Mode of delivery predicts postpartum maternal leukocyte telomere length.

BACKGROUND: Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging. STUDY DESIGN: Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma). RESULTS: Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction. CONCLUSION: Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.

Virtual simulation training for postpartum hemorrhage in low-to-moderate-volume hospitals in the US.

Background: Maternal mortality in the United States is rising and many deaths are preventable. Emergencies, such as postpartum hemorrhage, occur less frequently in non-teaching, rural, and urban low-birth volume hospitals. There is an urgent need for accessible, evidence-based, and sustainable inter-professional education that creates the opportunity for clinical teams to practice their response to rare, but potentially devastating events. Objective: To assess the feasibility of virtual simulation training for the management of postpartum hemorrhage in low-to-moderate-volume delivery hospitals. Study design: The study occurred between December 2021 and March 2022 within 8 non-academic hospitals in the United States with low-to-moderate-delivery volumes, randomized to one of two models: direct simulation training and train-the-trainer. In the direct simulation training model, simulation faculty conducted a virtual simulation training program with participants. In the train-the-trainer model, simulation faculty conducted virtual lessons with new simulation instructors on how to prepare and conduct a simulation course. Following this training, the instructors led their own simulation training program at their respective hospitals. The direct simulation training participants and students trained by new instructors from the train-the-trainer program were evaluated with a multiple-choice questionnaire on postpartum hemorrhage knowledge and a confidence and attitude survey at 3 timepoints: prior to, immediately after, and at 3 months post-training. Paired t-tests were performed to assess for changes in knowledge and confidence within teaching models across time points. ANOVA was performed to test cross-sectionally for differences in knowledge and confidence between teaching models at each time point. Results: Direct simulation training participants (n=22) and students of the train-the-trainer instructors (n=18) included nurses, certified nurse midwives and attending physicians in obstetrics, family practice or anesthesiology. Mean pre-course knowledge and confidence scores were not statistically different between direct simulation participants and the students of the instructors from the train-the-trainer course (79%+/-13 versus 75%+/-14, respectively, P-value=.45). Within the direct simulation group, knowledge and confidence scores significantly improved from pre- to immediately post-training (knowledge score mean difference 9.81 [95% CI 3.23-16.40], P-value<.01; confidence score mean difference 13.64 [95% CI 6.79-20.48], P-value<.01), which were maintained 3-months post-training. Within the train-the-trainer group, knowledge and confidence scores immediate post-intervention were not significantly different compared with pre-course or 3-month post-course scores. Mean knowledge scores were significantly greater for the direct simulation group compared to the train-the-trainer group immediately post-training (89%+/-7 versus 74%+/-8, P-value<.01) and at 3-months (88%+/-7 versus 76%+/-12, P-value<.01). Comparisons between groups showed no difference in confidence and attitude scores at these timepoints. Both direct simulation participants and train-the-trainer instructors preferred virtual education, or a hybrid structure, over in-person education. Conclusion: Virtual education for obstetric simulation training is feasible, acceptable, and effective. Utilizing a direct simulation model for postpartum hemorrhage management resulted in enhanced knowledge acquisition and retention compared to a train-the-trainer model.

Racial and Ethnic Disparities in Cervical Insufficiency, Cervical Cerclage, and Preterm Birth.

