Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases.

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Social determinants among Black people during pregnancy following a short interpregnancy interval.

BACKGROUND: Short interpregnancy interval has been shown to be a key contributor to infant mortality. Black pregnant people have a higher incidence of short interpregnancy interval than people of other races and ethnicities, as well as higher rates of infant mortality. Understanding the factors related to racial disparities in short interpregnancy interval and infant mortality are a public health priority. OBJECTIVE: This study aimed to examine the relationship between social determinants of health and interpregnancy interval in Black pregnant people by comparing those with a short interpregnancy interval defined as <18 months with those with a referent interpregnancy interval defined as ≥18 months. STUDY DESIGN: This was a nested case-control study from a prospective cohort analyzing social determinants of health in 576 postpartum patients at an urban medical center, 2011-2021. Sociodemographic, pregnancy, and maternal characteristic data were collected from participants' medical records. Structured interviews measured participants' health behaviors, physical environment, social support, health literacy, and structural drivers. Differences in social determinants of health among Black study participants were compared between those with a short interpregnancy interval (<18 months) and those with a referent interpregnancy interval (≥18 months). The odds ratios were calculated to assess the association between short interpregnancy interval and social determinants. Factors with significant differences between the short interpregnancy interval and referent interpregnancy interval groups in Black participants were compared with that of White groups for social context. RESULTS: Black participants with a short interpregnancy interval were more likely to report financial support from the Special Supplemental Nutrition Program for Women, Infants, and Children (odds ratio, 2.4; 95% confidence interval, 1.2-5.1), negative feelings toward the pregnancy (odds ratio, 2.4; 95% confidence interval, 1.2-4.9), choosing not to breastfeed because they do not like it (odds ratio ,12.0; 95% confidence interval, 1.5-543.1), not receiving prenatal care as early as desired (odds ratio, 3.4; 95% confidence interval, 1.6-7.2) because of consid- eration of pregnancy termination (odds ratio, 5.2; 95% confidence interval, 1.2-30.5) and less likely to report low levels of social support (odds ratio, 0.3; 95% confidence interval, 0.1-0.8) than Black participants with a referent interpregnancy interval. CONCLUSION: Social determinants of health that differed between participants with a short interpregnancy interval and those with a referent interpregnancy interval were Special Supplemental Nutrition Program for Women, Infants, and Children support, feelings toward the pregnancy, social support, breastfeeding intent, and delayed prenatal care because of consideration of abortion. Previous studies examining infant mortality risk factors used White people as the referent group when analyzing social determinants. Our study focused specifically on understanding the lives of Black pregnant people so that future public health initiatives focused on social determinants may attenuate the racial disparity of infant mortality in the United States.

Influence of social determinants of health on breastfeeding intent in the United States.

BACKGROUND: Breastfeeding rates in the United States are suboptimal despite public health recommendations that infants are fed breastmilk for their first year of life. This study aimed to characterize the influence of social determinants of health on intended breastfeeding duration. METHODS: This case-control study analyzed breastfeeding intent in 421 postpartum women. Data on social determinants and medical history were obtained from medical records and participant self-report. Logistic regression estimated the influence of demographic factors and social determinants on intent to breastfeed for durations of <6 months, 6-12 months, and at least 1 year. RESULTS: Thirty-five percent of mothers intended to breastfeed for at least 6 months, and 15% for 1 year. Social determinants that negatively predicted breastfeeding intent included not owning transportation and living in a dangerous neighborhood (p < 0.05). Women were more likely to intend to breastfeed for 12 months if they had knowledge of breastfeeding recommendations (adjusted odds ratio [aOR] 6.19, 95% confidence interval [CI 2.67-14.34]), an identifiable medical provider (aOR 2.64 [CI 1.22-5.72]), familial support (aOR 2.80 [CI 1.01-7.80]), or were married (aOR 2.55 [CI 1.01-6.46]). Sociodemographic factors that negatively influenced breastfeeding intent included non-Hispanic Black race, no high school diploma, cigarette use, income below $20,000, fewer than five prenatal visits, and WIC or Medicaid enrollment (p < 0.05). CONCLUSIONS: Women who lack familial support, an identifiable healthcare provider, or knowledge of breastfeeding guidelines are less likely to intend to breastfeed. Public health initiatives should address these determinants to improve breastfeeding and infant outcomes.

