Criteria for placental examination for obstetrical and neonatal providers.

Pathologic examination of the placenta can provide insight into likely (and unlikely) causes of antepartum and intrapartum events, diagnoses with urgent clinical relevance, prognostic information for mother and infant, support for practice evaluation and improvement, and insight into advancing the sciences of obstetrics and neonatology. Although it is true that not all placentas require pathologic examination (although alternative opinions have been expressed), prioritization of placentas for pathologic examination should be based on vetted indications such as maternal comorbidities or pregnancy complications in which placental pathology is thought to be useful for maternal or infant care, understanding pathophysiology, or practice modifications. Herein we provide placental triage criteria for the obstetrical and neonatal provider based on publications and expert opinion of 16 placental pathologists and a pathologists' assistant, formulated using a modified Delphi approach. These criteria include indications in which placental pathology has clinical relevance, such as pregnancy loss, maternal infection, suspected abruption, fetal growth restriction, preterm birth, nonreassuring fetal heart testing requiring urgent delivery, preeclampsia with severe features, or neonates with early evidence of multiorgan system failure including neurologic compromise. We encourage a focused gross examination by the provider or an attendant at delivery for all placentas and provide guidance for this examination. We recommend that any placenta that is abnormal on gross examination undergo a complete pathology examination. In addition, we suggest practice criteria for placental pathology services, including a list of critical values to be used by the relevant provider. We hope that these sets of triage indications, criteria, and practice suggestions will facilitate appropriate submission of placentas for pathologic examination and improve its relevance to clinical care.

Placental morphology in association with autism-related traits in the EARLI study.

BACKGROUND: In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. METHODS: Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). RESULTS: In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. CONCLUSIONS: Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers.

Congenital infection of SARS-CoV-2 appears to be exceptionally rare despite many cases of COVID-19 during pregnancy. Robust proof of placental infection requires demonstration of viral localization within placental tissue. Only two of the few cases of possible vertical transmission have demonstrated placental infection. None have shown placental expression of the ACE2 or TMPRSS2 protein, both required for viral infection. We examined 19 COVID-19 exposed placentas for histopathologic findings, and for expression of ACE2, and TMPRSS2 by immunohistochemistry. Direct placental SARS-CoV-2 expression was studied by two methods-nucleocapsid protein expression by immunohistochemistry, and RNA expression by in situ hybridization. ACE2 membranous expression in the syncytiotrophoblast (ST) of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the ST. In addition, cytotrophoblast and extravillous trophoblast express ACE2. No ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST. In 2 of 19 cases, SARS-CoV-2 RNA was present in the placenta focally in the ST and cytotrophoblast. There was no characteristic histopathology present in our cases including the two placental infections. We found that the placenta is capable of being infected but that this event is rare. We propose one explanation could be the polarized expression of ACE2 away from the maternal blood and pronounced paucity of TMPRSS2 expression in trophoblast.

Histologic Funisitis and Likelihood of Intrauterine Inflammation or Infection: A Case-Control Study.

OBJECTIVE: The objective of this study was to ascertain the likelihood of isolated maternal fever and suspected intrauterine inflammation or infection or both (Triple I) among cases of histologic chorioamnionitis with funisitis (HCF) at term. STUDY DESIGN: In this case-control study, placental pathology records were reviewed to identify term singleton laboring patients with HCF. Controls (1:1) were matched for gestational age. RESULTS: During the 6-month period, there were 2,399 term deliveries of laboring women. Of 1,552 (65%) term placentas examined, 4% (n = 60) had HCF.Features of Triple I were significantly more common among cases than controls: (1) isolated maternal fever of ≥100.4°F, twice, at least 30 minutes apart (p = 0.014); (2) fever with fetal tachycardia (p = 0.029); 3) fever with either fetal tachycardia or white blood cell count greater than 15,000 per mm3 (p = 0.034). The feature of Triple I with the highest sensitivity at 10% (95% confidence intervals [CI] 4-21%) was isolated maternal fever using ≥100.4°F on two occasions. The specificity for all features was consistently 100% (95% CI 91-100%). CONCLUSION: To our knowledge, this is the first report on HCF and Triple I features. Though the sensitivity of Triple I to identify HCF is low, specificity is excellent.

Autism risk classification using placental chorionic surface vascular network features.

