-1·11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2·5 concentration to 10 μg/m(3) during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term. INTERPRETATION:Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced. FUNDING:The European Union. 10.1016/S2213-2600(13)70192-9
    Traffic-related air pollution, particulate matter, and autism. Volk Heather E,Lurmann Fred,Penfold Bryan,Hertz-Picciotto Irva,McConnell Rob JAMA psychiatry CONTEXT:Autism is a heterogeneous disorder with genetic and environmental factors likely contributing to its origins. Examination of hazardous pollutants has suggested the importance of air toxics in the etiology of autism, yet little research has examined its association with local levels of air pollution using residence-specific exposure assignments. OBJECTIVE:To examine the relationship between traffic-related air pollution, air quality, and autism. DESIGN:This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment study in California. The mother's address from the birth certificate and addresses reported from a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. Traffic-related air pollution was assigned to each location using a line-source air-quality dispersion model. Regional air pollutant measures were based on the Environmental Protection Agency's Air Quality System data. Logistic regression models compared estimated and measured pollutant levels for children with autism and for control children with typical development. SETTING:Case-control study from California. PARTICIPANTS:A total of 279 children with autism and a total of 245 control children with typical development. MAIN OUTCOME MEASURES:Crude and multivariable adjusted odds ratios (AORs) for autism. RESULTS:Children with autism were more likely to live at residences that had the highest quartile of exposure to traffic-related air pollution, during gestation (AOR, 1.98 [95% CI, 1.20-3.31]) and during the first year of life (AOR, 3.10 [95% CI, 1.76-5.57]), compared with control children. Regional exposure measures of nitrogen dioxide and particulate matter less than 2.5 and 10 μm in diameter (PM2.5 and PM10) were also associated with autism during gestation (exposure to nitrogen dioxide: AOR, 1.81 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.08 [95% CI, 1.93-2.25]; exposure to PM10: AOR, 2.17 [95% CI, 1.49-3.16) and during the first year of life (exposure to nitrogen dioxide: AOR, 2.06 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.12 [95% CI, 1.45-3.10]; exposure to PM10: AOR, 2.14 [95% CI, 1.46-3.12]). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates. CONCLUSIONS:Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal. 10.1001/jamapsychiatry.2013.266
    Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. Cha Jeeyeon,Bartos Amanda,Egashira Mahiro,Haraguchi Hirofumi,Saito-Fujita Tomoko,Leishman Emma,Bradshaw Heather,Dey Sudhansu K,Hirota Yasushi The Journal of clinical investigation There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P4), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P4 may help reduce the incidence of preterm birth in high-risk women. 10.1172/JCI70098
    Association of Long-term Exposure to Airborne Particulate Matter of 1 μm or Less With Preterm Birth in China. Wang Yuan-Yuan,Li Qin,Guo Yuming,Zhou Hong,Wang Xiaobin,Wang Qiaomei,Shen Haiping,Zhang Yiping,Yan Donghai,Zhang Ya,Zhang Hongguang,Li Shanshan,Chen Gongbo,Zhao Jun,He Yuan,Yang Ying,Xu Jihong,Wang Yan,Peng Zuoqi,Wang Hai-Jun,Ma Xu JAMA pediatrics Importance:Airborne particulate matter pollution has been associated with preterm birth (PTB) in some studies. However, most of these studies assessed only populations living near monitoring stations, and the association of airborne particulate matter having a median diameter of 1 μm or less (PM1) with PTB has not been studied. Objective:To evaluate whether PM1 concentrations are associated with the risk of PTB. Design, Setting, and Participants:This national cohort study used National Free Preconception Health Examination Project data collected in 324 of 344 prefecture-level cities from 30 provinces of mainland China. In total, 1 300 342 healthy singleton pregnancies were included from women who were in labor from December 1, 2013, through November 30, 2014. Data analysis was conducted between December 1, 2016, and April 1, 2017. Exposures:Predicted weekly PM1 concentration data collected using satellite remote sensing, meteorologic, and land use information matched with the home addresses of pregnant women. Main Outcomes and Measures:Preterm birth (<37 gestational weeks). Gestational age was assessed using the time since the first day of the last menstrual period. Cox proportional hazards regression analysis was used to examine the associations between trimester-specific PM1 concentrations and PTB after controlling for temperature, seasonality, spatial variation, and individual covariates. Results:Of the 1 300 342 singleton live births at the gestational age of 20 to 45 weeks included in this study, 104 585 (8.0%) were preterm. In fully adjusted models, a PM1 concentration increase of 10 μg/m3 over the entire pregnancy was significantly associated with increased risk of PTB (hazard ratio [HR], 1.09; 95% CI, 1.09-1.10), very PTB as defined as gestational age from 28 through 31 weeks (HR, 1.20; 95% CI, 1.18-1.23), and extremely PTB as defined as 20 through 27 weeks' gestation (HR, 1.29; 95% CI, 1.25-1.34). Pregnant women who were older (30-50 years) at conception (HR, 1.13; 95% CI, 1.11-1.14), were overweight before pregnancy (HR, 1.13; 95% CI, 1.11-1.15), had a rural household registration (HR, 1.09; 95% CI, 1.09-1.10), worked as farmers (HR, 1.10; 95% CI, 1.09-1.11), and conceived in autumn (HR, 1.48; 95% CI, 1.46-1.50) appeared to be more sensitive to PM1 exposure than their counterparts. Conclusions and Relevance:Results from this national cohort study examining more than 1.3 million births indicated that exposure to PM1 air pollution was associated with an increased risk of PTB in China. These findings will provide evidence to inform future research studies, public health interventions, and environmental policies. 10.1001/jamapediatrics.2017.4872
