Spatial Patterning of Spontaneous and Medically Indicated Preterm Birth in Philadelphia.

Preterm birth (PTB) remains a key public health issue that disproportionately affects Black individuals. Since spontaneous PTB (sPTB) and medically indicated PTB (mPTB) may have different causes and interventions, we quantified racial disparities for sPTB and mPTB, and we characterized the geographic patterning of these phenotypes, overall and according to race/ethnicity. We examined a pregnancy cohort of 83,952 singleton births at 2 Philadelphia hospitals from 2008-2020, and classified each PTB as sPTB or mPTB. We used binomial regression to quantify the magnitude of racial disparities between non-Hispanic Black and non-Hispanic White individuals, then generated small area estimates by applying a Bayesian model that accounts for small numbers and smooths estimates of PTB risk by borrowing information from neighboring areas. Racial disparities in both sPTB and mPTB were significant (relative risk of sPTB = 1.83, 95% confidence interval: 1.70, 1.98; relative risk of mPTB = 2.20, 95% confidence interval: 2.00, 2.42). The disparity was 20% greater in mPTB than sPTB. There was substantial geographic variation in PTB, sPTB, and mPTB risks and racial disparity. Our findings underscore the importance of distinguishing PTB phenotypes within the context of public health and preventive medicine. Future work should consider social and environmental exposures that may explain geographic differences in PTB risk and disparities.

Impact of exposure to air pollution on cervicovaginal microbial communities.

PURPOSE: Vaginal microbial communities can be dominated by anaerobic (community state type IV, CST IV) or Lactobacillus (other CSTs) species. CST IV is a risk factor for spontaneous preterm birth (sPTB) and is more common among Black than White populations. In the US, average air pollution exposures are higher among Black compared to White people and exert systemic health effects. We sought to (1) quantify associations of air pollution, specifically particulate matter <2.5 µm in diameter (PM2.5), with CST IV and (2) explore the extent to which racial disparities in PM2.5 exposure might explain racial differences in the prevalence of CST IV. DESIGN: Methods: We performed a secondary analysis of 566 participants of the Motherhood & Microbiome study. PM2.5 exposures were derived from a machine learning model integrating NASA satellite and EPA ground monitor data. Previously, cervicovaginal swabs from 15 to 20 weeks' gestation were analyzed using 16 S rRNA sequencing and hierarchical clustering assigned CSTs. Multivariable logistic regression models calculated adjusted odds ratios of CST IV (vs. other CSTs) per interquartile range (IQR) increment of PM2.5. Race-stratified and mediation analyses were performed. RESULTS: Higher PM2.5 exposure was associated with CST IV (aOR 1.39, 95% CI 1.02-1.91). Further adjustment for race/ethnicity attenuated the association (aOR 1.34, 95% CI: 0.97-1.83). Black participants (vs. White) had higher median PM2.5 exposure (10.6 vs. 9.6 µg/m3, P < 0.001) and higher prevalence of CST IV (47% vs. 11%, P < 0.001). Mediation analysis revealed that higher PM2.5 exposure may explain 3.9% (P = 0.038) and 3.3% (P = 0.15) of the Black-White disparity in CST IV in unadjusted and adjusted models, respectively. CONCLUSION: PM2.5 was associated with CST IV, a risk factor for sPTB. Additionally, PM2.5 exposure may partially explain racial differences in the prevalence of CST IV. Further research is warranted to discover how environmental exposures affect microbial composition and perpetuate racial health disparities.

The impact of postpartum social support on postpartum mental health outcomes during the COVID-19 pandemic.

Social support is an influential component of postpartum recovery, adjustment, and bonding, which was disrupted by social distancing recommendations related to the COVID-19 pandemic. This study reports on changes in the availability of social support for postpartum women during the pandemic, investigates how those changes may have contributed to postpartum mental health, and probes how specific types of social support buffered against poor postpartum mental health and maternal-infant bonding impairment. Participants were 833 pregnant patients receiving prenatal care in an urban USA setting and using an electronic patient portal to access self-report surveys at two time points, during pregnancy (April-July 2020) and at ~12 weeks postpartum (August 2020-March 2021). Measures included an assessment of COVID-19 pandemic-related change in social support, sources of social support, ratings of emotional and practical support, and postpartum outcomes including depression, anxiety, and maternal-infant bonding. Overall self-reported social support decreased during the pandemic. Decreased social support was associated with an increased risk of postpartum depression, postpartum anxiety, and impaired parent-infant bonding. Among women reporting low practical support, emotional support appeared to protect against clinically significant depressive symptoms and impaired bonding with the infant. Decreases in social support are associated with a risk for poor postpartum mental health outcomes and impaired maternal-infant bonding. Evaluation and promotion of social support are recommended for healthy adjustment and functioning of postpartum women and families.

Association between Low Urban Neighborhood Greenness and Hypertensive Disorders of Pregnancy.

