Trends in antenatal depression and suicidal ideation diagnoses among commercially insured childbearing individuals in the United States, 2008-2018.

INTRODUCTION: Antenatal depression and suicidal ideation represent serious pregnancy-related complications, yet comprehensive estimates of the prevalence and predictors of these diagnoses among birthing people remain unclear. OBJECTIVE: This study aimed to characterize trends in the prevalence of depression and suicidal ideation diagnoses identified among pregnant individuals prior to giving birth. METHODS: This study included 536,647 individuals aged 15-44 years continuously enrolled in a single commercial health insurance plan for one year before childbirth from 2008 to 2018. The primary outcomes included depression or suicidal ideation based on identification of the relevant ICD-9 and ICD-10 diagnosis codes during pregnancy. RESULTS: Rates (95 % CIs) of depression increased by 39 % from 540 (520-560) per 10,000 individuals in 2008 to 750 (730-770) per 10,000 individuals in 2018. Suicidal ideation increased by 100 % from 15 (12-18) per 10,000 individuals in 2008 to 44 (39-50) per 10,000 individuals in 2018. Black birthing people experiencing the sharpest proportional increases. CONCLUSIONS: The prevalence of depression and suicidal ideation occurring during pregnancy substantially increased over a ten-year period. Further, suicidal ideation diagnosis increased the most for among Black birthing people compared to all groups, resulting in a need for future studies in this area to determine the reasons for an increase in diagnosis and any change in resulting treatment of follow up.

Towards precision quantification of contamination in metagenomic sequencing experiments.

Metagenomic next-generation sequencing (mNGS) experiments involving small amounts of nucleic acid input are highly susceptible to erroneous conclusions resulting from unintentional sequencing of occult contaminants, especially those derived from molecular biology reagents. Recent work suggests that, for any given microbe detected by mNGS, an inverse linear relationship between microbial sequencing reads and sample mass implicates that microbe as a contaminant. By associating sequencing read output with the mass of a spike-in control, we demonstrate that contaminant nucleic acid can be quantified in order to identify the mass contributions of each constituent. In an experiment using a high-resolution (n = 96) dilution series of HeLa RNA spanning 3-logs of RNA mass input, we identified a complex set of contaminants totaling 9.1 ± 2.0 attograms. Given the competition between contamination and the true microbiome in ultra-low biomass samples such as respiratory fluid, quantification of the contamination within a given batch of biological samples can be used to determine a minimum mass input below which sequencing results may be distorted. Rather than completely censoring contaminant taxa from downstream analyses, we propose here a statistical approach that allows separation of the true microbial components from the actual contribution due to contamination. We demonstrate this approach using a batch of n = 97 human serum samples and note that despite E. coli contamination throughout the dataset, we are able to identify a patient sample with significantly more E. coli than expected from contamination alone. Importantly, our method assumes no prior understanding of possible contaminants, does not rely on any prior collection of environmental or reagent-only sequencing samples, and does not censor potentially clinically relevant taxa, thus making it a generalized approach to any kind of metagenomic sequencing, for any purpose, clinical or otherwise.

Dynamic outcome prediction in a socio-demographically diverse population-based cohort of extremely preterm neonates.

OBJECTIVE: Accurate outcome prediction is crucial for counseling parents and providing individualized treatment to extremely premature infants. We sought to improve upon existing prediction model by using a diverse population-based cohort of extremely premature live births (⩽28 weeks' gestation) for survival and survival without severe neonatal morbidity at different times throughout the first week of life and to evaluate potential differences by race/ethnicity and maternal education. STUDY DESIGN: Retrospective cohort study of all California live births from 2007 through 2011 with linked birth, death and hospital discharge records. RESULTS: A total of 6009 infants were included. In the validation data set at time of delivery, the area under the receiver-operating characteristic curve for the model containing all predictors was 0.863 for survival and 0.789 for survival without severe morbidity. The marginal probability of survival without severe neonatal morbidity of an Asian infant born to a mother with <12 years of education compared with the reference (Caucasian infant, mother with ⩾12 years of education) was -0.23 (95% confidence interval (CI) -0.31 to -0.15) for all infants at time of birth and -0.28 (95% CI -0.39 to -0.18) for infants with attempted resuscitation. Notably, no other differences by racial/ethnic category and maternal education emerged. CONCLUSIONS: Probabilities of survival and survival without major morbidity change rapidly throughout the first week of life. Extremely premature infants born to Asian mothers with less than a high school education appear to have a lower probability to survive without significant morbidity compared with their Caucasian peers.