    Maternal fetal programming of birthweight among Australian Aboriginal infants: a population-based data linkage study. Gibberd Alison J,Simpson Judy M,McNamara Bridgette J,Eades Sandra J The Lancet. Global health BACKGROUND:Low birthweight, which is common among Australian Aboriginal infants, has been found to persist across generations because of shared genetic and environmental factors and possibly fetal programming. Fetal programming refers to the response of a fetus to hostile uterine conditions with lifelong effects and possibly, in turn, providing a poorer uterine environment for future offspring. Fetal programming might have a greater effect in populations that have undergone rapid lifestyle transitions-for example, Indigenous populations. Disentangling causal effects is difficult, but family-based approaches could provide insights. We explored whether poor maternal fetal growth caused low birthweight in Aboriginal infants. METHODS:In this data linkage study, we used linked administrative health records of 12 865 singleton Aboriginal infants born in Western Australia between 1980 and 2010 and their relatives (including siblings born in 2011). Electronic birth records included all births since 1980 with at least 20 weeks completed gestation or a birthweight of 400 g. We compared parental-offspring birthweight associations using three approaches-a regression analysis of the complete sample, adjusting for confounding variables; a comparison of the maternal-offspring and paternal-offspring associations; and a within-cousin group comparison. We used binary and continuous measures of birthweight. We categorised infants and their parents as small for gestational age (SGA) if their birthweight was below the first decile of birthweights for all singleton livebirths of the same sex and gestational age in Australia between 1998 and 2007. FINDINGS:The relative risk (RR) of SGA birth was higher for infants with SGA mothers than for those with non-SGA mothers (RR 1·65, 95% CI 1·49 to 1·83), after adjusting for grandmaternal parity. After additional adjustment for maternal height, the risk remained higher for those with non-SGA mothers (RR 1·51, 1·36 to 1·68). The maternal birthweight Z score coefficient was 0·17 (95% CI 0·14 to 0·20), compared with 0·13 (0·10 to 0·16) for paternal birthweight, a difference of 0·03 (-0·01 to 0·08). In the cousin analysis, the maternal-offspring association was fully attenuated (0·00, 95% CI -0·05 to 0·06). Conditions in the current pregnancy were strongly associated with offspring birthweight Z score. Smoking was associated with a mean decrease of 0·39 (95% CI -0·45 to -0·34) in offspring birthweight Z score, drug misuse with a decrease of 0·31 (-0·43 to -0·20), and diabetes with an increase of 0·58 (0·39 to 0·77). INTERPRETATION:We found little support for maternal fetal programming causing low offspring birthweight. The similar maternal and paternal influence on birthweight and our cousin analysis suggested transmission of genetic and environmental factors could explain much of the maternal-offspring birthweight association. Compared with other risk factors in the current pregnancy, fetal programming appears to have little or no role in the high numbers of infants with low birthweight among Aboriginal populations. FUNDING:National Health and Medical Research Council of Australia and Bellberry Ltd. 10.1016/S2214-109X(18)30561-8
    Association of Perinatal Risk Factors With Obsessive-Compulsive Disorder: A Population-Based Birth Cohort, Sibling Control Study. Brander Gustaf,Rydell Mina,Kuja-Halkola Ralf,Fernández de la Cruz Lorena,Lichtenstein Paul,Serlachius Eva,Rück Christian,Almqvist Catarina,D'Onofrio Brian M,Larsson Henrik,Mataix-Cols David JAMA psychiatry IMPORTANCE:Perinatal complications may increase the risk of obsessive-compulsive disorder (OCD). Previous reports were based on small, retrospective, specialist clinic-based studies that were unable to rigorously control for unmeasured environmental and genetic confounding. OBJECTIVE:To prospectively investigate a wide range of potential perinatal risk factors for OCD, controlling for unmeasured factors shared between siblings in the analyses. DESIGN, SETTING, AND PARTICIPANTS:This population-based birth cohort study included all 2 421 284 children from singleton births in Sweden from January 1, 1973, to December 31, 1996, who were followed up through December 31, 2013. From the 1 403 651 families in the cohort, differentially exposed siblings from the 743 885 families with siblings were evaluated; of these, 11 592 families included clusters of full siblings that were discordant for OCD. Analysis of the data was conducted from January, 26, 2015, to September, 5, 2016. EXPOSURES:Perinatal data were collected from the Swedish Medical Birth Register and included maternal smoking during pregnancy, labor presentation, obstetric delivery, gestational age (for preterm birth), birth weight, birth weight in relation to gestational age, 5-minute Apgar score, and head circumference. MAIN OUTCOMES AND MEASURES:Previously validated OCD codes (International Statistical Classification of Diseases and Health Related Problems, Tenth Revision, code F42) in the Swedish National Patient Register. RESULTS:Of 2 421 284 individuals included in the cohort, 17 305 persons were diagnosed with OCD. Of these, 7111 were men (41.1%). The mean (SD) age of individuals at first diagnosis of OCD was 23.4 (6.5) years. An increased risk for OCD