OBJECTIVE: Urban neighborhood greenness is associated with greater cardiovascular health in the general population, and with better pregnancy and neonatal outcomes. Hypertension in pregnancy is a leading cause of maternal mortality and long-term cardiovascular morbidity and mortality in women. We sought to examine the association between greenness and hypertensive disorders of pregnancy. STUDY DESIGN: This study is a secondary analysis of a prospective cohort study of 1,943 women who received prenatal care from December 2013 to December 2016 at a single, urban, and tertiary academic medical center in Philadelphia, PA. Greenness measure was quantified via residential tree canopy cover within circumferential buffers of 100- and 500-meter radii around participants' homes. Associations between greenness and hypertensive disorders of pregnancy (defined as gestational hypertension or preeclampsia) were estimated by using multilevel logistic regression accounting for maternal sociodemographic information (race-ethnicity, insurance status, and age) medical history (diabetes, body mass index, smoking history, and parity), neighborhood deprivation index, and including 1,225 Philadelphia residents for whom key exposure and outcome data were available. RESULTS: At baseline, the participants' mean (SD) age was 27.5 (5.9) years, (range: 14-44 years). The majority of participants were non-Hispanic Black (857, 70.2%). Participants with less residential tree canopy cover were significantly more likely to have hypertensive disorders of pregnancy. The multivariable-adjusted odds ratio of hypertensive disorders of pregnancy among participants with less than 10% compared with those with greater than 30% tree canopy cover was 2.14 (95% confidence interval [CI]: 1.11-4.15) within 100-meter buffer. CONCLUSION: In our cohort, greenness was associated with lower hypertensive disorders of pregnancy odds. Our findings add to evidence that greenness may confer health benefits and warrant further investigations in identifying whether there is a causal pathway through which greenness may be protective against hypertensive disorders of pregnancy. KEY POINTS: · Low residential tree canopy is associated with increased risk of hypertensive disorders of pregnancy. · 100-meter buffers are most sensitive in identifying associations between tree canopy and HDP risk. · The role of greenness against hypertensive disorders of pregnancy should be further studied experimentally.

Cervicovaginal Microbial-Immune State and Group B Streptococcus Colonization in Pregnancy.

OBJECTIVE: Maternal colonization with Group B Streptococcus (GBS) is a significant risk factor for serious neonatal morbidity. There are limited data on how the cervicovaginal (CV) microbiota and host immune factor ß-defensin-2 might influence GBS colonization in pregnant individuals. This study sought to determine if the CV microbiota is associated with GBS colonization in pregnant individuals, and if ß-defensin-2 modifies this relationship. STUDY DESIGN: This was a secondary analysis of a prospective cohort study of pregnant individuals with singleton pregnancies who had CV microbiota specimens analyzed at 16 to 20, 20 to 24, and 24 to 28 weeks' gestation, along with a third trimester GBS rectovaginal (RV) culture (n = 492). Microbiota data were analyzed with 16S rRNA gene sequencing and classified into community state types (CSTs). Log-binomial multivariable regression was used to model associations between CST and GBS RV status and to calculate risk ratios. ß-defensin-2, an immune factor known to modulate the relationship between CST and pregnancy outcomes, was examined as an effect modifier. RESULTS: Of 492 individuals, 34.3% were GBS RV + . Compared with individuals with CST I at 16 to 20 weeks, individuals with CST IV-A and CST II had a significantly elevated relative risk of subsequent GBS RV+ status. When stratified by high and low ß-defensin-2 levels, ß-defensin-2 was found to be an effect modifier of the association between CST IV-A and GBS RV+ status. In individuals with low ß-defensin-2 levels, CST VI-A was associated with GBS RV+ status, but among individuals with high ß-defensin-2 levels, there was no such association (interaction p-value = 0.03). CONCLUSION: Pregnant individuals with CV microbiota characterized by CST IV-A and CST II had significantly elevated risk of GBS RV colonization in the third trimester compared with those with CST I, and ß-defensin-2 was an effect modifier of the association between CST IV-A and GBS RV+ status. Future research should investigate if manipulation of the CV microbiota can prevent GBS colonization, thereby reducing intrapartum antibiotic prophylaxis and the risks of neonatal GBS infection. KEY POINTS: · The relationship between the CV microbiota and GBS RV colonization is unknown.. · A Lactobacillus-deficient, anaerobic rich vaginal community, CST IV-A, is associated with increased risk of GBS RV colonization.. · ß-defensin-2 is an effect modifier of the association between CST IV-A and GBS RV+ status..

The Uptake of Telemedicine in Obstetric Care During the Early Acute Phase of the Coronavirus 2019 Pandemic.

Introduction: The early acute phase of the coronavirus disease 2019 pandemic created rapid adaptation in health care delivery. Methods: Using electronic medical record data from two different institutions located in two different states, we examined how telemedicine was integrated into obstetric care. Results: With no telemedicine use prior, both institutions rapidly incorporated telemedicine into prenatal care (PNC). There were significant patient-level and institutional-level differences in telemedicine use. Telemedicine users initiated PNC earlier and had more total visits, earlier timing of ultrasounds, and earlier diabetes screening during pregnancy compared with nonusers. There were no significant differences in delivery mode or stillbirth associated with telemedicine use at either institution. Conclusions: Rapid adoption of obstetric telemedicine maintained adequate prenatal care provision during the early pandemic, but implementation varied across institutions.

