Multiethnic Growth Standards for Fetal Body Composition and Organ Volumes Derived from 3D Ultrasonography.

BACKGROUND: A major goal of contemporary obstetrical practice is to optimize fetal growth and development throughout pregnancy. To date, fetal growth during prenatal care is assessed by performing ultrasonographic measurement of two-dimensional fetal biometry to calculate an estimated fetal weight. Our group previously established two-dimensional fetal growth standards using sonographic data from a large cohort with multiple sonograms. A separate objective of that investigation involved the collection of fetal volumes from the same cohort. OBJECTIVE: The Fetal 3D Study was designed to establish standards for fetal soft tissue and organ volume measurements by three-dimensional ultrasonography and compare growth trajectories with conventional two-dimensional measures where applicable. STUDY DESIGN: The NICHD Fetal 3D Study included research-quality images of singletons collected in a prospective, racially and ethnically diverse, low-risk cohort of pregnant individuals at 12 U.S. sites, with up to five scans per fetus (N=1,730 fetuses). Abdominal subcutaneous tissue thickness was measured from two-dimensional images and fetal limb soft tissue parameters extracted from three-dimensional multiplanar views. Cerebellar, lung, liver and kidney volumes were measured using virtual organ computer aided analysis (VOCAL). Fractional arm and thigh total volumes, and fractional lean limb volumes were measured, with fractional limb fat volume calculated by subtracting lean from total. For each measure, weighted curves (5th, 50th, 95th percentiles) were derived from 15-41 weeks' using linear mixed models for repeated measures with cubic splines. RESULTS: Subcutaneous thickness of the abdomen, arm, and thigh increased linearly, with slight acceleration around 27-29 weeks. Fractional volumes of the arm, thigh, and lean limb volumes increased along a quadratic curvature, with acceleration around 29-30 weeks. In contrast, growth patterns for two-dimensional humerus and femur lengths demonstrated a logarithmic shape, with fastest growth in the 2nd trimester. The mid-arm area curve was similar in shape to fractional arm volume, with an acceleration around 30 weeks, whereas the curve for the lean arm area was more gradual. The abdominal area curve was similar to the mid-arm area curve with an acceleration around 29 weeks. The mid-thigh and lean area curves differed from the arm areas by exhibiting a deceleration at 39 weeks. The growth curves for the mid arm and thigh circumferences were more linear with some decelerations. Cerebellar two-dimensional diameter increased linearly, whereas cerebellar three-dimensional volume growth gradually accelerated until 32 weeks and then decelerated. Lung, kidney, and liver volumes all demonstrated gradual early growth followed by a linear acceleration beginning at 25 weeks for lungs, 26-27 weeks for kidneys, and 29 weeks for liver. CONCLUSION: Growth patterns and timing of maximal growth for three-dimensional lean and fat measures, limb and organ volumes differed from patterns revealed by traditional two-dimensional growth measures, suggesting these parameters reflect unique facets of fetal growth. Growth in these three-dimensional measures may be altered by genetic, nutritional, metabolic or environmental influences and pregnancy complications, in ways not identifiable using corresponding two-dimensional measures. Further investigation into the relationships of these three-dimensional standards to abnormal fetal growth, adverse perinatal outcomes, and health status in postnatal life is warranted.

Placental accelerated aging in antenatal depression.