Background: The frequency of cervical insufficiency differs among the major racial and ethnic groups, with limited data specific to Asian American and Native Hawaiian/Pacific Islander (AANHPI) subpopulations. We assessed cervical insufficiency diagnoses and related outcomes across 10 racial and ethnic groups, including disaggregated AANHPI subgroups, in a large population-based cohort. Study Design: We performed a retrospective cohort study of all singleton births between 20-42 weeks' gestation in California from 2007 to 2018. Logistic regression models were performed to estimate the odds of cervical insufficiency and, among people with cervical insufficiency, the odds of cerclage and preterm birth according to self-reported race and ethnicity. Results: Among 5,114,470 births, 38,605 (0.8%) had a diagnosis code for cervical insufficiency. Compared with non-Hispanic White people, non-Hispanic Black people had the highest odds of cervical insufficiency (adjusted odds ratio [aOR] 3.07; 95% confidence interval [CI], 2.97, 3.18), for cerclage placement and higher odds for preterm birth. Disaggregating AANHPI subgroups showed that Indian people had the highest odds (aOR 1.94; 95% CI, 1.82, 2.07) of cervical insufficiency and had significantly higher odds of cerclage without increased odds of preterm birth; Southeast Asian people had the highest odds of preterm birth. Conclusion: Within a large, diverse population-based cohort, non-Hispanic Black people experienced the highest rates of cervical insufficiency, and among those with cervical insufficiency, had among the highest rates of cerclage and preterm birth. Among AANHPI subgroups specifically, Indian people had the highest rates of cervical insufficiency and cerclage placement, without increased rates of preterm birth; Southeast Asian people had the highest rates of preterm birth, without increased rates of cerclage. Disaggregating AANHPI subgroups identifies important differences in obstetric risk factors and outcomes.

Vascular health years after a hypertensive disorder of pregnancy: The EPOCH study.

BACKGROUND: Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum. METHODS: Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound. RESULTS: Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses, cases (N = 68) were more likely than controls (N = 71) to have hypertension (18% vs 4%, P = .034), higher calculated ASCVD risk (0.6 vs 0.4, P = .02), higher blood pressures (systolic: 118.5 vs 111.6 mm Hg, P = .0004; diastolic: 75.2 vs 69.8 mm Hg, P = .0004), and higher augmentation index values (7.7 vs 2.3, P = .03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs 0.5, P = .29) or reactive hyperemia index (2.1 vs 2.1, P = .93), nor in pulse wave amplitude (416 vs 326, P = .11), carotid elastic modulus (445 vs 426, P = .36), or carotid beta stiffness (2.8 vs 2.8, P = .86). CONCLUSION: Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

Trends in Spontaneous and Medically Indicated Preterm Birth in Twins versus Singletons: A California Cohort 2007 to 2011.

OBJECTIVE: The study aimed to describe preterm birth (PTB) rates, subtypes, and risk factors in twins compared with singletons to better understand reasons for the decline in PTB rate between 2007 and 2011. STUDY DESIGN: This was a retrospective population-based analysis using the California linked birth certificates and maternal-infant hospital discharge records from 2007 to 2011. The main outcomes were overall, spontaneous (following spontaneous labor or preterm premature rupture of membranes), and medically indicated PTB at various gestational age categories: <37, <32, and 34 to 36 weeks in twins and singletons. RESULTS: Among the 2,290,973 singletons and 28,937 twin live births pairs included, overall PTB <37 weeks decreased by 8.46% (6.77-6.20%) in singletons and 7.17% (55.31-51.35%) in twins during the study period. In singletons, this was primarily due to a 24.91% decrease in medically indicated PTB with almost no change in spontaneous PTB, whereas in twins indicated PTB declined 7.02% and spontaneous PTB by 7.39%. CONCLUSION: Recent declines in PTB in singletons appear to be largely due to declines in indicated PTB, whereas both spontaneous and indicated PTB declined in twins. KEY POINTS: · The declines in PTB noted between 2006 and 2014 occurred in both singleton and twins.. · Declines were mostly in medically indicated PTB.. · Interventions proposed as causing the declines in singletons would not apply to twins..

Deleterious and Protective Psychosocial and Stress-Related Factors Predict Risk of Spontaneous Preterm Birth.