remained after controlling for shared familial confounders and measured covariates (including sex, year of birth, maternal and paternal age at birth, and parity), for smoking 10 or more cigarettes per day during pregnancy (hazard ratio [HR], 1.27; 95% CI, 1.02-1.58), breech presentation (HR, 1.35; 95% CI, 1.06-1.71), delivery by cesarean section (HR, 1.17; 95% CI, 1.01-1.34), preterm birth (HR, 1.24; 95% CI, 1.07-1.43), birth weight 1501 to 2500 g (HR, 1.30; 95% CI, 1.05-1.62) and 2501 to 3500 g (HR, 1.08; 95% CI, 1.01-1.16), being large for gestational age (HR, 1.23; 95% CI, 1.05-1.45), and Apgar distress scores at 5 minutes (HR, 1.50; 95% CI, 1.07-2.09). Gestational age and birth weight followed inverse dose-response associations, whereby an increasingly higher risk for OCD was noted in children with a shorter gestational age and lower birth weight. We also observed a dose-response association between the number of perinatal events and increased OCD risk, with HRs ranging from 1.11 (95% CI, 1.07-1.15) for 1 event to 1.51 (95% CI, 1.18-1.94) for 5 or more events. CONCLUSIONS AND RELEVANCE:A range of perinatal risk factors is associated with a higher risk for OCD independent of shared familial confounders, suggesting that perinatal risk factors may be in the causal pathway to OCD. 10.1001/jamapsychiatry.2016.2095
    Cardiovascular mortality in relation to birth weight of children and grandchildren in 500,000 Norwegian families. Naess Oyvind,Stoltenberg Camilla,Hoff Dominic A,Nystad Wenche,Magnus Per,Tverdal Aage,Davey Smith George European heart journal AIMS:Cardiovascular diseases (CVDs) have been related to low birth weight, suggesting the foetal environment may program future risk. Alternatively, common genetic factors for both low birth weight and CVD could explain such associations. We investigated associations between offspring birth weight and paternal and maternal cardiovascular mortality and offspring birth weight and cardiovascular mortality among all four grandparents, and further assessed the mediating role of maternal smoking during pregnancy. METHODS AND RESULTS:All births from 1967 to 2008 that could be linked to parents and grandparents comprised the population (n = 1,004,255). The mortality follow-up among parents was from 1970 to 2008 and among grandparents from 1960 to 2008. The association of grandparental mortality with maternal smoking during pregnancy was analysed in a subpopulation of those born after 1997 (n = 345,624). Per quintile higher in birth weight was related to 0.82 (0.75-0.89) hazard ratio from coronary heart disease in mothers and 0.94 (0.92-0.97) in fathers. For stroke, these were 0.85 (0.78-0.92) and 0.94 (0.89-1.00), respectively. In grandparents for cardiovascular causes, the effects were 0.95 (0.93-0.96) (maternal grandmother), 0.97 (0.96-0.98) (maternal grandfather), 0.96 (0.94-0.98) (paternal grandmother), and 0.98 (0.98-1.00) (paternal grandfather). Adjusting for maternal smoking in pregnancy in the subpopulation accounted for much of the effect on grandparental cardiovascular mortality in all categories of birth weight. For grandparental diabetes mortality, U-shaped associations were seen with grandchild birth weight for the maternal grandmother and inverse associations for all other grandparents. CONCLUSION:Associations between CVD mortality in all four grandparents and grandchild birth weight exist, and while genetic and environmental factors may contribute to these, it appears that there is an important role for maternal smoking during pregnancy (and associated paternal smoking) in generating these associations. For diabetes, however, it appears that intrauterine environmental influences and genetic factors contribute to the transgenerational associations. 10.1093/eurheartj/ehs298
    Environmental factors associated with allergy in urban and rural children from the South African Food Allergy (SAFFA) cohort. Levin Michael E,Botha Maresa,Basera Wisdom,Facey-Thomas Heidi E,Gaunt Ben,Gray Claudia L,Kiragu Wanjiku,Ramjith Jordache,Watkins Alexandra,Genuneit Jon The Journal of allergy and clinical immunology BACKGROUND:The prevalence of allergic diseases differs in urban and rural populations. OBJECTIVE:We sought to assess associations between environmental and dietary factors with allergic diseases in urban and rural South African children. METHODS:Toddlers aged 12 to 36 months were assessed for food allergen and aeroallergen sensitization, atopic dermatitis, allergic rhinitis, asthma, and challenge-proved food allergy. Information was collected on family history of allergic diseases, household size, socioeconomic status, delivery mode, antibiotic and probiotic use, exposure to fermented and unpasteurized milk, antihelminth treatment, sunlight exposure, pet and farm animal exposure, cigarette smoke, and household cooking and heating fuels. Antenatal exposures to pets, livestock, and cigarette smoke were assessed. A subsection completed questions on consumption of fruits and vegetables, fast foods, soft drinks/fruit juices, and fried/microwaved meat. RESULTS:Risk and protective factors differed between urban and rural settings. Exposure to farm animals in infants and their mothers during pregnancy was protective against allergic outcomes in the rural population. Consumption of unpasteurized milk is uncommon in this group of rural children and is unlikely to be an important factor in rural protection. In urban children birth by cesarean section is associated with food allergy, and consumption of fermented milk products is associated with reduced asthma and atopic dermatitis. In both cohorts antenatal maternal smoking and environmental smoking exposure were predominantly associated with asthma, and consumption of fast foods and fried meats were associated with allergy. CONCLUSION:In this rural environment exposure to livestock is the strongest protective factor. In urban communities, where animal contact is rare, risk factors include cesarian section, and protective factors include consumption of fermented milk products. Modifiable risk factors urgently require interventions to prevent increasing allergy rates in countries undergoing rapid urbanization. 10.1016/j.jaci.2019.07.048