COVID-19 booster vaccination during pregnancy enhances maternal binding and neutralizing antibody responses and transplacental antibody transfer to the newborn.

The immune response to COVID-19 booster vaccinations during pregnancy for mothers and their newborns and the functional response of vaccine-induced antibodies against Omicron variants are not well characterized. We conducted a prospective, multicenter cohort study of participants vaccinated during pregnancy with primary or booster mRNA COVID-19 vaccines from July 2021 to January 2022 at 9 academic sites. We determined SARS-CoV-2 binding and live virus and pseudovirus neutralizing antibody (nAb) titers pre- and post-vaccination, and at delivery for both maternal and infant participants. Immune responses to ancestral and Omicron BA.1 SARS-CoV-2 strains were compared between primary and booster vaccine recipients in maternal sera at delivery and in cord blood, after adjusting for days since last vaccination. A total of 240 participants received either Pfizer or Moderna mRNA vaccine during pregnancy (primary 2-dose series: 167; booster dose: 73). Booster vaccination resulted in significantly higher binding and nAb titers, including to the Omicron BA.1 variant, in maternal serum at delivery and in cord blood compared to a primary 2-dose series (range 0.44-0.88 log10 higher, p < 0.0001 for all comparisons). Live virus nAb to Omicron BA.1 were present at delivery in 9 % (GMT ID50 12.7) of Pfizer and 22 % (GMT ID50 14.7) of Moderna primary series recipients, and in 73 % (GMT ID50 60.2) of mRNA boosted participants (p < 0.0001), although titers were significantly lower than to the D614G strain. Transplacental antibody transfer was efficient for all regimens with median transfer ratio range: 1.55-1.77 for IgG, 1.00-1.78 for live virus nAb and 1.79-2.36 for pseudovirus nAb. COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood binding and neutralizing antibody levels, including against Omicron BA.1. Findings support the use of a booster dose of COVID-19 vaccine during pregnancy.

Influence of the COVID-19 pandemic on social determinants of health among an inner-city obstetrical population.

BACKGROUND: Social determinants of health are a well-described influencer of pregnancy-related morbidity and mortality. It is unclear how societal changes secondary to the COVID-19 pandemic altered the social determinants of health among pregnant patients. OBJECTIVE: This study aimed to investigate differences in the social determinants of health among patients who experienced pregnancy before and during the COVID-19 pandemic. STUDY DESIGN: This was a secondary analysis of an ongoing prospective cohort study examining the social determinants of health in postpartum patients at a single inner-city academic medical center. The planned secondary analysis was to compare the social determinants of health between patients that experienced societal changes before the pandemic and patients that experienced societal changes during the pandemic. Patients were included in the pandemic group if they delivered on or after March 30, 2020; moreover, patients in the pandemic group were compared with those who delivered before March 30, 2020 (referent group). Medical records were used to collect sociodemographic, pregnancy, and infant outcome data. The study participants were interviewed to collect detailed information regarding their perceived social, emotional, and physical environment as indicators of social determinants of health. Generalized linear modeling estimated the influence of social determinants of health  on births during the COVID-19 pandemic. RESULTS: Overall, 577 patients were enrolled in the study, of which 452 (78%) delivered before the COVID-19 pandemic and 125 (22%) delivered during the pandemic. Patients who delivered during the pandemic were more likely to report limited social or emotional support (relative risk, 1.62; 95% confidence interval, 1.02-2.59) and higher race-based discrimination (relative risk, 1.59; 95% confidence interval, 1.00-2.53). Mothers in the prepandemic group were more likely to have used federally funded programs, such as Medicaid, food stamps, and the Special Supplemental Nutrition Program for Women, Infants, and Children, during their pregnancy. Furthermore, the referent group reported more limited access to transportation. In addition, mothers in the prepandemic group were more likely to initiate prenatal care at a later gestational age and have fewer total prenatal care visits. CONCLUSION: The COVID-19 pandemic created unprecedented changes in pregnancy care, and these were reflected in social determinants of health. It is imperative that we focus on the social determinants of health that were mitigated during this time and their effects on maternal and infant health.

Neonatal Depression Is Associated With 1-Year Mortality in Critical Congenital Heart Disease.

