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1.
Environ Health ; 18(1): 80, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470855

RESUMO

BACKGROUND: Environmental exposure to phthalates and bisphenol A (BPA) may have endocrine disrupting effects that alter length of gestation. We assessed the association between the urinary concentrations of 11 phthalate metabolites and BPA with length of gestation in a cohort of women followed from before conception with daily 1st-morning urinary hormone measures that identified day of implantation. METHODS: Pre-implantation and post-implantation urinary phthalate metabolites and BPA concentrations were measured in pooled urine samples designed to limit single-measure variability due to the likely episodic nature of these exposures and the short half-life of these compounds. We estimated associations between these exposure biomarkers early in pregnancy with length of gestation from implantation to spontaneous birth. Cox proportional hazards models were used to estimate the hazard of birth among 125 naturally-conceived, singleton live births with censoring for medical interventions that artificially shortened pregnancy. RESULTS: Higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (a metabolite of di (2-ethylhexyl) phthalate (DEHP)) during the pre-implantation window were associated with reduced probability of birth, i.e., longer gestations (hazard ratio (HR): 0.55, 95% CI: 0.35, 0.86; p = 0.01). The HR for the molar sum of the four DEHP metabolites measured showed a similar association (HR: 0.67, 95% CI: 0.43, 1.05). Higher concentrations of mono (3-carboxypropyl) phthalate (MCPP), a non-specific metabolite of several high molecular-weight phthalates, measured post-implantation were associated with increased risk of earlier birth, i.e. shorter length of gestation, HR: 1.59, CI: 1.02, 2.49. CONCLUSIONS: Early gestational exposure to DEHP and possibly other high-molecular weight phthalates, (as reflected by urinary MCPP concentrations) may influence the length of pregnancy. Such effects could have consequences for neonatal and maternal health.

2.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
3.
Clin Epigenetics ; 11(1): 40, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832715

RESUMO

BACKGROUND: Isolated orofacial clefts are among the most common congenital birth defects. Although the underlying biological mechanisms remain largely unknown, clefts are thought to be complex disorders influenced by genetic, environmental, and potentially epigenetic factors. METHODS: In blood samples from 2- to 3-day-old infants (n = 747) collected in a nationwide population-based study of orofacial clefts in Norway, we measured DNA methylation profiles for more than 450,000 CpGs and then conducted epigenome-wide association analyses (EWAS). We tested methylation profile difference at each CpG between controls (n = 436) and each of the cleft subtypes (92 cleft lip only, CLO; 84 cleft palate only, CPO; 132 cleft lip and palate, CLP). We also compared controls to various combinations of case groups and compared case subtypes to each other. Finally, using the EWAS results, we searched for larger differentially methylated regions (DMRs) associated with orofacial clefts. RESULTS: In EWAS comparing controls to individual cleft subtypes, we found no significant associations at a Bonferroni P value threshold of 10-7. After pooling case groups, we found two significantly differentially methylated CpGs: cg09696939 near gene BICC1 is associated with CLO+CLP (P = 9.58 × 10-8); cg26985354 in gene CLASRP is associated with CPO+CLP (P = 7.38 × 10-8). In DMR analysis, we identified a total of 56 significant regions when comparing controls to individual cleft subtypes (10 for CLO, 6 for CPO, 41 for CLP). Only one DMR is shared among the three cleft groups. In combined case group analysis, we found 26 DMRs for CLP+CLO, 31 for CLP+CPO, and 37 when all subtypes are combined. Finally, in case-case comparisons of subtypes, we identified 10 DMRs when comparing CLP to CPO, 9 in CLP compared to CLO, and 13 in CLP compared to CPO. CONCLUSIONS: We identified two individual CpGs and multiple DMRs that differ between controls and cleft case subtypes. Although we find some evidence for the possible role of DNA methylation in etiology of orofacial clefts, our study does not support previous reports of widespread differences in blood DNA methylation between babies with and without facial clefts.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Proteínas de Ligação a RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Masculino , Noruega
4.
BMJ ; 364: l869, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894356