Risk of preterm birth among women using drugs during pregnancy with elevated α-fetoprotein.

OBJECTIVE: Examine the risk of preterm birth (PTB) among women who use drugs during pregnancy and have elevated α-fetoprotein (AFP). STUDY DESIGN: The sample included California singleton live births in 2005 to 2010 contained within a hospital discharge database linked to the Prenatal Screening Program. A selection of mothers who did not use drugs was selected at a ratio of 4:1. Risk of PTB was calculated using adjusted odds ratios and 95% confidence intervals (CIs) for women who did or did not use drugs by their AFP percentile. RESULTS: We identified 7190 women who used drugs and selected 28 760 women who did not. Of women using cocaine with AFP ⩾95th percentile, 43.8% delivered prematurely. Women using drugs with AFP ⩾95th percentile were 11 to 35 times as likely to deliver <32 weeks. CONCLUSION: The combination of drug use and elevated AFP results in high rates of PTB. This combination results in an additive risk.

Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis.

BACKGROUND: Intimate partner violence (IPV) is of particular concern during pregnancy when not one, but two lives are at risk. Previous meta-analyses have suggested an association between IPV and adverse birth outcomes; however, many large studies have since been published, illustrating the need for updated pooled effect estimates. OBJECTIVES: To evaluate the relationship between IPV during pregnancy and the risk of preterm birth (PTB), low-birthweight (LBW), and small-for-gestational-age (SGA) infants. SEARCH STRATEGY: We searched PubMed and SCOPUS (from inception until May 2015), and the reference lists of the relevant studies. SELECTION CRITERIA: Observational studies comparing the rates of at least one adverse birth outcome (SGA, LBW, or PTB) in women who experienced IPV during pregnancy and those who did not. DATA COLLECTION AND ANALYSIS: Data extracted from 50 studies were pooled and pooled odds ratios were calculated using random-effects models. MAIN RESULTS: Intimate partner violence (IPV) was significantly associated with PTB (OR 1.91, 95% CI 1.60-2.29) and LBW (OR 2.11, 95% CI 1.68-2.65), although a large level of heterogeneity was present for both (I(2)  = 84 and 91%, respectively). The association with SGA was less pronounced and marginally significant (OR 1.37, 95% CI 1.02-1.84), although fewer studies were available for meta-analysis (n = 7). CONCLUSIONS: Our meta-analysis indicates that women who experienced IPV during pregnancy are at increased risk of having a PTB, and an LBW or an SGA infant. More studies examining the association between IPV and SGA are needed. TWEETABLE ABSTRACT: Meta-analysis of IPV during pregnancy finds increased risk for preterm birth, LBW and SGA infants.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth.

OBJECTIVE: To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes. DESIGN: Population-based cohort. SETTING: California, United States of America. POPULATION: From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included. METHODS: Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results. MAIN OUTCOME MEASURE: PTB by subtype. RESULTS: In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2). CONCLUSIONS: Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies. TWEETABLE ABSTRACT: Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.

Maternal lipid levels during pregnancy and gestational diabetes: a systematic review and meta-analysis.

BACKGROUND: Lipid levels during pregnancy in women with gestational diabetes mellitus (GDM) have been extensively studied; however, it remains unclear whether dyslipidaemia is a potential marker of preexisting insulin resistance. OBJECTIVE: To evaluate the relationship between lipid measures throughout pregnancy and GDM. SEARCH STRATEGY: We searched PubMed-MedLine and SCOPUS (inception until January 2014) and reference lists of relevant studies. SELECTION CRITERIA: Publications describing original data with at least one raw lipid (total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], or triglyceride) measurement during pregnancy in women with GDM and healthy pregnant controls were retained. DATA COLLECTION AND ANALYSIS: Data extracted from 60 studies were pooled and weighted mean difference (WMD) in lipid levels was calculated using random effects models. Meta-regression was also performed to identify sources of heterogeneity. MAIN RESULTS: Triglyceride levels were significantly elevated in women with GDM compared with those without GDM (WMD 30.9, 95% confidence interval [95% CI] 25.4-36.4). This finding was consistent in the first, second and third trimesters of pregnancy. HDL-C levels were significantly lower in women with GDM compared with those without GDM in the second (WMD -4.6, 95% CI -6.2 to -3.1) and third (WMD -4.1, 95% CI -6.5 to -1.7) trimesters of pregnancy. There were no differences in aggregate total cholesterol or LDL-C levels between women with GDM and those without insulin resistance. AUTHOR'S CONCLUSIONS: Our meta-analysis shows that triglycerides are significantly elevated among women with GDM compared with women without insulin resistance and this finding persists across all three trimesters of pregnancy.