BACKGROUND: Antenatal maternal depression is associated with poor pregnancy outcomes and long-term effects on the offspring. Previous studies have identified links between antenatal depression and placental DNA methylation and between placental epigenetic aging and poor pregnancy outcomes, such as preterm labor and preeclampsia. The relationship between antenatal depression and poor pregnancy outcomes may be partly mediated via placental aging. OBJECTIVE: This study aimed to investigate whether antenatal depressive symptoms are associated with placental epigenetic age acceleration, an epigenetic aging clock measure derived from the difference between methylation age and gestational age at delivery. STUDY DESIGN: The study included 301 women who provided placenta samples at delivery as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies - Singletons that recruited participants from diverse race and ethnic groups at 12 US clinical sites (2009-2013). Women underwent depression screening using the Edinburgh Postnatal Depression Scale up to 6 times across the 3 trimesters of pregnancy. Depressive symptoms status was determined for each pregnancy trimester using an Edinburgh Postnatal Depression Scale score, in which a score of ≥10 was defined as having depressive symptoms and a score of <10 was defined as not having depressive symptoms. Placental DNA methylation was profiled from placenta samples. Placental epigenetic age was estimated using a methylation-based age estimator (placental "epigenetic clock") that has previously been found to have high placental gestational age prediction accuracy for uncomplicated term pregnancies. Placental age acceleration was defined to be the residual upon regressing the estimated epigenetic age on gestational age at delivery. Associations between an Edinburgh Postnatal Depression Scale score of ≥10 and an Edinburgh Postnatal Depression Scale score of <10 in the first, second, and third trimesters of pregnancy (ie, depressive symptoms vs none in each trimester) and placental age acceleration were tested using multivariable linear regression adjusting for maternal age, parity, race and ethnicity, and employment. RESULTS: There were 31 (10.3%), 48 (16%), and 49 (16.4%) women with depressive symptoms (ie, Edinburgh Postnatal Depression Scale score of ≥10) in the first, second, and third trimesters of pregnancy, respectively. Of these women, 21 (7.2%) had sustained first- and second-trimester depressive symptoms, 19 (7%) had sustained second- and third-trimester depressive symptoms, and 12 (4.8%) had sustained depressive symptoms throughout pregnancy. Women with depressive symptoms in the second trimester of pregnancy had 0.41 weeks higher placental age acceleration than women without depressive symptoms during the second trimester of pregnancy (ß=0.21 weeks [95% confidence interval, -0.17 to 0.58; P=.28] during the first trimester of pregnancy; ß=0.41 weeks [95% confidence interval, 0.10-0.71; P=.009] during the second trimester of pregnancy; ß=0.17 weeks [95% confidence interval, -0.14 to 0.47; P=.29] during the third trimester of pregnancy). Sustained first- and second-trimester depressive symptoms were associated with 0.72 weeks higher placental age acceleration (95% confidence interval, 0.29-1.15; P=.001) than no depressive symptom in the 2 trimesters. The association between second-trimester depressive symptoms and higher placental epigenetic age acceleration strengthened in the analysis of pregnancies with male fetuses (ß=0.53 weeks; 95% confidence interval, 0.06-1.08; P=.03) but was not significant in pregnancies with female fetuses. CONCLUSION: Antenatal depressive symptoms during the second trimester of pregnancy were associated with an average of 0.41 weeks of increased placental age acceleration. Accelerated placental aging may play an important role in the underlying mechanism linking antenatal depression to pregnancy complications related to placental dysfunction.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

Prenatal social support in low-risk pregnancy shapes placental epigenome.

BACKGROUND: Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans. METHODS: In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta. RESULTS: The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22-25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies. CONCLUSIONS: The findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes. TRIAL REGISTRATION: NCT00912132 ( ClinicalTrials.gov ).

Plasma Amino Acids in Early Pregnancy and Midpregnancy and Their Interplay With Phospholipid Fatty Acids in Association With the Risk of Gestational Diabetes Mellitus: Results From a Longitudinal Prospective Cohort.

OBJECTIVE: We prospectively evaluated plasma amino acids (AAs) in early pregnancy and midpregnancy and their interplay with phospholipid fatty acids (FAs) in association with gestational diabetes mellitus (GDM) risk. RESEARCH DESIGN AND METHODS: From a longitudinal pregnancy cohort of 2,802 individuals, concentrations of 24 plasma AAs at 10-14 and 15-26 gestational weeks (GW) were assessed among 107 GDM case subjects and 214 non-GDM control subjects. We estimated adjusted odds ratios (OR) and 95% CI for the associations of plasma AAs and the joint associations of plasma AAs and phospholipid FAs with GDM risk, adjusting for risk factors including age, prepregnancy BMI, and family history of diabetes. RESULTS: Glycine at 10-14 GW was inversely associated with GDM (adjusted OR [95% CI] per SD increment: 0.55 [0.39-0.79]). Alanine, aspartic acid, and glutamic acid at 10-14 GW were positively associated with GDM (1.43 [1.08-1.88], 1.41 [1.11-1.80], and 1.39 [0.98-1.98]). At 15-26 GW, findings for glycine, alanine, aspartic acid, and the glutamine-to-glutamic acid ratio were consistent with the directions observed at 10-14 GW. Isoleucine, phenylalanine, and tyrosine were positively associated with GDM (1.64 [1.19-2.27], 1.15 [0.87-1.53], and 1.56 [1.16-2.09]). All P values for linear trend were <0.05. Several AAs and phospholipid FAs were significantly and jointly associated with GDM. For instance, the lowest risk was observed among women with higher glycine and lower even-chain saturated FAs at 10-14 GW (adjusted OR [95% CI] 0.15 [0.06, 0.37]). CONCLUSIONS: Plasma AAs may be implicated in GDM development starting in early pregnancy. Associations of AAs with GDM may be enhanced in the copresence of phospholipid FA profile.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Genomic study of maternal lipid traits in early pregnancy concurs with four known adult lipid loci.