    Environment and women's reproductive health. Caserta D,Mantovani A,Marci R,Fazi A,Ciardo F,La Rocca C,Maranghi F,Moscarini M Human reproduction update BACKGROUND:There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health. METHODS:Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. RESULTS:Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). CONCLUSIONS:A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health. 10.1093/humupd/dmq061
    In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Ng Ka Ying Bonnie,Mingels Roel,Morgan Hywel,Macklon Nick,Cheong Ying Human reproduction update BACKGROUND:Despite advances in ART, implantation and pregnancy rates per embryo transfer still remain low. IVF laboratories strive to ensure that the process of handling gametes in vitro closely mimics the in vivo environment. However, there remains a lack of knowledge regarding the in vivo regulation and dynamic variation in biophysical parameters such as oxygen concentration, pH and temperature within the reproductive tract. OBJECTIVE AND RATIONALE:To undertake a systematic review of the current understanding of the physico-chemical parameters of oxygen tension (pO2), pH and temperature within the female reproductive tract, and their potential implications in clinical and pathological processes related to fertility and those pertaining to limited reproductive capacity. SEARCH METHODS:A comprehensive literature search was performed using electronic databases including Medline, Embase, Cochrane Library and Pubmed to identify original and review articles addressing the biophysical parameters (pO2, pH and temperature) in the female reproductive tract of any species. The search included all studies published between 1946 and November 2015. Search terms included 'oxygen', 'pH', 'hydrogen ion concentration', 'acid base' and others terms. We also used special features and truncations to identify synonyms and broaden the search. Studies were excluded if they only assessed embryo culture conditions, fetal acid-base status, oxidative stress, outcomes of pregnancy and measurements of these parameters in non-reproductive organs. OUTCOMES:Our search generated 18 685 records and 60 articles were included. pO2 within the female reproductive tract shows cyclical variation and minute-to-minute oscillations, which may be influenced by uterine contractility, hormones, the autonomic system, cardiac pulsatility, and myometrial and smooth muscle integrity. Fine balanced control of pO2 and avoidance of overwhelming oxidative stress is crucial for embryogenesis and implantation. The pH in the female reproductive tract is graduated, with lowest pH in the vagina (~pH 4.42) increasing toward the Fallopian tubes (FTs) (~pH 7.94), reflecting variation in the site-specific microbiome and acid-base buffering at the tissue/cellular level. The temperature variation in humans is cyclical by day and month. In humans, it is biphasic, increasing in the luteal phase; with the caudal region of the oviduct 1-2 degrees cooler than the cranial portion. Temperature variation is influenced by hormones, density of pelvic/uterine vascular beds and effectiveness of heat exchange locally, crucial for sperm motility and embryo development. We have identified significant deficiencies and inconsistencies in the methods used to assess these biophysical factors within the reproductive tract. We have suggested that the technological solutions including the development of methods and models for real time, in vivo recordings of biophysical parameters. WIDER IMPLICATIONS:The notion of 'back to nature' in assisted conception suggested 20 years ago has yet to be translated into clinical practice. While the findings from this systematic review do not provide evidence to change current in vitro protocols, it highlights our current inability to assess the in vivo reproductive tract environment in real time. Data made available through future development of sensing technology in utero may help to provide new insights into how best to optimize the in vitro embryo environment and allow for more precise and personalized fertility treatment. 10.1093/humupd/dmx028
    Genetic sensitivity to the environment, across lifetime. Homberg Judith R The Behavioral and brain sciences The target article by Charney convincingly argues that genomic plasticity perinatally induced by the environment creates a complication in determining which parts of behavior are attributed to nature and which to nurture. I argue that real life is even more complex because (1) genotype influences sensitivity to environmental stimuli, and (2) the genome continues to be modified throughout life. 10.1017/S0140525X1200101X
    Pre-natal and post-natal environment monitoring to prevent non-alcoholic fatty liver disease development. Alisi Anna,Vajro Pietro Journal of hepatology 10.1016/j.jhep.2017.04.016
    Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study. Travis Ruth C,Reeves Gillian K,Green Jane,Bull Diana,Tipper Sarah J,Baker Krys,Beral Valerie,Peto Richard,Bell John,Zelenika Diana,Lathrop Mark, Lancet (London, England) BACKGROUND:Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. METHODS:We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). FINDINGS:After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). INTERPRETATION:Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. FUNDING:Cancer Research UK and the UK Medical Research Council. 10.1016/S0140-6736(10)60636-8
