A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection.

BACKGROUND: Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS: In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS: From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS: Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).

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.

Short Term Coping-Behaviors and Postpartum Health in a Population-Based Study of Women with a Live Birth, Stillbirth, or Neonatal Death.

OBJECTIVE: Responding to the National Institutes of Health Working Group's call for research on the psychological impact of stillbirth, we compared coping-related behaviors by outcome of an index birth (surviving live birth or perinatal loss - stillbirth or neonatal death) and, among individuals with loss, characterized coping strategies and their association with depressive symptoms 6-36 months postpartum. METHODS: We used data from the Stillbirth Collaborative Research Network follow-up study (2006-2008) of 285 individuals who experienced a stillbirth, 691 a livebirth, and 49 a neonatal death. We conducted a thematic analysis of coping strategies individuals recommended following their loss. We fit logistic regression models, accounting for sampling and inverse probability of follow-up weights to estimate associations between pregnancy outcomes and coping-related behaviors and, separately, coping strategies and probable depression (Edinburgh Postnatal Depression Scale > 12) for those with loss. RESULTS: Compared to those with a surviving live birth and adjusting for pre-pregnancy drinking and smoking, history of stillbirth, and age, individuals who experienced a loss were more likely to report increased drinking or smoking in the two months postpartum (adjusted OR: 2.7, 95% CI = 1.4-5.4). Those who smoked or drank more had greater odds of probable depression at 6 to 36 months postpartum (adjusted OR 6.4, 95% CI = 2.5-16.4). Among those with loss, recommended coping strategies commonly included communication, support groups, memorializing the loss, and spirituality. DISCUSSION: Access to a variety of evidence-based and culturally-appropriate positive coping strategies may help individuals experiencing perinatal loss avoid adverse health consequences.

Association of Mild Iodine Insufficiency during Pregnancy with Child Neurodevelopment in Patients with Subclinical Hypothyroidism or Hypothyroxinemia.

OBJECTIVE: Our objective was to evaluate whether iodine status in pregnant patients with either subclinical hypothyroidism or hypothyroxinemia in the first half of pregnancy is associated with measures of behavior and neurodevelopment in children through the age of 5 years. STUDY DESIGN: This is a secondary analysis of a multicenter study consisting of two randomized, double-masked, placebo-controlled treatment trials conducted in parallel. Patients with a singleton gestation before 20 weeks' gestation underwent thyroid screening using serum thyrotropin and free thyroxine. Participants with subclinical hypothyroidism or hypothyroxinemia were randomized to levothyroxine replacement or an identical placebo. At randomization, maternal urine was collected and stored for subsequent urinary iodine excretion analysis. Urinary iodine concentrations greater than 150 µg/L were considered iodine sufficient, and concentrations of 150 µg/L or less were considered iodine insufficient. The primary outcome was a full-scale intelligence quotient (IQ) score at the age of 5 years, the general conceptual ability score from the Differential Ability Scales-II at the age of 3 if IQ was not available, or death before 3 years. RESULTS: A total of 677 pregnant participants with subclinical hypothyroidism and 526 with hypothyroxinemia were randomized. The primary outcome was available in 1,133 (94%) of children. Overall, 684 (60%) of mothers were found to have urinary iodine concentrations >150 µg/L. Children of iodine-sufficient participants with subclinical hypothyroidism had similar primary outcome scores when compared to children of iodine-insufficient participants (95 [84-105] vs. 96 [87-109], P adj = 0.73). After adjustment, there was also no difference in IQ scores among children of participants with hypothyroxinemia at 5 to 7 years of age (94 [85 - 102] and 91 [81 - 100], Padj 1/4 0.11). Treatment with levothyroxine was not associated with neurodevelopmental or behavioral outcomes regardless of maternal iodine status (p > 0.05). CONCLUSION: Maternal urinary iodine concentrations ≤150 µg/L were not associated with abnormal cognitive or behavioral outcomes in offspring of participants with either subclinical hypothyroidism or hypothyroxinemia. KEY POINTS: · Most pregnant patients with subclinical thyroid disease are iodine sufficient.. · Mild maternal iodine insufficiency is not associated with lower offspring IQ at 5 years.. · Iodine supplementation in subclinical thyroid disease is unlikely to improve IQ..

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Systemic Effects of Prenatal Carotenoid Supplementation in the Mother and her Child: The Lutein and Zeaxanthin in Pregnancy (L-ZIP) Randomized Trial -Report Number 1.