The Influence of Pandemic-Related Worries During Pregnancy on Child Development at 12 Months.

The COVID-19 pandemic has been linked to increased risk for perinatal anxiety and depression among parents, as well as negative consequences for child development. Less is known about how worries arising from the pandemic during pregnancy are related to later child development, nor if resilience factors buffer negative consequences. The current study addresses this question in a prospective longitudinal design. Data was collected from a sub-study (n = 184) of a longitudinal study of pregnant individuals (total n = 1173). During pregnancy (April 17-July 8, 2020) and the early postpartum period (August 11, 2020-March 2, 2021), participants completed online surveys. At 12 months postpartum (June 17, 2021-March 23, 2022), participants completed online surveys and a virtual laboratory visit, which included parent-child interaction tasks. We found more pregnancy-specific pandemic worries were prospectively related to lower levels of child socioemotional development based on parent report (B = - 1.13, SE = .43, p = .007) and observer ratings (B = - 0.13, SE = .07, p = .045), but not to parent-reported general developmental milestones. Parental emotion regulation in the early postpartum period moderated the association between pregnancy-specific pandemic worries and child socioemotional development such that pregnancy-specific pandemic worries did not relate to worse child socioemotional development among parents with high (B = - .02, SE = .10, t = - .14, p = .89) levels of emotion regulation. Findings suggest the negative consequences of parental worry and distress during pregnancy on the early socioemotional development of children in the context of the COVID-19 pandemic. Results highlight that parental emotion regulation may represent a target for intervention to promote parental resilience and support optimized child development.

Second trimester short cervix is associated with decreased abundance of cervicovaginal lipid metabolites.

BACKGROUND: A short cervix is a risk factor for preterm birth. The molecular drivers of a short cervix remain elusive. Metabolites may function as mediators of pathologic processes. OBJECTIVE: We sought to determine if a distinct cervicovaginal metabolomic profile is associated with a short cervix (<25 mm) to unveil the potential mechanisms by which premature cervical remodeling leads to a short cervix. STUDY DESIGN: This was a secondary analysis of a completed prospective pregnancy cohort. Cervicovaginal fluid was obtained between 20 and 24 weeks' gestation. The participants selected for metabolomic profiling were frequency-matched by birth outcome and cervicovaginal microbiota profile. This analysis included 222 participants with cervical length measured. A short cervix was defined as one having length <25 mm, as measured by transvaginal ultrasound. Unpaired t-tests were performed with a Bonferroni correction for multiple comparisons. RESULTS: There were 27 participants with a short cervix, and 195 with normal cervical length. Of the 637 metabolites detected, 26 differed between those with a short cervix and those with normal cervical lengths; 22 were decreased, of which 21 belonged to the lipid metabolism pathway (all P<.000079). Diethanolamine, erythritol, progesterone, and mannitol or sorbitol were increased in the cases of short cervix. Among participants with Lactobacillus-deficient microbiota, only diethanolamine and mannitol or sorbitol differed between short cervix (n=17) and normal cervical length (n=75), both increased. CONCLUSION: A short cervix is associated with decreased cervicovaginal lipid metabolites, particularly sphingolipids. This class of lipids stabilizes cell membranes and protects against environmental exposures. Increased diethanolamine-an immunostimulatory xenobiotic-is associated with a short cervix. These observations begin to identify the potential mechanisms by which modifiable environmental factors may invoke cell damage in the setting of biological vulnerability, thus promoting premature cervical remodeling in spontaneous preterm birth.

Perinatal and early childhood biomarkers of psychosocial stress and adverse experiences.

The human brain develops through a complex interplay of genetic and environmental influences. During critical periods of development, experiences shape brain architecture, often with long-lasting effects. If experiences are adverse, the effects may include the risk of mental and physical disease, whereas positive environments may increase the likelihood of healthy outcomes. Understanding how psychosocial stress and adverse experiences are embedded in biological systems and how we can identify markers of risk may lead to discovering new approaches to improve patient care and outcomes. Biomarkers can be used to identify specific intervention targets and at-risk children early when physiological system malleability increases the likelihood of intervention success. However, identifying reliable biomarkers has been challenging, particularly in the perinatal period and the first years of life, including in preterm infants. This review explores the landscape of psychosocial stress and adverse experience biomarkers. We highlight potential benefits and challenges of identifying risk clinically and different sub-signatures of stress, and in their ability to inform targeted interventions. Finally, we propose that the combination of preterm birth and adversity amplifies the risk for abnormal development and calls for a focus on this group of infants within the field of psychosocial stress and adverse experience biomarkers. IMPACT: Reviews the landscape of biomarkers of psychosocial stress and adverse experiences in the perinatal period and early childhood and highlights the potential benefits and challenges of their clinical utility in identifying risk status in children, and in developing targeted interventions. Explores associations between psychosocial stress and adverse experiences in childhood with prematurity and identifies potential areas of assessment and intervention to improve outcomes in this at-risk group.