    Asthma medication use during pregnancy, wheeze and estimated exposure to ambient nitrogen dioxide. Gent Janneane F,Kezik Julie M,Hill Melissa E,McKay Lisa A,Holford Theodore R,Leaderer Brian P,Bracken Michael B The European respiratory journal 10.1183/09031936.00161514
    Traffic pollution is linked to poor pregnancy outcomes. Stock Sarah J,Clemens Tom BMJ (Clinical research ed.) 10.1136/bmj.j5511
    Prenatal Air Pollution and Newborns' Predisposition to Accelerated Biological Aging. Martens Dries S,Cox Bianca,Janssen Bram G,Clemente Diana B P,Gasparrini Antonio,Vanpoucke Charlotte,Lefebvre Wouter,Roels Harry A,Plusquin Michelle,Nawrot Tim S JAMA pediatrics Importance:Telomere length is a marker of biological aging that may provide a cellular memory of exposures to oxidative stress and inflammation. Telomere length at birth has been related to life expectancy. An association between prenatal air pollution exposure and telomere length at birth could provide new insights in the environmental influence on molecular longevity. Objective:To assess the association of prenatal exposure to particulate matter (PM) with newborn telomere length as reflected by cord blood and placental telomere length. Design, Setting, and Participants:In a prospective birth cohort (ENVIRONAGE [Environmental Influence on Ageing in Early Life]), a total of 730 mother-newborn pairs were recruited in Flanders, Belgium between February 2010 and December 2014, all with a singleton full-term birth (≥37 weeks of gestation). For statistical analysis, participants with full data on both cord blood and placental telomere lengths were included, resulting in a final study sample size of 641. Exposures:Maternal residential PM2.5 (particles with an aerodynamic diameter ≤2.5 μm) exposure during pregnancy. Main Outcomes and Measures:In the newborns, cord blood and placental tissue relative telomere length were measured. Maternal residential PM2.5 exposure during pregnancy was estimated using a high-resolution spatial-temporal interpolation method. In distributed lag models, both cord blood and placental telomere length were associated with average weekly exposures to PM2.5 during pregnancy, allowing the identification of critical sensitive exposure windows. Results:In 641 newborns, cord blood and placental telomere length were significantly and inversely associated with PM2.5 exposure during midgestation (weeks 12-25 for cord blood and weeks 15-27 for placenta). A 5-µg/m3 increment in PM2.5 exposure during the entire pregnancy was associated with 8.8% (95% CI, -14.1% to -3.1%) shorter cord blood leukocyte telomeres and 13.2% (95% CI, -19.3% to -6.7%) shorter placental telomere length. These associations were controlled for date of delivery, gestational age, maternal body mass index, maternal age, paternal age, newborn sex, newborn ethnicity, season of delivery, parity, maternal smoking status, maternal educational level, pregnancy complications, and ambient temperature. Conclusions and Relevance:Mothers who were exposed to higher levels of PM2.5 gave birth to newborns with shorter telomere length. The observed telomere loss in newborns by prenatal air pollution exposure indicates less buffer for postnatal influences of factors decreasing telomere length during life. Therefore, improvements in air quality may promote molecular longevity from birth onward. 10.1001/jamapediatrics.2017.3024
    Reproduction in females: the role of the early life environment. Sloboda Deborah M,Hickey Martha,Hart Roger Human reproduction update BACKGROUND:There is now compelling evidence that long-term health and physiological function are modified by events that occur early in life and involve interactions between the genome and the developmental environment. That reproductive function may similarly be influenced by early life events has been established in selected human populations, and investigations into underlying mechanisms are the subject of current animal studies. METHODS:No systematic literature search was conducted. This review highlights early life influences on reproduction with a particular focus on nutritional impacts, and provides a brief overview with reference to some key studies in both the human and animal literature. We highlight the controversies, current unanswered questions and mechanisms underlying the association between the early life environment and long-term reproductive function. RESULTS AND CONCLUSIONS:Currently, the impact of early life events on reproductive health and disease risk is poorly understood. It is clear, however, that nutrition spanning the entire developmental lifespan plays an integral role. Improved insight into the underlying mechanisms is likely to have significant implications for our current understanding of reproductive disorders, and therefore for the health and reproductive potential of future generations. 10.1093/humupd/dmq048
    Environmental phthalate exposure and preterm birth. Ferguson Kelly K,McElrath Thomas F,Meeker John D JAMA pediatrics IMPORTANCE:Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE:To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS:This nested case-control study was conducted at Brigham and Women's Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE:Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES:We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n = 57). RESULTS:Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and  Σ DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP,  Σ DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE:Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy. 10.1001/jamapediatrics.2013.3699
    Revisiting the Link Between Precipitation and the Risk of Autism: The Role of Environmental Nitrous Oxide Exposure. Fluegge Keith JAMA pediatrics 10.1001/jamapediatrics.2017.0050