BACKGROUND: Autism Spectrum Disorder (ASD) is one of the fastest-growing developmental disorders in the United States. It was hypothesized that variations in the placental chorionic surface vascular network (PCSVN) structure may reflect both the overall effects of genetic and environmentally regulated variations in branching morphogenesis within the conceptus and the fetus' vital organs. This paper provides sound evidences to support the study of ASD risks with PCSVN through a combination of feature-selection and classification algorithms. METHODS: Twenty eight arterial and 8 shape-based PCSVN attributes from a high-risk ASD cohort of 89 placentas and a population-based cohort of 201 placentas were examined for ranked relevance using a modified version of the random forest algorithm, called the Boruta method. Principal component analysis (PCA) was applied to isolate principal effects of arterial growth on the fetal surface of the placenta. Linear discriminant analysis (LDA) with a 10-fold cross validation was performed to establish error statistics. RESULTS: The Boruta method selected 15 arterial attributes as relevant, implying the difference in high and low ASD risk can be explained by the arterial features alone. The five principal features obtained through PCA, which accounted for about 88% of the data variability, indicated that PCSVNs associated with placentas of high-risk ASD pregnancies generally had fewer branch points, thicker and less tortuous arteries, better extension to the surface boundary, and smaller branch angles than their population-based counterparts. CONCLUSION: We developed a set of methods to explain major PCSVN differences between placentas associated with high risk ASD pregnancies and those selected from the general population. The research paradigm presented can be generalized to study connections between PCSVN features and other maternal and fetal outcomes such as gestational diabetes and hypertension.

First Trimester Detection of Placental Disease: Challenges and Opportunities.

It is generally agreed that placental pathology accounts for the majority of perinatal morbidity and mortality. If a placental prodrome could be diagnosed in vivo, risk for maternal or fetal complications could be estimated and acted upon before clinical symptoms are apparent. This is especially relevant in early diagnoses of gestational diabetes mellitus, which can be controlled through carefully monitored diet and activity changes. To meet this important need, there have been increased efforts to identify early gestation biomarkers of placental dysfunction using innovative imaging technologies. Here we outline innovative quantitative markers of placental shape and their relationship to placental function, clinical implications of these quantifiers, and the most recent mathematical models that utilize placental images to delineate at risk from normal pregnancies. We propose that novel contexts of readily available placental measures and routine collection of in vivo placental images in all pregnancies may be all that are needed to advance the identification of early risk determination of complicated pregnancies from placental images.

Maternal affective symptoms and sleep quality have sex-specific associations with placental topography.

BACKGROUND: The impacts of prenatal maternal affective symptoms on the placental structure are not well-established. Employing Geographic Information System (GIS) spatial autocorrelation, Moran's I, can help characterize placental thickness uniformity/variability and evaluate the impacts of maternal distress on placental topography. METHODS: This study (N = 126) utilized cohort data on prenatal maternal affective symptoms and placental 2D and 3D morphology. Prenatal maternal depression, stress, anxiety and sleep quality were scored for each trimester using the Edinburgh Postnatal Depression Scale (EPDS), Stressful Life Event Scale (SLE), Penn State Worry Questionnaire (PSWQ), and Pittsburgh Sleep Quality Index (PSQI), respectively. Placental shape was divided into Voronoi cells and thickness variability among these cells was computed using Moran's I for 4-nearest neighbors and neighbors within a 10 cm radius. Sex-stratified Spearman correlations and linear regression were used to study associations between mean placental thickness, placental GIS variables, placental weight and the average score of each maternal variable. RESULTS: For mothers carrying boys, poor sleep was associated with higher mean thickness (r = 0.308,p = 0.035) and lower placental thickness uniformity (r = -0.36,p = 0.012). Lower placental weight (r = 0.395,p = 0.003), higher maternal depression (r = -0.318,p = 0.019) and worry/anxiety (r = -0.362,p = 0.007) were associated with lower placental thickness uniformity for mothers carrying girls. LIMITATIONS: The study is exploratory and not all GIS models were developed. Excluding high-risk pregnancies prevented investigating pregnancy complications related hypotheses. A larger sample size is needed for greater confidence for clinical application. CONCLUSIONS: Placental topography can be studied using GIS theory and has shown that prenatal maternal affective symptoms and sleep have sex-specific associations with placental thickness.