RESUMO

OBJECTIVES: To estimate the burden of miscarriage in the Norwegian population and to evaluate the associations with maternal age and pregnancy history. DESIGN: Prospective register based study. SETTING: Medical Birth Register of Norway, the Norwegian Patient Register, and the induced abortion register. PARTICIPANTS: All Norwegian women that were pregnant between 2009-13. MAIN OUTCOME MEASURE: Risk of miscarriage according to the woman's age and pregnancy history estimated by logistic regression. RESULTS: There were 421 201 pregnancies during the study period. The risk of miscarriage was lowest in women aged 25-29 (10%), and rose rapidly after age 30, reaching 53% in women aged 45 and over. There was a strong recurrence risk of miscarriage, with age adjusted odds ratios of 1.54 (95% confidence interval 1.48 to 1.60) after one miscarriage, 2.21 (2.03 to 2.41) after two, and 3.97 (3.29 to 4.78) after three consecutive miscarriages. The risk of miscarriage was modestly increased if the previous birth ended in a preterm delivery (adjusted odds ratio 1.22, 95% confidence interval 1.12 to 1.29), stillbirth (1.30, 1.11 to 1.53), caesarean section (1.16, 1.12 to 1.21), or if the woman had gestational diabetes in the previous pregnancy (1.19, 1.05 to 1.36). The risk of miscarriage was slightly higher in women who themselves had been small for gestational age (1.08, 1.04 to 1.13). CONCLUSIONS: The risk of miscarriage varies greatly with maternal age, shows a strong pattern of recurrence, and is also increased after some adverse pregnancy outcomes. Miscarriage and other pregnancy complications might share underlying causes, which could be biological conditions or unmeasured common risk factors.


Assuntos
Aborto Espontâneo/epidemiologia , Idade Materna , Aborto Habitual/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Fatores Etários , Feminino , Humanos , Pessoa de Meia-Idade , Noruega/epidemiologia , Gravidez , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Recidiva , Sistema de Registros , História Reprodutiva , Medição de Risco/métodos , Fatores de Risco , Natimorto/epidemiologia , Adulto Jovem
5.
Environ Res ; 168: 254-260, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321738

RESUMO

BACKGROUND: Phthalates and bisphenol A (BPA) are environmental contaminants that may affect early embryonic development. OBJECTIVE: To assess the association between phthalate metabolites and BPA with early pregnancy endpoints in a cohort of women followed from before conception. METHODS: We quantified 11 phthalate metabolites and BPA in 137 conception cycles from naturally conceived clinical pregnancies. Phthalate metabolites and BPA concentrations were measured in a pooled sample of three daily morning urine specimens. Daily urinary hormone measurements had previously been used to define ovulation, implantation, and corpus luteum rescue. We assessed associations between conception cycle exposures (phthalate biomarkers and BPA) and 1) time from ovulation to implantation; 2) type of corpus luteum rescue (timing and pattern of rise in progesterone: early, late, or no rise); and 3) rate of initial rise in hCG. RESULTS: Mono(3-carboxypropyl) phthalate (MCPP) and mono-isobutyl phthalate (MiBP) were associated with earlier implantation (6-8 days vs. 9 days (the most commonly observed); per natural log-unit, OR (95% CI) = 2.8 (1.2, 6.7) and OR (CI) = 2.1 (1.2, 3.7), respectively). Monoethyl phthalate (MEP) was associated with later implantation (10-12 days vs. 9 days); OR (CI) = 1.5 (1.0, 2.1). Compared with implantation on day 9, BPA was significantly associated with both earlier and later implantation (OR=2.2 for both). Women with concentrations above the median of monobenzyl phthalate (MBzP) (p = 0.04) or above the median of the molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) (p = 0.08) had a slower initial rise in hCG. Increasing MCPP was associated with an increased odds of a late rise rescue (OR (CI) = 2.9 (1.0, 8.5); late rise vs. early rise), while increasing MEP was associated with a no rise rescue (OR (CI) = 1.6 (0.9, 2.8); no rise vs. early rise). CONCLUSIONS: The reported associations varied in their direction of effect, some potentially protective, others adverse. This may reflect the complexity with which these potential endocrine disrupting chemicals can be acting, but chance findings are also possible. Given that women continue to be exposed to these compounds (or their precursors), continued research on the effects they may have on pregnancy is warranted.


