Variations in Inflammatory and Cell Cycle Genes and Preterm Birth, Small for Gestational Age and Hypertensive Disorders of Pregnancy

The maternal outcome of preeclampsia and the fetal outcomes of preterm birth and poor intrauterine growth often occur together, share placental pathology and are marked by changes in inflammatory biomarkers. Genetic polymorphisms in inflammatory genes have been investigated with respect to all of these outcomes with conflicting results. In previous studies case groups have been small or non-representative of US populations, and coverage of candidate genes has been sparse. We sought to expand coverage of inflammatory genes related to natural killer cells and T cells and in addition included candidate genes related to cell cycle function. In a sample of 1646 women from a bi-racial prospective pregnancy cohort, we examined the relationship between 503 tagSNPs in 40 genes and the outcomes of preterm birth, small for gestational age, gestational hypertension and preeclampsia. Six genes involved in natural killer cell function (IL12A, CSF2, IFNGR2 and KIR3DL2) and Th2 immunity (IL13 and IL4) were associated with preterm birth among European Americans with some evidence of an association for African Americans as well (IL12A and CSF2). IL6 and KLRD1 were associated with term small for gestational age births among African Americans with similar results for IL6 alone among European Americans. LTA, TNF and TBKBP1 were associated with preeclampsia among European Americans only. There were no associations with any cell cycle genes or with the outcome of gestational hypertension. In summary, this study found novel associations with a number of genes related to natural killer cells, Th2 immunity and TNF signaling pathways and the outcomes of preterm birth, poor fetal growth and preeclampsia among both European and African Americans.Doctor of Philosoph

Intake of Lycopene and other Carotenoids and Incidence of Uterine Leiomyomata: A Prospective Ultrasound Study

BACKGROUND: Uterine leiomyomata (UL) are the leading indication for hysterectomy in the United States. Dietary supplementation with lycopene was associated with reduced size and incidence of oviduct leiomyoma in the Japanese quail. Two US prospective cohort studies of women reported little association between intake of lycopene, or other carotenoids, and UL incidence. However, these studies relied on self-reported physician-diagnosed UL, which is prone to misclassification. OBJECTIVE: This study examines the association between dietary intake of carotenoids and UL incidence. DESIGN: Data were derived from the Study of the Environment, Lifestyle, and Fibroids, a prospective cohort study. Women completed self-administered baseline questionnaires on demographic characteristics, reproductive history, and lifestyle, including a 110-item validated food frequency questionnaire, from which dietary intakes of carotenoids-including alpha carotene, beta carotene, cryptoxanthin, lutein-zeaxanthin, and lycopene-and vitamin A were estimated. PARTICIPANTS/SETTING: One thousand two hundred thirty Black women aged 23 to 35 years who did not have a previous diagnosis of UL, cancer, or autoimmune disease were eligible for enrollment (2010-2012). Participants were residents of the Detroit, MI, metropolitan area. MAIN OUTCOME MEASURES: Transvaginal ultrasound was used to assess UL at baseline and 20, 40, and 60 months of follow-up. STATISTICAL ANALYSES PERFORMED: Cox regression was used to estimate hazard ratios and 95% CIs, adjusted for energy intake, age at menarche, education, body mass index, parity, age at first birth, years since last birth, current use of oral contraceptives or progestin-only injectables, alcohol intake, and cigarette smoking. RESULTS: Among 1,230 women without prevalent UL at baseline, 301 incident UL cases during follow-up were identified. Intakes of lycopene, other carotenoids, and vitamin A were not appreciably associated with UL incidence. Hazard ratios comparing quartiles 2 (2,376 to 3,397 μg/day), 3 (3,398 to 4,817 μg/day), and 4 (≥4,818 μg/day) with quartile 1 (\u3c2,376 μg/day) of lycopene intake were 1.03 (95% CI 0.72 to 1.47), 1.22 (95% CI 0.86 to 1.72), and 0.95 (95% CI 0.67 to 1.36), respectively. CONCLUSIONS: Study findings do not support the hypothesis that greater carotenoid intake is associated with reduced UL incidence

Depot Medroxyprogesterone Acetate Use and Blood Lead Levels in a Cohort of Young Women