Clinician-reported childbirth outcomes, patient-reported childbirth trauma, and risk for postpartum depression.

Childbirth trauma is common and increases risk for postpartum depression (PPD). However, we lack brief measures to reliably identify individuals who experience childbirth trauma and who may be at greater prospective risk for PPD. To address this gap, we used data from a racially diverse prospective cohort (n=1082). We collected survey data during pregnancy and at 12 weeks postpartum, as well as clinician-reported data from medical records. A new three-item measure of patient-reported childbirth trauma was a robust and independent risk factor for PPD, above and beyond other known risk factors for PPD, including prenatal anxiety and depression. Cesarean birth, greater blood loss, and preterm birth were each associated with greater patient-reported childbirth trauma. Finally, there were prospective indirect pathways whereby cesarean birth and higher blood loss were related to higher patient-reported childbirth trauma, in turn predicting greater risk for PPD. Early universal postpartum screening for childbirth trauma, targeted attention to individuals with childbirth complications, and continued screening for depression and anxiety can identify individuals at risk for PPD. Such efforts can inform targeted interventions to improve maternal mental health, which plays a vital role in infant development.

Black-White disparities in maternal in-hospital mortality according to teaching and Black-serving hospital status.

BACKGROUND: Maternal mortality is higher among Black than White people in the United States. Whether Black-White disparities in maternal in-hospital mortality during the delivery hospitalization vary across hospital types (Black-serving vs nonBlack-serving and teaching vs nonteaching) and whether overall maternal mortality differs across hospital types is not known. OBJECTIVE: The aims of this study were to determine whether risk-adjusted Black-White disparities in maternal mortality during the delivery hospitalization vary by hospital types (this is analysis of disparities in mortality within hospital types) and compare risk-adjusted in-hospital maternal mortality among Black-serving and nonBlack-serving teaching and nonteaching hospitals regardless of race (this is an analysis of overall mortality across hospital types). STUDY DESIGN: We performed a population-based, retrospective cohort study of 5,679,044 deliveries among Black (14.2%) and White patients (85.8%) in 3 states (California, Missouri, and Pennsylvania) from 1995 to 2009. A hospital discharge disposition of "death" defined maternal in-hospital mortality. Black-serving hospitals had at least 7% Black obstetrical patients (top quartile). We performed risk adjustment by calculating expected death rates using predictions from logistic regression models incorporating sociodemographics, rurality, comorbidities, multiple gestations, gestational age at delivery, year, state, and mode of delivery. We calculated risk-adjusted risk ratios of mortality by comparing observed-to-expected ratios among Black and White patients within hospital types and then examined mortality across hospital types, regardless of patient race. We quantified the proportion of Black-White disparities in mortality attributable to delivering in Black-serving hospitals using causal mediation analysis. RESULTS: There were 330 maternal deaths among 5,679,044 patients (5.8 per 100,000). Black patients died more often (11.5 per 100,000) than White patients (4.8 per 100,000) (relative risk, 2.38; 95% confidence interval, 1.89-2.98). Examination of Black-White disparities revealed that after risk adjustment, Black patients had significantly greater risk of death (adjusted relative risk, 1.44; 95% confidence interval, 1.17-1.79) and that the disparity was similar within each of the hospital types. Comparison of mortality, regardless of race, across hospital types revealed that among teaching hospitals, mortality was similar in Black-serving and nonBlack-serving hospitals. However, among nonteaching hospitals, mortality was significantly higher in Black-serving vs nonBlack-serving hospitals (adjusted relative risk, 1.47; 95% confidence interval, 1.15-1.87). Notably, 53% of Black patients delivered in nonteaching, Black-serving hospitals compared with just 19% of White patients. Among nonteaching hospitals, 47% of Black-White disparities in maternal in-hospital mortality were attributable to delivering at Black-serving hospitals. CONCLUSION: Maternal in-hospital mortality during the delivery hospitalization among Black patients is more than double that of White patients. Our data suggest this disparity is caused by excess mortality among Black patients within each hospital type, in addition to excess mortality in nonteaching, Black-serving hospitals where most Black patients deliver. Addressing downstream effects of racism to achieve equity in maternal in-hospital mortality will require transparent reporting of quality metrics by race to reduce differential care and outcomes within hospital types, improvements in care delivery at Black-serving hospitals, overcoming barriers to accessing high-quality care among Black patients, and eventually desegregation of healthcare.

Adverse psychosocial factors in pregnancy and preterm delivery.

BACKGROUND: Mental health symptoms, stress, and low psychosocial resources are associated with preterm delivery. It is unknown if there are groups of women who experience similar patterns of these adverse psychosocial factors during pregnancy and if the risk of preterm delivery differs among these groups. OBJECTIVE: To identify groups of women with similar patterns of adverse psychosocial factors during pregnancy and determine whether the risk of preterm delivery differs among these groups. METHODS: Spontaneous Prematurity and Epigenetics of the Cervix (SPEC) is a prospective cohort study of pregnant women, aged 18 and older. In this analysis, we included women who enrolled after 24 August 2014 and delivered by 20 January 2019. As women could enrol more than once, our cohort included 774 women with 787 pregnancies. We conducted a latent class analysis to identify groups of women with similar patterns of adverse psychosocial factors during pregnancy based on their responses to measures assessing depression, perceived stress, anxiety (pregnancy-related and generalised), stressful life events, resilience, and social support (partner and friend/family). After identifying the latent classes, we used log-binomial regression to compare the incidence of preterm delivery among the classes. RESULTS: The median age among participants was 33.2 years (interquartile range 30.3-36.3), and the majority were non-Hispanic white (56.9%). We identified three classes of adverse psychosocial factors (few, some, and many factors). In total, 63 (8.0%) pregnancies resulted in a preterm delivery. Compared to participants with few factors, the risk of preterm delivery was no different among participants with some (RR 1.23, 95% CI 0.68, 2.25) and many adverse factors (RR 1.62, 95% CI 0.73, 3.62). CONCLUSIONS: We identified three groups of pregnant women with similar patterns of adverse psychosocial factors. We did not observe a difference in the risk of preterm delivery among the classes.

Urban residential tree canopy and perceived stress among pregnant women.

OBJECTIVE: To examine the association of urban residential tree canopy cover with perceived stress in a cohort of pregnant women in Philadelphia, PA, and explore whether this association differed among participants with a history of anxiety and depression. STUDY DESIGN: We performed a secondary analysis of 1294 participants of the Motherhood & Microbiome (M&M) pregnancy cohort who lived in Philadelphia, with first visit perceived stress (Cohen's Perceived Stress Scale, PSS-14), and key covariate data. Tree canopy cover was calculated as percent cover within 100 and 500 m radii buffers around participants' homes. We performed multilevel mixed effects linear regression models, with perceived stress as the dependent variable. The main independent variable was tree canopy coverage. Individual-level covariates included season of last menstrual period, history of depression or anxiety, race/ethnicity, insurance, parity, and age. Census tract neighborhood deprivation index was used to account for area-level socioeconomic confounding variables. We also examined whether a history of anxiety or depression, modified the association between tree canopy coverage and perceived stress. RESULTS: Most participants were non-Hispanic Black (70.6%, n = 913), on Medicaid or uninsured (60.4%, n = 781), and 15.8% (n = 204) of participants had a prior history of depression or anxiety. We did not detect associations between tree canopy coverage and perceived stress overall. However, we detected effect modification; among participants with a history of depression or anxiety, each standard deviation increase in tree canopy cover was associated with lower PSS-14 in 100 m buffers (ß -1.0, 95% CI -1.8, -0.2), but not among participants with no histories of depression or anxiety (ß 0.2, 95% CI -0.3, 0.7) (interaction P = 0.007). Results were similar in directionality but not statistically significant within 500 m buffers. CONCLUSION: Residential tree canopy coverage was associated with reduced perceived stress among urban-dwelling pregnant women with history of anxiety or depression. Future studies of the effects of greenness and other stress-reducing efforts should consider underlying mental health conditions as effect modifiers.

Associations of public water system trihalomethane exposure during pregnancy with spontaneous preterm birth and the cervicovaginal microbial-immune state.

BACKGROUND: Water total trihalomethanes (TTHMs) are disinfectant byproducts found in municipal water supplies. TTHM exposure has been linked to cancer and may be associated with adverse reproductive outcomes. A non-optimal cervicovaginal microbiota and low cervicovaginal beta-defensin-2 levels are associated with increased risk of spontaneous preterm birth. Whether TTHM exposure increases the risk of spontaneous preterm birth or alters the cervicovaginal microbial or immune state is unknown. OBJECTIVE: Investigate associations of water TTHM levels with spontaneous preterm birth, a non-optimal cervicovaginal microbiota, and beta-defensin-2 levels in a completed, diverse, urban pregnancy cohort. We hypothesized that higher TTHM levels would be associated with spontaneous preterm birth, a non-optimal cervicovaginal microbiota, and lower beta-defensin-2 levels. DESIGN: Methods: This was a secondary analysis of participants (n = 474) in the Motherhood & Microbiome (M&M) study (n = 2000), who lived in Philadelphia and had cervicovaginal samples analyzed for cervicovaginal microbiota composition and beta-defensin-2 levels. The microbiota was classified into community state types (CSTs). CST IV (non-optimal microbiota) is characterized by a paucity of Lactobacillus species and wide array of anaerobes. Municipal water TTHM levels were obtained from 16 sites monthly across the city of Philadelphia to establish mean residential water supply levels for each participant for the first four months of pregnancy (prior to vaginal swab collection at 16-20 weeks' gestation). Associations of water TTHM levels with spontaneous preterm birth and a non-optimal cervicovaginal microbiota birth were analyzed using multivariable logistic regression. Multivariable linear regression was used to model associations of water TTHM levels with log-transformed cervicovaginal beta-defensin-2 levels. Since water TTHM levels vary by season and beta-defensin-2 levels have been shown to differ by race, stratified models by warm (April-September) and cold (October-March) seasons as well as by self-identified race were utilized. RESULTS: Participants' water supply TTHM levels (mean µg/L [SD]) were higher in the warm (53.5 [9.4]) than cold (33.4 [7.5]) season (p < 0.0001). TTHM levels were non-significantly higher among Black participants than non-Black participants (44.8 [13.5] vs. 41.8 [11.8], p = 0.07). No associations were detected between TTHM with spontaneous preterm birth (per SD increment of TTHM, aOR 0.94, 95%CI: 0.66, 1.34) or with CST IV (aOR 0.94, 95%CI: 0.86, 1.16). Counter to our hypothesis, we observed positive associations of water TTHM with log-transformed cervicovaginal beta-defensin-2 levels in unadjusted models (ß 0.20 [95%CI: 0.02, 0.39]) per SD increment of TTHM), but the association was null after adjustment for season. However, in models adjusted for covariates including season and stratified by race, TTHM was significantly associated with lower beta-defensin-2 levels among non-Black participants (ß -0.75 [95%CI: -1.43, -0.08]) but not among Black participants (ß 0.17 [95%CI: -0.15, 0.49]), interaction p = 0.013). CONCLUSION: We did not detect associations of water TTHM levels with spontaneous preterm birth or the structure of the cervicovaginal microbiota. However, the finding of a significant interaction between TTHM and race on beta-defensin-2 levels suggest that environmental exposures may contribute to differences in reproductive tract innate immune function by race. Future studies to delineate environmental contributions to the cervicovaginal microbial-immune state, a potentially important biologic underpinning for preterm birth, are warranted.

Surface mining and low birth weight in central appalachia.

BACKGROUND: Surface mining has become a significant method of coal mining in the Central Appalachian region of the eastern United States alongside the traditional underground mining. Concerns have been raised about the health effects of this surface mining, particularly mountaintop removal mining where coal is mined upon steep mountaintops by removing the mountaintop through clearcutting forests and explosives. METHODS: We used a control group design with a pretest and a posttest to assess the associations of surface mining in Central Appalachia with low birth weight and other adverse birth outcomes. The pretest period is 1977-1989, a period of low surface mining activity. We consider three posttest periods: 1990-1998, 1999-2011 and 2012-2017, with 1999-2011 as the primary analysis and the other periods as secondary analyses. Surface mining in Central Appalachia increased after 1989, partly resulting from the Clean Air Act Amendments of 1990 which made surface mining in Appalachia more financially attractive. For the primary analysis, we fit a logistic regression model of the primary outcome (low birth weight, <2500 g) on dummy variables for county and year; individual level maternal/infant covariates (maternal race, maternal age, infant sex and whether birth was a multiple birth); and the amount of surface mining during the year of the birth in the maternal county of residence. RESULTS: Our analysis sample consisted of 783,328 infants -- 482,284 infants born from 1977 to 2017 to women residing in substantial surface mining activity counties and 301,044 infants born from 1977 to 2017 to women residing in matched control counties. Compared to the pre-period of low surface mining from 1977 to 1989, for the primary analysis posttest period of 1999-2011, there was an estimated relative increase in low birth weight in surface mining counties compared to matched control counties that was not statistically significant (odds ratio for a 5 percentage point increase in area disturbed by surface mining: 1.07, 95% confidence interval (0.96, 1.20), p-value: .22). For the secondary analysis posttest period of 1990-1998, there was no increase (odds ratio: 0.91, 95% confidence interval: (0.74, 1.13), p-value: .41). For the secondary analysis posttest period of 2012-2017, there was a statistically significant relative increase (odds ratio: 1.28, 95% confidence interval: (1.08, 1.50), p-value: .004). Qualitatively similar results were found for the outcomes of very low birth weight, preterm birth and small-for-gestational age. CONCLUSIONS: We examined the hypothesis that surface mining activity in Central Appalachia contributes to low birth weight using an observational study. We found evidence in secondary analyses that surface mining was associated with low birth weight in the 2012-2017 time period and potentially beginning in the early to mid 2000's. Evidence for an association was not found prior to 2000. A potential explanation for this pattern of association is that surface mining caused an increase in low birth weight but its onset was delayed. Future research is needed to clarify the findings and if replicated, identify the mechanism necessary to mitigate the impacts of mining on adverse birth outcomes.

Effect of a Nonoptimal Cervicovaginal Microbiota and Psychosocial Stress on Recurrent Spontaneous Preterm Birth.