OBJECTIVES: The aim of the study was to: (1) Identify (early in pregnancy) psychosocial and stress-related factors that predict risk of spontaneous preterm birth (PTB, gestational age <37 weeks); (2) Investigate whether "protective" factors (e.g., happiness/social support) decrease risk; (3) Use the Dhabhar Quick-Assessment Questionnaire for Stress and Psychosocial Factors (DQAQ-SPF) to rapidly quantify harmful or protective factors that predict increased or decreased risk respectively, of PTB. STUDY DESIGN: This is a prospective cohort study. Relative risk (RR) analyses investigated association between individual factors and PTB. Machine learning-based interdependency analysis (IDPA) identified factor clusters, strength, and direction of association with PTB. A nonlinear model based on support vector machines was built for predicting PTB and identifying factors that most strongly predicted PTB. RESULTS: Higher levels of deleterious factors were associated with increased RR for PTB: General anxiety (RR = 8.9; 95% confidence interval [CI] = 2.0,39.6), pain (RR = 5.7; CI = 1.7,17.0); tiredness/fatigue (RR = 3.7; CI = 1.09,13.5); perceived risk of birth complications (RR = 4; CI = 1.6,10.01); self-rated health current (RR = 2.6; CI = 1.0,6.7) and previous 3 years (RR = 2.9; CI = 1.1,7.7); and divorce (RR = 2.9; CI = 1.1,7.8). Lower levels of protective factors were also associated with increased RR for PTB: low happiness (RR = 9.1; CI = 1.25,71.5); low support from parents/siblings (RR = 3.5; CI = 0.9,12.9), and father-of-baby (RR = 3; CI = 1.1,9.9). These factors were also components of the clusters identified by the IDPA: perceived risk of birth complications (p < 0.05 after FDR correction), and general anxiety, happiness, tiredness/fatigue, self-rated health, social support, pain, and sleep (p < 0.05 without FDR correction). Supervised analysis of all factors, subject to cross-validation, produced a model highly predictive of PTB (AUROC or area under the receiver operating characteristic = 0.73). Model reduction through forward selection revealed that even a small set of factors (including those identified by RR and IDPA) predicted PTB. CONCLUSION: These findings represent an important step toward identifying key factors, which can be assessed rapidly before/after conception, to predict risk of PTB, and perhaps other adverse pregnancy outcomes. Quantifying these factors, before, or early in pregnancy, could identify women at risk of delivering preterm, pinpoint mechanisms/targets for intervention, and facilitate the development of interventions to prevent PTB. KEY POINTS: · Newly designed questionnaire used for rapid quantification of stress and psychosocial factors early during pregnancy.. · Deleterious factors predict increased preterm birth (PTB) risk.. · Protective factors predict decreased PTB risk..

Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning.

Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches. Objectives: The primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions. Materials and Methods: In a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF). Results: Jointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs. Conclusions: Elucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.

Population-based associations between maternal pre-pregnancy body mass index and spontaneous and medically indicated preterm birth using restricted cubic splines in California.

BACKGROUND: The literature pertaining to risk of spontaneous preterm birth (sPTB) as related to body mass index (BMI), specifically high BMI, is conflicting. OBJECTIVE: To assess the relationships between maternal prepregnancy BMI and sPTB separately for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Asians. METHODS: Population-based cohort study of mothers who delivered a singleton livebirth in California from 2007 to 2012. Associations between BMI and sPTB were estimated from Cox proportional hazard models. BMI was modelled with restricted cubic splines to account for nonlinear relationships. RESULTS: A total of 2,645,950 births were included in the analysis, 135,357 (5.12%) in which the mother had a sPTB. Compared to mothers within the same race/ethnicity and a BMI of 26 kg/m2, all mothers with a BMI 28 kg/m2 or higher had significantly elevated adjusted hazard ratios for sPTB. Asian mothers with a BMI between 16 and 25 kg/m2 had significantly decreased hazard ratios for sPTB while a of BMI 20 kg/m2 or less among non-Hispanic White, non-Hispanic Black, and Hispanic mothers showed increased hazard ratios. CONCLUSION: This study observed that mothers with high prepregnancy BMIs were more likely to experience sPTB across all race/ethnicities.

Leukocyte telomere dynamics across gestation in uncomplicated pregnancies and associations with stress.

BACKGROUND: Short leukocyte telomere length is a biomarker associated with stress and morbidity in non-pregnant adults. Little is known, however, about maternal telomere dynamics in pregnancy. To address this, we examined changes in maternal leukocyte telomere length (LTL) during uncomplicated pregnancies and explored correlations with perceived stress. METHODS: In this pilot study, maternal LTL was measured in blood collected from nulliparas who delivered live, term, singleton infants between 2012 and 2018 at a single institution. Participants were excluded if they had diabetes or hypertensive disease. Samples were collected over the course of pregnancy and divided into three time periods: < 200/7 weeks (Timepoint 1); 201/7 to 366/7 weeks (Timepoint 2); and 370/7 to 9-weeks postpartum (Timepoint 3). All participants also completed a survey assessing a multivariate profile of perceived stress at the time of enrollment in the first trimester. LTL was measured using quantitative polymerase chain reaction (PCR). Wilcoxon signed-rank tests were used to compare LTL differences within participants across all timepoint intervals. To determine whether mode of delivery affected LTL, we compared postpartum Timepoint 3 LTLs between participants who had vaginal versus cesarean birth. Secondarily, we evaluated the association of the assessed multivariate stress profile and LTL using machine learning analysis. RESULTS: A total of 115 samples from 46 patients were analyzed. LTL (mean ± SD), expressed as telomere to single copy gene (T/S) ratios, were: 1.15 ± 0.26, 1.13 ± 0.23, and 1.07 ± 0.21 for Timepoints 1, 2, and 3, respectively. There were no significant differences in LTL between Timepoints 1 and 2 (LTL T/S change - 0.03 ± 0.26, p = 0.39); 2 and 3 (- 0.07 ± 0.29, p = 0.38) or Timepoints 1 and 3 (- 0.07 ± 0.21, p = 0.06). Participants who underwent cesareans had significantly shorter postpartum LTLs than those who delivered vaginally (T/S ratio: 0.94 ± 0.12 cesarean versus 1.12 ± 0.21 vaginal, p = 0.01). In secondary analysis, poor sleep quality was the main stress construct associated with shorter Timepoint 1 LTLs (p = 0.02) and shorter mean LTLs (p = 0.03). CONCLUSIONS: In this cohort of healthy pregnancies, maternal LTLs did not significantly change across gestation and postpartum LTLs were shorter after cesarean than after vaginal birth. Significant associations between sleep quality and short LTLs warrant further investigation.

A data-driven health index for neonatal morbidities.

Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.

Newborn screen metabolic panels reflect the impact of common disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero. METHODS: A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010. RESULTS: A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations. CONCLUSIONS: Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth. IMPACT: Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.

Interpregnancy intervals and adverse birth outcomes in high-income countries: An international cohort study.

BACKGROUND: Most evidence for interpregnancy interval (IPI) and adverse birth outcomes come from studies that are prone to incomplete control for confounders that vary between women. Comparing pregnancies to the same women can address this issue. METHODS: We conducted an international longitudinal cohort study of 5,521,211 births to 3,849,193 women from Australia (1980-2016), Finland (1987-2017), Norway (1980-2016) and the United States (California) (1991-2012). IPI was calculated based on the time difference between two dates-the date of birth of the first pregnancy and the date of conception of the next (index) pregnancy. We estimated associations between IPI and preterm birth (PTB), spontaneous PTB, and small-for-gestational age births (SGA) using logistic regression (between-women analyses). We also used conditional logistic regression comparing IPIs and birth outcomes in the same women (within-women analyses). Random effects meta-analysis was used to calculate pooled adjusted odds ratios (aOR). RESULTS: Compared to an IPI of 18-23 months, there was insufficient evidence for an association between IPI <6 months and overall PTB (aOR 1.08, 95% CI 0.99-1.18) and SGA (aOR 0.99, 95% CI 0.81-1.19), but increased odds of spontaneous PTB (aOR 1.38, 95% CI 1.21-1.57) in the within-women analysis. We observed elevated odds of all birth outcomes associated with IPI ≥60 months. In comparison, between-women analyses showed elevated odds of adverse birth outcomes for <12 month and >24 month IPIs. CONCLUSIONS: We found consistently elevated odds of adverse birth outcomes following long IPIs. IPI shorter than 6 months were associated with elevated risk of spontaneous PTB, but there was insufficient evidence for increased risk of other adverse birth outcomes. Current recommendations of waiting at least 24 months to conceive after a previous pregnancy, may be unnecessarily long in high-income countries.

Association of Gestational Age with Postpartum Hemorrhage: An International Cohort Study.

BACKGROUND: Risk factors for postpartum hemorrhage, such as chorioamnionitis and multiple gestation, have been identified in previous epidemiologic studies. However, existing data describing the association between gestational age at delivery and postpartum hemorrhage are conflicting. The aim of this study was to assess the association between gestational age at delivery and postpartum hemorrhage. METHODS: The authors conducted a population-based retrospective cohort study of women who underwent live birth delivery in Sweden between 2014 and 2017 and in California between 2011 and 2015. The primary exposure was gestational age at delivery. The primary outcome was postpartum hemorrhage, classified using International Classification of Diseases, Ninth Revision-Clinical Modification codes for California births and a blood loss greater than 1,000 ml for Swedish births. The authors accounted for demographic and obstetric factors as potential confounders in the analyses. RESULTS: The incidences of postpartum hemorrhage in Sweden (23,323/328,729; 7.1%) and in California (66,583/2,079,637; 3.2%) were not comparable. In Sweden and California, the incidence of postpartum hemorrhage was highest for deliveries between 41 and 42 weeks' gestation (7,186/75,539 [9.5%] and 8,921/160,267 [5.6%], respectively). Compared to deliveries between 37 and 38 weeks, deliveries between 41 and 42 weeks had the highest adjusted odds of postpartum hemorrhage (1.62 [95% CI, 1.56 to 1.69] in Sweden and 2.04 [95% CI, 1.98 to 2.09] in California). In both cohorts, the authors observed a nonlinear (J-shaped) association between gestational age and postpartum hemorrhage risk, with 39 weeks as the nadir. In the sensitivity analyses, similar findings were observed among cesarean deliveries only, when postpartum hemorrhage was classified only by International Classification of Diseases, Tenth Revision-Clinical Modification codes, and after excluding women with abnormal placentation disorders. CONCLUSIONS: The postpartum hemorrhage incidence in Sweden and California was not comparable. When assessing a woman's risk for postpartum hemorrhage, clinicians should be aware of the heightened odds in women who deliver between 41 and 42 weeks' gestation.

Male-to-Female Ratios, Race/Ethnicity, and Spontaneous Preterm Birth among 11 Million California Infants.

OBJECTIVE: An observed disparity in population-scale data are a larger number of males among preterm births (PTBs). We investigated spontaneous PTB risk among women of various race/ethnic groups in combination with infants' sex. STUDY DESIGN: This observational study was conducted in > 10 million California births (1991-2012) using birth certificates linked with maternal and infant hospital discharge data. RESULTS: Male-to-female ratios among term (37-42 weeks) infants exhibited the narrow ratio range 1.02 to 1.06 across race/ethnic groups. Such ratios among spontaneous PTBs were generally larger for all race/ethnic groups except non-Hispanic blacks. For blacks, ratios tended to be lower and similar to their term birth counterpart, 1.03. Hazard ratios adjusted for maternal age and education for non-Hispanic blacks were 0.99 (95% confidence interval [CI] 0.90-1.09), 1.01 (95% CI 0.95-1.08), 0.98 (95% CI 0.94-1.03), and 1.03 (95% CI 1.01-1.05), respectively, for gestational week groupings of 20 to 23, 24 to 27, 28 to 321, and 32 to 36. Hazard ratios for non-Hispanic whites for the same groupings were 1.08 (95% CI 0.98-1.18), 1.13 (95% CI 1.07-1.19), 1.21 (95% CI 1.17-1.25), and 1.18 (95% CI 1.17-1.19). CONCLUSION: Why male-to-female ratios are similar across gestational ages in blacks but substantially higher in other race/ethnic groups is theoretically considered relative to inflammation, stress, and other influences.

Parental age and preterm birth: a population-based cohort of nearly 3 million California livebirths from 2007 to 2012.

PURPOSE: To assess the relationships between parental ages and preterm birth subtypes. METHODS: A population-based cohort analysis of California livebirths 2007-2012. Associations between maternal and paternal age with spontaneous and medically indicated preterm birth were estimated from Cox proportional hazard models. Parental age was modeled with restricted cubic splines to account for nonlinear relationships. RESULTS: Young paternal age was associated with increased hazard ratios for spontaneous and medically indicated preterm birth. Older fathers showed elevated hazards for preterm birth in crude analysis but after adjustment the relationship was generally not observed. Aging mothers showed increased hazard ratios for both preterm birth phenotypes. CONCLUSIONS: After adjusting for parental demographics, births to younger fathers and older mothers had the highest risks for spontaneous preterm birth. The paternal influence on preterm birth was observed to be independent of maternal factors.

Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index.

Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.

Stillbirths and live births in the periviable period.

PURPOSE: We use data from California, where 13% of US births occur, to address two questions arising from efforts in the first decade of this century to avoid stillbirths before 25 6/7 weeks of gestation (i.e., in the periviable period). First, did stillbirths decline in the first decade of this century? Second, if stillbirths did decline, did periviable live births increase simultaneously? Answering these questions is important given that periviable infants represent less than 1% of live births but account for roughly 40% of infant mortality and 20% of hospital-based obstetric costs in the United States. METHODS: We constructed 240 monthly conception cohorts, starting with that conceived in January 1991, from 9,880,536 singleton pregnancies that reached the 20 0/7 week of gestation. We used time-series design and Box-Jenkins methods that address confounding by autocorrelation, including secular trends and seasonality to answer our questions. RESULTS: We detected a downward shift in stillbirths in April 2007 that coincided with an upward shift in periviable live births. CONCLUSIONS: Our findings imply that, since 2007, fewer Californians than expected from history and from the size of conception cohorts reaching 20 0/7 weeks of gestation have had to contend with the sequelae of stillbirths, but more than expected likely have had to contend with those of periviable births.

Preterm birth outcomes among Asian women by maternal place of birth.

OBJECTIVE: To investigate overall, spontaneous, and medically indicated preterm birth (PTB) rates between US-born and non-US-born Asian women living in California. STUDY DESIGN: Nulliparous women with a singleton livebirth and Asian race in California between 2007 and 2011 were investigated. The prevalence of overall (<37 weeks), spontaneous, and medically indicated PTB was examined by self-reported race and place of birth among ten Asian subgroups. RESULTS: There were marked differences in PTB rates between the individual Asian subgroups. After adjustments, non-US-born Chinese, Japanese, Vietnamese, and Indian women had lower odds of overall PTB and Chinese, Vietnamese, Cambodian, and Indian women had lower odds of spontaneous PTB compared with their US-born counterparts. CONCLUSION: Further investigation of biological and social factors contributing to these lower odds of spontaneous PTB among the non-US-born Asian population could potentially offer clues for reducing the burden of PTB among the US born.

Short interpregnancy interval as a risk factor for preterm birth in non-Hispanic Black and White women in California.

OBJECTIVE: Short interpregnancy interval (IPI) is associated with adverse pregnancy outcomes, including preterm birth (PTB < 37 weeks GA). We investigated whether short IPI (< 6 months) contributes to the higher PTB frequency among non-Hispanic Blacks (NHB). STUDY DESIGN: Using a linked birth cohort > 1.5 million California live births, we examined frequencies of short IPI between racial/ethnic groups and estimated risks by multivariable logistic regression for spontaneous PTB. We expanded the study to births 1991-2012 and utilized a "within-mother" approach to permit methodologic inquiry about residual confounding. RESULTS: NHB women had higher frequency (7.6%) of short IPI than non-Hispanic White (NHW) women (4.4%). Adjusted odds ratios for PTB and short IPI were 1.64 (95% CI 1.54, 1.76) for NHW and 1.49 (1.34, 1.65) for NHB. Using within-mother analysis did not produce substantially different results. CONCLUSIONS: Short IPI is associated with PTB but does not explain risk disparity between NHWs and NHBs.