Background Low 5-minute Apgar scores (AS) are predictive of term and preterm neonatal mortality but have not been well studied in the critical congenital heart disease (CCHD) population. We analyzed US national vital statistics data to evaluate the association between neonatal depression (AS 0-3) and 1-year mortality in CCHD. Methods and Results We performed a retrospective cohort study using 2014 to 2018 Centers for Disease Control and Prevention cohort-linked birth certificate and infant death records. Five-minute AS were categorized as ≤3, 4 to 6, or ≥7. We calculated birth rates and associated mortality rates by AS group in infants with and without CCHD. Multivariable logistic regression analyzed neonatal, maternal, and pregnancy-related risk factors for neonatal depression and 1-year mortality. Of 11 642 neonates with CCHD (0.06% of all births), the 5.8% with AS 0 to 3 accounted for 23.3% of all 1-year CCHD mortality, with 69.9% of deaths occurring within 1 month of life. Gestational age at birth, growth restriction, extracardiac defects, race, and low maternal education were associated with an increased odds of AS 0 to 3 in neonates with CCHD relative to those with AS 7 to 10 on multivariable analysis. AS 0 to 3 was associated with 1-year CCHD mortality after adjusting for these factors, prenatal care, and delivery location (adjusted odds ratio, 14.57 [95% CI, 11.73-18.10]). Conclusions The AS is a routine clinical measure providing important prognostic information in CCHD. These findings suggest that prenatal and perinatal factors, beyond those included in current risk stratification tools, are important for CCHD outcomes. Multidisciplinary collaboration to understand the pathophysiology underlying neonatal depression may help identify interventions to improve CCHD mortality rates.

Association of Antenatal Corticosteroid Exposure and Infant Survival at 22 and 23 Weeks.

OBJECTIVE: In 2014, the leading obstetric societies published an executive summary of a joint workshop to establish obstetric interventions to be considered for periviable births. Antenatal corticosteroid administration between 220/7 and 226/7 weeks was not recommended given existing evidence. We sought to evaluate whether antenatal steroid exposure was associated with improved survival among resuscitated newborns delivered between 22 and 23 weeks of gestation. STUDY DESIGN: We conducted a population-based cohort study of all resuscitated livebirths delivered between 220/7 and 236/7 weeks of gestation in the United States during 2009 to 2014 utilizing National Center for Health Statistics data. The primary outcome was rate of survival to 1 year of life (YOL) between infant cohorts based on antenatal steroid exposure. Multivariable logistic regression estimated the association of antenatal steroid exposure on survival outcomes. RESULTS: In the United States between 2009 and 2014, there were 2,635 and 7,992 infants who received postnatal resuscitation after delivery between 220/7 to 226/7 and 230/7 to 236/7 weeks of gestation, respectively. Few infants born at 22 (15.9%) and 23 (26.0%) weeks of gestation received antenatal corticosteroids (ANCS). Among resuscitated neonates, survival to 1 YOL was 45.2 versus 27.8% (adjusted relative risk [aRR]: 1.6, 95% confidence interval [CI]: 1.2-2.1) and 57.9 versus 47.7% (aRR: 1.3, 95% CI: 1.1-1.5) for infants exposed to ANCS compared with those not exposed at 22 and 23 weeks of gestation, respectively. When stratified by 100 g birth weight category, ANCS were associated with survival among neonates weighing 500 to 599 g (aRR: 1.9, 95% CI: 1.3-2.9) and 600 to 699 g (aRR: 1.7, 95% CI: 1.1-2.6) at 22 weeks. CONCLUSION: Exposure to ANCS was associated with higher survival rates to 1 YOL among resuscitated infants born at 22 and 23 weeks. National guidelines recommending against ANCS utilization at 22 weeks should be re-evaluated given emerging evidence of benefit. KEY POINTS: · Exposure to antenatal steroids was associated with higher survival rates at 22 and 23 weeks of gestation.. · Women exposed to antenatal steroids were more likely to have an adverse outcome.. · The association between steroids and survival was observed among infants with birth weights > 500 g..

Comparison of Pregnancy Outcomes of Previable and Periviable Rupture of Membranes After Laser Photocoagulation for Twin-Twin Transfusion Syndrome.

