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1.
Hum Reprod ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600381

RESUMO

STUDY QUESTION: Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age? SUMMARY ANSWER: Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age. WHAT IS KNOWN ALREADY: A study of 397 young Filipino women (ages 20-22) observed increasing epigenetic age with an increasing number of pregnancies. STUDY DESIGN, SIZE, DURATION: We used data from 2356 non-Hispanic white women (ages 35-74) enrolled in the Sister Study cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina's HumanMethylation450 BeadChip. We estimated association ß-values and 95% CIs using linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: ß = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: ß = 0.12, 95% CI = -0.04, 0.27, P = 0.14; Levine: ß = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (ß = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (ß = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7). LIMITATIONS, REASONS FOR CAUTION: We relied on retrospective recall to ascertain reproductive history and pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

2.
Hypertension ; 74(2): 375-383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230546

RESUMO

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

4.
J Womens Health (Larchmt) ; 27(10): 1278-1284, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29897832

RESUMO

BACKGROUND: Bacterial vaginosis (BV), the leading cause of vaginal discharge, is associated with multiple adverse health outcomes; however, its etiology is unknown. BV treatment is not very effective, thus prevention approaches are needed. Studies investigating the impact of vitamin D on the risk of BV have had mixed findings, including two studies reporting increased risk of recurrent BV for women with higher vitamin D. MATERIALS AND METHODS: Participants were nonpregnant women in a prospective fibroid study of African Americans (ages 23-34 years) from the Detroit area. The exposure was seasonally adjusted annual mean serum 25-hydroxyvitamin D [25(OH)D] at enrollment. The outcome was self-reported doctor-diagnosed BV over ∼20 months between baseline and follow-up. Multivariable-adjusted binomial regression models estimated the risk of BV for a doubling of 25(OH)D and sufficient (≥20 ng/mL) versus deficient (<20 ng/mL) 25(OH)D. RESULTS: In total, 1459 women were included. Median 25(OH)D was 15.2 ng/mL and 73% were deficient. Sixteen percent of participants reported BV diagnoses over follow-up, 78% of whom had recurrent BV. In multivariable-adjusted analyses, a doubling of 25(OH)D was associated with an increased, rather than the hypothesized decreased, risk of self-reported BV (risk ratio [RR] 1.22, 95% confidence interval 1.02-1.48). Sufficient women also had a significantly higher, rather than lower, risk of self-reported BV (RR 1.31). Results were robust to sensitivity analyses, and post hoc analyses showed no evidence of reverse causation. CONCLUSIONS: Overall, our findings do not support vitamin D deficiency as a risk factor for BV in these young, nonpregnant African American women.

5.
Front Genet ; 9: 67, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29545823

RESUMO

Genetic factors likely influence individuals' concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D exposure previously linked to reduced risk of several chronic diseases. We conducted a genome-wide association study of serum 25(OH)D (assessed using liquid chromatography-tandem mass spectrometry) and 386,449 single nucleotide polymorphisms (SNPs). Our sample consisted of 1,829 participants randomly selected from the Sister Study, a cohort of women who had a sister with breast cancer but had never had breast cancer themselves. 19,741 SNPs were associated with 25(OH)D (p < 0.05). We re-assessed these hits in an independent sample of 1,534 participants who later developed breast cancer. After pooling, 32 SNPs had genome-wide significant associations (p < 5 × 10-8). These were located in or near GC, the vitamin D binding protein, or CYP2R1, a cytochrome P450 enzyme that hydroxylates vitamin D to form 25(OH)D. The top hit was rs4588, a missense GC polymorphism associated with a 3.5 ng/mL decrease in 25(OH)D per copy of the minor allele (95% confidence interval [CI]: -4.1, -3.0; p = 4.5 × 10-38). The strongest SNP near CYP2R1 was rs12794714, a synonymous variant (p = 3.8 × 10-12; ß = 1.8 ng/mL decrease in 25(OH)D per minor allele [CI: -2.2, -1.3]). Serum 25(OH)D concentrations from samples collected from some participants 3-10 years after baseline (811 cases, 780 non-cases) were also strongly associated with both loci. These findings augment our understanding of genetic influences on 25(OH)D and the possible role of vitamin D binding proteins and cytochrome P450 enzymes in determining measured levels. These results may help to identify individuals genetically predisposed to vitamin D insufficiency.