Assuntos
Compostos Benzidrílicos/urina , Poluentes Ambientais/urina , Fenóis/urina , Ácidos Ftálicos/urina , Disruptores Endócrinos/urina , Exposição Ambiental , Feminino , Humanos , Exposição Materna , Gravidez
6.
Thorax ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514789

RESUMO

BACKGROUND: It remains unclear what underlies the greater risk of asthma reported among children conceived by assisted reproductive technologies (ART). OBJECTIVE: Our aim was to clarify the role of parental subfertility and unmeasured confounding on the association between ART and childhood asthma, and to examine the possibility for common mechanisms underlying parental subfertility and miscarriages influencing asthma pathogenesis. METHODS: We used data from national Norwegian health registries (n=474 402) and the Norwegian Mother and Child Cohort Study (MoBa) (n=75 797). We used log-linear regression to estimate overall associations, and fixed-effects logistic regression to estimate associations within siblings. RESULTS: ART offspring had greater asthma risk, the adjusted relative risk (aRR) was 1.20 (95% CI 1.09 to 1.32) in the registry-based cohort, and 1.42 (95% CI 1.14 to 1.76) in MoBa. The sibling analysis yielded similar associations, although the CI included the null value. The elevated asthma risk among ART offspring was attenuated when they were compared with spontaneously conceived offspring with time to conception >12 months, aRR 1.22 (95% CI 0.95 to 1.57). Asthma risk also increased with maternal history of early miscarriages (≤12 weeks), with an aRR of 1.07 (95% CI 1.03 to 1.11) for one, aRR 1.18 (95% CI 1.10 to 1.26) for two and aRR 1.24 (95% CI 1.12 to 1.37) for three or more. CONCLUSION: Our findings indicate that both parental subfertility and characteristics related to the ART procedure itself might increase offspring asthma risk, although this needs to be confirmed in future studies, and further suggest that common mechanisms underlying parental subfertility and recurrent miscarriages might influence offspring asthma pathogenesis.

8.
Int J Epidemiol ; 47(4): 1298-1306, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29947785

RESUMO

Background: We investigated whether the risk of cerebral palsy (CP) in the child varies by parents' socioeconomic status, in Denmark and Norway. Methods: We included almost 1.3 million children born in Demark during 1981-2007 and 2.4 million children born in Norway during 1967-2007, registered in the Medical Birth registries. Data on births were linked to Statistics Denmark and Norway to retrieve information on parents' education and relationship status and, in Denmark, also income. CP diagnoses were obtained from linkage with national registries. We used multivariate log-binominal regression models to estimate relative risk (RR) of CP according to parental socioeconomic status. Results: There was a strong trend of decreasing risk of CP with additional education of both the mother and the father. These trends were nearly identical for the two parents, with a one-third reduction in risk for those with the highest education compared with parents with the lowest education. When both parents had high education, risk of CP was further reduced (RR 0.58, 0.53-0.63). Women with partners had a reduction in risk (RR 0.79, 0.74-0.85) compared with single mothers overall. Risk patterns were stable over time, across countries and within spastic bilateral and unilateral CP. Household income was not associated with risk of CP. Conclusions: Risk of CP in two Scandinavian countries was lower among educated parents and mothers with a partner, but unrelated to income. Factors underlying this stable association with education are unknown, but could include differences in potentially modifiable lifestyle factors and health behaviours.