BACKGROUND: Injectable contraceptive use is common, with 74 million users worldwide. Use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) is associated with bone mineral density loss. We hypothesize that increased bone resorption with DMPA use allows for mobilization of the toxic metal lead stored in bone to blood, presenting users with increased systemic exposure to lead. OBJECTIVE: The objective of our study was to investigate the association between current DMPA use and blood lead concentrations. METHODS: We conducted a cross-sectional analysis using enrollment data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1,693 African-American women who were 23-35 years of age. Data on DMPA use were collected by computer-assisted telephone interview. Blood lead concentrations were measured in whole blood samples among 1,548 participants (91% of cohort). We estimated the adjusted percent difference in blood lead concentrations and 95% confidence intervals (CI) between current DMPA users and nonusers using multivariable linear regression. RESULTS: Geometric mean blood lead concentration was 0.69 μg/dL (95% CI: 0.67, 0.71). After adjustment, current DMPA users (7% of cohort) had blood lead concentrations that were 18% higher than those of nonusers (95% CI: 8%, 29%). Similar associations were observed with additional analyses to assess for potential bias from smoking, DMPA-induced amenorrhea, use of estrogen-containing contraceptives, having given birth in the prior year, and history of medical conditions or current medication use associated with bone loss./ DISCUSSION: Our results indicate that current DMPA use is associated with increased blood lead concentrations. Further research, particularly in populations highly exposed to lead, is warranted to consider tradeoffs between the adverse effects of lead on human health and the importance of DMPA as a contraceptive option to prevent unintended pregnancy. https://doi.org/10.1289/EHP7017

Long-term cardiovascular mortality in women with twin pregnancies by lifetime reproductive history

Background: Women with one lifetime singleton pregnancy have increased risk of cardiovascular disease (CVD) mortality compared with women who continue reproduction particularly if the pregnancy had complications. Women with twins have higher risk of pregnancy complications, but CVD mortality risk in women with twin pregnancies has not been fully described. Objectives: We estimated risk of long-term CVD mortality in women with naturally conceived twins compared to women with singleton pregnancies, accounting for lifetime number of pregnancies and pregnancy complications. Methods: Using linked data from the Medical Birth Registry of Norway and the Norwegian Cause of Death Registry, we identified 974,892 women with first pregnancy registered between 1967 and 2013, followed to 2020. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for maternal CVD mortality were estimated by Cox regression for various reproductive history (exposure categories): (1) Only one twin pregnancy, (2) Only one singleton pregnancy, (3) Only two singleton pregnancies, (4) A first twin pregnancy and continued reproduction, (5) A first singleton pregnancy and twins in later reproduction and (6) Three singleton pregnancies (the referent group). Exposure categories were also stratified by pregnancy complications (pre-eclampsia, preterm delivery or perinatal loss). Results: Women with one lifetime pregnancy, twin or singleton, had increased risk of CVD mortality (adjusted hazard [HR] 1.72, 95% confidence interval [CI] 1.21, 2.43 and aHR 1.92, 95% CI 1.78, 2.07, respectively), compared with the referent of three singleton pregnancies. The hazard ratios for CVD mortality among women with one lifetime pregnancy with any complication were 2.36 (95% CI 1.49, 3.71) and 3.56 (95% CI 3.12, 4.06) for twins and singletons, respectively. Conclusions: Women with only one pregnancy, twin or singleton, had increased long-term CVD mortality, however highest in women with singletons. In addition, twin mothers who continued reproduction had similar CVD mortality compared to women with three singleton pregnancies.publishedVersio

Behavioral Influences on Preterm Birth: Integrated Analysis of the Pregnancy, Infection, and Nutrition Study

Most previous studies of preterm birth have considered risk factors in isolation rather than examining the collective impact of multiple candidate determinants. In order to examine the combined impact of a set of behavioral risk factors on the risk of preterm birth, we analyzed data collected for the Pregnancy, Infection, and Nutrition Study on a range of sociodemographic, behavioral, and related factors. Women who received prenatal care at selected clinics in central North Carolina and gave birth in the period 1995–2005 were recruited into a prospective cohort study, with 4,251 women providing the required information on risk factors and pregnancy outcome. A number of demographic and behavioral attributes were modestly associated with preterm birth, with odds ratios of 1.3–1.5, including age >35, African-American ethnicity, height of 63 inches or less, parity 2+, and delivery at the academic medical center. Despite weak associations for individual risk factors, changes in a constellation of behaviors during pregnancy predict substantial shifts in the risk of preterm birth, suggesting a reduction from 8 to 3% preterm among those with a low-risk baseline profile, and a reduction from 18 to 7% pre-term among those with a high-risk baseline profile. While inferences are limited by the incomplete range of available predictors, uncertainty regarding whether observed associations are causal, and substantial challenges in changing component behaviors, the possibility of substantial reduction in risk merits more serious consideration of whether behavioral interventions could markedly reduce the risk of preterm birth

Associations of adherence to the New Nordic Diet with risk of preeclampsia and preterm delivery in the Norwegian Mother and Child Cohort Study (MoBa)

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

Prioritizing individual genetic variants after kernel machine testing using variable selection: He et al.

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 do 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

Risk of Fetal Death With Preeclampsia

To estimate gestational-age-specific risks of fetal death in pregnancies complicated by preeclampsia

Association of Polymorphisms in Natural Killer Cell-Related Genes With Preterm Birth

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

Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?

Under embargo until: 2022-11-28Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. Study Design We conducted a nested case–control study within the Norwegian Mother, Father and Child Birth Cohort (1999–2008) of 2,596 mother–child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). Conclusion Evidence for gene–smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene–environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures.acceptedVersio