6.
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.

7.
Paediatr Perinat Epidemiol ; 32(1): 1-12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881463

RESUMO

BACKGROUND: Preeclampsia is thought to originate during placentation, with incomplete remodelling and perfusion of the spiral arteries leading to reduced placental vascular capacity. Nitric oxide (NO) and carbon monoxide (CO) are powerful vasodilators that play a role in the placental vascular system. Although family clustering of preeclampsia has been observed, the existing genetic literature is limited by a failure to consider both mother and child. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Birth Cohort of 1545 case-pairs and 995 control-pairs from 2540 validated dyads (2011 complete pairs, 529 missing mother or child genotype). We selected 1518 single-nucleotide polymorphisms (SNPs) with minor allele frequency >5% in NO and CO signalling pathways. We used log-linear Poisson regression models and likelihood ratio tests to assess maternal and child effects. RESULTS: One SNP met criteria for a false discovery rate Q-value <0.05. The child variant, rs12547243 in adenylate cyclase 8 (ADCY8), was associated with an increased risk (relative risk [RR] 1.42, 95% confidence interval [CI] 1.20, 1.69 for AG vs. GG, RR 2.14, 95% CI 1.47, 3.11 for AA vs. GG, Q = 0.03). The maternal variant, rs30593 in PDE1C was associated with a decreased risk for the subtype of preeclampsia accompanied by early delivery (RR 0.45, 95% CI 0.27, 0.75 for TC vs. CC; Q = 0.02). None of the associations were replicated after correction for multiple testing. CONCLUSIONS: This study uses a novel approach to disentangle maternal and child genotypic effects of NO and CO signalling genes on preeclampsia.


Assuntos
Monóxido de Carbono/metabolismo , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/genética , Transdução de Sinais/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genes/genética , Predisposição Genética para Doença/genética , Técnicas de Genotipagem , Humanos , Recém-Nascido , Noruega/epidemiologia , Distribuição de Poisson , Polimorfismo de Nucleotídeo Único/genética , Gravidez
8.
J Clin Endocrinol Metab ; 101(9): 3370-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27490916

RESUMO

CONTEXT: Small studies suggest exogenous estrogen may improve vitamin D status, but the etiology is unclear because women who use hormones may make lifestyle choices that differentially affect vitamin D status. OBJECTIVE: Our objective was to investigate the association between use of hormonal contraception and 25-hydroxy-vitamin D (25(OH)D). DESIGN: We used linear regression modeling of cross-sectional data to estimate percent change in season-adjusted serum 25(OH)D with estrogen use after adjustment for other factors. SETTING: At the enrollment clinic visit (2010-2012) into a cohort study of uterine fibroids, each subject provided a blood sample, had anthropomorphic variables and skin reflectance measured, and answered questionnaires on demographics, dietary and supplement intake, contraceptive use, reproductive and medical history, and behaviors. PARTICIPANTS: A total of 1662 African American women, community volunteers, 23-34 years old, living in the Detroit, Michigan, area were included. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Serum 25(OH)D was measured. RESULTS: Serum 25(OH)D concentrations were low (70% <20 ng/ml). Current use of an estrogen-containing contraceptive was associated with a 20% (95% confidence interval: 14-27) increase in 25(OH)D after adjustment. There was no increase in 25(OH)D among participants who had used estrogen in the past, but were not current users, indicating that results were unlikely to be due to unmeasured confounding by factors related to contraceptive choice. CONCLUSIONS: The increase in 25(OH)D with use of estrogen-containing contraceptives raise mechanistic questions regarding the biological pathways involved, and highlights the need for studies that examine possible endogenous estrogen effects on vitamin D.