9.
Eur J Epidemiol ; 33(6): 523-530, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29516296

RESUMO

Preterm delivery is one of the strongest predictors of neonatal mortality. A given exposure may increase neonatal mortality directly, or indirectly by increasing the risk of preterm birth. Efforts to assess these direct and indirect effects are complicated by the fact that neonatal mortality arises from two distinct denominators (i.e. two risk sets). One risk set comprises fetuses, susceptible to intrauterine pathologies (such as malformations or infection), which can result in neonatal death. The other risk set comprises live births, who (unlike fetuses) are susceptible to problems of immaturity and complications of delivery. In practice, fetal and neonatal sources of neonatal mortality cannot be separated-not only because of incomplete information, but because risks from both sources can act on the same newborn. We use simulations to assess the repercussions of this structural problem. We first construct a scenario in which fetal and neonatal factors contribute separately to neonatal mortality. We introduce an exposure that increases risk of preterm birth (and thus neonatal mortality) without affecting the two baseline sets of neonatal mortality risk. We then calculate the apparent gestational-age-specific mortality for exposed and unexposed newborns, using as the denominator either fetuses or live births at a given gestational age. If conditioning on gestational age successfully blocked the mediating effect of preterm delivery, then exposure would have no effect on gestational-age-specific risk. Instead, we find apparent exposure effects with either denominator. Except for prediction, neither denominator provides a meaningful way to define gestational-age-specific neonatal mortality.

10.
Menopause ; 25(7): 811-816, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29509595

RESUMO

OBJECTIVE: The aim of the study was to examine the associations between 25-hydroxyvitamin D (25(OH)D) and biomarkers of ovarian reserve in a large community-based sample of women. METHODS: In 2010 to 2016, women aged 30 to 44 years without any known fertility problems were recruited from the Chapel Hill, NC area for a prospective time-to-pregnancy cohort study. At enrollment 561 women provided a blood sample that was used to measure 25(OH)D, anti-Müllerian hormone (AMH), follicle-stimulating hormone, and inhibin-B. Unadjusted associations were estimated with Spearman correlation coefficients. Multivariable linear regression was used to estimate associations of 25(OH)D with ovarian reserve biomarkers, after adjusting for age, race, body mass index, smoking history, and recent use of hormonal birth control. RESULTS: The mean 25(OH)D was 36 ng/mL (SD = 11 ng/mL). 25(OH)D was not correlated with AMH, follicle-stimulating hormone, or inhibin-B (all r < 0.03). Multivariable results with continuous hormonal outcomes were also null. For dichotomous outcomes, there was a tendency for insufficient 25(OH)D (<30 ng/mL) to be associated with low AMH (<0.7 ng/mL) (odds ratio [95% CI]: 1.8 [0.9-4]). CONCLUSIONS: For the most part, 25(OH)D was not associated with ovarian reserve biomarkers in a group of women trying to become pregnant. We found some evidence that low 25(OH)D (<30 ng/mL) was associated with low AMH, but this should be confirmed in studies with a higher prevalence of low 25(OH)D.

11.
Epidemiology ; 29(3): 388-396, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29337846

RESUMO

BACKGROUND: Vitamin D insufficiency is associated with subfertility and prolonged estrus cycles in animals, but humans have not been well studied. METHODS: A prospective time-to-pregnancy study, Time to Conceive (2010-2015), collected up to 4 months of daily diary data. Participants were healthy, late reproductive-aged women in North Carolina who were attempting pregnancy. We examined menstrual cycle length as a continuous variable and in categories: long (35+ days) and short (≤25 days). Follicular phase length and luteal phase length were categorized as long (18+ days) or short (≤10 days). We estimated associations between those lengths and serum 25-hydroxyvitamin D (25[OH]D) using linear mixed models and marginal models. RESULTS: There were 1,278 menstrual cycles from 446 women of whom 5% were vitamin D deficient (25[OH]D, <20 ng/ml), 69% were between 20 and 39 ng/ml, and 26% were 40 ng/ml or higher. There was a dose-response association between vitamin D levels and cycle length. Compared with the highest 25(OH)D level (≥40 ng/ml), 25(OH)D deficiency was associated with almost three times the odds of long cycles (adjusted odds ratio [aOR] = 2.8 [95% confidence interval (CI) = 1.0, 7.5]). The aOR was 1.9 (1.1, 3.5) for 20 to <30 ng/ml. The probability of a long follicular phase and the probability of a short luteal phase both increased with decreasing 25(OH)D. CONCLUSIONS: Lower levels of 25(OH)D are associated with longer follicular phase and an overall longer menstrual cycle. Our results are consistent with other evidence supporting vitamin D's role in the reproductive axis, which may have broader implications for reproductive success.

