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.

Pregnancy Outcomes of Nifedipine Compared With Labetalol for Oral Treatment of Mild Chronic Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Optimal Timing of Delivery for Pregnant Individuals With Mild Chronic Hypertension.

OBJECTIVE: To investigate the optimal gestational age to deliver pregnant people with chronic hypertension to improve perinatal outcomes. METHODS: We conducted a planned secondary analysis of a randomized controlled trial of chronic hypertension treatment to different blood pressure goals. Participants with term, singleton gestations were included. Those with fetal anomalies and those with a diagnosis of preeclampsia before 37 weeks of gestation were excluded. The primary maternal composite outcome included death, serious morbidity (heart failure, stroke, encephalopathy, myocardial infarction, pulmonary edema, intensive care unit admission, intubation, renal failure), preeclampsia with severe features, hemorrhage requiring blood transfusion, or abruption. The primary neonatal outcome included fetal or neonatal death, respiratory support beyond oxygen mask, Apgar score less than 3 at 5 minutes, neonatal seizures, or suspected sepsis. Secondary outcomes included intrapartum cesarean birth, length of stay, neonatal intensive care unit admission, respiratory distress syndrome (RDS), transient tachypnea of the newborn, and hypoglycemia. Those with a planned delivery were compared with those expectantly managed at each gestational week. Adjusted odds ratios (aORs) with 95% CIs are reported. RESULTS: We included 1,417 participants with mild chronic hypertension; 305 (21.5%) with a new diagnosis in pregnancy and 1,112 (78.5%) with known preexisting hypertension. Groups differed by body mass index (BMI) and preexisting diabetes. In adjusted models, there was no association between planned delivery and the primary maternal or neonatal composite outcome in any gestational age week compared with expectant management. Planned delivery at 37 weeks of gestation was associated with RDS (7.9% vs 3.0%, aOR 2.70, 95% CI, 1.40-5.22), and planned delivery at 37 and 38 weeks was associated with neonatal hypoglycemia (19.4% vs 10.7%, aOR 1.97, 95% CI, 1.27-3.08 in week 37; 14.4% vs 7.7%, aOR 1.82, 95% CI, 1.06-3.10 in week 38). CONCLUSION: Planned delivery in the early-term period compared with expectant management was not associated with a reduction in adverse maternal outcomes. However, it was associated with increased odds of some neonatal complications. Delivery timing for individuals with mild chronic hypertension should weigh maternal and neonatal outcomes in each gestational week but may be optimized by delivery at 39 weeks.

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..

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.

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.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

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.

Prediction of metabolic syndrome following a first pregnancy.

BACKGROUND: The prevalence of metabolic syndrome is rapidly increasing in the United States. We hypothesized that prediction models using data obtained during pregnancy can accurately predict the future development of metabolic syndrome. OBJECTIVE: This study aimed to develop machine learning models to predict the development of metabolic syndrome using factors ascertained in nulliparous pregnant individuals. STUDY DESIGN: This was a secondary analysis of a prospective cohort study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study [nuMoM2b-HHS]). Data were collected from October 2010 to October 2020, and analyzed from July 2023 to October 2023. Participants had in-person visits 2 to 7 years after their first delivery. The primary outcome was metabolic syndrome, defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, which was measured within 2 to 7 years after delivery. A total of 127 variables that were obtained during pregnancy were evaluated. The data set was randomly split into a training set (70%) and a test set (30%). We developed a random forest model and a lasso regression model using variables obtained during pregnancy. We compared the area under the receiver operating characteristic curve for both models. Using the model with the better area under the receiver operating characteristic curve, we developed models that included fewer variables based on SHAP (SHapley Additive exPlanations) values and compared them with the original model. The final model chosen would have fewer variables and noninferior areas under the receiver operating characteristic curve. RESULTS: A total of 4225 individuals met the inclusion criteria; the mean (standard deviation) age was 27.0 (5.6) years. Of these, 754 (17.8%) developed metabolic syndrome. The area under the receiver operating characteristic curve of the random forest model was 0.878 (95% confidence interval, 0.846-0.909), which was higher than the 0.850 of the lasso model (95% confidence interval, 0.811-0.888; P<.001). Therefore, random forest models using fewer variables were developed. The random forest model with the top 3 variables (high-density lipoprotein, insulin, and high-sensitivity C-reactive protein) was chosen as the final model because it had the area under the receiver operating characteristic curve of 0.867 (95% confidence interval, 0.839-0.895), which was not inferior to the original model (P=.08). The area under the receiver operating characteristic curve of the final model in the test set was 0.847 (95% confidence interval, 0.821-0.873). An online application of the final model was developed (https://kawakita.shinyapps.io/metabolic/). CONCLUSION: We developed a model that can accurately predict the development of metabolic syndrome in 2 to 7 years after delivery.

Decreased vascular reactivity associated with increased IL-8 in 6-month-old infants of mothers with pre-eclampsia.

BACKGROUND: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy. METHODS: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed. RESULTS: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001). CONCLUSION: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers. IMPACT STATEMENT: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia.

NuMoM2b Study Insights: Primary Exposures, Outcomes, and Directions for Future Research.