    Maternal and environmental risk factors for neonatal AKI and its long-term consequences. Perico Norberto,Askenazi David,Cortinovis Monica,Remuzzi Giuseppe Nature reviews. Nephrology Acute kidney injury (AKI) is a common and life-threatening complication in critically ill neonates. Gestational risk factors for AKI include premature birth, intrauterine growth restriction and low birthweight, which are associated with poor nephron development and are often the consequence of pre-gestational and gestational factors, such as poor nutritional status. Our understanding of how to best optimize renal development and prevent AKI is in its infancy; however, the identification of pre-gestational and gestational factors that increase the risk of adverse neonatal outcomes and the implementation of interventions, such as improving nutritional status early in pregnancy, have the potential to optimize fetal growth and reduce the risk of preterm birth, thereby improving kidney health. The overall risk of AKI among critically ill and premature neonates is exacerbated postnatally as these infants are often exposed to dehydration, septic shock and potentially nephrotoxic medications. Strategies to improve outcomes - for example, through careful evaluation of nephrotoxic drugs - may reduce the incidence of AKI and its consequences among this population. Management strategies and updated technology that will support neonates with AKI are greatly needed. Extremely premature infants and those who survive an episode of AKI should be screened for chronic kidney disease until early adulthood. Here, we provide an overview of our current understanding of neonatal AKI, focusing on its relationship to preterm birth and growth restriction. We describe factors that prevent optimal nephrogenesis during pregnancy and provide a framework for future explorations designed to maximize outcomes in this vulnerable population. 10.1038/s41581-018-0054-y
    Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data. Kilcoyne Karen R,Mitchell Rod T Human reproduction update BACKGROUND:Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance. OBJECTIVE AND RATIONALE:The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis. SEARCH METHODS:For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including 'endocrine disruptor', 'human', 'fetal', 'testis', 'germ cells', 'testosterone' and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches. OUTCOMES:A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. WIDER IMPLICATIONS:Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal-human differences in susceptibility. 10.1093/humupd/dmz004
    Fish Intake in Pregnancy and Child Growth: A Pooled Analysis of 15 European and US Birth Cohorts. Stratakis Nikos,Roumeliotaki Theano,Oken Emily,Barros Henrique,Basterrechea Mikel,Charles Marie-Aline,Eggesbø Merete,Forastiere Francesco,Gaillard Romy,Gehring Ulrike,Govarts Eva,Hanke Wojciech,Heude Barbara,Iszatt Nina,Jaddoe Vincent W,Kelleher Cecily,Mommers Monique,Murcia Mario,Oliveira Andreia,Pizzi Costanza,Polańska Kinga,Porta Daniela,Richiardi Lorenzo,Rifas-Shiman Sheryl L,Schoeters Greet,Sunyer Jordi,Thijs Carel,Viljoen Karien,Vrijheid Martine,Vrijkotte Tanja G M,Wijga Alet H,Zeegers Maurice P,Kogevinas Manolis,Chatzi Leda JAMA pediatrics IMPORTANCE:Maternal fish intake in pregnancy has been shown to influence fetal growth. The extent to which fish intake affects childhood growth and obesity remains unclear. OBJECTIVE:To examine whether fish intake in pregnancy is associated with offspring growth and the risk of childhood overweight and obesity. DESIGN, SETTING, AND PARTICIPANTS:Multicenter, population-based birth cohort study of singleton deliveries from 1996 to 2011 in Belgium, France, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, and Massachusetts. A total of 26,184 pregnant women and their children were followed up at 2-year intervals until the age of 6 years. EXPOSURES:Consumption of fish during pregnancy. MAIN OUTCOMES AND MEASURES:We estimated offspring body mass index percentile trajectories from 3 months after birth to 6 years of age. We defined rapid infant growth as a weight gain z score greater than 0.67 from birth to 2 years and childhood overweight/obesity at 4 and 6 years as body mass index in the 85th percentile or higher for age and sex. We calculated cohort-specific effect estimates and combined them by random-effects meta-analysis. RESULTS:This multicenter, population-based birth cohort study included the 26,184 pregnant women and their children. The median fish intake during pregnancy ranged from 0.5 times/week in Belgium to 4.45 times/week in Spain. Women who ate fish more than 3 times/week during pregnancy gave birth to offspring with higher body mass index values from infancy through middle childhood compared with women with lower fish intake (3 times/week or less). High fish intake during pregnancy (>3 times/week) was associated with increased risk of rapid infant growth, with an adjusted odds ratio (aOR) of 1.22 (95% CI, 1.05-1.42) and increased risk of offspring overweight/obesity at 4 years (aOR, 1.14 [95% CI, 0.99-1.32]) and 6 years (aOR, 1.22 [95% CI, 1.01-1.47]) compared with an intake of once per week or less. Interaction analysis showed that the effect of high fish intake during pregnancy on rapid infant growth was greater among girls (aOR, 1.31 [95% CI, 1.08-1.59]) than among boys (aOR, 1.11 [95% CI, 0.92-1.34]; P = .02 for interaction). CONCLUSIONS AND RELEVANCE:High maternal fish intake during pregnancy was associated with increased risk of rapid growth in infancy and childhood obesity. Our findings are in line with the fish intake limit proposed by the US Food and Drug Administration and Environmental Protection Agency. 10.1001/jamapediatrics.2015.4430