Ethnic differences in the relationship between birth weight and type 2 diabetes mellitus in postmenopausal women.

AIM: The objective of this study is to examine the relationship between self-reported birth weight and the adult occurrence of type 2 diabetes mellitus in a large multi-ethnic population of women. METHODS: Baseline data from the Women's Health Initiative Observational Study [n=75,993] was used to examine the association between participant birth weight category and prevalent type 2 diabetes mellitus. Models were adjusted for age, ethnicity, body mass index and other pertinent risk factors. Sub-analyses were performed stratifying by ethnicity. RESULTS: There was a strong inverse association between birth weight and type 2 diabetes mellitus with a birth weight of <6 pounds (lbs) (OR: 1.16, 95% CI: 1.01, 1.33) significantly associated with an increased risk of type 2 diabetes mellitus and a birth weight of ≥10 lbs (OR: 0.72, 95% CI: 0.57, 0.92) associated with a decreased risk of type 2 diabetes mellitus compared to women who reported their birth weight between 7 and 8 lbs 15 ounces (oz). Stratifying by ethnicity, the inverse association between birth weight and type 2 diabetes mellitus was only apparent in White women, but not Black, Hispanic or Asian women. CONCLUSION: Lower birth weight was associated with increased T2D risk in American White and Black post-menopausal women.

The heritability of metabolic profiles in newborn twins.

Identifying genetic and metabolic biomarkers in neonates has the potential to improve diagnosis and treatment of common complex neonatal diseases, and potentially lead to risk assessment and preventative measures for common adulthood illnesses such as diabetes and cardiovascular disease. There is a wealth of information on using fatty acid, amino acid and organic acid metabolite profiles to identify rare inherited congenital diseases through newborn screening, but little is known about these metabolic profiles in the context of the 'healthy' newborn. Recent studies have implicated many of the amino acid and fatty acid metabolites utilized in newborn screening in common complex adult diseases such as cardiovascular disease, insulin resistance and obesity. To determine the heritability of metabolic profiles in newborns, we examined 381 twin pairs obtained from the Iowa Neonatal Metabolic Screening Program. Heritability was estimated using multilevel mixed-effects linear regression adjusting for gestational age, gender, weight and age at time of sample collection. The highest heritability was for short-chain acylcarnitines, specifically C4 (h²=0.66, P=2 × 10⁻¹6), C4-DC (h²=0.83, P<10⁻¹6) and C5 (h²=0.61, P=1 × 10⁻9). Thyroid stimulating hormone (h²=0.58, P=2 × 10⁻5) and immunoreactive trypsinogen (h²=0.52, P=3 × 10⁻9) also have a strong genetic component. This is direct evidence for a strong genetic contribution to the metabolic profile at birth and that newborn screening data can be utilized for studying the genetic regulation of many clinically relevant metabolites.

Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population.

OBJECTIVE: To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNPs) in candidate genes and population genetic admixture. STUDY DESIGN: Genotyping was performed in 389 families. Maternal, paternal and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males. RESULT: Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; P=0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; P=0.01). Gestational age associated with PTB in PGR rs1942836 at 32-36 weeks (P=0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes. CONCLUSION: This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.

Genetic associations of surfactant protein D and angiotensin-converting enzyme with lung disease in preterm neonates.

OBJECTIVE: To replicate genetic associations with respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in genes related to surfactant deficiency, inflammation and infection, and the renin-angiotensin system. STUDY DESIGN: We examined eight candidate genes for associations with RDS and BPD in 433 preterm birth (PTB-<37 weeks) infants (251 with RDS and 134 with BPD). Both case-control and family-based analyses were performed in preterm (<37 weeks) and very preterm birth (VPTB-<32 weeks) infants. RESULT: We replicated a previous finding that rs1923537, a marker downstream of surfactant protein D (SFTPD) is associated with RDS in VPTB infants in that the T allele was overtransmitted from parents to offspring with RDS (P=8.4 × 10(-3)). We also observed the A allele of rs4351 in the angiotensin-converting enzyme (ACE) gene was overtransmitted from parents to VPTB offspring with BPD (P=9.8 × 10(-3)). CONCLUSION: These results give further insight into the genetic risk factors for complex neonatal respiratory diseases and provide more evidence of the importance of SFTPD and ACE in the etiology of RDS and BPD, respectively.

Multifactor dimensionality reduction analysis of MTHFR, PAI-1, ACE, PON1, and eNOS gene polymorphisms in patients with early onset coronary artery disease.