12.
Int J Epidemiol ; 47(1): 121-130, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29149272

RESUMO

Background: It has been debated whether mild analgesics, mainly paracetamol, adversely affect aspects of neurodevelopment. We examined whether mother's use of paracetamol, aspirin or ibuprofen in pregnancy is associated with increased risk of cerebral palsy (CP) in the child. Method: We included 185 617 mother-child pairs from the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study. We created harmonized definitions of analgesic use in pregnancy, as well as indications for analgesic use and other potential confounders. Children with CP were identified in nationwide registers. We estimated the average causal effect of analgesics on risk of CP using marginal structural models with stabilized inverse probability weights. Results: Paracetamol use was reported in 49% of all pregnancies, aspirin in 3% and ibuprofen in 4%. Prenatal exposure to paracetamol ever in pregnancy was associated with increased risk of overall CP [adjusted odds ratio (aOR) 1.3, 95% confidence interval (CI): 1.0-1.7] and unilateral spastic CP (aOR 1.5, 95% CI: 1.0-2.2). The association appeared to be driven by an increased risk of unilateral spastic CP in children exposed in second trimester (aOR 1.6, 95% CI: 1.0-2.5). Children ever prenatally exposed to aspirin in pregnancy had an elevated risk of bilateral spastic CP (aOR 2.4, 95% CI: 1.1-5.3) compared with unexposed. Conclusion: We observed an increased risk of spastic CP in children prenatally exposed to paracetamol and aspirin. Although we controlled for several important indications for analgesic use, we cannot exclude the possibility of confounding by underlying diseases.

13.
Hum Reprod ; 32(11): 2298-2304, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29025107

RESUMO

STUDY QUESTION: Among babies born by ART, do singleton survivors of a vanishing twin have lower birth weight than other singletons? SUMMARY ANSWER: Vanishing twin syndrome (VTS) was associated with lower birth weight among ART singletons; a sibship analysis indicated that the association was not confounded by maternal characteristics that remain stable between deliveries. WHAT IS KNOWN ALREADY: Previous studies indicate that ART singletons with VTS have increased risk of adverse pregnancy outcomes, compared with other ART singletons. The potential contribution of unmeasured maternal background characteristics has been unclear. STUDY DESIGN, SIZE AND DURATION: This was a Norwegian population-based registry study, including 17 368 mothers with 20 410 ART singleton deliveries between January 1984 and December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 17 291 ART singletons without VTS, 638 ART singletons with VTS and 2418 ART singletons with uncertain vanishing twin status. We estimated differences in birth weight and gestational age comparing ART singletons with VTS first to all ART singletons without VTS, and subsequently to their ART siblings without VTS, using random- and fixed-effects linear regression, respectively. The corresponding comparisons for the associations with preterm birth and small for gestational age (SGA) were conducted using random-and fixed-effects logistic regression. The sibling analysis of preterm birth included 587 discordant siblings, while the sibling analysis of SGA included 674 discordant siblings. MAIN RESULTS AND THE ROLE OF CHANCE: ART singletons with VTS had lower birth weight when compared to all ART singletons without VTS, with an adjusted mean difference (95% CI) of -116 g (-165, -67). When we compared ART singletons with VTS to their ART singletons sibling without VTS, the adjusted mean difference was -112 g (-209, -15). ART singletons with VTS also had increased risk of being born SGA, with an adjusted odds ratio (OR) (95% CI) of 1.48 (1.07, 2.03) compared to all ART singletons without VTS, and 2.79 (1.12, 6.91) in the sibship analyses. ART singletons with VTS were also more likely to be born preterm, although this difference did not reach statistical significance. LIMITATIONS REASONS FOR CAUTION: We did not have information on maternal socio-economic status, but this factor is accounted for in the sibship analyses. We also had no information on whether fresh or frozen embryos were replaced. WIDER IMPLICATIONS OF THE FINDINGS: The reduction in birth weight and increased risk of SGA in ART singletons with VTS may suggest the presence of harmful intrauterine factors with long-term health impact. While vanishing twins are not routinely observed in naturally conceived pregnancies, loss of a twin is potentially a risk factor for the surviving foetus in any pregnancy. This could be further explored in large samples of naturally conceived pregnancies with the necessary information. STUDY FUNDING/COMPETING INTEREST(S): The authors of this study are supported in part by the UK Medical Research Council, US National Institute of Environmental Health Sciences and the Norwegian Research Council. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Aborto Espontâneo , Peso ao Nascer/fisiologia , Resultado da Gravidez , Gravidez de Gêmeos , Técnicas de Reprodução Assistida , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
14.
PLoS One ; 12(9): e0184358, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898263