PFAS alters placental arterial vasculature in term human placentae: A prospective pregnancy cohort study.

INTRODUCTION: Perfluoroalkyl substances (PFAS) are synthetic chemicals used in industrial and consumer goods that are widely detected in human populations and are associated with adverse health outcomes, including perinatal health risks and child health. One mechanism of influence may be the impact of PFAS exposure on placental structure and function. OBJECTIVES: The objective of this study is to investigate the relationship between maternal prenatal exposure to PFAS and measures of placental vascularization, and to assess whether changes in vascularization play a role in mediating the impact of PFAS on birth outcomes. METHODS: Using data from a prospective cohort study, we examined associations between second trimester PFAS (individually and as mixtures using Bayesian kernel machine regression) and placental arterial vasculature in term placentae (N = 158); secondarily we evaluated the degree to which alterations in placental arterial vasculature explained associations between PFAS exposure and birth outcomes. Placental arterial vasculature features were collected from arterial tracings of each placental image. RESULTS: In both linear regression and mixture models, natural log-transformed perfluorooctanoic acid concentrations were negatively associated with surface vasculature, indexed by the mean distance from arterial end point to perimeter (ß = -0.23, 95% CI: -0.41, -0.041); additionally, maximum arterial tortuosity was negatively associated with placental weight (ß = -0.19, 95% CI: -0.34, -0.051). There were no reliable differences in effect by fetal sex. DISCUSSION: The findings provide some of the first evidence of PFAS exposure shaping a key measure of placental vascular function, which may underlie the impact of PFAS on perinatal and child health risks.

Induction of labor at 41 weeks of pregnancy among primiparas with an unfavorable Bishop score.

OBJECTIVE: To determine the rate and factors associated with the successful Induction of Labor (IOL) in nulliparous patients undergoing scheduled IOL at 41 weeks of gestational age (GA) with an unfavorable cervix. DESIGN: This was a retrospective analysis that included nulliparous patients who presented to the Labor and Delivery unit at the Bronx Lebanon Hospital Center between 2011 and 2012 for elective IOL at 41 weeks of GA. The Bishop score was assessed upon admission and IOL agents were used in compliance with ACOG guidelines in different combinations, based on the obstetrical team preference. SETTING: Labor and Delivery Unit of the Bronx Lebanon Hospital. POPULATION: Nulliparous patients with 41 weeks of pregnancy for elective induction of labor. SAMPLE: Seventy-six patients were included in the study. GA was confirmed using a combination of the last menstrual period and a dating sonogram during pregnancy. METHODS: This was a retrospective chart review that included nulliparous patients who presented to the Labor and Delivery unit at the Bronx Lebanon Hospital Center between October 2011 and October 2012 for elective IOL at 41 weeks of gestational age with an unfavorable cervix defined as a Bishop score of 6 or less. MAIN OUTCOME MEASURES: The overall successful rate of IOL in a combination of different maternal factors with different agents for induction in nulliparous patients undergoing scheduled IOL with an unfavorable Bishop score at 41 weeks of GA was 51.32 %. RESULTS: Factors associated with successful IOL were younger age [22.3 years vs. 25.1(p = 0.015)], lower BMI [25 vs. 28.1(p = 0.46)] and lower maternal weight [64.75 kg vs. 74.02 (p = 0.28)]. Maternal height was not a contributing factor; the artificial rupture of membranes, epidural anesthesia and the prostaglandins used did not contribute. Use of cervical balloon and oxytocin was associated with failed IOL. CONCLUSIONS: Patients undergoing IOL at 41 weeks with an unfavorable cervix had a successful rate of 51.32 %. Younger maternal age, lower weight, and lower BMI were associated with successful IOL.

Comparison of methanol fixation versus cryopreservation of the placenta for metabolomics analysis.