    Association Between Pesticide Residue Intake From Consumption of Fruits and Vegetables and Pregnancy Outcomes Among Women Undergoing Infertility Treatment With Assisted Reproductive Technology. Chiu Yu-Han,Williams Paige L,Gillman Matthew W,Gaskins Audrey J,Mínguez-Alarcón Lidia,Souter Irene,Toth Thomas L,Ford Jennifer B,Hauser Russ,Chavarro Jorge E, JAMA internal medicine Importance:Animal experiments suggest that ingestion of pesticide mixtures at environmentally relevant concentrations decreases the number of live-born offspring. Whether the same is true in humans is unknown. Objective:To examine the association of preconception intake of pesticide residues in fruits and vegetables (FVs) with outcomes of infertility treatment with assisted reproductive technologies (ART). Design, Setting, and Participants:This analysis included 325 women who completed a diet assessment and subsequently underwent 541 ART cycles in the Environment and Reproductive Health (EARTH) prospective cohort study (2007-2016) at a fertility center at a teaching hospital. We categorized FVs as having high or low pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. Cluster-weighted generalized estimating equations were used to analyze associations of high- and low-pesticide residue FV intake with ART outcomes. Main Outcomes and Measures:Adjusted probabilities of clinical pregnancy and live birth per treatment cycle. Results:In the 325 participants (mean [SD] age, 35.1 [4.0] y; body mass index, 24.1 [4.3]), mean (SD) intakes of high- and low-pesticide residue FVs were 1.7 (1.0) and 2.8 (1.6) servings/d, respectively. Greater intake of high-pesticide residue FVs was associated with a lower probability of clinical pregnancy and live birth. Compared with women in the lowest quartile of high-pesticide FV intake (<1.0 servings/d), women in the highest quartile (≥2.3 servings/d) had 18% (95% CI, 5%-30%) lower probability of clinical pregnancy and 26% (95% CI, 13%-37%) lower probability of live birth. Intake of low-pesticide residue FVs was not significantly related to ART outcomes. Conclusions and Relevance:Higher consumption of high-pesticide residue FVs was associated with lower probabilities of pregnancy and live birth following infertility treatment with ART. These data suggest that dietary pesticide exposure within the range of typical human exposure may be associated with adverse reproductive consequences. 10.1001/jamainternmed.2017.5038
    Environmental and developmental origins of ovarian reserve. Richardson M C,Guo M,Fauser B C J M,Macklon N S Human reproduction update BACKGROUND Oocyte number is established early in life before a gradual loss of this ovarian reserve during reproductive life until oocyte availability becomes limiting at the menopause. Although there is a large genetic component to the ovarian reserve achieved before birth, other influences including the maternal endocrine and nutritional milieu, and environmental factors may represent important developmental determinants. Environmental and nutritional factors may also modify the downward trajectory of ovarian reserve in adult life. The combination of these early and later life influences has the potential to lead to diminished ovarian reserve, compromising fertility in later reproductive years and altering age at natural menopause. METHODS Literature searches of the ISI Web of Knowledge database were carried out using the main terms 'ovarian reserve' and 'menopause AND age' in conjunction with a range of other terms encompassing a variety of factors with potential effects on ovarian reserve. The various searches were inspected manually and the relevant papers selected for critical analysis and interpretation. RESULTS Evidence was identified supporting the view that elevated prenatal androgens have an adverse effect on the early establishment of ovarian reserve, although the implications for ovarian reserve in the polycystic ovary syndrome (which may also be programmed through prenatal androgen exposure) remain uncertain. Recent evidence is cited suggesting that effects of maternal nutrient restriction on ovarian reserve may also involve changes in prenatal androgen exposure. A general rationale is developed through examination of evidence which emphasizes the roles of the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) systems in ovarian reserve modulation. Because of their similarity to the natural ligands, many environmental compounds have the ability to bind to these receptors (albeit at lower affinities) and thereby have the potential to influence either the initial setting of ovarian reserve during development or the trajectory of ovarian reserve during adult life. For example, exposure to compounds in cigarette smoke may accelerate loss of ovarian reserve in smokers leading to diminished ovarian reserve, earlier age at last child and earlier menopause. Socioenocomic factors are clearly associated with age at natural menopause, with correlations with economic status and education level. However, such effects in western societies are in general small, and the underlying mechanisms remain unclear. CONCLUSIONS Exposure to many environmental compounds, particularly to those that leach from plastics and other synthetic materials, is commonplace in modern societies to the extent that many are found at measurable concentrations in body fluids within most of the population. Relating fluid levels of individual compounds to parameters reflecting ovarian reserve in selected populations appears to be an effective way forward and, indeed, some early-stage findings do show some cause for concern. There is a pressing need for the development of practical advice enabling women to minimize their intake of AHR/ER ligands, perhaps through dietary/cosmetic choices or improved food packaging. 10.1093/humupd/dmt057