OBJECTIVE: While select cervicovaginal microbiota and psychosocial factors have been associated with spontaneous preterm birth, their effect on the risk of recurrence remains unclear. It is also unknown whether psychosocial factors amplify underlying biologic risk. This study sought to determine the effect of nonoptimal cervicovaginal microbiota and perceived stress on the risk of recurrent spontaneous preterm birth. STUDY DESIGN: This was a secondary analysis of a prospective pregnancy cohort, Motherhood and Microbiome. The Cohen's Perceived Stress Scale (PSS-14) was administered and cervical swabs were obtained between 16 and 20 weeks of gestation. PSS-14 scores ≥30 reflected high perceived stress. We analyzed cervicovaginal microbiota using 16S rRNA sequencing and classified microbial communities into community state types (CSTs). CST IV is a nonoptimal cervicovaginal microbial community characterized by anaerobes and a lack of Lactobacillus. The final cohort included a predominantly non-Hispanic Black population of women with prior spontaneous preterm birth who had recurrent spontaneous preterm birth or term birth and had stress measurements (n = 181). A subanalysis was performed in the subset of these women with cervicovaginal microbiota data (n = 74). Multivariable logistic regression modeled adjusted associations between CST IV and recurrent spontaneous preterm birth, high stress and recurrent spontaneous preterm birth, as well as high stress and CST IV. RESULTS: Among the 181 women with prior spontaneous preterm birth, 45 (24.9%) had high perceived stress. We did not detect a significant association between high stress and recurrent spontaneous preterm birth (adjusted odds ratio [aOR] 1.67, 95% confidence interval [CI]: 0.73-3.85). Among the 74 women with prior spontaneous preterm birth and cervicovaginal microbiota analyzed, 29 (39.2%) had CST IV; this proportion differed significantly among women with recurrent spontaneous preterm birth (51.4%) compared with women with term birth (28.2%) (p = 0.04). In models adjusted for race and marital status, the association between CST IV and recurrent spontaneous preterm birth persisted (aOR 3.58, 95% CI: 1.25-10.24). There was no significant interaction between stress and CST IV on the odds of spontaneous preterm birth (p = 0.328). When both stress and CST IV were introduced into the model, their associations with recurrent spontaneous preterm birth were slightly stronger than when they were in the model alone. The aOR for stress with recurrent spontaneous preterm birth was 2.02 (95% CI: 0.61-6.71) and for CST IV the aOR was 3.83 (95% CI: 1.30-11.33). Compared to women with neither of the two exposures, women with both high stress and CST IV had the highest odds of recurrent spontaneous preterm birth (aOR = 6.01, 95% CI: 1.002-36.03). CONCLUSION: Among a predominantly non-Hispanic Black cohort of women with a prior spontaneous preterm birth, a nonoptimal cervicovaginal microbiota is associated with increased odds of recurrent spontaneous preterm birth. Adjustment for perceived stress may amplify associations between CST IV and recurrent spontaneous preterm birth. Identification of modifiable social or behavioral factors may unveil novel nonpharmacologic interventions to decrease recurrent spontaneous preterm birth among women with underlying biologic risk. KEY POINTS: · CST IV, a nonoptimal microbiota, is associated with increased odds of recurrent spontaneous preterm birth.. · Adjustment for perceived stress amplified associations between CST IV and recurrent spontaneous preterm birth.. · Identification of modifiable psychosocial factors may unveil novel nonpharmacologic interventions to decrease recurrent preterm birth..

Associations of DNA Methylation Mortality Risk Markers with Congenital Microcephaly from Zika Virus: A Study of Brazilian Children Less than 4 Years of Age.

BACKGROUND: Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes-potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang's mortality score (ZMS). METHODS: Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5-40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships. RESULTS: We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; ß = -2453.06 pg/ml, 95% confidence interval (CI) -3652.96, -1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (ß = -0.06, 95% CI -0.09, -0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (ß = -2448.70 pg/ml, 95% CI -4384.45, -512.95, p = 0.01) and cg14975410 (ß = 0.01, 95% CI -0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant. CONCLUSION: Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.

Cervicovaginal microbial communities deficient in Lactobacillus species are associated with second trimester short cervix.