RESUMO

Cleft palate only is a common birth defect with high heritability. Only a small fraction of this heritability is explained by the genetic variants identified so far, underscoring the need to investigate other disease mechanisms, such as gene-environment (GxE) interactions and parent-of-origin (PoO) effects. Furthermore, PoO effects may vary across exposure levels (PoOxE effects). Such variation is the focus of this study. We upgraded the R-package Haplin to enable direct tests of PoOxE effects at the genome-wide level. From a previous GWAS, we had genotypes for 550 case-parent trios, of mainly European and Asian ancestry, and data on three maternal exposures (smoking, alcohol, and vitamins). Data were analyzed for Europeans and Asians separately, and also for all ethnicities combined. To account for multiple testing, a false discovery rate method was used, where q-values were generated from the p-values. In the Europeans-only analyses, interactions with maternal smoking yielded the lowest q-values. Two SNPs in the 'Interactor of little elongation complex ELL subunit 1' (ICE1) gene had a q-value of 0.14, and five of the 20 most significant SNPs were in the 'N-acetylated alpha-linked acidic dipeptidase-like 2' (NAALADL2) gene. No evidence of PoOxE effects was found in the other analyses. The connections to ICE1 and NAALADL2 are novel and warrant further investigation. More generally, the new methodology presented here is easily applicable to other traits and exposures in which a family-based study design has been implemented.


Assuntos
Fissura Palatina/genética , Interação Gene-Ambiente , Exposição Materna/efeitos adversos , Polimorfismo de Nucleotídeo Único , Consumo de Bebidas Alcoólicas/epidemiologia , Grupo com Ancestrais do Continente Asiático , Deficiência de Vitaminas/epidemiologia , Proteínas de Transporte/genética , Fissura Palatina/epidemiologia , Fissura Palatina/etnologia , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Glutamato Carboxipeptidase II/genética , Humanos , Masculino , Fumar/epidemiologia
15.
Environ Health Perspect ; 125(6): 067022, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28669933

RESUMO

BACKGROUND: Preeclampsia (PE) is a dangerous and unpredictable pregnancy complication. A seasonal pattern of risk would suggest that there are potentially preventable environmental contributors, but prior analyses have not adjusted for confounding by PE risk factors that are associated with season of conception. METHODS: Seasonal effects were modeled and tested by representing each day of the year as an angle on a unit circle and using trigonometric functions of those angles in predictive models, using "harmonic analysis." We applied harmonic Cox regression to model confounder-adjusted effects of the estimated day of the year of conception on risk of PE for births from the Medical Birth Registry of Norway for deliveries between 1999 and 2009. We also examined effect measure modification by parity, latitude (region), fetal sex, and smoking. RESULTS: In adjusted models, PE risk was related to season, with higher risk in spring conceptions and lower risk in autumn conceptions, with a risk amplitude (maximum compared with minimum) of about 20%. The pattern replicated across subpopulations defined by parity, latitude (region), fetal sex, and smoking. CONCLUSIONS: These results suggest that there is a seasonal driver for PE, with effects that are not modified by parity, latitude, fetal sex, or smoking. https://doi.org/10.1289/EHP963.