Assuntos
Biomarcadores/sangue , Anticoncepção , Estrogênios/farmacologia , Leiomioma/sangue , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Estudos de Coortes , Anticoncepcionais Orais Hormonais/administração & dosagem , Estudos Transversais , Feminino , Seguimentos , Humanos , Leiomioma/tratamento farmacológico , Prognóstico , Vitamina D/sangue
9.
Genet Epidemiol ; 40(8): 722-731, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27488097

RESUMO

Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach.


Assuntos
Peso ao Nascer/genética , Interpretação Estatística de Dados , Estudos de Associação Genética , Marcadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Seleção Genética/genética , Ferimentos e Lesões/genética , Endotelina-1/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Modelos Genéticos , Fenótipo
10.
Epidemiology ; 27(5): 716-25, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27196806

RESUMO

BACKGROUND: Phytoestrogen exposure from soy formula feeding during infancy may disrupt reproductive system development, resulting in altered menstrual bleeding in adulthood. METHODS: We investigated this relationship in a cohort of 1,696 young African American women using enrollment data from the Study of Environment, Lifestyle, & Fibroids (2010-2012). Questionnaire data on soy formula feeding were available for 1,553 participants, 89% based on mother's report. Menstrual bleeding outcomes including those indicative of heavy menstrual bleeding were ascertained by interview. We estimated relative risks (RRs) and 95% confidence intervals (CI) for associations between soy formula feeding and menstrual bleeding outcomes using log-binomial regression and log-multinomial regression, comparing participants ever fed and never fed soy formula. RESULTS: We observed associations between soy formula feeding and variables indicating a history of heavy menstrual bleeding, including ever experiencing heavy, gushing-type bleeding (RR: 1.2, 95% CI: 1.0, 1.4), ever use of nonsteroidal anti-inflammatory drugs for heavy bleeding (RR: 1.3, 95% CI: 1.0, 1.6), and ever use of a contraceptive method for heavy bleeding (RR: 1.2, 95% CI, 0.9, 1.6). Among the subset of participants with menses in the past year who did not use medication that may alter menstrual flow (n = 762), our data suggested that soy formula feeding was associated with heavier flow and the adverse impact of menstrual bleeding on quality of life, but CIs were wide. CONCLUSIONS: Our data suggested that soy formula feeding is associated with heavy menstrual bleeding. Our results support the idea that infancy is a susceptible developmental window for female reproductive function.


Assuntos
Afro-Americanos/estatística & dados numéricos , Fórmulas Infantis/estatística & dados numéricos , Menorragia/epidemiologia , Alimentos de Soja/estatística & dados numéricos , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Humanos , Lactente , Menarca , Menorragia/terapia , Paridade , Qualidade de Vida , Análise de Regressão , Fatores de Risco , Adulto Jovem
11.
Fertil Steril ; 106(1): 172-179.e2, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26997249

RESUMO

OBJECTIVE: To examine the association between serum 25-hydroxyvitamin D [25(OH)D] and menstrual cycle length and regularity. DESIGN: Community-based, cross-sectional study of serum 25(OH)D (adjusted for seasonal differences in timing of blood draw) and menstrual cycle length. Women aged 23-34 years reported their gynecologic history. Menstrual cycles were described with four independent categories (normal, short, long, irregular). We used polytomous logistic regression to estimate the association between a doubling of seasonally adjusted 25(OH)D and the odds of each cycle category. SETTING: Not applicable. PATIENT(S): A total of 1,102 African American women. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Self-reported menstrual cycle length over the previous 12 months, excluding women who were using cycle-regulating medications over the entire year. Women who reported that their cycles were "too irregular to estimate" were classified as having irregular cycles. A typical cycle length of <27 days was considered "short," >34 days was "long," and 27-34 days was "normal." RESULT(S): The median 25(OH)D level was 14.7 ng/mL (interquartile range, 10.9-19.6 ng/mL). A doubling of 25(OH)D was associated with half the odds of having long menstrual cycles: adjusted odds ratio (aOR) 0.54, 95% confidence interval (CI) 0.32-0.89. 25-Hydroxyvitamin D was not associated with the occurrence of short (aOR 1.03, 95% CI 0.82-1.29) or irregular (aOR 1.46, 95% CI 0.88-2.41) menstrual cycles. Results were robust to several sensitivity analyses. CONCLUSION(S): These findings suggest that vitamin D status may influence the menstrual cycle and play a role in ovarian function. Further investigation of 25(OH)D and ovarian hormones, and prospective studies of 25(OH)D and cycle length, are needed.