BACKGROUND: Blood lipids during pregnancy are associated with cardiovascular diseases and adverse pregnancy outcomes. Genome-wide association studies (GWAS) in predominantly male European ancestry populations have identified genetic loci associated with blood lipid levels. However, the genetic architecture of blood lipids in pregnant women remains poorly understood. OBJECTIVE: Our goal was to identify genetic loci associated with blood lipid levels among pregnant women from diverse ancestry groups and to evaluate whether previously known lipid loci in predominantly European adults are transferable to pregnant women. METHODS: The trans-ancestry GWAS were conducted on serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides during first trimester among pregnant women from four population groups (608 European-, 623 African-, 552 Hispanic- and 235 East Asian-Americans) recruited in the NICHD Fetal Growth Studies cohort. The four GWAS summary statistics were combined using trans-ancestry meta-analysis approaches that account for genetic heterogeneity among populations. RESULTS: Loci in CELSR2 and APOE were genome-wide significantly associated (p-value < 5×10-8) with total cholesterol and LDL levels. Loci near CETP and ABCA1 approached genome-wide significant association with HDL (p-value = 2.97×10-7 and 9.71×10-8, respectively). Less than 20% of previously known adult lipid loci were transferable to pregnant women. CONCLUSION: This trans-ancestry GWAS meta-analysis in pregnant women identified associations that concur with four known adult lipid loci. Limited replication of known lipid-loci from predominantly European study populations to pregnant women underlines the need for genomic studies of lipids in ancestrally diverse pregnant women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

The association between first-trimester omega-3 fatty acid supplementation and fetal growth trajectories.

BACKGROUND: Prenatal omega-3 fatty acid supplementation, particularly docosahexaenoic acid and eicosapentaenoic acid, has been associated with greater birthweight in clinical trials; however, its effect on fetal growth throughout gestation is unknown. OBJECTIVE: This study aimed to examine the association between first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation and growth trajectories of estimated fetal weight and specific fetal biometrics measured longitudinally from the second trimester of pregnancy to delivery. STUDY DESIGN: In a multisite, prospective cohort of racially diverse, low-risk pregnant women, we used secondary data analysis to examine fetal growth trajectories in relation to self-reported (yes or no) first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation. Fetal ultrasonographic measurements, including abdominal circumference, biparietal diameter, femur length, head circumference, and humerus length, were measured at enrollment (8-13 weeks) and up to 5 follow-up visits. Estimated fetal weight and head circumference-to-abdominal circumference ratio (a measure of growth symmetry) were calculated. Fetal growth trajectories were modeled for each measure using a linear mixed model with cubic splines. If significant differences in fetal growth trajectories between groups were observed (global P<.05), weekly comparisons were performed to determine when in gestation these differences emerged. Analyses were adjusted for maternal sociodemographics, parity, infant sex, total energy consumption, and diet quality score. All analyses were repeated using dietary docosahexaenoic acid and eicosapentaenoic acid intake, dichotomized at the recommended cutoff for pregnant and lactating women (≥0.25 vs <0.25 g/d), among women who did not report supplement intake in the first trimester of pregnancy were repeated. RESULTS: Among 1535 women, 143 (9%) reported docosahexaenoic acid and eicosapentaenoic acid supplementation in the first trimester of pregnancy. Overall, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with statistically significant differences (P-value <.05) in fetal growth trajectories during pregnancy. Specifically, estimated fetal weight was larger among women with docosahexaenoic acid and eicosapentaenoic acid supplementation than among those without supplementation (global P=.028) with significant weekly differences in median estimated fetal weight most apparent between 38 to 41 weeks of gestation (median estimated fetal weight difference at 40 weeks of gestation, 114 g). Differences in fetal growth trajectories for abdominal circumference (P=.003), head circumference (P=.003), and head circumference-to-abdominal circumference ratio (P=.0004) were also identified by supplementation status. In weekly comparisons, docosahexaenoic acid and eicosapentaenoic acid supplement use was associated with larger median abdominal circumference (changed from 2 to 9 mm) in midpregnancy onward (19 to 41 weeks), larger median head circumference between 30 to 33 weeks of gestation, and smaller median head circumference-to-abdominal circumference ratio in the second and third trimesters of pregnancy. There was no specific weekly difference in fetal femur length or humerus length by docosahexaenoic acid and eicosapentaenoic acid supplementation. First-trimester dietary sources of docosahexaenoic acid and eicosapentaenoic acid among women with no first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation (n=1392) were associated with differences in fetal biparietal diameter (P=.043), but not other metrics of fetal growth. At the recommended dietary docosahexaenoic acid and eicosapentaenoic acid levels compared with below-recommended levels, biparietal diameter was larger between 38 to 41 weeks of gestation. CONCLUSION: In this racially diverse pregnancy cohort, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with significant increases in fetal growth, specifically greater estimated fetal abdominal circumference in the second and third trimesters of pregnancy.