Methods for collection of placental tissue at room temperature for metabolic profiling are described. Specimens were excised from the maternal side of the placenta and immediately flash frozen or fixed and stored for 1, 6, 12, 24, or 48 h in 80% methanol. Untargeted metabolic profiling was performed on both the methanol-fixed tissue and the methanol extract. Data were analyzed using Gaussian generalized estimating equations, two sample t-tests with false discovery rate (FDR) corrections, and principal components analysis. Methanol-fixed tissue samples and methanol extracts had a similar number of metabolites (p = 0.45, p = 0.21 in positive vs. negative ion mode). In positive ion mode, when compared to flash frozen tissue, both the methanol extract and methanol-fixed tissue (6 h) had a higher number of metabolites detected (146 additional metabolites, pFDR = 0.020; 149 additional metabolites, pFDR = 0.017; respectively), but these associations were not found in negative ion mode (all pFDR ≥ 0.05). Principle components analysis demonstrated separation of the metabolite features in the methanol extract, but similarity between methanol-fixed tissue and flash frozen tissue. These results show that placental tissue samples collected in 80% methanol at room temperature can yield similar metabolic data to flash frozen specimens.

Examining associations between prenatal biomarkers of oxidative stress and ASD-related outcomes using quantile regression.

We examined associations between prenatal oxidative stress (OS) and child autism-related outcomes. Women with an autistic child were followed through a subsequent pregnancy and that younger sibling's childhood. Associations between glutathione (GSH), glutathione disulfide (GSSG), 8-oxo-deoxyguanine (8-OHdG), and nitrotyrosine and younger sibling Social Responsiveness Scale (SRS) scores were examined using quantile regression. Increasing GSH:GSSG (suggesting decreasing OS) was associated with minor increases in SRS scores (50th percentile ß: 1.78, 95% CI: 0.67, 3.06); no other associations were observed. Results from this cohort with increased risk for autism do not support a strong relationship between OS in late pregnancy and autism-related outcomes. Results may be specific to those with enriched autism risk; future work should consider other timepoints and biomarkers.

Comparison of trace element concentrations in paired formalin-fixed paraffin-embedded and frozen human placentae.

INTRODUCTION: There is increasing interest in measuring metals concentrations in human placentas to better understand physiology, disease, and toxic and diagnostic exposures. For these purposes, formalin-fixed paraffin embedded (FFPE) tissues obtained at clinical pathology examination represent a valuable potential store of well-characterized tissues for analysis. However, the limited data that exist comparing metal concentrations in FFPE tissue to recently collected frozen tissues paints a confusing picture, and there is no published data directly comparing frozen and FFPE placental villus tissues. METHODS: Paired samples of fresh frozen and FFPE tissue from 22 rapidly processed human singleton placentae were weighed and digested using standard clean laboratory procedures and subsequently analyzed for a suite of 13 metals using a PerkinElmer DRC II ICP-MS. The analytical results were compared using either a paired t-test or a sign test depending on data normality. RESULTS: Concentrations of metals (aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), gadolinium (Gd), mercury (Hg), manganese (Mn), lead (Pb), strontium (Sr), and zinc (Zn)) measured in both types of tissue preparations (frozen and FFPE) displayed a consistent range with other studies and did not display significantly different values from each of the paired specimens for any of the 13 specific metals analyzed. DISCUSSION: Within placentae, metals concentrations of measured trace, toxic and diagnostic elements (Al, As, Ba, Cd, Cr, Cu, Fe, Gd, Hg, Mn, Pb, Sr, and Zn) are consistent between FFPE and fresh placental villus tissue, without indications of systematic element loss or bias. FFPE from archived pathology specimens may offer an important and convenient alternative for measuring trace metals in human frozen placental tissues.

Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters.

PURPOSE: To examine how the timing of hypoxic exposure results in specific childhood outcomes and whether there is a differential effect by sex. METHODS: A sample of 10,879 prospectively followed pregnancies was drawn from the Boston and Providence sites (New England, NE) of the National Collaborative Perinatal Project. Based on placental pathology, we developed and validated a measure of probable chronic placental hypoxia (CHP) and contrasted the effects of acute perinatal hypoxia on age 7 emotional, behavioral, and cognitive outcomes. RESULTS: Perinatal hypoxia had a significant impact on multiple behavioral and cognitive outcomes in boys and girls by age 7, in contrast to probable CHP which had a differential effect on girls and boys such that there was decreased verbal IQ and increased inhibition in females alone. CONCLUSIONS: Findings underscore the importance of considering the timing of obstetric complications and offspring sex in investigations of the impact of fetal and perinatal hypoxia on offspring's outcomes throughout the life course.

Placental pathology associated with maternal age and maternal obesity in singleton pregnancy.

OBJECTIVE: Maternal age, maternal obesity and neonatal sex dimorphism are known to affect pregnancy and neonatal outcome. However, the effects of these factors on specific placental pathology are less well-documented. STUDY DESIGN: Clinical information, placental pathology and neonatal data from singleton delivery were collected at our hospital in March 2020 to October 2021 and correlation studies were performed. RESULTS: A total 3,119 singleton placentas were examined between March 2020 and October 2021 in conjunction with clinical information and neonatal birth data. Advanced maternal age (>35) was significantly associated with a variety of pregnancy complications and placental pathology including preeclampsia/pregnancy induced hypertension (Pre/PIH), gestational diabetes mellitus (GDM2), intrauterine growth restriction (IUGR), and increased maternal body mass index (BMI) at delivery. Maternal obesity (BMI >30 at the time of delivery) was significantly associated with a variety of clinical features and placental pathology including PRE/PIH, GDM2 and decidual vasculopathy (mural arterial hypertrophy). No specific placental pathology was associated with neonatal sex except for more maternal inflammatory response (MIR, chronic deciduitis) in neonates of male sex. CONCLUSION: Maternal age and maternal obesity were associated with not only clinical complications of pregnancy and neonatal birth weight but also specific placental pathology. Understanding the effects of maternal and environmental factors will help improve pregnancy outcome.

Ultrasonographic study of umbilical cord twist direction during second trimester.

OBJECTIVE: To explore/study/evaluate the relationships among umbilical twist direction, the degree of umbilical twist and differences of umbilical arterial diameters (UAD). METHODS: All obstetric patients presenting for prenatal care of singleton fetuses between 18 and 25 weeks gestation to a single provider (MN) from 2015 to 2018 had detailed umbilical cord Doppler measurements. Data including the cord twist direction, degree of twist and number of twists per cord segment length, and the diameters of each UA (UAD) and the umbilical vein (UVD) were extracted from the records. UAs were described as right or left depending on their position at the fetal cord insertion. Three groups were identified: Group A: right UAD > left UAD and Group B: left UAD > right UAD Group C: equal UAD. The coiling index was calculated as the inverse of the length of cord required for one complete 360 degrees wrap of the UA around the cord. According to the difference of UADs, the variables of right and left UADs, the coiling index, and frequencies of umbilical twist direction were analyzed using non-parametric methods. RESULTS: 485 singleton fetuses and umbilical cords were examined. The value of the antenatal coiling index in cases with left UAD greater than right was 0.43 ± 0.16, which was significantly higher than 0.38 ± 0.16 with right UAD greater than left (p = .001). There were significant differences between the two groups in the values of right and left UAD, value of right minus left UAD, absolute value between right and left UAD, antenatal coiling index, antenatal coiling index due to umbilical twist direction and frequencies of cord twist direction. CONCLUSION: The direction of umbilical twist may be in part dependent on differences in diameters of the umbilical arteries, in addition to other fetal characteristics such as fetal movement, or handedness of fetus or mother, fetal hemodynamic forces and structure of muscles of umbilical vessels.

Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.

Placental morphologic features and chorionic surface vasculature at term are highly correlated with 3-dimensional sonographic measurements at 11 to 14 weeks.

OBJECTIVES: The purpose of this study was to examine the potential for 3-dimensional sonographic measurement of the early placenta in predicting ultimate placental morphologic features at delivery. METHODS: In this prospective cohort study, we collected 3-dimensional sonographic volume sets of placentas at 11 to 14 weeks and then collected the placentas after delivery. The sonographic data were manipulated to obtain various novel measurements of early gross placental morphologic features and the umbilical cord insertion location. The placental weight, chorionic plate area, cord location, and mean chorionic vascular density were obtained from the delivered postpartum placentas. Analyses were performed to identify potential early placental characteristics that were correlated with the ultimate placental morphologic features. The placental weight, cord marginality, and mean chorionic vascular density served as the outcome measures of interest. RESULTS: Measurements of the early placental volume correlated with the delivered placental weight. An irregular early placental shape, as measured by sonography, was significantly inversely correlated with placental weight (P < .05). The placental morphologic index, a measure of a flatter placenta, was inversely correlated with both the placental weight and chorionic plate area, possibly indicating the importance of placental thickness even in the first trimester before villous arborization. In addition, early sonographic measures of the location of the umbilical cord insertion were significantly correlated with the ultimate marginality of the cord insertion as well as the mean chorionic vascular density (P < .05). CONCLUSIONS: Many important ultimate placental morphologic features are likely predetermined early in pregnancy. Three-dimensional sonography may play an increasing role in the in utero evaluation of the early placenta.

Differences in clinical and laboratory biomarkers for short and long-term respiratory outcomes in preterm neonates.

BACKGROUND: Pulmonary outcome of premature neonates has focused more on short-term than long-term respiratory morbidities. OBJECTIVE: Describe risk factors/biomarkers associated with short-term (bronchopulmonary dysplasia [BPD]) (supplemental oxygen use at 36 weeks postmenstrual age [PMA]) and longer-term (chronic respiratory morbidity [CRM]) (respiratory related symptoms, medications, medical/emergency visits, hospitalizations at 6-12 months corrected gestational age [CGA]) respiratory outcomes in a longitudinal cohort. DESIGN/METHODS: Neonates born at 24-29-week gestation were prospectively followed to 6-12-month CGA. Associations between clinical and laboratory risk factors/biomarkers of BPD and CRM were explored. RESULTS: Of 86 subjects, 94% survived. Outcomes were available for 89% at 36-week PMA (BPD present in 42% of infants) and 72% at 6-12-month CGA (CRM present in 47% of infants). For the 54 infants with known outcomes for both BPD and CRM, diagnoses were discordant in 41%. BPD was associated with lower birthweight and birthweight Z-score for GA, lower Apgar scores, more surfactant doses, higher SNAPPE-II scores, highest Day 1 inspired oxygen concentration, Day 7 oxygen use, prolonged ventilatory support, bacteremia, necrotizing enterocolitis, and treated patent ductus arteriosus. CRM was associated with lower Apgar scores, Day 7 oxygen use and higher urine vascular endothelial growth factor. Patterns of plasma and urine lipid oxidation products differed in the two outcomes. CONCLUSION: In this hypothesis generating and exploratory study, BPD and CRM were associated with different risk factors/biomarker patterns. Concordance between these two outcomes was weak. Strategies for reducing CRM should be studied in cohorts identified by appropriate early risk factors/biomarkers.

Cohort profile: Understanding Pregnancy Signals and Infant Development (UPSIDE): a pregnancy cohort study on prenatal exposure mechanisms for child health.

PURPOSE: Extensive research suggests that maternal prenatal distress is reliably related to perinatal and child health outcomes-which may persist into adulthood. However, basic questions remain regarding mechanisms involved. To better understand these mechanisms, we developed the Understanding Pregnancy Signals and Infant Development (UPSIDE) cohort study, which has several distinguishing features, including repeated assessments across trimesters, analysis of multiple biological pathways of interest, and incorporation of placental structure and function as mediators of child health outcomes. PARTICIPANTS: Women with normal risk pregnancies were recruited at <14 weeks gestation. Study visits occurred in each trimester and included extensive psychological, sociodemographic, health behaviour and biospecimen collection. Placenta and cord blood were collected at birth. Child visits (ongoing) occur at birth and 1, 6, 12, 24, 36 and 48 months of age and use standard anthropometric, clinical, behavioural, biological and neuroimaging methods to assess child physical and neurodevelopment. FINDINGS TO DATE: We recruited 326 pregnancies; 294 (90%) were retained through birth. Success rates for prenatal biospecimen collection were high across all trimesters (96%-99% for blood, 94%-97% for urine, 96%-99% for saliva, 96% of placentas, 88% for cord blood and 93% for buccal swab). Ninety-four per cent of eligible babies (n=277) participated in a birth examination; postnatal visits are ongoing. FUTURE PLANS: The current phase of the study follows children through age 4 to examine child neurodevelopment and physical development. In addition, the cohort participates in the National Institutes of Health's Environmental influences on Child Health Outcomes programme, a national study of 50 000 families examining early environmental influences on perinatal outcomes, neurodevelopment, obesity and airway disease. Future research will leverage the rich repository of biological samples and clinical data to expand research on the mechanisms of child health outcomes in relation to environmental chemical exposures, genetics and the microbiome.