Vascular health years after a hypertensive disorder of pregnancy: The EPOCH study.

BACKGROUND: Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum. METHODS: Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound. RESULTS: Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses, cases (N = 68) were more likely than controls (N = 71) to have hypertension (18% vs 4%, P = .034), higher calculated ASCVD risk (0.6 vs 0.4, P = .02), higher blood pressures (systolic: 118.5 vs 111.6 mm Hg, P = .0004; diastolic: 75.2 vs 69.8 mm Hg, P = .0004), and higher augmentation index values (7.7 vs 2.3, P = .03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs 0.5, P = .29) or reactive hyperemia index (2.1 vs 2.1, P = .93), nor in pulse wave amplitude (416 vs 326, P = .11), carotid elastic modulus (445 vs 426, P = .36), or carotid beta stiffness (2.8 vs 2.8, P = .86). CONCLUSION: Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

A search for factors associated with reduced carbohydrate intake and NTD risk in two population-based studies.

BACKGROUND: Two population-based case-control studies have reported an increased risk of neural tube defect (NTD)-affected pregnancies among women with low carbohydrate diet in the periconceptional period. Given that only two studies have investigated this association, it is unclear to what degree the findings could be impacted by residual confounding. Here, we further interrogated both studies that observed this association with the objective to identify factors from a much larger number of factors that might explain the association. METHODS: By employing a machine learning algorithm (random forest), we investigated a baseline set of over 200 variables. These analyses produced the top 10 variables in each data set for cases and controls that predicted periconceptional low carbohydrate intake. RESULTS: Examining those prediction variables with logistic regression modeling, we did not observe any particular variable that substantially contributed to the NTD-low carbohydrate association in either data set. CONCLUSIONS: If there are underlying factors that explain the association, our findings suggest that none of the 200+ variables we examined were sufficiently correlated with what that true explanatory exposure may be. Alternatively, our findings may suggest that there are other unidentified factor(s) at play, or the association observed in two independent data sets is directly related to low carbohydrate intake.

Corrigendum: Advances and potential of omics studies for understanding the development of food allergy.

[This corrects the article DOI: 10.3389/falgy.2023.1149008.].

Hydroxychloroquine in Lupus Pregnancy and Risk of Preeclampsia.

OBJECTIVE: Systemic lupus erythematosus (SLE) disproportionately affects women during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of pregnancies in lupus patients, although reports vary by parity and multifetal gestation. We investigated whether taking HCQ early in pregnancy may reduce the risk of preeclampsia. METHODS: We studied 1,068 live birth singleton pregnancies among 1,020 privately insured patients with SLE (2007-2016). HCQ treatment was defined as three months preconception through the first trimester, and prescription fills were a proxy for taking HCQ. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (CIs), stratified by parity. Propensity scores accounted for confounders, and stratified analyses examined effect modification. RESULTS: Approximately 15% of pregnant patients were diagnosed with preeclampsia. In 52% of pregnancies, patients had one or more HCQ fills. Pregnant patients exposed to HCQ had more comorbidities, SLE activity, and azathioprine treatment. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR 1.26 [95% CI 0.82-1.93]) and multiparous pregnancies (RR 1.20 [95% CI 0.80-1.70]). Additional controls for confounding decreased the RRs toward the null (nulliparous pregnancy, propensity score-adjusted [PS-adj] RR 1.09 [95% CI 0.68-1.76]; multiparous pregnancy, PS-adj RR 1.01 [95% CI 0.66-1.53]). CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ treatment in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in pregnant patients with SLE and among persons at greater risk of hypertensive disorders of pregnancy.

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

Pregnancy Outcomes in a Diverse US Lupus Cohort.

OBJECTIVE: Although the population of patients with systemic lupus erythematosus (SLE) is racially and ethnically diverse, many study populations are homogeneous. Further, data are often lacking on critical factors, such as antiphospholipid antibodies (aPLs). We investigated live birth rates in patients with SLE at Kaiser Permanente Northern California, including race and ethnicity and aPL data. METHODS: Electronic health records of pregnancies with outcomes observed from 2011 to 2020 were identified among patients with SLE. Prevalent SLE was defined as two or more International Classification of Diseases-coded visits seven or more days apart before the last menstrual period. We summarized patient characteristics, medication orders, health care use, and medication use. Pregnancy outcomes (live birth, stillbirth, spontaneous abortion, ectopic pregnancy, and molar pregnancy) were presented overall and stratified by race and ethnicity, aPL status, and nephritis history. RESULTS: We identified 657 pregnancies among 453 patients with SLE. The cohort was diverse, reflecting the Northern California population (27% Asian, 26% Hispanic, 26% Non-Hispanic White, 13% Non-Hispanic Black, 5% multiracial, and approximately 2% Pacific Islander and Native American). Approximately 74% of observed pregnancies ended in live birth, 23% resulted in spontaneous abortion, 2% were ectopic or molar pregnancies, and <1% were stillbirths. There was limited variability in live births by race and ethnic group (72%-79%), aPL status (69.5%-77%), and nephritis history (71%-75%). CONCLUSION: Our findings are consistent with previous studies; however, some methodologic differences may yield a range of live birth rates. We found that approximately 74% of pregnancies in patients with SLE ended in live birth, with modest variability in spontaneous abortion by race and ethnicity, nephritis history, and aPL status.