OBJECTIVE: To describe the pregnancy outcomes of patients who experienced previable and periviable prelabor rupture of membranes (PROM) after the treatment of twin-twin transfusion syndrome. METHODS: We conducted a retrospective cohort study of patients whose pregnancies were complicated by twin-twin transfusion syndrome who were treated with fetoscopic laser photocoagulation at a single fetal center and subsequently experienced PROM from April 2010 to June 2019. Outcomes were infant survival and latency from PROM to delivery. Patients were grouped by gestational age at PROM (before 26 weeks of gestation and 26 weeks or later). The group with PROM before 26 weeks of gestation was stratified by gestational age at PROM for further description of outcomes. RESULTS: Two-hundred fifty of 653 patients (38%) developed PROM, 81 before 26 weeks of gestation and 169 after 26 weeks of gestation. In the setting of PROM before 26 weeks of gestation, the rate of survival of both twins to neonatal intensive care unit (NICU) discharge was 46.3%, compared with 76.9% in the setting of PROM at 26 weeks of gestation or later ( P <.001); the survival rate of at least one twin was 61.2% and 98.5%, respectively ( P <.001). Fourteen, 22, and 45 patients experienced PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, respectively. Survival of both twins and at least one twin to NICU discharge was 25.0%, 47.4%, 52.8% (for two) and 33.3%, 47.4%, and 77.8% (for at least one), respectively, among those groups. Fifty-seven of the 81 patients with PROM before 26 weeks of gestation experienced a latency longer than 48 hours. In the setting of PROM before 26 weeks of gestation, when latency lasted longer than 48 hours, overall survival was improved (69.6% vs 53.7%, respectively, P =.017). With latency longer than 48 hours and PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, survival of both twins to NICU discharge was 60.0%, 61.5%, and 60.7%, respectively, and survival of at least one twin was 80.0%, 61.5%, and 85.7%, respectively. CONCLUSION: Earlier gestational age at PROM after laser photocoagulation is associated with longer latency but lower rates of survival. When PROM occurs before 26 weeks of gestation and latency exceeds 48 hours, rates of neonatal survival are significantly improved.

Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on magnetic resonance imaging in very preterm infants.

BACKGROUND: The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance imaging at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly. OBJECTIVE: This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging-determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis. STUDY DESIGN: This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks' gestational age with acute moderate to severe histologic chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic chorioamnionitis and brain abnormality score using mediation analysis. RESULTS: Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (ß=2.84; 1.51-4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities after the significant indirect effects of preterm birth were accounted for. CONCLUSION: Acute histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.

Factors Associated with Receiving No Maternal or Neonatal Interventions among Periviable Deliveries.

OBJECTIVE: The aim of this study was to quantify the influence of maternal sociodemographic, medical, and pregnancy characteristics on not receiving maternal and neonatal interventions with deliveries occurring at 22 to 23 weeks of gestation. STUDY DESIGN: This was a case-control study of U.S. live births at 220/6 to 236/7 weeks of gestation using vital statistics birth records from 2012 to 2016. We analyzed births that received no interventions for periviable delivery. Births were defined as having no interventions if they did not receive maternal (cesarean delivery, maternal hospital transfer, or antenatal corticosteroid administration) or neonatal interventions (neonatal intensive care unit admission, surfactant administration, antibiotic administration, or assisted ventilation). Logistic regression estimated the influence of maternal and pregnancy factors on the receipt of no interventions when delivery occurred at 22 to 23 weeks. RESULTS: Of 19,844,580 U.S. live births in 2012-2016, 24,379 (0.12%) occurred at 22 to 23 weeks; 54.3% of 22-week deliveries and 15.7% of 23-week deliveries received no interventions. Non-Hispanic Black maternal race was associated with no maternal interventions at 22 and 23 weeks. Private insurance, singleton pregnancy, and small for gestational age were associated with receiving no neonatal interventions at 22 and 23 weeks of gestation. CONCLUSIONS: Withholding or refusing maternal and neonatal interventions occurs frequently at the threshold of viability. Our data highlight various sociodemographic, pregnancy, and medical factors associated with decisions to not offer or receive maternal or neonatal interventions when birth occurs at the threshold of viability. The data elucidate observed practices and may assist in the development of further research. KEY POINTS: · Non-Hispanic Black race was associated with receiving no maternal interventions.. · Indicators of high socioeconomic status were associated with no neonatal inventions.. · Patient-level factors influence the receipt of no interventions for periviable birth..