OBJECTIVE: To summarize the publications to date from a large obstetric cohort of nulliparous individuals. STUDY DESIGN: We summarized all of the publications from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). We descriptively summarized the most common outcomes and exposures reported in current publications. RESULTS: Fifty-six publications to date are discussed. The most common primary exposures reported are participant baseline characteristics such as body mass index (24%), sociodemographic characteristics (22%), and sleep factors (16%). These exposures were most commonly measured in the first trimester (77%). The most commonly reported primary outcomes were related to adverse pregnancy outcomes (APOs, 51.6%), with 25% using a composite of multiple APOs as the primary outcome. At least 8,000 participants were used in the analyses of over half of the publications. CONCLUSION: The nuMoM2b study has generated a diverse array of publications and conclusions on factors associated with APOs. The publicly available data set from the nuMoM2b study continues to hold potential for considerable advances, new insights, and future research opportunities to optimize pregnancy and pregnancy-related health. KEY POINTS: · The nuMoM2b pregnancy cohort has generated 56 publications thus far.. · The main findings of these publications are summarized and categorized in this work.. · The data and specimens from this cohort are available and can answer many clinical questions..

The Association between Sleep and Depression during Late Pregnancy and the Early Postpartum Period.

Objective To assess and correlate sleep quality and depressed mood symptoms in the late pregnancy and early postpartum periods. Study Design In a prospective pilot observational study, participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Edinburgh Postnatal Depression Scale (EPDS) questionnaires at delivery, 1, and 2 months postpartum. Pearson's correlation coefficients and PROC MIXED function estimated overall correlation for repeated measures. Results Twenty-six women were enrolled with a mean gestational age at delivery of 38.4 (± 2.4) weeks. Sleep quality and mood data were available at the three time points for 24, 16, and 11 participants, respectively. Poor sleep scores were noted by 75.0, 87.5, and 72.7% of women at the three time points. An elevated EPDS score of 10 or higher was claimed by 20.8, 12.5, and 18.2% of women, respectively. Higher PSQI scores were positively associated with higher EPDS scores overall ( r = 0.71, p < 0.001) and at each of the individual time points ( r = 0.79, p < 0.0001; r = 0.52, p = 0.04; and r = 0.70, p = 0.016, respectively). None of the women reporting good sleep quality had elevated EPDS scores. Conclusion Poor sleep is commonly reported around delivery, and at 1 and 2 months postpartum, and there is an association between poor sleep and depression symptoms.

COHESION: a core outcome set for the treatment of neonatal encephalopathy.

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE. METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics. RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment. CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS. IMPACT: We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Cannabis Exposure and Adverse Pregnancy Outcomes Related to Placental Function.

Importance: Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain. Objective: To evaluate the association between maternal cannabis use and adverse pregnancy outcomes known to be related to placental function. Design, Setting, and Participants: Ancillary analysis of nulliparous individuals treated at 8 US medical centers with stored urine samples and abstracted pregnancy outcome data available. Participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort were recruited from 2010 through 2013; the drug assays and analyses for this ancillary project were completed from June 2020 through April 2023. Exposure: Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol using frozen stored urine samples from study visits during the pregnancy gestational age windows of 6 weeks and 0 days to 13 weeks and 6 days (visit 1); 16 weeks and 0 days to 21 weeks and 6 days (visit 2); and 22 weeks and 0 days to 29 weeks and 6 days (visit 3). Positive results were confirmed with liquid chromatography tandem mass spectrometry. The timing of cannabis exposure was defined as only during the first trimester or ongoing exposure beyond the first trimester. Main Outcome and Measure: The dichotomous primary composite outcome included small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy ascertained by medical record abstraction by trained perinatal research staff with adjudication of outcomes by site investigators. Results: Of 10 038 participants, 9257 were eligible for this analysis. Of the 610 participants (6.6%) with cannabis use, 32.4% (n = 197) had cannabis exposure only during the first trimester and 67.6% (n = 413) had ongoing exposure beyond the first trimester. Cannabis exposure was associated with the primary composite outcome (25.9% in the cannabis exposure group vs 17.4% in the no exposure group; adjusted relative risk, 1.27 [95% CI, 1.07-1.49]) in the propensity score-weighted analyses after adjustment for sociodemographic characteristics, body mass index, medical comorbidities, and active nicotine use ascertained via urine cotinine assays. In a 3-category cannabis exposure model (no exposure, exposure only during the first trimester, or ongoing exposure), cannabis use during the first trimester only was not associated with the primary composite outcome; however, ongoing cannabis use was associated with the primary composite outcome (adjusted relative risk, 1.32 [95% CI, 1.09-1.60]). Conclusions and Relevance: In this multicenter cohort, maternal cannabis use ascertained by biological sampling was associated with adverse pregnancy outcomes related to placental dysfunction.

The Effects of Preeclamptic Milieu on Cord Blood Derived Endothelial Colony-Forming Cells.

Preeclampsia is one of the leading causes of infant and maternal mortality worldwide. Many infants born from preeclamptic pregnancies are born prematurely with higher risk of developing cardiovascular later in their life. A key mechanism by which these complications occur is through stress-induced dysfunction of endothelial progenitor cells (EPCs), including endothelial colony-forming cells (ECFCs). To gain insight into this, cord blood derived ECFCs isolated from preeclamptic pregnancies (PRECs) were analyzed and compared to their healthy counterparts. While PRECs preserve key endothelial markers, they upregulate several markers associated with oxidative stress and inflammatory response. Compared to ECFCs, PRECs also exhibit lower migratory behaviors and impaired angiogenic potential. Interestingly, treatment of neuropilin-1 can improve tube formation in vitro. Collectively, this study reports that preeclamptic milieu influence phenotypes and functionality of PRECs, which can be rejuvenated using exogenous molecules. Promising results from this study warrant future investigations on the prospect of the rejuvenated PRECs to improve lung function of infants born from preeclamptic pregnancies.