BACKGROUND: Association studies in the Turkish population have investigated the single locus effects of different gene polymorphisms on coronary artery disease (CAD). CAD is a complex polygenic disease that involves complex interactions among multiple genetic and environmental conditions. DESIGN: We evaluated associations of five candidate genetic polymorphisms (methylene tetrahydrofolate reductase C677T, plasminogen activator inhibitor 4G/5G, endothelial nitric oxide synthase (eNOS) 3-27 base pair repeat, insertion, or deletion of a 287 bp Alu repeat sequence polymorhism of angiotensin I converting enzyme, and paraoxonase Gln192Arg PON1 polymorphisms) with the presence and extent of early onset CAD. METHODS: DNA was isolated and amplified from 90 consecutive patients with angiographically proven early onset CAD (ages 41 ± 5 for men, 49 ± 7 for women) and also from 90 control subjects with no significant coronary obstruction angiographically (ages 42 ± 5 for men, 48 ± 6 for women). Multifactor dimensionality reduction (MDR) analysis was performed to identify a model of CAD based on both genetic and conventional risk factors. RESULTS: MDR analysis detected a significant model with four genes (prediction success ∼ 61%, p = 0.03). When the total number of the conventional risk factors is analysed with the candidate polymorphisms, a different model is identified that includes three of the four genes from the above model and achieves a similar prediction of CAD as the gene only model. CONCLUSION: These data indicate that gene-gene and gene-environmental risk interactions form significant models in predicting early onset CAD.

Genetic association of Toll-like receptor 4 with cervical cytokine concentrations during pregnancy.

Toll-like receptors (TLRs) are critical components of innate immunity, recognizing bacterial microorganisms and initiating local inflammatory responses. In this study, we assessed the impact of genetic variation in TLR genes on cervical concentrations of pro- and anti-inflammatory cytokines, and determined whether this relationship is influenced by bacterial vaginosis (BV). A total of 4 single nucleotide polymorphisms (SNPs) in TLR2 and 12 in TLR4 were examined for associations with 10 cervical pro- and anti-inflammatory cytokine concentrations in 91 African-American (AA) and 97 European-American (EA) women in the first trimester of pregnancy. In EAs, individuals with the TT genotype at rs1554973 (TLR4) had higher cervical concentrations of interleukin-1 beta (IL-1b) compared with those with the CT or TT genotypes (P=1.5 x 10(-5)), which remains significant after correction for multiple testing. This association was more significant in women with BV (P=5 x 10(-3)) than those without BV (P=0.02). This SNP was also associated with cervical concentrations of IL-1a, IL-6, IL-8 and IP10 (interferon-gamma-inducible protein 10) (P=6 x 10(-3), 0.03, 0.05, 6 x 10(-3), respectively). Our study demonstrates that TLR4 is an important mediator of pro-inflammatory cervical immune responses, particularly in EA women and especially in those with microbial disorders such as BV.

Predicting risk of bacterial vaginosis: the role of race, smoking and corticotropin-releasing hormone-related genes.

Bacterial vaginosis (BV) is one of the most prevalent vaginal disorders in adult women and is associated with adverse pregnancy outcomes such as pre-term birth. Genetic factors, particularly in genes involved in inflammation and infection, are associated with this condition. Additionally, environmental risk factors including stress and smoking are associated with BV. The purpose of this study was to identify genetic variants in stress-related genes such as corticotropin-releasing hormone (CRH), receptor 1, receptor 2 and binding protein (CRH-BP) that associate with BV. Also gene-environment effects with smoking are determined. BV was quantified using the Nugent score in 82 white and 65 black women in the first trimester of pregnancy. Associations between Nugent score, genotype and smoking were analyzed using Kruskal-Wallis and Wilcoxon rank sum non-parametric tests. In white women, non-smokers with the CT genotype at CRH-BP + 17487 have lower Nugent scores (median: 0, range: 0-0) than non-smokers with the TT genotype (median: 2, range: 0-8) (P = 0.002); whereas smokers with the CT genotype have higher Nugent scores (median: 6, range: 0-10) than smokers with the TT genotype (median: 1, range: 0-10) (P = 0.021). In black women, the AG genotype at CRH + 3362 or CRH - 1667 is associated with lower Nugent scores (median for both: 3, range: 0-10) compared with the homozygous genotypes (median for each homozygous genotype: 8, range: 0-10). Also, in black women, models remain significant after adjusting for smoking (P = 0.04 for both). These data indicate that susceptibility to BV is affected by patterns of genetic variation in stress-related genes and smoking plays an important role.