BACKGROUND: Adding carotenoids, particularly lutein (L) and zeaxanthin (Z), to prenatal micronutrient formulations has been promoted to enhance infant visual and neural development and to maintain maternal health. Although these claims are biologically plausible, they are not yet supported by a compelling prospective trial. OBJECTIVE: We investigated the effect of prenatal carotenoid supplementation on biomarkers of maternal and infant systemic carotenoid status. METHODS: We randomly assigned 47 first trimester pregnant subjects by 1:1 allocation to receive standard-of-care prenatal vitamins plus a 10 mg L and 2 mg Z softgel (the Carotenoid group) or standard-of-care prenatal vitamins with a placebo softgel (the Control group) for 6-8 mo. Maternal carotenoid concentrations in the serum and skin at the end of each trimester and postpartum were measured with HPLC and resonance Raman spectroscopy, respectively. Infants' systemic carotenoid status was assessed using similar techniques but optimized for infants. Repeated measures and paired t-tests were determined, and a P value < 0.05 was considered statistically significant. RESULTS: After supplementation, there was a statistically significant increase in maternal serum L + Z concentrations, serum total carotenoid concentrations, and skin carotenoid status (P < 0.001 for all) in the Carotenoid group relative to the Control group at all study time points. Similarly, infants whose mothers were in the Carotenoid group had a significant 5-fold increase in cord blood L + Z concentrations, over a 3-fold increase in cord blood total carotenoids, and a 38% increase in skin carotenoids compared with the Control group (P < 0.0001 for all). In addition, there was a strong positive, statistically significant correlation between postpartum maternal and infant systemic carotenoid status (P < 0.0001). CONCLUSION: Prenatal carotenoid supplementation significantly increased maternal and infant systemic (skin and serum) carotenoid status, which may benefit pregnant women and their infants' health. This trial was registered at clinicaltrials.gov as NCT03750968.

Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial.

BACKGROUND: Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits. OBJECTIVE: We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation. STUDY DESIGN: This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSION: Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

Long-term maternal mortality risk following spontaneous preterm birth: A retrospective cohort study.

OBJECTIVE: To determine whether women with spontaneous preterm birth (PTB) have increased risks for long-term mortality. DESIGN: Retrospective cohort. SETTING: Births in Utah between 1939 and 1977. POPULATION: We included women with a singleton live birth ≥20 weeks who survived at least 1 year following delivery. We excluded those who had never lived in Utah, had improbable birthweight/gestational age combinations, underwent induction (except for preterm membrane rupture) or had another diagnosis likely to cause PTB. METHODS: Exposed women had ≥1 spontaneous PTB between 20+0 weeks and 37+0 weeks. Women with >1 spontaneous PTB were included only once. Unexposed women had all deliveries at or beyond 38+0 weeks. Exposed women were matched to unexposed women by birth year, infant sex, maternal age group and infant birth order. Included women were followed up to 39 years after index delivery. MAIN OUTCOME MEASURES: Overall and cause-specific mortality risks were compared using Cox regression. RESULTS: We included 29 048 exposed and 57 992 matched unexposed women. There were 3551 deaths among exposed (12.2%) and 6013 deaths among unexposed women (10.4%). Spontaneous PTB was associated with all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.21-1.31), death from neoplasms (aHR 1.10, 95% CI 1.02-1.18), circulatory disease (aHR 1.35, 95% CI 1.25-1.46), respiratory disease (aHR 1.73, 95% CI 1.46-2.06), digestive disease (aHR 1.33, 95% CI 1.12-1.58), genito-urinary disease (aHR 1.60, 95% CI 1.15-2.23) and external causes (aHR 1.39, 95% CI 1.22-1.58). CONCLUSIONS: Spontaneous PTB is associated with modestly increased risks for all-cause and some cause-specific mortality.

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.

Thrombotic Markers in Pregnant Patients with and without SARS-CoV-2 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities and increased risk for venous and arterial thrombi. This study aimed to evaluate D-dimer levels and lupus anticoagulant (LAC) positivity in pregnant individuals with and without Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: This was a prospective cohort study of pregnant individuals delivering at a single academic institution from April 2020 to March 2022. Individuals with a positive SARS-CoV-2 result during pregnancy were compared with a convenience sample of those without a positive SARS-CoV-2 result. For individuals with SARS-CoV-2 infection, severity was assessed based on the National Institutes of Health classification system. The primary outcome was D-dimer level measured during delivery admission. The secondary outcomes were LAC positivity and thromboembolic events. Outcomes were compared between individuals with and without a positive SARS-CoV-2 result, and further by disease severity. RESULTS: Of 98 participants, 77 (78.6%) were SARS-CoV-2 positive during pregnancy. Among individuals with SARS-CoV-2 infection, severity was asymptomatic in 20 (26.0%), mild in 13 (16.9%), moderate in 4 (5.2%), severe in 38 (49.4%), and critical in 2 (2.6%). The D-dimer concentration at delivery did not significantly differ between those with a SARS-CoV-2 positive result compared with those without (mean 2.03 µg/mL [95% confidence interval {CI} 1.72-2.40] vs. 2.37 µg/mL [95% CI 1.65-3.40]; p = 0.43). Three individuals (4%) with SARS-CoV-2 infection and none (0%) without infection were LAC positive (p = 0.59). There were no clinically apparent thromboses in either group. D-dimer concentrations and LAC positive results did not differ by COVID-19 severity. CONCLUSION: Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection; however, high rates of LAC positivity were detected. KEY POINTS: · Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection.. · Higher than expected rates of LAC positivity were detected.. · There were no clinically apparent thromboses..

The Association of Race and Ethnicity with Severe Maternal Morbidity among Individuals Diagnosed with Hypertensive Disorders of Pregnancy.

OBJECTIVE: This study aimed to examine whether there are racial disparities in severe maternal morbidity (SMM) in patients with hypertensive disorders of pregnancy (HDP). STUDY DESIGN: Secondary analysis of an observational study of 115,502 patients who had a live birth at ≥20 weeks in 25 hospitals in the United States from 2008 to 2011. Only patients with HDP were included in this analysis. Race and ethnicity were categorized as non-Hispanic White, non-Hispanic Black (NHB), and Hispanic and were abstracted from the medical charts. Patients of other races and ethnicities were excluded. Associations were estimated between race and ethnicity, and the primary outcome of SMM, defined as any of the following, was estimated by unadjusted logistic and multivariable backward logistic regressions: blood transfusion ≥4 units, unexpected surgical procedure, need for a ventilator ≥12 hours, intensive care unit (ICU) admission, or failure of ≥1 organ system. Multivariable models were run classifying HDP into three levels as follows: (1) gestational hypertension; (2) preeclampsia (mild, severe, or superimposed); and (3) eclampsia or HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. RESULTS: A total of 9,612 individuals with HDP met inclusion criteria. No maternal deaths occurred in this cohort. In univariable analysis, non-Hispanic White patients were more likely to present with gestational hypertension whereas NHB and Hispanic patients were more likely to present with preeclampsia. The frequency of the primary outcome, composite SMM, was higher in NHB patients compared with that in non-Hispanic White or Hispanic patients (11.8 vs. 4.5% in non-Hispanic White and 4.8% in Hispanic, p < 0.001). This difference was driven by a higher frequency of blood transfusions and ICU admissions among NHB individuals. Prior to adjusting the analysis for confounding factors, the odds ratio (OR) of primary composite outcomes in NHB individuals was 2.85 (95% confidence interval [CI]: 2.38, 3.42) compared with non-Hispanic White. After adjusting for sociodemographic and clinical factors, hospital site, and the severity of HDP, the OR of composite SMM did not differ between the groups (adjusted OR [aOR] = 1.26, 95% CI: 0.95, 1.67 for NHB, and aOR = 1.29, 95% CI: 0.94, 1.77 for Hispanic, compared with non-Hispanic White patients). Sensitivity analysis was done to exclude one single site that was an outliner with the highest ICU admissions and demonstrated no difference in ICU admission by maternal race and ethnicity. CONCLUSION: NHB patients with HDP had higher rates of the composite SMM compared with non-Hispanic White patients, driven mainly by a higher frequency of blood transfusions and ICU admissions. However, once severity and other confounding factors were taken into account, the differences did not persist. KEY POINTS: · Black patients with HDP had higher frequency of SMM compared with non-Hispanic White patients.. · The SMM disparities were driven by blood transfusions and ICU admissions.. · After adjustment for confounders, including HDP severity, the significant difference in SMM did not persist..

Oral Glucose Tolerance Test in Pregnancy and Subsequent Maternal Hypertension.

OBJECTIVE: The aim of the study is to evaluate whether values and the shape of the glucose curve during the oral glucose tolerance test (OGTT) in pregnancy identify women at risk of developing hypertension (HTN) later in life. STUDY DESIGN: This category includes the secondary analysis of a follow-up from a mild gestational diabetes mellitus (GDM) study that included a treatment trial for mild GDM (n = 458) and an observational cohort of participants with abnormal 1-hour glucose loading test only (normal OGTT, n = 430). Participants were assessed at a median of 7 (IQR 6-8) years after their index pregnancy, and trained staff measured their blood pressure (systolic blood pressure [SBP]; diastolic blood pressure [DBP]). The association between values and the shape of the glucose curve during OGTT in the index pregnancy and the primary outcome defined as elevated BP (SBP ≥120, DBP ≥80 mm Hg, or receiving anti-HTN medications), and secondary outcome defined as stage 1 or higher (SBP ≥130, DBP ≥80 mm Hg, or receiving anti-HTN medications) at follow-up were evaluated using multivariable regression, adjusting for maternal age, body mass index, and pregnancy-associated hypertension during the index pregnancy. RESULTS: There was no association between fasting, 1-hour OGTT, and the outcomes. However, the 2-hour OGTT value was positively associated (adjusted odds ratio [aRR] per 10-unit increase 1.04, 95% CI 1.01-1.08), and the 3-hour was inversely associated (aRR per 10-unit increase 0.96, 95% CI 0.93-0.99) with the primary outcome. When the shape of the OGTT curve was evaluated, a monophasic OGTT response (peak at 1 hour followed by a decline in glucose) was associated with increased risk of elevated BP (41.3vs. 23.5%, aRR 1.66, 95% CI 1.17-2.35) and stage 1 HTN or higher (28.5 vs. 14.7%, aRR 1.83, 95% CI 1.15-2.92), compared with a biphasic OGTT response. CONCLUSION: Among persons with mild GDM or lesser degrees of glucose intolerance, the shape of the OGTT curve during pregnancy may help identify women who are at risk of HTN later in life, with biphasic shape to be associated with lower risk. KEY POINTS: · The shape of the Oral Glucose Tolerance Test curve may help identify patients who are at risk of having elevated BP or HTN 5 to 10 years following pregnancy.. · The 2-hour Oral Glucose Tolerance Test values is positively associated with elevated BP 5 to 10 years following pregnancy.. · This supports the concept of pregnancy as a window to future health and represents a potential novel biomarker for maternal cardiovascular health screening..

Long-Term Maternal Metabolic and Cardiovascular Phenotypes after a Pregnancy Complicated by Mild Gestational Diabetes Mellitus or Obesity.

OBJECTIVE: The aim of this study was to evaluate the association of mild gestational diabetes mellitus (GDM) and obesity with metabolic and cardiovascular markers 5 to 10 years after pregnancy. STUDY DESIGN: This was a secondary analysis of 5- to 10-year follow-up study of a mild GDM treatment trial and concurrent observational cohort of participants ineligible for the trial with abnormal 1-hour glucose challenge test only. Participants with 2-hour glucose tolerance test at follow-up were included. The primary exposures were mild GDM and obesity. The outcomes were insulinogenic index (IGI), 1/homeostatic model assessment of insulin resistance (HOMA-IR), and cardiovascular markers vascular endothelial growth factor, (VEGF), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 40 ligand (CD40L), growth differentiation factor 15 (GDF-15), and suppression of tumorgenesis 2 (ST-2). Multivariable linear regression estimated the association of GDM and obesity with biomarkers. RESULTS: Of 951 participants in the parent study, 642 (68%) were included. Lower 1/HOMA-IR were observed in treated and untreated GDM groups, compared with non-GDM (mean differences, -0.24 and -0.15; 95% confidence intervals [CIs], -0.36 to -0.12 and -0.28 to -0.03, respectively). Lower VCAM-1 (angiogenesis) was observed in treated GDM group (mean difference, -0.11; 95% CI, -0.19 to -0.03). GDM was not associated with IGI or other biomarkers. Obesity was associated with lower 1/HOMA-IR (mean difference, -0.42; 95% CI, -0.52 to -0.32), but not other biomarkers. CONCLUSION: Prior GDM and obesity are associated with more insulin resistance but not insulin secretion or consistent cardiovascular dysfunction 5 to 10 years after delivery. KEY POINTS: · Mild GDM increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Obesity increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Neither mild GDM nor obesity increased the risk of cardiovascular dysfunction 5 to 10 years postpartum..

Hypertensive Disorders of Pregnancy and Long-Term Maternal Cardiovascular and Metabolic Biomarkers.

OBJECTIVE: This study aimed to measure the association between hypertensive disorders of pregnancy (HDP) and long-term maternal metabolic and cardiovascular biomarkers. STUDY DESIGN: Follow-up study of patients who completed glucose tolerance testing 5 to 10 years after enrollment in a mild gestational diabetes mellitus (GDM) treatment trial or concurrent non-GDM cohort. Maternal serum insulin concentrations and cardiovascular markers VCAM-1, VEGF, CD40L, GDF-15, and ST-2 were measured, and insulinogenic index (IGI, pancreatic ß-cell function) and 1/ homeostatic model assessment (insulin resistance) were calculated. Biomarkers were compared by presence of HDP (gestational hypertension or preeclampsia) during pregnancy. Multivariable linear regression estimated the association of HDP with biomarkers, adjusting for GDM, baseline body mass index (BMI), and years since pregnancy. RESULTS: Of 642 patients, 66 (10%) had HDP: 42 with gestational hypertension and 24 with preeclampsia. Patients with HDP had higher baseline and follow-up BMI, higher baseline blood pressure, and more chronic hypertension at follow-up. HDP was not associated with metabolic or cardiovascular biomarkers at follow-up. However, when HDP type was evaluated, patients with preeclampsia had lower GDF-15 levels (oxidative stress/cardiac ischemia), compared with patients without HDP (adjusted mean difference: -0.24, 95% confidence interval: -0.44, -0.03). There were no differences between gestational hypertension and no HDP. CONCLUSION: In this cohort, metabolic and cardiovascular biomarkers 5 to 10 years after pregnancies did not differ by HDP. Patients with preeclampsia may have less oxidative stress/cardiac ischemia postpartum; however, this may have been observed due to chance alone given multiple comparisons. Longitudinal studies are needed to define the impact of HDP during pregnancy and interventions postpartum. KEY POINTS: · Hypertensive disorders of pregnancy were not associated with metabolic dysfunction.. · Cardiovascular dysfunction was not consistently seen after pregnancy hypertension.. · Longitudinal studies with postpartum interventions after preeclampsia are needed..

Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants.

OBJECTIVE: This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants. STUDY DESIGN: We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case-control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort. RESULTS: Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10-4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2-1.0; p = 0.039). CONCLUSION: A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants. KEY POINTS: · Early preterm and ELBW infants have dramatically increased risks of CP and developmental delay.. · A genetic variant in SERPINE1 is associated with CP or death among ELBW infants.. · The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor..

The Association between Infant Birth Weight, Head Circumference, and Neurodevelopmental Outcomes.

OBJECTIVE: The aim of this study was to evaluate whether being small for gestational age (SGA) or large for gestational age (LGA) or having a small or large head circumference (HC) at birth is associated with adverse neurodevelopmental outcomes. STUDY DESIGN: This is a secondary analysis of a multicenter negative randomized trial of thyroxine therapy for subclinical hypothyroid disorders in pregnancy. The primary outcome was child intelligence quotient (IQ) at 5 years of age. Secondary outcomes included several neurodevelopmental measures. Associations between the outcomes in children with SGA (<10th percentile) or LGA (>90th percentile) birth weights, using ethnicity- and sex-specific population nomogram as well as nomograms from the National Fetal Growth (NFG) study, were compared with the referent of those with appropriate for gestational age (AGA) birth weight. Similar analyses were performed for HC. RESULTS: Using the population nomogram, 90 (8.2%) were SGA and 112 (10.2%) were LGA. SGA neonates were more likely to be born preterm to mothers who were younger, smoked, and were less likely to have less than a high school education, whereas LGA neonates were more likely to be born to mothers who were older and have higher body mass index, compared with AGA neonates. SGA at birth was associated with a decrease in the child IQ at 5 years of age by 3.34 (95% confidence interval [CI], 0.54-6.14) points, and an increase in odds of child with an IQ < 85 (adjusted odds ratio [aOR], 1.9; 95% CI, 1.1-3.2). There was no association between SGA and other secondary outcomes, or between LGA and the primary or secondary outcomes. Using the NFG standards, SGA at birth remained associated with a decrease in the child IQ at 5 years of age by 3.14 (95% CI, 0.22-6.05) points and higher odds of an IQ < 85 (aOR, 2.3; 95% CI, 1.3-4.1), but none of the other secondary outcomes. HC was not associated with the primary outcome, and there were no consistent associations of these standards with the secondary outcomes. CONCLUSION: In this cohort of pregnant individuals with hypothyroid disorders, SGA birth weight was associated with a decrease in child IQ and greater odds of child IQ < 85 at 5 years of age. Using a fetal growth standard did not appear to improve the detection of newborns at risk of adverse neurodevelopment.

Respiratory Viral Infections and Infection Prevention Practices Among Women With Acute Respiratory Illness During Delivery Hospitalizations During the 2019-2020 Influenza Season.

BACKGROUND: We conducted a cross-sectional study of pregnant women with acute respiratory illness during delivery hospitalizations during influenza season to describe clinical testing for respiratory viruses and infection prevention practices. METHODS: Women had nasal swabs tested for influenza and other respiratory viruses. Among 91 enrolled women, 22 (24%) had clinical testing for influenza. RESULTS: Based on clinical and study testing combined, 41 of 91 (45%) women had samples positive for respiratory viruses. The most common virus was influenza (17 of 91, 19%); 53% (9 of 17) of influenza virus infections were identified through study testing alone. Only 16% of women were on droplet precautions. CONCLUSIONS: Peripartum respiratory infections may be underrecognized.

Incidence and Clinical Characteristics of and Risk Factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Pregnant Individuals in the United States.

BACKGROUND: Data about the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among pregnant individuals are needed to inform infection-prevention guidance and counseling for this population. METHODS: We prospectively followed a cohort of pregnant individuals during August 2020-March 2021 at 3 US sites. The 3 primary outcomes were incidence rates of any SARS-CoV-2 infection, symptomatic infection, and asymptomatic infection, during pregnancy during periods of SARS-CoV-2 circulation. Participants self-collected weekly midturbinate nasal swabs for SARS-CoV-2 reverse transcription-polymerase chain reaction testing, completed weekly illness symptom questionnaires, and submitted additional swabs with coronavirus disease 2019 (COVID-19)-like symptoms. An overall SARS-CoV-2 infection incidence rate weighted by population counts of women of reproductive age in each state was calculated. RESULTS: Among 1098 pregnant individuals followed for a mean of 10 weeks, 9% (99/1098) had SARS-CoV-2 infections during the study. Population-weighted incidence rates of SARS-CoV-2 infection were 10.0 per 1000 (95% confidence interval, 5.7-14.3) person-weeks for any infection, 5.7 per 1000 (1.7-9.7) for symptomatic infections, and 3.5 per 1000 (0-7.1) for asymptomatic infections. Among 96 participants with SARS-CoV-2 infections and symptom data, the most common symptoms were nasal congestion (72%), cough (64%), headache (59%), and change in taste or smell (54%); 28% had measured or subjective fever. Median symptom duration was 10 (interquartile range, 6-16) days. CONCLUSIONS: Pregnant individuals in this study had a 1% risk of SARS-CoV-2 infection per week, underscoring the importance of COVID-19 vaccination and other prevention measures during pregnancy while SARS-CoV-2 is circulating in the community.

Differential Gene Expression in Cord Blood of Infants Diagnosed with Cerebral Palsy: A Pilot Analysis of the Beneficial Effects of Antenatal Magnesium Cohort.

The Beneficial Effects of Antenatal Magnesium clinical trial was conducted between 1997 and 2007, and demonstrated a significant reduction in cerebral palsy (CP) in preterm infants who were exposed to peripartum magnesium sulfate (MgSO4). However, the mechanism by which MgSO4 confers neuroprotection remains incompletely understood. Cord blood samples from this study were interrogated during an era when next-generation sequencing was not widely accessible and few gene expression differences or biomarkers were identified between treatment groups. Our goal was to use bulk RNA deep sequencing to identify differentially expressed genes comparing the following four groups: newborns who ultimately developed CP treated with MgSO4 or placebo, and controls (newborns who ultimately did not develop CP) treated with MgSO4 or placebo. Those who died after birth were excluded. We found that MgSO4 upregulated expression of SCN5A only in the control group, with no change in gene expression in cord blood of newborns who ultimately developed CP. Regardless of MgSO4 exposure, expression of NPBWR1 and FTO was upregulated in cord blood of newborns who ultimately developed CP compared with controls. These data support that MgSO4 may not exert its neuroprotective effect through changes in gene expression. Moreover, NPBWR1 and FTO may be useful as biomarkers and may suggest new mechanistic pathways to pursue in understanding the pathogenesis of CP. The small number of cases ultimately available for this secondary analysis, with male predominance and mild CP phenotype, is a limitation of the study. In addition, differentially expressed genes were not validated by qRT-PCR.

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

BACKGROUND: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. OBJECTIVES: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. METHODS: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. RESULTS: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. CONCLUSIONS: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.