Assuntos
Afro-Americanos , Ciclo Menstrual/etnologia , Distúrbios Menstruais/etnologia , Deficiência de Vitamina D/etnologia , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Ciclo Menstrual/sangue , Distúrbios Menstruais/sangue , Distúrbios Menstruais/diagnóstico , Distúrbios Menstruais/fisiopatologia , Michigan , Razão de Chances , Ovário/fisiopatologia , Ovulação , Fatores de Risco , Estações do Ano , Fatores de Tempo , Regulação para Cima , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Adulto Jovem
12.
Environ Health Perspect ; 124(6): 769-75, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26565393

RESUMO

BACKGROUND: Early-life soy phytoestrogen exposure has been shown in Eker rats to increase uterine fibroid incidence in adulthood. Two large epidemiologic cohorts have provided some support for increased fibroid risk with infant soy formula feeding in women, but both cohorts relied on self-report of clinically diagnosed fibroids. OBJECTIVE: We evaluated the relationship between infant soy formula feeding and ultrasound-detected fibroids. METHODS: The Study of Environment, Lifestyle & Fibroids (SELF) is an ongoing cohort study of 1,696 African-American women ages 23-34 years with baseline ultrasound screening to detect and measure fibroids ≥ 0.5 cm in diameter. Questionnaire data on soy formula feeding during infancy was ascertained for 1,553 participants (89% based on mother's report), of whom 345 were found to have fibroids. We estimated the association between soy formula feeding and fibroid prevalence and tumor number using log-binomial regression. Among those with fibroids, we compared fibroid size between soy formula-exposed and unexposed women using multivariable linear regression. RESULTS: We did not observe an association between soy formula feeding and fibroid prevalence [adjusted prevalence ratio (aPR) 0.9, 95% CI: 0.7, 1.3]. Nor were exposed women with fibroids more likely to have ≥ 2 tumors than unexposed women with fibroids (aPR 1.0, 95% CI: 0.7, 1.6). However, exposed women with fibroids had significantly larger fibroids than unexposed women with fibroids. On average, soy formula feeding was associated with a 32% increase in the diameter of the largest fibroid (95% CI: 6%, 65%) and a 127% increase in total tumor volume (95% CI: 12%, 358%). CONCLUSIONS: Our observation that women fed soy formula as infants have larger fibroids than unexposed women provides further support for persistent effects of early life phytoestrogen exposure on the uterus. CITATION: Upson K, Harmon QE, Baird DD. 2016. Soy-based infant formula feeding and ultrasound-detected uterine fibroids among young African-American women with no prior clinical diagnosis of fibroids. Environ Health Perspect 124:769-775; http://dx.doi.org/10.1289/ehp.1510082.


Assuntos
Fórmulas Infantis/estatística & dados numéricos , Leiomioma/epidemiologia , Leite de Soja/estatística & dados numéricos , Adulto , Afro-Americanos , Estudos de Coortes , Feminino , Humanos , Leiomioma/diagnóstico , Prevalência , Autorrelato , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
13.
J Womens Health (Larchmt) ; 24(11): 907-15, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26334691

RESUMO

BACKGROUND: Uterine fibroids are common, benign, smooth-muscle tumors that can cause major morbidity for reproductive-age women, often requiring invasive treatment. Despite this personal and public health burden, no prior study has attempted to periodically screen fibroid-free women with ultrasound to detect incident disease and identify risk factors. METHODS: We designed a study to prospectively investigate development of fibroids by enrolling women without a clinical diagnosis of fibroids and screening for fibroids with ultrasound at baseline. Enrollment procedures included extensive questionnaires and specimen collection (blood, urine, vaginal swabs). The cohort is followed at approximately 20-month intervals. At each follow-up there are updates to the questionnaire data, further specimen collection, and an ultrasound examination. We identify incident disease and measure tumor growth. The two exposures of primary interest are vitamin D insufficiency and reproductive tract infections. This manuscript provides a detailed description of the study methods, recruitment results, and participant characteristics. RESULTS: The Study of Environment, Lifestyle and Fibroids enrolled 1,696 African American women aged 23-34 years. "Family and friends" was a leading recruitment source. More than 95% of participants contributed all the requested biological specimens at baseline. Study ultrasound examinations revealed undiagnosed fibroids in 378 women (22% of participants). The retention rate for the first follow-up was 87%. CONCLUSIONS: Study design aspects likely to be important for long-term studies in young African Americans include personalized recruitment, multiple steps to the enrollment process that rely on the initiative of the participant, and methods for tracing highly mobile study subjects.


Assuntos
Afro-Americanos/estatística & dados numéricos , Leiomioma/diagnóstico por imagem , Seleção de Pacientes , Infecções do Sistema Genital/etnologia , Neoplasias Uterinas/diagnóstico por imagem , Deficiência de Vitamina D/complicações , Adulto , Feminino , Seguimentos , Humanos , Incidência , Leiomioma/etnologia , Estudos Prospectivos , Projetos de Pesquisa , Inquéritos e Questionários , Ultrassonografia , Estados Unidos/epidemiologia , Neoplasias Uterinas/etnologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/etnologia , Adulto Jovem
14.
Obstet Gynecol ; 125(3): 628-35, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25730226

RESUMO

OBJECTIVE: To estimate gestational age-specific risks of fetal death in pregnancies complicated by preeclampsia. METHODS: Population-based cohort study comprising all singleton births (N=554,333) without preexisting chronic hypertension recorded in the Norwegian Medical Birth Registry from 1999 to 2008. Additional data come from a subset of preeclamptic pregnancies enrolled in the Norwegian Mother and Child Cohort Study with available medical records (n=3,037). The risk of fetal death, expressed per 1,000 fetuses exposed to preeclampsia, was calculated using a life table approach. RESULTS: Preeclampsia was recorded in 3.8% (n=21,020) of all pregnancies. Risk of stillbirth was 3.6 per 1,000 overall and 5.2 per 1,000 among pregnancies with preeclampsia (relative risk 1.45, 95% confidence interval [CI] 1.20-1.76). However, relative risk of stillbirth was markedly elevated with preeclampsia in early pregnancy. At 26 weeks of gestation, there were 11.6 stillbirths per 1,000 pregnancies with preeclampsia compared with 0.1 stillbirths per 1,000 pregnancies without (relative risk 86, 95% CI 46-142). Fetal risk with preeclampsia declined as pregnancy advanced, but at 34 weeks of gestation remained more than sevenfold higher than pregnancies without preeclampsia. CONCLUSION: For clinical purposes, the fetal risk of death associated with preeclampsia begins when preeclampsia becomes clinically apparent. Using a method that takes into account the clinical diagnosis of preeclampsia and the population of fetuses at risk, we find a remarkably high relative risk of fetal death among pregnancies diagnosed with preeclampsia in the preterm period. LEVEL OF EVIDENCE: II.


Assuntos
Morte Fetal/etiologia , Pré-Eclâmpsia/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adulto , Estudos de Coortes , Feminino , Humanos , Noruega/epidemiologia , Gravidez , Medição de Risco , Adulto Jovem
16.
Eur J Epidemiol ; 29(10): 753-65, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25193741