Assuntos
Pré-Eclâmpsia/epidemiologia , Fumar/epidemiologia , Feminino , Fertilização , Humanos , Noruega/epidemiologia , Gravidez , Complicações na Gravidez
16.
Epidemiology ; 28(4): 575-579, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28346268

RESUMO

BACKGROUND: Early-life factors can be associated with future health outcomes and are often measured by maternal recall. METHODS: We used data from the North Carolina Early Pregnancy Study and Follow-up to characterize long-term maternal recall. We used data from the Early Pregnancy Study as the gold standard to evaluate the accuracy of prepregnancy weight, early pregnancy behaviors, symptoms and duration of pregnancy, and child's birthweight reported at follow-up, for 109 women whose study pregnancies had resulted in a live birth. RESULTS: Most (81%) participants reported a prepregnancy weight at follow-up that correctly classified them by BMI category. Women reported experiencing pregnancy symptoms later at follow-up than what they reported in the Early Pregnancy Study. Accuracy of reporting of early pregnancy behaviors varied based on exposure. Overall, women who had abstained from a behavior were more likely to be classified correctly. Sensitivity of reporting was 0.14 for antibiotics, 0.30 for wine, 0.71 for brewed coffee, and 0.82 for vitamins. Most misclassification at follow-up was due to false-negative reporting. Among women who gave birth to singletons, 94% could report their child's correct birthweight within ½ pound and 86% could report duration of pregnancy within 7 days at follow-up. CONCLUSIONS: Self-report of prepregnancy weight, duration of pregnancy, and child's birthweight after almost 30 years was good, whereas self-reported pregnancy-related exposures resulted in higher levels of reporting error. Social desirability appeared to influence women's report of their behaviors at follow-up. Self-reported assessment of confidence in the recalled information was unrelated to accuracy.


Assuntos
Idade Gestacional , Saúde Materna , Resultado da Gravidez , Nascimento Prematuro , Autorrelato , Adolescente , Adulto , Peso ao Nascer , Estudos Transversais , Feminino , Humanos , Recém-Nascido , Idade Materna , North Carolina , Gravidez , Medição de Risco , Inquéritos e Questionários
17.
Ann Epidemiol ; 27(2): 103-107.e2, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28202134

RESUMO

PURPOSE: To examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts. METHODS: We studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors. RESULTS: We found a significant negative smoking-BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39-1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34-1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22-1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04-1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92-1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only. CONCLUSIONS: Our findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking-BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women.


Assuntos
Índice de Massa Corporal , Fenda Labial/etiologia , Fissura Palatina/etiologia , Obesidade/complicações , Fumar/efeitos adversos , Adolescente , Adulto , Estudos de Casos e Controles , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Dinamarca/epidemiologia , Feminino , Humanos , Modelos Logísticos , Noruega/epidemiologia , Razão de Chances , Gravidez , Primeiro Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
18.
BMJ Open ; 6(11): e012894, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27884847