Including diverse and admixed populations in genetic epidemiology research.

The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.

Recreational physical activity before and during pregnancy and placental DNA methylation-an epigenome-wide association study.

BACKGROUND: Physical activity (PA) prior to and during pregnancy may have intergenerational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiologic studies on longitudinal PA and placental DNA methylation. OBJECTIVES: We evaluated the association between PA before and during pregnancy and placental DNA methylation. METHODS: Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy Physical Activity Questionnaire, women recalled periconception PA (past 12 mo) at 8-13 wk of gestation and PA since last visit at 4 follow-up visits at 16-22, 24-29, 30-33, and 34-37 wk. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis. RESULTS: Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, and 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2 , which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05; 95% CI: -0.06, -0.03 per metabolic equivalent of task-h/wk at 30-33 wk). Most significantly enriched pathways include cardiac hypertrophy signaling, B-cell receptor signaling, and netrin signaling. Significant CpGs and enriched pathways varied by visit. CONCLUSIONS: Recreational PA in the year prior and during pregnancy was associated with placental DNA methylation. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. This study was registered at clinicaltrials.gov as NCT00912132.

Placental multi-omics integration identifies candidate functional genes for birthweight.

Abnormal birthweight is associated with increased risk for cardiometabolic diseases in later life. Although the placenta is critical to fetal development and later life health, it has not been integrated into largescale functional genomics initiatives, and mechanisms of birthweight-associated variants identified by genome wide association studies (GWAS) are unclear. The goal of this study is to provide functional mechanistic insight into the causal pathway from a genetic variant to birthweight by integrating placental methylation and gene expression with established GWAS loci for birthweight. We identify placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. We find that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in placenta. Multi-trait colocalization identifies PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. These findings reveal candidate functional pathways that underpin the genetic regulation of birthweight via placental epigenetic and transcriptomic mechanisms. Clinical trial registration; ClinicalTrials.gov, NCT00912132.

Sex-specific placental gene expression signatures of small for gestational age at birth.

INTRODUCTION: Small for gestational age at birth (SGA), often a consequence of placental dysfunction, is a risk factor for neonatal morbidity and later life cardiometabolic diseases. There are sex differences in placental gene expression and fetal growth. Here, we investigated sex-specific associations between gene expression in human placenta measured using RNA sequencing and SGA status using data from ethnic diverse pregnant women in the NICHD Fetal Growth Studies cohort (n = 74). METHODS: Gene expression measures were obtained using RNA-Sequencing and differential gene expression between SGA (birthweight <10th percentile) and appropriate for gestational age (AGA: ≥10th and <90th percentile) was tested separately in males (12 SGA and 27 AGA) and females (9 SGA and 26 AGA) using a weighted mean of log ratios method with adjustment for mode of delivery and ethnicity. RESULTS: At 5% false discovery rate (FDR), we identified 40 differentially expressed genes (DEGs) related to SGA status among males (95% up- and 5% down-regulated) and 314 DEGs among females (32.5% up- and 67.5% down-regulated). Seven female-specific DEGs overlapped with known imprinted genes (AXL, CYP24A1, GPR1, PLAGL1, CMTM1, DLX5, LY6D). The DEGs in males were significantly enriched for immune response and inflammation signaling pathways whereas the DEGs in females were enriched for organ development signaling pathways (FDR<0.05). Sex-combined analysis identified no additional DEGs, rather 98% of the sex-specific DEGs were no longer significant and the remaining 2% were attenuated. DISCUSSION: This study revealed sex-specific human placental gene expression changes and molecular pathways associated with SGA and underscored that unravelling the pathogenesis of SGA warrants consideration of fetal sex as a biological variable. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov, Unique identifier: NCT00912132.

Maternal-fetal genetic interactions, imprinting, and risk of placental abruption.

RESULTS: Abruption cases were more likely to experience preeclampsia, have shorter gestational age, and deliver infants with lower birthweight compared with controls. Models with MFGI effects provided improved fit than models with only maternal and fetal genotype main effects for SNP rs12530904 (p-value = 1.2e-04) in calcium/calmodulin-dependent protein kinase [CaM kinase] II beta (CAMK2B), and, SNP rs73136795 (p-value = 1.9e-04) in peroxisome proliferator-activated receptor-gamma (PPARG), both MB genes. We identified 320 SNPs in 45 maternally-imprinted genes (including potassium voltage-gated channel subfamily Q member 1 [KCNQ1], neurotrimin [NTM], and, ATPase phospholipid transporting 10 A [ATP10A]) associated with abruption. Top hits included rs2012323 (p-value = 1.6E-16) and rs12221520 (p-value1.3e-13) in KCNQ1, rs8036892 (p-value = 9.3E-17) and rs188497582 in ATP10A, rs12589854 (p-value = 2.9E-11) and rs80203467 (p-value = 4.6e-11) in maternally expressed 8, small nucleolar RNA host (MEG8), and rs138281088 in solute carrier family 22 member 2 (SLC22A2) (p-value = 6.8e-9). CONCLUSIONS: We identified novel PA-related maternal-fetal MB gene interactions and imprinting effects that highlight the role of the fetus in PA risk development. Findings can inform mechanistic investigations to understand the pathogenesis of PA.

Associations of maternal blood pressure-raising polygenic risk scores with fetal weight.

Maternal blood pressure (BP) is associated with variations in fetal weight, an important determinant of neonatal and adult health. However, the association of BP-raising genetic risk with fetal weight is unknown. We tested the associations of maternal BP-raising polygenic risk scores (PRS) with estimated fetal weights (EFWs) at 13, 20, 27, and 40 weeks of gestation. This study included 622 White, 637 Black, 568 Hispanic, and 238 Asian pregnant women with genotype data from the NICHD Fetal Growth Studies. PRS of systolic (SBP) and diastolic BP (DBP) were calculated for each participant based on summary statistics from a recent genome-wide association study. Linear regression models were used to compare mean EFW differences between the highest versus lowest tertile of PRS, adjusting for maternal age, education, parity, genetic principal components and fetal sex. Hispanics in the highest DBP PRS tertile, compared to those in the lowest, had 8.1 g (95% CI: -15.1, -1.1), 32.4 g (-58.4, -6.4) and 119.4 g (-218.1, -20.7) lower EFW at 20, 27 and 40 weeks, respectively. Similarly, Asians in the highest DBP PRS tertile had 137.2 g (-263.5, -10.8) lower EFW at week 40, and those in the highest tertile of SBP PRS had 3.2 g (-5.8, -0.7), 12.9 g (-23.5, -2.4), and 39.8 g (-76.9, -2.7) lower EFWs at 13, 20, and 27 weeks. The findings showed that pregnant women's genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.

Ancestry-Matched and Cross-Ancestry Genetic Risk Scores of Type 2 Diabetes in Pregnant Women and Fetal Growth: A Study in an Ancestrally Diverse Cohort.