RESUMO

Preeclampsia and preterm delivery are serious complications of pregnancy and leading causes of perinatal mortality and morbidity worldwide. Dietary factors might be associated with these adverse outcomes. We investigated whether adherence to the New Nordic Diet (NND) was associated with preeclampsia and preterm delivery risks in the Norwegian Mother and Child Cohort Study (MoBa). Participants were recruited from all over Norway during the period 1999-2008. A previously constructed diet score assessing meal frequency, and the consumption of Nordic fruits, root vegetables, cabbages, potatoes, oatmeal porridge, whole grains, wild fish, game, berries, milk and water, was used to assess NND adherence. Associations between NND adherence and the outcomes were estimated in adjusted multivariate logistic regression models. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated. A total of 72,072 women was included in the study. High versus low NND adherence was associated with lower risk of total preeclampsia (OR 0.86; 95 % CI 0.78-0.95) and early preeclampsia (OR 0.71; 95 % CI 0.52-0.96). High compared with low NND adherence was associated with a lower risk of spontaneous preterm delivery among nulliparous women (OR 0.77; 95 % CI 0.66-0.89), whereas multiparous women with high NND adherence had a marginally significant higher risk of preterm delivery (OR 1.24; 95 % CI 1.00-1.53). High NND adherence was associated with a lower relative risk of preeclampsia and of spontaneous preterm delivery among nulliparous women; however, among multiparous women there was a higher relative risk of preterm delivery.


Assuntos
Dieta , Comportamento Alimentar , Pré-Eclâmpsia/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Inquéritos sobre Dietas , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Mães , Análise Multivariada , Noruega/epidemiologia , Razão de Chances , Cooperação do Paciente/estatística & dados numéricos , Pré-Eclâmpsia/prevenção & controle , Gravidez , Nascimento Prematuro/prevenção & controle , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
17.
Paediatr Perinat Epidemiol ; 28(5): 362-71, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25040774

RESUMO

BACKGROUND: The Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based pregnancy cohort, is a valuable database for studying causes of pre-eclampsia. Pre-eclampsia data in MoBa come from the Medical Birth Registry of Norway (MBRN); thus, we wanted to study the validity of MBRN pre-eclampsia registration for MoBa women. METHODS: We selected all MoBa pregnancies with pre-eclampsia registered in the MBRN (n = 4081) and a random control group (n = 2000) without pre-eclampsia registrations. After excluding two delivery units not participating in MoBa and one no longer operating, units were asked to provide copies of antenatal charts with blood pressure and urinary measurements from all antenatal visits during pregnancy, and hospital discharge codes from the delivery stay. We received data for 5340 pregnancies delivered 1999-2010 (87% of all eligible). We calculated positive predictive value (PPV), and sensitivity and specificity of MBRN registration, using hypertension and proteinuria on the antenatal charts and/or hospital discharge codes indicating pre-eclampsia as gold standard. RESULTS: Overall PPV was 83.9% [95% CI 82.7, 85.1] and was higher when women were primiparous, or delivered preterm or low birthweight infants. Severe pre-eclampsia in the MBRN was found to be a true severe pre-eclampsia in 70% of cases. Extrapolating to the total MoBa population, the estimated sensitivity was low - 43.0% (38.7, 48.2) - while specificity was high - 99.2% (99.2, 99.3). False negative cases seemed to have mild forms of pre-eclampsia. CONCLUSIONS: PPV and specificity of pre-eclampsia registration in the MBRN during 1999-2010 was satisfactory, while sensitivity was low.


Assuntos
Pré-Eclâmpsia/diagnóstico , Sistema de Registros , Estudos de Casos e Controles , Feminino , Humanos , Noruega/epidemiologia , Pré-Eclâmpsia/epidemiologia , Gravidez , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade
18.
Am J Reprod Immunol ; 71(5): 472-84, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24702779

RESUMO

PROBLEM: Inflammatory biomarkers are associated with preeclampsia (PE) and poor fetal growth; however, genetic epidemiologic studies have been limited by reduced gene coverage and the exclusion of African American mothers. METHOD OF STUDY: Cases and controls (N = 1646) from a pregnancy cohort were genotyped for 503 tagSNPs in 40 genes related to inflammation. Gene-set analyses were stratified by race and were followed by a single SNP analysis within significant gene sets. RESULTS: Gene-level associations were found for IL6 and KLRD1 for term small for gestational age (SGA) among African Americans. LTA/TNF and TBX21 were associated with PE among European Americans. The strongest association was for PE among European Americans for an upstream regulator of TNF with RR = 1.8 (95% CI 1.1-2.7). CONCLUSION: Although previous studies have suggested null associations, increased tagging and stratification by genetic ancestry suggests important associations between IL6 and term SGA for African Americans, and a TNF regulator and PE among European Americans (N = 149).