RESUMO

OBJECTIVE: To assess the association between perinatal losses and mother's long-term mortality and modification by surviving children and attained education. DESIGN: A population-based cohort study. SETTING: Norwegian national registries. PARTICIPANTS: We followed 652 320 mothers with a first delivery from 1967 and completed reproduction before 2003, until 2010 or death. We excluded mothers with plural pregnancies, without information on education (0.3%) and women born outside Norway. MAIN OUTCOME MEASURES: Main outcome measures were age-specific (40-69 years) cardiovascular and non-cardiovascular mortality. We calculated mortality in mothers with perinatal losses, compared with mothers without, and in mothers with one loss by number of surviving children in strata of mothers' attained education (<11 years (low), ≥11 years (high)). RESULTS: Mothers with perinatal losses had increased crude mortality compared with mothers without; total: HR 1.3 (95% CI 1.3 to 1.4), cardiovascular: HR 1.8 (1.5 to 2.1), non-cardiovascular: HR 1.3 (1.2 to 1.4). Childless mothers with one perinatal loss had increased mortality compared with mothers with one child and no loss; cardiovascular: low education HR 2.7 (1.7 to 4.3), high education HR 0.91 (0.13 to 6.5); non-cardiovascular: low education HR 1.6 (1.3 to 2.2), high education HR 1.8 (1.1 to 2.9). Mothers with one perinatal loss, surviving children and high education had no increased mortality, whereas corresponding mothers with low education had increased mortality; cardiovascular: two surviving children HR 1.7 (1.2 to 2.4), three or more surviving children HR 1.6 (1.1 to 2.4); non-cardiovascular: one surviving child HR 1.2 (1.0 to 1.5), two surviving children HR 1.2 (1.1 to 1.4). CONCLUSIONS: Irrespective of education, we find excess mortality in childless mothers with a perinatal loss. Increased mortality in mothers with one perinatal loss and surviving children was limited to mothers with low education.


Assuntos
Doenças Cardiovasculares/mortalidade , Escolaridade , Mortalidade Materna , Mortalidade Perinatal , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Noruega , Gravidez , Sistema de Registros , Fatores de Risco
19.
Pediatrics ; 138(4)2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27609826

RESUMO

OBJECTIVES: To investigate the association between maternal pre-pregnancy BMI and risk of cerebral palsy (CP) in offspring. METHODS: The study population consisted of 188 788 children in the Mothers and Babies in Norway and Denmark CP study, using data from 2 population-based, prospective birth cohorts: the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort. Prepregnancy BMI was classified as underweight (BMI <18.5), lower normal weight (BMI 18.5-22.9), upper normal weight (BMI 23.0-24.9), overweight (BMI 25.0-29.9), and obese (BMI ≥30). CP diagnoses were obtained from the national CP registries. Associations between maternal prepregnancy BMI and CP in offspring were investigated by using log-binomial regression models. RESULTS: The 2 cohorts had 390 eligible cases of CP (2.1 per 1000 live-born children). Compared with mothers in the lower normal weight group, mothers in the upper normal group had a 40% excess risk of having a child with CP (relative risk [RR], 1.35; 95% confidence interval [CI], 1.03-1.78). Excess risk was 60% (RR, 1.56; 95% CI, 1.21-2.01) for overweight mothers and 60% (RR, 1.55; 95% CI 1.11-2.18) for obese mothers. The risk of CP increased ∼4% for each unit increase in BMI (RR, 1.04; 95% CI, 1.02-1.06). Estimates changed little with adjustment for mother's occupational status, age, and smoking habits. CONCLUSIONS: Higher prepregnancy maternal BMI was associated with increased risk of CP in offspring.


Assuntos
Índice de Massa Corporal , Paralisia Cerebral/epidemiologia , Mães , Sobrepeso/epidemiologia , Adulto , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Noruega/epidemiologia , Gravidez , Prevalência , Risco , Adulto Jovem
20.
BMJ Open ; 6(9): e012777, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27591025

RESUMO

PURPOSE: The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. PARTICIPANTS: MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts-the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. FINDINGS TO DATE: Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going. FUTURE PLANS: Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children.


Assuntos
Paralisia Cerebral/etiologia , Complicações na Gravidez , Adulto , Estudos de Coortes , Dinamarca , Feminino , Humanos , Lactente , Masculino , Noruega , Gravidez , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Inquéritos e Questionários
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