BACKGROUND: The cervix functions as a barrier to ascending pathogens in pregnancy. Short cervical length and lack of cervicovaginal Lactobacillus species are risk factors for spontaneous preterm birth; however, whether they interact to increase risk remains unknown. OBJECTIVE: We sought to examine the relationship between cervicovaginal microbiota and short cervix as well as their combined impact on spontaneous preterm birth risk. STUDY DESIGN: This was a secondary analysis of a prospective nested, case-control pregnancy study. Cervical swabs were collected between 16 and 20 weeks of gestation. Cervical length was measured per standard clinical care during a clinically indicated ultrasound at approximately 20 weeks of gestation. Cervicovaginal microbiota were analyzed with 16S ribosomal RNA gene sequencing and classified into community state types among 67 cases of spontaneous preterm birth, 47 cases of medically indicated preterm birth, and 358 cases of term births. Logistic regression was used to model associations of community state type IV, a community characterized by a paucity of Lactobacillus species and a wide array of anaerobic bacteria, and short cervix (<25 mm) as well as to model the association of a combination of short cervix and community state type IV with the odds of spontaneous preterm birth. RESULTS: Among the 472 women in the data set, there were 38 with short cervix (8.1%) and 177 with community state type IV (37.5%). Short cervix was associated with spontaneous preterm birth (adjusted odds ratio, 15.59; 95% confidence interval, 6.77-35.92). Women with community state type IV had higher odds of short cervix (adjusted odds ratio, 2.17; 95% confidence interval, 1.04-4.53) as well as spontaneous preterm birth (adjusted odds ratio, 1.97; 95% confidence interval, 1.06-3.65). While the interaction of community state type IV and short cervix was not significant (P = .771), women with both short cervix and community state type IV (n = 20) had higher odds of spontaneous preterm birth compared with women with both normal cervical length and community state types I, II, III, or V (n = 277) (adjusted odds ratio, 21.8; 95% confidence interval, 6.78-70.2). CONCLUSION: Community state type IV, characterized by a diverse set of strict and facultative anaerobes and a paucity of Lactobacillus species, is associated with increased odds of short cervix. Women with both community state type IV and short cervix have higher odds of spontaneous preterm birth than women with either factor alone. Determining the cascade of events leading to premature cervical shortening, including dysbiosis, may be critical in preventing spontaneous preterm birth.

The promise and pitfalls of precision medicine to resolve black-white racial disparities in preterm birth.

Differences in preterm birth rates between black and white women are the largest contributor to racial disparities in infant mortality. In today's age of precision medicine, analysis of the genome, epigenome, metabolome, and microbiome has generated interest in determining whether these biomarkers can help explain racial disparities. We propose that there are pitfalls as well as opportunities when using precision medicine analyses to interrogate disparities in health. To conclude that racial disparities in complex conditions are genetic in origin ignores robust evidence that social and environmental factors that track with race are major contributors to disparities. Biomarkers measured in omic assays that may be more environmentally responsive than genomics, such as the epigenome or metabolome, may be on the causal pathway of race and preterm birth, but omic observational studies suffer from the same limitations as traditional cohort studies. Confounding can lead to false conclusions about the causal relationship between omics and preterm birth. Methodological strategies (including stratification and causal mediation analyses) may help to ensure that associations between biomarkers and exposures, as well as between biomarkers and outcomes, are valid signals. These epidemiologic strategies present opportunities to assess whether precision medicine biomarkers can uncover biology underlying perinatal health disparities.

Maternal blood arsenic levels and associations with birth weight-for-gestational age.

BACKGROUND: Among highly exposed populations, arsenic exposure in utero may be associated with decreased birth weight, however less is known about potential effects of arsenic exposure in urban communities without contaminated sources such as drinking water. OBJECTIVE: Investigate the association of blood arsenic levels with birth weight-for-gestational age categories within a prospective birth cohort study. DESIGN/METHODS: We analyzed 730 mother-infant dyads within the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) cohort in Mexico City. Total arsenic was measured in maternal blood samples from the 2nd and 3rd trimesters, at delivery, as well as from infant umbilical cord blood samples. Multivariable, multinomial logistic regression models adjusting for maternal age at enrollment, pre-pregnancy body mass index, parity, infant sex, socioeconomic position, and prenatal environmental tobacco smoke exposure were used to calculate odds ratios of small-for-gestational age (<10th percentile, SGA) and large-for-gestational age (>90th percentile, LGA) compared to appropriate-for-gestational age (AGA) per unit increase of log-transformed arsenic. RESULTS: Median (IQR) blood arsenic levels for maternal second trimester were 0.72 (0.33) µg/L, maternal third trimester 0.75 (0.41) µg/L, maternal at delivery 0.85 (0.70) µg/L, and infant cord 0.78 (0.65) µg/L. Maternal delivery and infant cord blood samples were most strongly correlated (spearman r = 0.65, p < 0.0001). Maternal arsenic levels at delivery were associated with significantly higher odds of both SGA (adj. OR = 1.44, 95% CI: 1.08-1.93) and LGA (adj. OR = 2.03, 95% CI: 1.12-3.67) compared to AGA. Results were similar for cord blood. There were 130 SGA infants and 22 LGA infants. Earlier in pregnancy, there were no significant associations of arsenic and birth weight-for-gestational age. However, we observed non-significantly higher odds of LGA among women with higher arsenic levels in the 3rd trimester (adj. OR = 1.46, 95% CI: 0.67-3.12). CONCLUSION: We found that in a Mexico City birth cohort, higher maternal blood arsenic levels at delivery were associated with higher odds of both SGA and LGA. However, sources and species of arsenic were not known and the number of LGA infants was small, limiting the interpretation of this finding and highlighting the importance of future large studies to incorporate arsenic speciation. If our findings were confirmed in studies that addressed these limitations, determining modifiable factors that could be mitigated, such as sources of arsenic exposure, may be important for optimizing fetal growth to improve long-term health of children.