Preconception dietary glycemic index and risk for large-for-gestational age births.

OBJECTIVES: Diets with a high glycemic index (GI) leading to elevated postprandial glucose levels and hyperinsulinemia during pregnancy have been inconsistently linked to an increased risk for large-for-gestational-age (LGA) births. The effects of prepregnancy dietary GI on LGA risk are, to our knowledge, unknown. We examined the association of prepregnancy dietary GI with LGA births and joint associations of GI and maternal overweight/obesity and infant sex with LGA births among 10 188 infants born without congenital anomalies from 1997 to 2011, using data from the National Birth Defects Prevention Study (NBDPS). The aim of this study was to investigate this association among infants without major congenital anomalies (controls) who participated in the NBDPS and to evaluate how prepregnancy BMI and infant sex may modify this association on the additive scale. METHODS: Dietary intake was ascertained using a 58-item food frequency questionnaire. We dichotomized dietary GI into high and low categories using spline regression models. Infants with a birth weight at or above the 90th percentile for gestational age and sex, according to a U.S. population reference, were considered LGA. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of the infants, 859 (9%) had a high dietary GI (cut-point: 59), and 1244 infants (12%) were born LGA. Unadjusted analysis suggested an inverse association between high dietary GI and LGA (OR, 0.79; 95% CI, 0.62-0.99). No association was observed in multivariable models when comparing high dietary GI intake between LGA births and all other births (OR, 0.94; 95% CI, 0.74-1.20) or when excluding small-for-gestational-age (SGA) births (OR, 0.94; 95% CI, 0.73-1.19). No joint associations with maternal overweight/obesity or infant sex were observed. CONCLUSION: High prepregnancy maternal GI was not associated with LGA births independently of or jointly with other factors.

Large-scale proteomics in the first trimester of pregnancy predict psychopathology and temperament in preschool children: an exploratory study.

BACKGROUND: Understanding the prenatal origins of children's psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties. METHODS: Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children's (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist). RESULTS: We found that machine learning models of prenatal proteomics predict 5%-10% of the variance in children's sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children's outcomes. CONCLUSIONS: Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures.

Maternal physical activity, sitting, and risk of non-cardiac birth defects.

BACKGROUND: The relationship between maternal physical activity (PA)/sitting and birth defects is largely unexplored. We examined whether pre-pregnancy PA/sitting were associated with having a pregnancy affected by a birth defect. METHODS: We used data from two United States population-based case-control studies: 2008-2011 deliveries from the National Birth Defects Prevention Study (NBDPS; 9 states) and 2014-2018 deliveries from the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS; 7 states). Cases with one of 12 non-cardiac birth defects (n = 3798) were identified through population-based registries. Controls (n = 2682) were live-born infants without major birth defects randomly sampled using vital/hospital records. Mothers self-reported pre-pregnancy PA/sitting. Unconditional logistic regression models estimated associations between PA/sitting categories and the 12 birth defects. RESULTS: Mothers engaging in pre-pregnancy PA was associated with a reduced odds of five (spina bifida, cleft palate, anorectal atresia, hypospadias, transverse limb deficiency) and a higher odds of two (anencephaly, gastroschisis) birth defects. Mothers spending less time sitting in pre-pregnancy was associated with a reduced odds of two (anorectal atresia, hypospadias) and a higher odds of one (cleft lip with or without cleft palate) birth defect. CONCLUSIONS: Reasonable next steps include replication of these findings, improved exposure assessment, and elucidation of biologic mechanisms. IMPACT: Using data from two population-based case-control studies, we found that mothers engaging in different types of physical activity in the 3 months before pregnancy had an infant with a reduced odds of five and a higher odds of two birth defects. Mothers spending less time sitting in the 3 months before pregnancy had an infant with a reduced odds of two and a higher odds of one birth defect. Clarification and confirmation from additional studies are needed using more precise exposure measures, distinguishing occupational from leisure-time physical activity, and elucidation of mechanisms supporting these associations.

Factors associated with infant sex and preterm birth status for selected birth defects from the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS). METHODS: The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect. RESULTS: We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects. CONCLUSIONS: We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.

Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study.

BACKGROUND: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking. OBJECTIVES: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS. METHODS: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR. RESULTS: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02). CONCLUSIONS: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.

BACKGROUND: Neural tube defects (NTDs) still occur among some women who consume 400 µg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. OBJECTIVES: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. METHODS: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 µg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. RESULTS: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. CONCLUSIONS: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate.

Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10-8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10-6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.

Deep representation learning identifies associations between physical activity and sleep patterns during pregnancy and prematurity.

Preterm birth (PTB) is the leading cause of infant mortality globally. Research has focused on developing predictive models for PTB without prioritizing cost-effective interventions. Physical activity and sleep present unique opportunities for interventions in low- and middle-income populations (LMICs). However, objective measurement of physical activity and sleep remains challenging and self-reported metrics suffer from low-resolution and accuracy. In this study, we use physical activity data collected using a wearable device comprising over 181,944 h of data across N = 1083 patients. Using a new state-of-the art deep learning time-series classification architecture, we develop a 'clock' of healthy dynamics during pregnancy by using gestational age (GA) as a surrogate for progression of pregnancy. We also develop novel interpretability algorithms that integrate unsupervised clustering, model error analysis, feature attribution, and automated actigraphy analysis, allowing for model interpretation with respect to sleep, activity, and clinical variables. Our model performs significantly better than 7 other machine learning and AI methods for modeling the progression of pregnancy. We found that deviations from a normal 'clock' of physical activity and sleep changes during pregnancy are strongly associated with pregnancy outcomes. When our model underestimates GA, there are 0.52 fewer preterm births than expected (P = 1.01e - 67, permutation test) and when our model overestimates GA, there are 1.44 times (P = 2.82e - 39, permutation test) more preterm births than expected. Model error is negatively correlated with interdaily stability (P = 0.043, Spearman's), indicating that our model assigns a more advanced GA when an individual's daily rhythms are less precise. Supporting this, our model attributes higher importance to sleep periods in predicting higher-than-actual GA, relative to lower-than-actual GA (P = 1.01e - 21, Mann-Whitney U). Combining prediction and interpretability allows us to signal when activity behaviors alter the likelihood of preterm birth and advocates for the development of clinical decision support through passive monitoring and exercise habit and sleep recommendations, which can be easily implemented in LMICs.

Neighborhood Deprivation and Neural Tube Defects.

BACKGROUND: Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk. METHODS: The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery. RESULTS: Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity. CONCLUSIONS: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.

Is gastroschisis associated with county-level socio-environmental quality during pregnancy?

BACKGROUND: Gastroschisis prevalence more than doubled between 1995 and 2012. While there are individual-level risk factors (e.g., young maternal age, low body mass index), the impact of environmental exposures is not well understood. METHODS: We used the U.S. Environmental Protection Agency's Environmental Quality Index (EQI) as a county-level estimate of cumulative environmental exposures for five domains (air, water, land, sociodemographic, and built) and overall from 2006 to 2010. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were estimated from logistic regression models between EQI tertiles (better environmental quality (reference); mid; poorer) and gastroschisis in the National Birth Defects Prevention Study from births delivered between 2006 and 2011. Our analysis included 594 cases with gastroschisis and 4105 infants without a birth defect (controls). RESULTS: Overall EQI was modestly associated with gastroschisis (aOR [95% CI]: 1.29 [0.98, 1.71]) for maternal residence in counties with poorer environmental quality, compared to the reference (better environmental quality). Within domain-specific indices, only the sociodemographic domain (aOR: 1.51 [0.99, 2.29]) was modestly associated with gastroschisis, when comparing poorer to better environmental quality. CONCLUSIONS: Future work could elucidate pathway(s) by which components of the sociodemographic domain or possibly related psychosocial factors like chronic stress potentially contribute to risk of gastroschisis.

Exome sequencing findings in children with annular pancreas.

BACKGROUND: Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution. METHODS: We conducted exome sequencing in 115 affected infants from the California birth defects registry. RESULTS: Seven cases had a single heterozygous missense variant in IQGAP1, five of them with CADD scores >20; seven other infants had a single heterozygous missense variant in NRCAM, five of them with CADD scores >20. We also looked at genes previously associated with AP and found two rare heterozygous missense variants, one each in PDX1 and FOXF1. CONCLUSION: IQGAP1 and NRCAM are crucial in cell polarization and migration. Mutations result in decreased motility which could possibly cause the ventral bud to not migrate normally. To our knowledge, this is the first study reporting a possible association for IQGAP1 and NRCAM with AP. Our findings of rare genetic variants involved in cell migration in 15% of our population raise the possibility that AP may be related to abnormal cell migration.

Comparative predictive power of serum vs plasma proteomic signatures in feto-maternal medicine.

BACKGROUND: Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures. OBJECTIVE: This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome. STUDY DESIGN: Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins. RESULTS: A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42-0.79; P=3.5×10-6) than the serum signature (R=0.45; confidence interval, 0.18-0.66; P=2.2×10-3). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34-0.75; P=4.8×10-5), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27-0.72; P=2.6×10-4). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins. CONCLUSION: Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix.