Oxytocin regimen used for induction of labor and pregnancy outcomes.

BACKGROUND: Following the results of the ARRIVE trial, which demonstrated a reduction in cesarean delivery with no increase in adverse perinatal outcomes after elective induction of labor (IOL) in low-risk nulliparous patients at 39 weeks' gestation compared with expectant management, the use of induction has increased. Current evidence is insufficient to recommend mid-high-dose over low-dose regimens for routine IOL. OBJECTIVE(S): We sought to evaluate the association of oxytocin regimen with cesarean delivery and an adverse perinatal composite outcome in low-risk nulliparous patients undergoing IOL at 39 weeks of gestation or greater. STUDY DESIGN: This is a secondary analysis of the NICHD Maternal-Fetal Medicine Units Network ARRIVE randomized trial. Patients induced with a mid-to high-dose oxytocin regimen (MHD; starting or incremental increase >2 mU/min) were compared with those receiving a low-dose oxytocin regimen (LD; starting and incremental increase ≤2 mU/min). The co-primary outcomes for this secondary analysis were 1) cesarean delivery and 2) composite of perinatal death or severe neonatal complications. Multivariable Poisson regression was used to estimate adjusted relative risks (aRR) and 97.5% confidence intervals (CI) for the co-primary endpoints, 95% CI for binomial outcomes and multinomial logistic regression was used to estimate adjusted odds ratios (aOR) and 95% CIs for multinomial outcomes. RESULTS: Of 6,106 participants enrolled in the primary trial, 2,933 underwent induction with oxytocin: 861 in the MHD group and 2,072 in the LD group. The lower frequency of cesarean delivery in the MHD group compared with the LD group (20.3% vs. 25.2%, RR 0.81, 95%CI (0.69-0.94)) was not significant after adjustment (aRR 0.90, 97.5%CI (0.76-1.07)). The composite of perinatal death or severe neonatal complications was more frequent in the MHD group compared with the LD group (6.7% vs. 4.3%, RR 1.55, 95%CI (1.13-2.14)) and remained significant after adjustment (aRR 1.61, 97.5%CI (1.11-2.35)). The majority of the cases in the composite were from the respiratory support (5.2% vs. 3.1%) component with an increase in transient tachypnea of the newborn (3.8% vs. 2.5%, aRR 1.63, 95% CI (1.04-2.54)). The duration of neonatal respiratory support for one day was significantly higher in the MHD group compared with the LD group (3.5% vs. 1.4%, aRR 2.59, 95%CI (1.52-4.39)); however, support beyond one day was not different between the two groups. The MHD group, when compared with the LD group had a higher operative vaginal delivery rate (10.0% vs. 7.0%, aRR 1.54, 95%CI (1.18-2.00)) and shorter duration of time from start of oxytocin to delivery [crude median (interquartile range) 12 (8-17) vs. 13 (9-19) hours, adjusted median difference -2 (-2 to -1), p<0.001], respectively. CONCLUSION(S): Mid-high-dose oxytocin regimen use for IOL in nulliparas at ≥ 39 weeks' gestation was not associated with improved maternal or neonatal outcomes compared with low-dose regimens. Although mid-high-dose oxytocin regimen use was associated with a shorter duration of labor, there was an increase in self-limited neonatal respiratory support and no difference in cesarean rates. More evidence is needed to define the magnitude of potential maternal and neonatal benefits and risks associated with oxytocin regimens.

Pre-pregnancy substance use and first trimester cardiovascular health among nulliparous pregnant people: The nuMoM2b Study.

BACKGROUND: Suboptimal pre-pregnancy health, including substance use and cardiovascular risk factors, is associated with higher risks of maternal-foetal morbidity and mortality. OBJECTIVE: To determine if pre-pregnancy substance use is associated with early pregnancy cardiovascular health (CVH). It is hypothesised that pre-pregnancy use of substances is associated with worse CVH in the first trimester of pregnancy. METHODS: This is a secondary analysis from the 2010-2015 United States nuMoM2b cohort (n = 9895). Pre-pregnancy alcohol, tobacco, marijuana, and illicit substance use were assessed through questionnaires. Latent class analysis categorised participants based on their 3-month pre-pregnancy or ever(*) substance use: (1) Illicit substances*, marijuana*, and alcohol use (n = 1234); (2) marijuana* and alcohol use (n = 2066); (3) tobacco and alcohol use (n = 636); and (4) alcohol only use (n = 3194). The referent group reported no pre-pregnancy substance use (n = 2765). First trimester CVH score from 0 (least healthy) to 100 (most healthy) was calculated using a modified American Heart Association Life's Essential 8 framework and included body mass index (BMI), blood pressure, blood glucose, non-HDL cholesterol, diet, sleep, and physical activity. Multiple linear regression evaluated the relationship between pre-pregnancy substance use classes and CVH scores. RESULTS: CVH score varied by class: No substance use (mean: 65, SD: ±1.3), illicit substances*, marijuana*, and alcohol use (68 ± 1.3), marijuana* and alcohol use (67 ± 1.3), tobacco and alcohol use (62 ± 1.4), and alcohol only use (67 ± 1.3). In adjusted models, those who used tobacco and alcohol compared to the no substance use class had a lower CVH score (-2.82); other classes had scores ranging from 1.81 to 2.44 points higher than the no substance use class. Individual CVH component scores followed similar patterns. CONCLUSIONS: All groups, but most markedly those who used tobacco and alcohol prior to pregnancy, began pregnancy with only moderate CVH and may benefit from CVH promotion efforts along with substance use treatment.

A Pilot Study of Ultrasound Assessment of Umbilical Cord and Placental Vascular Flow for Cord Accident Stillbirth Prevention.

OBJECTIVE: Our objective was to determine the feasibility and interobserver reliability of umbilical cord and placental arteriolar flow assessment in low-risk pregnancies near term. METHODS: This was a prospective pilot study in low-risk pregnancies at 36 weeks with anterior placentas. We excluded any with an indication for antenatal testing or delivery before 39 weeks. Each participant underwent two ultrasounds by different examiners, which included arterial and venous velocimetry at three cord sites (fetal, free loop, and placental) in addition to maternal and fetal placental arterioles. The interobserver reliability was quantified using the Pearson correlation coefficient with that of standard clinical parameters serving as a benchmark for interpretation. RESULTS: Among 53 participants scanned at 356/7-371/7 weeks, the mean examination duration was 20.5 ± 4.2 minutes. Ascertainment success was high for measures at the free loop, placental cord insertion, and fetal placental arterioles (range 90.6%-99.1%) and was lower at the fetal cord insertion and maternal spiral arterioles (range 47.2%-87.7%). Interobserver reliability estimates for free-loop systolic/diastolic and pulsatility index ranged from 0.38 to 0.44. Interobserver reliability for experimental parameters varied by measurement site, and all were poor at the fetal insertion and in placental arterioles. Parameters had significant variation across cord sites (range 4.3%-21.7%). CONCLUSION: In our cohort, flow assessments of the free loop, placental insertion, and placental arterioles are feasible, but interrater reliability varies by measurement type and cord site. Future studies are needed to establish feasibility and reliability in nonanterior placentation and to assess clinical relevance.

Vascular Placental Pathology and Cardiac Structure in Stillborn Fetuses.

OBJECTIVE: Adverse pregnancy outcomes, including preterm birth and preeclampsia, are associated with worse cardiovascular outcomes for offspring. Examination of the placenta is important for understanding how the prenatal period shapes long-term cardiovascular health. We sought to investigate the association between placental vascular malperfusion and fetal cardiac structure. STUDY DESIGN: Data obtained from the Stillbirth Collaborative Research Network included stillbirths with placental pathology and autopsy. Stillbirths were classified in two ways: based on the severity of placental maternal vascular malperfusion (MVM) and based on the cause of death (MVM, fetal vascular malperfusion [FVM], or acute infection/controls). Organ weight and heart measures were standardized by gestational age (GA) and compared across groups. RESULTS: We included 329 stillbirths in the analysis by MVM severity and 76 in the analysis by cause of death (COD). While z-scores for most organ weights/heart measures were smaller when COD was attributed to MVM as compared with FVM or controls, heart weight and brain weight z-scores did not differ by COD (p > 0.05). In analyses accounting for body size, the difference between heart and body weight z-score was -0.05 (standard deviation [SD]: 0.53) among those with MVM as a COD and -0.20 (SD: 0.95) among those with severe MVM. Right and left ventricle thicknesses and tricuspid, pulmonary, mitral, and aortic valve circumferences were consistently as expected or larger than expected for GA and body weight. In the analysis investigating the severity of MVM, those with the most severe MVM had heart measures that were as expected or larger than expected for body weight while those with only mild to moderate MVM had heart measures that were generally small relative to body weight. CONCLUSION: When assessed as COD or based on severity, MVM was associated with heart measures that were as expected or larger than expected for GA and body weight, indicating possible heart sparing. KEY POINTS: · Fetal deaths with MVM show smaller organ weights.. · Heart weight sparing is seen with fetal death attributed to MVM.. · Heart weight sparing is more pronounced with severe MVM..

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).

Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy.

Importance: There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia. Objective: To determine predictive ability in early pregnancy of large-scale proteomics for prediction of HDP. Design, Setting, and Participants: This was a nested case-control study, conducted in 2022 to 2023, using clinical data and plasma samples collected between 2010 and 2013 during the first trimester, with follow-up until pregnancy outcome. This multicenter observational study took place at 8 academic medical centers in the US. Nulliparous individuals during first-trimester clinical visits were included. Participants with HDP were selected as cases; controls were selected from those who delivered at or after 37 weeks without any HDP, preterm birth, or small-for-gestational-age infant. Age, self-reported race and ethnicity, body mass index, diabetes, health insurance, and fetal sex were available covariates. Exposures: Proteomics using an aptamer-based assay that included 6481 unique human proteins was performed on stored plasma. Covariates were used in predictive models. Main Outcomes and Measures: Prediction models were developed using the elastic net, and analyses were performed on a randomly partitioned training dataset comprising 80% of study participants, with the remaining 20% used as an independent testing dataset. Primary measure of predictive performance was area under the receiver operating characteristic curve (AUC). Results: This study included 753 HDP cases and 1097 controls with a mean (SD) age of 26.9 (5.5) years. Maternal race and ethnicity were 51 Asian (2.8%), 275 non-Hispanic Black (14.9%), 275 Hispanic (14.9%), 1161 non-Hispanic White (62.8% ), and 88 recorded as other (4.8%), which included those who did not identify according to these designations. The elastic net model, allowing for forced inclusion of prespecified covariates, was used to adjust protein-based models for clinical and demographic variables. Under this approach, no proteins were selected to augment the clinical and demographic covariates. The predictive performance of the resulting model was modest, with a training set AUC of 0.64 (95% CI, 0.61-0.67) and a test set AUC of 0.62 (95% CI, 0.56-0.68). Further adjustment for study site yielded only minimal changes in AUCs. Conclusions and Relevance: In this case-control study with detailed clinical data and stored plasma samples available in the first trimester, an aptamer-based proteomics panel did not meaningfully add to predictive utility over and above clinical and demographic factors that are routinely available.

Placental somatic mutation in human stillbirth and live birth: A pilot case-control study of paired placental, fetal, and maternal whole genomes.

INTRODUCTION: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7). DISCUSSION: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.

MRI assessed placental volume and adverse pregnancy outcomes: Secondary analysis of prospective cohort study.

INTRODUCTION: Our goal was to evaluate the potential utility of magnetic resonance imaging (MRI) placental volume as an assessment of placental insufficiency. METHODS: Secondary analysis of a prospective cohort undergoing serial placental MRIs at two academic tertiary care centers. The population included 316 participants undergoing MRI up to three times throughout gestation. MRI was used to calculate placental volume in milliliters (ml). Placental-mediated adverse pregnancy outcome (cAPO) included preeclampsia with severe features, abnormal antenatal surveillance, and perinatal mortality. Serial measurements were grouped as time point 1 (TP1) <22 weeks, TP2 22 0/7-29 6/7 weeks, and TP3 ≥30 weeks. Mixed effects models compared change in placental volume across gestation between cAPO groups. Association between cAPO and placental volume was determined using logistic regression at each TP with discrimination evaluated using area under receiver operator curve (AUC). Placental volume was then added to known clinical predictive variables and evaluated with test characteristics and calibration. RESULTS: 59 (18.7 %) of 316 participants developed cAPO. Placental volume growth across gestation was slower in the cAPO group (p < 0.001). Placental volume was lower in the cAPO group at all time points, and alone was moderately predictive of cAPO at TP3 (AUC 0.756). Adding placental volume to clinical variables had moderate discrimination at all time points, with strongest test characteristics at TP3 (AUC 0.792) with sensitivity of 77.5 % and specificity of 75.3 % at a predicted probability cutoff of 15 %. DISCUSSION: MRI placental volume warrants further study for assessment of placental insufficiency, particularly later in gestation.

Diet quality, community food access, and glycemic control among nulliparous individuals with diabetes.

Better diet quality regardless of community food access was associated with a higher likelihood of glycemic control in early pregnancy among nulliparous individuals with pregestational diabetes. These findings highlight the need for interventions that address nutrition insecurity for pregnant individuals living with diabetes.

Maternal Preconception Omega-6, Omega-3, and Omega-6:Omega-3 Intake and Uterine Artery Indices in Mid-Gestation.

OBJECTIVE: Maternal preconception diet influences pregnancy health and fetal outcomes. We examined the relationship between preconception fatty acid (FA) intake and uterine artery indices in mid-gestation in a large, heterogeneous cohort of nulliparous individuals. STUDY DESIGN: This is a secondary analysis of the nuMom2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be) study. Dietary ω-6 and ω-3 FA intake was assessed with food frequency questionnaires and uterine artery indices were obtained via Doppler studies in the second trimester. For our primary outcome of pulsatility index (PI) > 1.6, we compared proportions by each dichotomous FA exposure and tested differences with chi-square test. RESULTS: For PI > 1.6, odds ratio for the unfavorable FA quartile compared with remaining quartiles for the exposures were 0.96 to 1.25, p = 0.157 (ω-6 FA); 0.97 to 1.26, p = 0.124 (ω-3 FA); 0.87 to 1.14, p = 1.00 (ω-6:ω-3 FA ratio). CONCLUSION: No significant associations between self-reported maternal preconception ω-6 and ω-3 FA intake and uterine artery Doppler indices measured during the second trimester were observed. KEY POINTS: · Maternal diet impacts pregnancy health/fetal outcomes.. · ω-3 and ω-6 FA intake influences cardiovascular health.. · FA intake may affect blood flow to fetoplacental unit.. · Results are limited by inadequate adherence to dietary recommendations..

Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Low-dose aspirin, maternal cardiometabolic health, and offspring respiratory health 9 to 14 years after delivery: Findings from the EAGeR Follow-up Study.

BACKGROUND: Accumulating evidence shows that peri-conceptional and in-utero exposures have lifetime health impacts for mothers and their offspring. OBJECTIVES: We conducted a Follow-Up Study of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial with two objectives. First, we determined if women who enrolled at the Utah site (N = 1001) of the EAGeR trial (2007-2011, N = 1228) could successfully be contacted and agree to complete an online questionnaire on their reproductive, cardio-metabolic, and offspring respiratory health 9-14 years after original enrollment. Second, we evaluated if maternal exposure to low-dose aspirin (LDA) during pregnancy was associated with maternal cardio-metabolic health and offspring respiratory health. METHODS: The original EAGeR study population included women, 18-40 years of age, who had 1-2 prior pregnancy losses, and who were trying to become pregnant. At follow-up (2020-2021), participants from the Utah cohort completed a 13-item online questionnaire on reproductive and cardio-metabolic health, and those who had a live birth during EAGeR additionally completed a 7-item questionnaire on the index child's respiratory health. Primary maternal outcomes included hypertension and hypercholesterolemia; primary offspring outcomes included wheezing and asthma. RESULTS: Sixty-eight percent (n = 678) of participants enrolled in the follow-up study, with 10% and 15% reporting maternal hypertension and hypercholesterolemia, respectively; and 18% and 10% reporting offspring wheezing and asthma. We found no association between maternal LDA exposure and hypertension (risk difference [RD] -0.001, 95% confidence interval [CI] -0.05, 0.04) or hypercholesterolemia (RD -0.01, 95% CI -0.06, 0.05) at 9-14 years follow-up. Maternal LDA exposure was not associated with offspring wheezing (RD -0.002, 95% CI -0.08, 0.08) or asthma (RD 0.13, 95% CI 0.11, 0.37) at follow-up. Findings remained robust after considering potential confounding and selection bias. CONCLUSIONS: We observed no association between LDA exposure during pregnancy and maternal cardiometabolic or offspring respiratory health.

Genetic polymorphisms associated with adverse pregnancy outcomes in nulliparas.

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Socioeconomic disadvantage in pregnancy and postpartum risk of cardiovascular disease.

BACKGROUND: Pregnancy is an educable and actionable life stage to address social determinants of health (SDOH) and lifelong cardiovascular disease (CVD) prevention. However, the link between a risk score that combines multiple neighborhood-level social determinants in pregnancy and the risk of long-term CVD remains to be evaluated. OBJECTIVE: To examine whether neighborhood-level socioeconomic disadvantage measured by the Area Deprivation Index (ADI) in early pregnancy is associated with a higher 30-year predicted risk of CVD postpartum, as measured by the Framingham Risk Score. STUDY DESIGN: An analysis of data from the prospective Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be Heart Health Study longitudinal cohort. Participant home addresses during early pregnancy were geocoded at the Census-block level. The exposure was neighborhood-level socioeconomic disadvantage using the 2015 ADI by tertile (least deprived [T1], reference; most deprived [T3]) measured in the first trimester. Outcomes were the predicted 30-year risks of atherosclerotic cardiovascular disease (ASCVD, composite of fatal and nonfatal coronary heart disease and stroke) and total CVD (composite of ASCVD plus coronary insufficiency, angina pectoris, transient ischemic attack, intermittent claudication, and heart failure) using the Framingham Risk Score measured 2 to 7 years after delivery. These outcomes were assessed as continuous measures of absolute estimated risk in increments of 1%, and, secondarily, as categorical measures with high-risk defined as an estimated probability of CVD ≥10%. Multivariable linear regression and modified Poisson regression models adjusted for baseline age and individual-level social determinants, including health insurance, educational attainment, and household poverty. RESULTS: Among 4309 nulliparous individuals at baseline, the median age was 27 years (interquartile range [IQR]: 23-31) and the median ADI was 43 (IQR: 22-74). At 2 to 7 years postpartum (median: 3.1 years, IQR: 2.5, 3.7), the median 30-year risk of ASCVD was 2.3% (IQR: 1.5, 3.5) and of total CVD was 5.5% (IQR: 3.7, 7.9); 2.2% and 14.3% of individuals had predicted 30-year risk ≥10%, respectively. Individuals living in the highest ADI tertile had a higher predicted risk of 30-year ASCVD % (adjusted ß: 0.41; 95% confidence interval [CI]: 0.19, 0.63) compared with those in the lowest tertile; and those living in the top 2 ADI tertiles had higher absolute risks of 30-year total CVD % (T2: adj. ß: 0.37; 95% CI: 0.03, 0.72; T3: adj. ß: 0.74; 95% CI: 0.36, 1.13). Similarly, individuals living in neighborhoods in the highest ADI tertile were more likely to have a high 30-year predicted risk of ASCVD (adjusted risk ratio [aRR]: 2.21; 95% CI: 1.21, 4.02) and total CVD ≥10% (aRR: 1.35; 95% CI: 1.08, 1.69). CONCLUSION: Neighborhood-level socioeconomic disadvantage in early pregnancy was associated with a higher estimated long-term risk of CVD postpartum. Incorporating aggregated SDOH into existing clinical workflows and future research in pregnancy could reduce disparities in maternal cardiovascular health across the lifespan, and requires further study.

A multisite study to develop and validate first trimester, circulating microparticle biomarkers for tiered risk stratification of spontaneous preterm birth in nulliparas.

BACKGROUND: Despite much research, advances in early prediction of spontaneous preterm birth (sPTB) has been slow. The evolving field of circulating microparticle (CMP) biology may identify novel blood-based, and clinically useful, biomarkers. OBJECTIVE: To test the ability of a previously identified, 7-marker set of CMP-derived proteins from the first trimester of pregnancy, in the form of an in vitro diagnostic multivariate index assay (IVDMIA), to stratify pregnant patients according to their risk for sPTB. STUDY DESIGN: We employed a previously validated set of CMP protein biomarkers, utilizing mass spectrometry assays and a nested case-control design in a subset of participants from the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b). We evaluated these biomarkers in the form of an IVDMIA to predict risk for sPTB at different gestational ages. Plasma samples collected at 9- to 13-weeks' gestation were analyzed. The IVDMIA assigned subjects to 1 of 3 sPTB risk categories: low risk (LR), moderate risk (MR), or high risk (HR). Independent validation on a set-aside set confirmed the IVDMIA's performance in risk stratification. RESULTS: Samples from 400 participants from the nuMoM2b cohort were used for the study; of these, 160 delivered<37 weeks and 240 delivered at term. Through Monte Carlo simulation in which the validation results were adjusted based on actual weekly sPTB incidence rates in the nuMoM2b cohort, the IVDMIA stratifications demonstrated statistically significant differences among the risk groups in time-to-event (birth) analysis (P<.0001). The incidence-rate adjusted cumulative risks of sPTB at ≤32 weeks' gestation were 0.4%, 1.6%, and 7.5%, respectively for the LR, MR, and HR groups, respectively. Compared to the LR group, the corresponding risk ratios of the IVDMIA assigned MR and HR group were 4.25 (95% confidence interval [CI] 2.2-7.9) and 19.92 (95% CI 10.4-37.4), respectively. CONCLUSION: A first trimester CMP protein biomarker panel can be used to stratify risk for sPTB at different gestational ages. Such a multitiered stratification tool could be used to assess risk early in pregnancy to enable timely clinical management and interventions, and, ultimately, to enable the development of tailored care pathways for sPTB prevention.