Factors Associated with Occurrence of Stillbirth before 32 Weeks of Gestation in a Contemporary Cohort.

OBJECTIVE: We sought to quantify the distribution of stillbirths by gestational age (GA) in a contemporary cohort and to determine identifiable risk factors associated with stillbirth prior to 32 weeks of gestation. STUDY DESIGN: Population-based case-control study of all stillbirths in the United States during the year 2014, utilizing vital statistics data, obtained from the National Center for Health Statistics. Distribution of stillbirths were stratified by 20 to 44 weeks of GA, in women diagnosed with stillbirth in the antepartum period. Pregnancy characteristics were compared between those diagnosed with stillbirth <32 versus ≥32 weeks of gestation. Multivariate logistic regression estimated the relative influence of various factors on the outcome of stillbirth prior to 32 weeks of gestation. RESULTS: There were 15,998 nonlaboring women diagnosed with stillbirth during 2014 in the United States between 20 and 44 weeks. Of them, 60.1% (n = 9,618) occurred before antenatal fetal surveillance (ANFS) is typically initiated (<32 weeks) and 39.9% (n = 6,380) were diagnosed at ≥32 weeks. Women with stillbirth prior to 32 weeks were more likely to be of non-Hispanic Black race (29.0 vs. 23.9%, p < 0.001), nulliparous (53.8 vs. 50.6%, p = 0.001), have chronic hypertension (CHTN; 6.0 vs. 4.3%, p < 0.001), and fetal growth restriction as evidenced by small for GA (SGA < 10th%) birth weight (44.8 vs. 42.1%, p < 0.001) as opposed to women with stillbirth after 32 weeks. After adjustment, SGA birth weight (adjusted odds ratio [aOR] = 1.2, 95% confidence interval [CI]: 1.1-1.3), Black race (aOR = 1.2, 95% CI: 1.1-1.3), and CHTN (aOR = 1.3, 95% CI: 1.1-1.5) were associated with stillbirth prior to 32 weeks of gestation as opposed to stillbirth after 32 weeks. CONCLUSION: More than 6 out of 10 stillbirths in this study occurred <32 weeks of gestation, before ANFS is typically initiated under American College of Obstetricians and Gynecologists recommendations. Among identifiable risk factors, CHTN, Black race, and fetal growth restriction were associated with higher risk of stillbirth before 32 weeks of gestation. Earlier ANFS may be warranted at in certain "at risk" women. KEY POINTS: · Six out of 10 stillbirths occur before 32 weeks of gestation.. · We evaluated factors associated with stillbirth <32 weeks.. · Hypertension and fetal growth restriction were associated with early stillbirth..

Severe maternal morbidity associated with cerclage use in pregnancy.

OBJECTIVE: To quantify the frequency of serious maternal complications associated with cerclage use during pregnancy. STUDY DESIGN: We performed a retrospective population-based cohort study of all live births in Ohio from 2006 to 2015. Maternal sociodemographic, medical, and obstetric characteristics were compared for births in which cerclage was utilized during the pregnancy versus those without cerclage. The primary outcome for the study was a composite of adverse outcome including maternal intensive care unit (ICU) admission, blood product transfusion, uterine rupture and unplanned hysterectomy in all births. Secondary outcomes included each of the individual adverse outcomes as well as maternal hospital transfer to a tertiary facility, unplanned operation after delivery and chorioamnionitis. Each outcome was also analyzed separately in singleton and twin births. Generalized linear modeling was used to estimate the relative risk of adverse maternal outcomes associated with cerclage placement after adjustment for coexisting risk factors. RESULTS: Of the 1,428,655 singleton and twin live births in Ohio from 2006 to 2015, 4595 [0.3%] were recorded on the birth certificate as having cerclage during pregnancy. Of those, 11.7% experienced a serious adverse maternal outcome, compared to 3.7% without cerclage, adjRR 2.7 [95% CI 2.5, 3.0]. The rate of the composite maternal adverse outcome was significantly increased for pregnancies with cerclage versus those without overall, and in singleton and twin pregnancies when measured individually [all p ≤ .001]. Even after adjustment for coexisting risk factors, cerclage remained significantly associated with composite adverse outcome in each of these groups. CONCLUSIONS: Over 1 in 10 women with cerclage experience an adverse maternal outcome. Even after adjusting for gestational age at delivery and other risk factors, maternal risk for serious adverse event remains over twofold increased for pregnancies with cerclage. This information may be helpful in counseling women regarding potential maternal risk when considering neonatal benefit of cerclage in pregnancies at high risk of preterm birth.

Maternal age-specific drivers of severe maternal morbidity.

BACKGROUND: The maternal age influences the risk of adverse pregnancy outcomes, including severe maternal morbidity. However, the leading drivers of severe maternal morbidity may differ between the maternal age groups. OBJECTIVE: To compare the contribution of different risk factors to the risk of severe maternal morbidity between various maternal age groups and estimate their population-attributable risks. STUDY DESIGN: This was a retrospective, population-based cohort study of all US live births from 2012 to 2016 using birth certificate records. The demographic, medical, and pregnancy factors were compared between the 4 maternal age strata (<18 years, 18-34 years, 35-39 years, and ≥40 years). The primary outcome was composite severe maternal morbidity, defined as having maternal intensive care unit admission, eclampsia, unplanned hysterectomy, or a ruptured uterus. Multivariate logistic regression estimated the relative influence of the risk factors associated with severe maternal morbidity among the maternal age categories. Population-attributable fraction calculations assessed the contribution of the individual risk factors to overall severe maternal morbidity. RESULTS: Of 19,473,910 births in the United States from 2012 to 2016, 80,553 (41 cases per 10,000 delivery hospitalizations) experienced severe maternal morbidity. The highest rates of severe maternal morbidity were observed at the extremes of maternal age: 45 per 10,000 at <18 years (risk ratio, 1.31; 95% confidence interval, [1.16-1.48]) and 73 per 10,000 (risk ratio, 2.02; 95% confidence interval, [1.96-2.09]) for ≥40 years. In all the age groups, preterm delivery, cesarean delivery, chronic hypertension, and preeclampsia were significantly associated with an increased adjusted relative risk of severe maternal morbidity. Cesarean delivery and preeclampsia increased the severe maternal morbidity risk among all the age groups and were more influential among the youngest mothers. The risk factors with the greatest population-attributable fractions were non-Hispanic Black race (5.4%), preeclampsia (10.9%), preterm delivery (29.4%), and cesarean delivery (38.1%). On the basis of these estimates, the births occurring in mothers at the extremes of maternal age (<18 and ≥35 years) contributed 4 severe maternal morbidity cases per 10,000 live births. Preterm birth and cesarean delivery contributed 12 and 15 cases of severe maternal morbidity per 10,000 live births, respectively. CONCLUSION: Both adolescent and advanced-age pregnancies have an increased risk of severe maternal morbidity. However, there are age-specific differences in the drivers of severe maternal morbidity. This information may allow for better identification of those at a higher risk of severe maternal morbidity and may ultimately aid in patient counseling. KEY WORDS: adolescents, advanced-age pregnancy, maternal morbidity, population-attributable fraction.

Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth.

Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg/day of docosahexaenoic acid (DHA) was superior to 200 mg/day in preventing both early preterm birth (less than 34 weeks' gestation) and preterm birth (less than 37 weeks' gestation). The goal of this secondary study is to compare the effects of 1000 mg/day versus 200 mg/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12-20 weeks' gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1ß, TNFα, and INFγ were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (<37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.

Higher dose docosahexaenoic acid supplementation during pregnancy and early preterm birth: A randomised, double-blind, adaptive-design superiority trial.

BACKGROUND: Several meta analyses have concluded n-3 fatty acids, including docosahexaenoic acid (DHA), reduce early preterm birth (EPB, < 34 weeks), however, the amount of DHA required is unclear. We hypothesized that 1000 mg DHA per day would be superior to 200 mg, the amount in most prenatal supplements. METHODS: This randomised, multicentre, double-blind, adaptive-design, superiority trial was conducted in three USA medical centres. Women with singleton pregnancies and 12 to 20 weeks gestation were eligible. randomization was generated in SAS® by site in blocks of 4. The planned adaptive design periodically generated allocation ratios favoring the better performing dose. Managing study personnel were blind to treatment until 30 days after the last birth. The primary outcome was EPB by dose and by enrolment DHA status (low/high). Bayesian posterior probabilities (pp) were determined for planned efficacy and safety outcomes using intention-to-treat. The study is registered with ClinicalTrials.gov (NCT02626299) and closed to enrolment. FINDINGS: Eleven hundred participants (1000 mg, n = 576; 200 mg, n = 524) were enrolled between June 8, 2016 and March 13, 2020 with the last birth September 5, 2020. 1032 (n = 540 and n = 492) were included in the primary analyses. The higher dose had a lower EPB rate [1.7% (9/540) vs 2.4% (12/492), pp=0.81] especially if participants had low DHA status at enrolment [2.0% (5/249) vs 4.1%, (9/219), pp=0.93]. Participants with high enrolment DHA status did not realize a dose effect [1000 mg: 1.4% (4/289); 200 mg: 1.1% (3/271), pp = 0.57]. The higher dose was associated with fewer serious adverse events (maternal: chorioamnionitis, premature rupture of membranes and pyelonephritis; neonatal: feeding, genitourinary and neurologic problems, all pp>0.90). INTERPRETATION: Clinicians could consider prescribing 1000 mg DHA daily during pregnancy to reduce EPB in women with low DHA status if they are able to screen for DHA. FUNDING: The National Institutes of Health Child Health and Human Development (NICHD) funded the study. Life's DHA™-S oil, DSM Nutritional Products LLC, Switzerland provided all capsules.

Association between mode of delivery and infant survival at 22 and 23 weeks of gestation.

BACKGROUND: Cesarean delivery is currently not recommended before 23 weeks' gestation unless for maternal indications, even in the setting of malpresentation. These recommendations are based on a lack of evidence of improved neonatal outcomes and survival following cesarean delivery and the maternal risks associated with cesarean delivery at this early gestational age. However, as neonatal resuscitative measures and obstetrical interventions improve, studies evaluating the potential neonatal benefit of periviable cesarean delivery have reported inconsistent findings. OBJECTIVE: This study aimed to compare the survival rates at 1 year of life among resuscitated infants delivered by cesarean delivery with those delivered vaginally at 22 and 23 weeks of gestation. STUDY DESIGN: We conducted a population-based cohort study of all resuscitated livebirths delivered between 22 0/7 and 23 6/7 weeks of gestational age in the United States between 2007 and 2013. The primary outcome was the rate of infant survival at 1 year of life for different routes of delivery (cesarean vs vaginal delivery) at both 22 and 23 weeks of gestation. The secondary outcome variables included infant survival rates for neonates who survived beyond 24 hours of life, neonatal survival, and the length of survival. A secondary analysis also included a comparison of the infant survival rates between the different routes of delivery cohorts stratified by fetal presentation, steroid exposure, and ventilation. Information about composite adverse maternal outcomes were limited to infants who were delivered between 2011 and 2013 (when these items were first reported) and were defined as a requirement for blood transfusion, an unplanned operating room procedure following delivery, unplanned hysterectomy, and intensive care unit admission; the composite adverse maternal outcomes were also compared between the different delivery route cohorts for deliveries occurring between 22 and 23 weeks of gestation. Multivariable logistic regression analysis was used to determine the association between cesarean delivery and infant survival and other neonatal and maternal outcomes. RESULTS: Resuscitated infants delivered by cesarean delivery had higher rates of survival at 22 weeks (44.9 vs 23.0%; P<.001) and at 23 weeks (53.3 vs 43.4%; P<.001) of gestation regardless of fetal presentation. Multivariable logistic regression analysis demonstrated that infants who were delivered by cesarean delivery at 22 weeks (adjusted relative risk, 2.3; 95% confidence interval, 1.9-2.8) and 23 weeks (adjusted relative risk, 1.4; 95% confidence interval, 1.2-1.5) of gestation were more likely to survive than those delivered vaginally. When the cohort was limited to neonates who survived beyond the first 24 hours of life, vertex neonates born by cesarean delivery were not more likely to survive at 22 weeks (adjusted relative risk, 1.2; 95% confidence interval, 0.9-1.7) or 23 weeks (adjusted relative risk, 1.1; 95% confidence interval, 0.9-1.3) of gestation. An increased risk for composite adverse maternal outcomes (adjusted relative risk, 1.7; 95% confidence interval, 1.1-2.7) was associated with cesarean delivery at 22 to 23 weeks of gestation. CONCLUSION: Cesarean delivery is associated with increased survival at 1 year of life among resuscitated, periviable infants born between 22 0/7 and 23 6/7 weeks of gestation, especially in the setting of nonvertex presentation. However, cesarean delivery is associated with increased maternal morbidity.

Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis in US Mothers and Children Aged 0-2: PREVAIL Cohort Study.

BACKGROUND: Acute gastroenteritis (AGE) and acute respiratory infections (ARIs) cause significant pediatric morbidity and mortality. Developing childhood vaccines against major enteric and respiratory pathogens should be guided by the natural history of infection and acquired immunity. The United States currently lacks contemporary birth cohort data to guide vaccine development. OBJECTIVE: The PREVAIL (Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis Longitudinal) Cohort study was undertaken to define the natural history of infection and immune response to major pathogens causing AGE and ARI in US children. METHODS: Mothers in Cincinnati, Ohio, were enrolled in their third trimester of pregnancy, with intensive child follow-up to 2 years. Blood samples were obtained from children at birth (cord), 6 weeks, and 6, 12, 18, and 24 months. Whole stool specimens and midturbinate nasal swabs were collected weekly and tested by multipathogen molecular assays. Saliva, meconium, maternal blood, and milk samples were also collected. AGE (≥3 loose or watery stools or ≥1 vomiting episode within 24 hours) and ARI (cough or fever) cases were documented by weekly cell phone surveys to mothers via automated SMS text messaging and review of medical records. Immunization records were obtained from registries and providers. follow-up ended in October 2020. Pathogen-specific infections are defined by a PCR-positive sample or rise in serum antibody. RESULTS: Of the 245 enrolled mother-child pairs, 51.8% (n=127) were White, 43.3% (n=106) Black, 55.9% (n=137) publicly insured, and 86.5% (n=212) initiated breastfeeding. Blood collection was 100.0% for mothers (n=245) and 85.7% for umbilical cord (n=210). A total of 194/245 (79.2%) mother-child pairs were compliant based on participation in at least 70% (≥71/102 study weeks) of child-weeks and providing 70% or more of weekly samples during that time, or blood samples at 18 or 24 months. Compliant participants (n=194) had 71.0% median nasal swab collection (IQR 30.0%-90.5%), with 98.5% (191/194) providing either an 18- or 24-month blood sample; median response to weekly SMS text message surveys was 95.1% (IQR 76.5%-100%). Compliant mothers reported 2.0 AGE and 4.5 ARI cases per child-year, of which 25.5% (160/627) and 38.06% (486/1277) of cases, respectively, were medically attended; 0.5% of AGE (3/627) and 0.55% of ARI (7/1277) cases were hospitalized. CONCLUSIONS: The PREVAIL Cohort demonstrates intensive follow-up to document the natural history of enteric and respiratory infections and immunity in children 0-2 years of age in the United States and will contribute unique data to guide vaccine recommendations. Testing for pathogens and antibodies is ongoing. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/22222.

Regional Contribution of Previable Infant Deaths to Infant Mortality Rates in the United States.

OBJECTIVE: Lack of standardization of infant mortality rate (IMR) calculation between regions in the United States makes comparisons potentially biased. This study aimed to quantify differences in the contribution of early previable live births (<20 weeks) to U.S. regional IMR. STUDY DESIGN: Population-based cohort study of all U.S. live births and infant deaths recorded between 2007 and 2014 using Centers for Disease Control and Prevention's (CDC's) WONDER database linked birth/infant death records (births from 17-47 weeks). Proportion of infant deaths attributable to births <20 vs. 20 to 47 weeks, and difference (ΔIMR) between reported and modified (births ≥20 weeks) IMRs were compared across four U.S. census regions (North, South, Midwest, and West). RESULTS: Percentages of infant deaths attributable to birth <20 weeks were 6.3, 6.3, 5.3, and 4.1% of total deaths for Northeast, Midwest, South, and West, respectively, p < 0.001. Contribution of < 20-week deaths to each region's IMR was 0.34, 0.42, 0.37, and 0.2 per 1,000 live births. Modified IMR yielded less regional variation with IMRs of 5.1, 6.2, 6.6, and 4.9 per 1,000 live births. CONCLUSION: Live births at <20 weeks contribute significantly to IMR as all result in infant death. Standardization of gestational age cut-off results in more consistent IMRs among U.S. regions and would result in U.S. IMR rates exceeding the healthy people 2020 goal of 6.0 per 1,000 live births.