    Particulate urban air pollution affects the functional morphology of mouse placenta. Veras Mariana Matera,Damaceno-Rodrigues Nilsa Regina,Caldini Elia Garcia,Maciel Ribeiro Antonio A C,Mayhew Terry M,Saldiva Paulo H N,Dolhnikoff Marisa Biology of reproduction In humans, adverse pregnancy outcomes (low birth weight, prematurity, and intrauterine growth retardation) are associated with exposure to urban air pollution. Experimental data have also shown that such exposure elicits adverse reproductive outcomes. We hypothesized that the effects of urban air pollution on pregnancy outcomes could be related to changes in functional morphology of the placenta. To test this, future dams were exposed during pregestational and gestational periods to filtered or nonfiltered air in exposure chambers. Placentas were collected from near-term pregnancies and prepared for microscopical examination. Fields of view on vertical uniform random tissue slices were analyzed using stereological methods. Volumes of placental compartments were estimated, and the labyrinth was analyzed further in terms of its maternal vascular spaces, fetal capillaries, trophoblast, and exchange surface areas. From these primary data, secondary quantities were derived: vessel calibers (expressed as diameters), trophoblast thickness (arithmetic mean), and total and mass-specific morphometric diffusive conductances for oxygen of the intervascular barrier. Two-way analysis of variance showed that both periods of exposure led to significantly smaller fetal weights. Pregestational exposure to nonfiltered air led to significant increases in fetal capillary surface area and in total and mass-specific conductances. However, the calibers of maternal blood spaces were reduced. Gestational exposure to nonfiltered air was associated with reduced volumes, calibers, and surface areas of maternal blood spaces and with greater fetal capillary surfaces and diffusive conductances. The findings indicate that urban air pollution affects placental functional morphology. Fetal weights are compromised despite attempts to improve diffusive transport across the placenta. 10.1095/biolreprod.108.069591
    Placental thickness in the second trimester: a pilot study to determine the normal range. Lee Anna J,Bethune Michael,Hiscock Richard J Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine OBJECTIVES:We sought to determine the normal sonographically measured placental thickness in millimeters at the second-trimester scan (18 weeks to 22 weeks 6 days) and determine whether the measurement should be adjusted for gestational age and the placental site. METHODS:We conducted a cross-sectional observational pilot study involving 114 consecutive patients with singleton pregnancies presenting for routine second-trimester sonography between 18 weeks and 22 weeks 6 days. RESULTS:The unadjusted overall mean placental thickness was 24.6 (SD, 7.29) mm. The placental thickness was normally distributed. On multivariable analysis, the predicted mean thickness was 6.6 mm (95% confidence interval, 4.4 to 8.8 mm; P < .001) less in anterior compared to posterior or fundal placentas and increased by 0.6 mm (95% confidence interval, -0.5 to 1.7 mm; P = .27) for each week increase in gestation after 18 weeks CONCLUSIONS:The placental position and possibly gestational age need to be considered when determining placental thickness. Anterior placentas are approximately 7 mm thinner than posterior or fundal placentas. Anterior placentas of greater than 33 mm and posterior placentas of greater than 40 mm should be considered abnormally thick.
    The effects of air pollution and smoking on placental cadmium, zinc concentration and metallothionein expression. Sorkun Hulya Cetin,Bir Ferda,Akbulut Metin,Divrikli Umit,Erken Gulten,Demirhan Huriye,Duzcan Ender,Elci Latif,Celik Ismail,Yozgatli Unsal Toxicology This study is designed to determine the placental zinc (Zn) and cadmium (Cd) levels in mothers who were smokers, mothers who were thought to be exposed to air pollution, and mothers who were non-smokers and to investigate the relationship between the expression of placental metallothionein (MT) binding these metals and blood progesterone level. Placental Zn and Cd levels were measured by atomic absorption spectrometry. Presence of placental MT was determined immunohistochemically. Placental changes were examined by light microscope after H&E and PAS staining. Immunohistochemical MT staining of syncytiotrophoblastic and villous interstitial cells were scored as positive or negative. Among the 92 mothers included in the study, 33 were smokers (Group I), 29 had been exposed to air pollution (Group II) and 30 were non-smoker rural residents who had never been exposed to air pollution (Group III). Mean off-spring birth weight of 3198.62+/-380.01 g and mean placenta weight of 561.38+/-111.55 g of Group II were lower when compared with those of other two groups. In Group I, mean placental Cd and Zn were 0.063+/-0.022 microg/g and 39.84+/-15.5 microg/g, respectively, being higher than in other groups. In Group II, mean placental Cd and Zn levels were higher than those of Group III. Blood progesterone levels of subjects in Group I (121 ng/ml) were the lowest of all groups. While the mean count of villi was the highest in Group III; the highest mean count of syncytial knots was in Group II. Thickening of vasculo-syncytial membrane was most prominent in Group I. Similarly, MT staining was positive and very dense in 72.7% (24/33) of cases in Group I (p<or=0.05). MT staining was positive in 69.0% (29/20) and denser in Group II cases compared to 36% (11/30) in Group III (p<or=0.05). This study showed that smoking increased Cd levels in placenta and accompanied an increase in placental MT expression immunohistochemically. The effects of exposure to air pollution are equally harmful as smoking related effects. 10.1016/j.tox.2007.05.020