Maternal genetic variants associated with offspring birth weight and adult type 2 diabetes (T2D) risk loci show some overlap. Whether T2D genetic risk influences longitudinal fetal weight and the gestational timing when these relationships begin is unknown. We investigated the associations of T2D genetic risk scores (GRS) with longitudinal fetal weight and birth weight among 1,513 pregnant women from four ancestral groups. Women had up to five ultrasonography examinations. Ancestry-matched GRS were constructed separately using 380 European- (GRSeur), 104 African- (GRSafr), and 189 East Asian- (GRSeas) related T2D loci discovered in different population groups. Among European Americans, the highest quartile GRSeur was significantly associated with 53.8 g higher fetal weight (95% CI 19.2-88.5) over the pregnancy. The associations began at gestational week 24 and continued through week 40, with a 106.8 g (95% CI 6.5-207.1) increase in birth weight. The findings were similar in analysis further adjusted for maternal glucose challenge test results. No consistent association was found using ancestry-matched or cross-ancestry GRS in non-Europeans. In conclusion, T2D genetic susceptibility may influence fetal growth starting at midsecond trimester among Europeans. Absence of similar associations in non-Europeans urges the need for further genetic T2D studies in diverse ancestries.

Placental Gene Co-expression Network for Maternal Plasma Lipids Revealed Enrichment of Inflammatory Response Pathways.

Maternal dyslipidemia during pregnancy has been associated with suboptimal fetal growth and increased cardiometabolic diseasse risk in offspring. Altered placental function driven by placental gene expression is a hypothesized mechanism underlying these associations. We tested the relationship between maternal plasma lipid concentrations and placental gene expression. Among 64 pregnant women from the NICHD Fetal Growth Studies-Singleton cohort with maternal first trimester plasma lipids we extracted RNA-Seq on placental samples obtained at birth. Placental gene co-expression networks were validated by regulatory network analysis that integrated transcription factors and gene expression, and genome-wide transcriptome analysis. Network analysis detected 24 gene co-expression modules in placenta, of which one module was correlated with total cholesterol (r = 0.27, P-value = 0.03) and LDL-C (r = 0.31, P-value = 0.01). Genes in the module (n = 39 genes) were enriched in inflammatory response pathways. Out of the 39 genes in the module, three known lipid-related genes (MPO, PGLYRP1 and LTF) and MAGEC2 were validated by the regulatory network analysis, and one known lipid-related gene (ALX4) and two germ-cell development-related genes (MAGEC2 and LUZP4) were validated by genome-wide transcriptome analysis. Placental gene expression signatures associated with unfavorable maternal lipid concentrations may be potential pathways underlying later life offspring cardiometabolic traits. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00912132.

Association between early gestation passive smoke exposure and neonatal size among self-reported non-smoking women by race/ethnicity: A cohort study.

Understanding implications of passive smoke exposure during pregnancy is an important public health issue under the Developmental Origins of Health and Disease paradigm. In a prospective cohort of low-risk non-smoking pregnant women (NICHD Fetal Growth Studies-Singletons, 2009-2013, N = 2055), the association between first trimester passive smoke exposure and neonatal size was assessed by race/ethnicity. Plasma biomarker concentrations (cotinine, nicotine) assessed passive smoke exposure. Neonatal anthropometric measures included weight, 8 non-skeletal, and 2 skeletal measures. Linear regression evaluated associations between continuous biomarker concentrations and neonatal anthropometric measures by race/ethnicity. Cotinine concentrations were low and the percent above limit of quantification varied by maternal race/ethnicity (10% Whites; 14% Asians; 15% Hispanics; 49% Blacks). The association between cotinine concentration and infant weight differed by race/ethnicity (Pinteraction = 0.034); compared to women of the same race/ethnicity, per 1 log-unit increase in cotinine, weight increased 48g (95%CI -44, 139) in White and 51g (95%CI -81, 183) in Hispanic women, but decreased -90g (95%CI -490, 309) in Asian and -93g (95%CI -151, -35) in Black women. Consistent racial/ethnic differences and patterns were found for associations between biomarker concentrations and multiple non-skeletal measures for White and Black women (Pinteraction<0.1). Among Black women, an inverse association between cotinine concentration and head circumference was observed (-0.20g; 95%CI -0.38, -0.02). Associations between plasma cotinine concentration and neonatal size differed by maternal race/ethnicity, with increasing concentrations associated with decreasing infant size among Black women, who had the greatest biomarker concentrations. Public health campaigns should advocate for reducing pregnancy exposure, particularly for vulnerable populations.