Assuntos
Recém-Nascido Pequeno para a Idade Gestacional , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/etnologia , Pré-Eclâmpsia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Afro-Americanos , Grupo com Ancestrais do Continente Europeu , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Inflamação/etnologia , Inflamação/genética , Inflamação/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Linfotoxina-alfa/genética , Linfotoxina-alfa/imunologia , Subfamília D de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Pré-Eclâmpsia/imunologia , Gravidez , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Estados Unidos/epidemiologia
19.
Am J Epidemiol ; 178(8): 1208-18, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23982189

RESUMO

Inflammation is implicated in preterm birth, but genetic studies of inflammatory genes have yielded inconsistent results. Maternal DNA from 1,646 participants in the Pregnancy, Infection, and Nutrition Cohort, enrolled in Orange and Wake counties, North Carolina (1995-2005), were genotyped for 432 tag single-nucleotide polymorphisms (SNPs) in 30 candidate genes. Gene-level and SNP associations were modeled within strata of genetic ancestry. Six genes were associated with preterm birth among European Americans: interleukin 12A (IL12A); colony-stimulating factor 2 (CSF2); interferon γ receptor 2 (IFNGR2); killer cell immunoglobulin-like receptor, three domain, long cytoplasmic tail, 2 (KIR3DL2); interleukin 4 (IL4); and interleukin 13 (IL13). Of these, relatively strong single-SNP associations were seen in IFNGR2 and KIR3DL2. Among the 4 genes related to natural killer cell function, 2 (IL12A and CSF2) were consistently associated with reduced risk of prematurity for both European and African Americans. SNPs tagging a locus control region for IL4 and IL13 were associated with an increased risk of spontaneous preterm birth for European Americans (rs3091307; risk ratio = 1.9; 95% confidence interval: 1.4, 2.5). Although gene-level associations were detected only in European Americans, single-SNP associations among European and African Americans were often similar in direction, though estimated with less precision among African Americans. In conclusion, we identified novel associations between variants in the natural killer cell immune pathway and prematurity in this biracial US population.


Assuntos
Células Matadoras Naturais , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Afro-Americanos/genética , Estudos de Casos e Controles , Fatores Estimuladores de Colônias/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Técnicas de Genotipagem , Humanos , Interleucinas/genética , Células Matadoras Naturais/fisiologia , Desequilíbrio de Ligação , Gravidez , Nascimento Prematuro/etnologia , Receptores de Interferon/genética , Receptores KIR3DL2/genética , Linfócitos T
20.
Genet Epidemiol ; 37(3): 267-75, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23471868

RESUMO

Joint testing for the cumulative effect of multiple single-nucleotide polymorphisms grouped on the basis of prior biological knowledge has become a popular and powerful strategy for the analysis of large-scale genetic association studies. The kernel machine (KM)-testing framework is a useful approach that has been proposed for testing associations between multiple genetic variants and many different types of complex traits by comparing pairwise similarity in phenotype between subjects to pairwise similarity in genotype, with similarity in genotype defined via a kernel function. An advantage of the KM framework is its flexibility: choosing different kernel functions allows for different assumptions concerning the underlying model and can allow for improved power. In practice, it is difficult to know which kernel to use a priori because this depends on the unknown underlying trait architecture and selecting the kernel which gives the lowest P-value can lead to inflated type I error. Therefore, we propose practical strategies for KM testing when multiple candidate kernels are present based on constructing composite kernels and based on efficient perturbation procedures. We demonstrate through simulations and real data applications that the procedures protect the type I error rate and can lead to substantially improved power over poor choices of kernels and only modest differences in power vs. using the best candidate kernel.


Assuntos
Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Software , Simulação por Computador , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Recém-Nascido , Fenótipo , Gravidez
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