Placental Lesions Associated With Stillbirth by Gestational Age, as Related to Cause of Death: Follow-Up Results From the Stillbirth Collaborative Research Network.

BACKGROUND: We previously identified placental lesions associated with stillbirths of varying gestational ages (GA) using advanced feature analysis. We further investigated the relationships between placental lesions and cause of death in stillbirths within these GA ranges. METHODS: Using data from the Stillbirth Collaborative Research Network, we derived a sample of stillbirths who underwent placental examination and Initial Causes of Fetal Death (INCODE) evaluation for determining cause of death. We then compared the rates of causes of death within and among GA ranges (extreme preterm stillbirth [PTSB] [<28 weeks], early PTSB [28-336/7 weeks], late PTSB [34-366/7 weeks], term stillbirth [≥37 weeks]) according to the presence of these lesions. RESULTS: We evaluated 352 stillbirths. In extreme PTSB, obstetric complications and infections were associated with acute funisitis. In early PTSB, uteroplacental insufficiency was associated with parenchymal infarcts. In term stillbirth (vs early PTSB), increased syncytial knots were associated with umbilical cord causes and infection. CONCLUSIONS: Placental lesions of high importance in distinguishing stillbirths at different GAs are associated with specific causes of death. This information is important in relating the presence of placental lesions and fetal death and in helping to understand etiologies of stillbirths at different GAs.

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

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

Causal Genetic Variants in Stillbirth.

BACKGROUND: In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied. METHODS: We generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case-control analyses stratified according to the degree of depletion of functional variation (described here as "intolerance" to variation). RESULTS: We identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study. CONCLUSIONS: Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown. (Funded by the Institute for Genomic Medicine.).

Identifying risk of stillbirth using machine learning.

BACKGROUND: Previous predictive models using logistic regression for stillbirth do not leverage the advanced and nuanced techniques involved in sophisticated machine learning methods, such as modeling nonlinear relationships between outcomes. OBJECTIVE: This study aimed to create and refine machine learning models for predicting stillbirth using data available before viability (22-24 weeks) and throughout pregnancy, as well as demographic, medical, and prenatal visit data, including ultrasound and fetal genetics. STUDY DESIGN: This is a secondary analysis of the Stillbirth Collaborative Research Network, which included data from pregnancies resulting in stillborn and live-born infants delivered at 59 hospitals in 5 diverse regions across the United States from 2006 to 2009. The primary aim was the creation of a model for predicting stillbirth using data available before viability. Secondary aims included refining models with variables available throughout pregnancy and determining variable importance. RESULTS: Among 3000 live births and 982 stillbirths, 101 variables of interest were identified. Of the models incorporating data available before viability, the random forests model had 85.1% accuracy (area under the curve) and high sensitivity (88.6%), specificity (85.3%), positive predictive value (85.3%), and negative predictive value (84.8%). A random forests model using data collected throughout pregnancy resulted in accuracy of 85.0%; this model had 92.2% sensitivity, 77.9% specificity, 84.7% positive predictive value, and 88.3% negative predictive value. Important variables in the previability model included previous stillbirth, minority race, gestational age at the earliest prenatal visit and ultrasound, and second-trimester serum screening. CONCLUSION: Applying advanced machine learning techniques to a comprehensive database of stillbirths and live births with unique and clinically relevant variables resulted in an algorithm that could accurately identify 85% of pregnancies that would result in stillbirth, before they reached viability. Once validated in representative databases reflective of the US birthing population and then prospectively, these models may provide effective risk stratification and clinical decision-making support to better identify and monitor those at risk of stillbirth.

Copy number variants and fetal growth in stillbirths.

BACKGROUND: Fetal growth abnormalities are associated with a higher incidence of stillbirth, with small and large for gestational age infants incurring a 3 to 4- and 2 to 3-fold increased risk, respectively. Although clinical risk factors such as diabetes, hypertension, and placental insufficiency have been associated with fetal growth aberrations and stillbirth, the role of underlying genetic etiologies remains uncertain. OBJECTIVE: This study aimed to assess the relationship between abnormal copy number variants and fetal growth abnormalities in stillbirths using chromosomal microarray. STUDY DESIGN: A secondary analysis utilizing a cohort study design of stillbirths from the Stillbirth Collaborative Research Network was performed. Exposure was defined as abnormal copy number variants including aneuploidies, pathogenic copy number variants, and variants of unknown clinical significance. The outcomes were small for gestational age and large for gestational age stillbirths, defined as a birthweight <10th percentile and greater than the 90th percentile for gestational age, respectively. RESULTS: Among 393 stillbirths with chromosomal microarray and birthweight data, 16% had abnormal copy number variants. The small for gestational age outcome was more common among those with abnormal copy number variants than those with a normal microarray (29.5% vs 16.5%; P=.038). This finding was consistent after adjusting for clinically important variables. In the final model, only abnormal copy number variants and maternal age remained significantly associated with small for gestational age stillbirths, with an adjusted odds ratio of 2.22 (95% confidence interval, 1.12-4.18). Although large for gestational age stillbirths were more likely to have an abnormal microarray: 6.2% vs 3.3% (P=.275), with an odds ratio of 2.35 (95% confidence interval, 0.70-7.90), this finding did not reach statistical significance. CONCLUSION: Genetic abnormalities are more common in the setting of small for gestational age stillborn fetuses. Abnormal copy number variants not detectable by traditional karyotype make up approximately 50% of the genetic abnormalities in this population.

Composition of the maternal gastrointestinal microbiome as a predictor of neonatal birth weight.

BACKGROUND: The biological mechanism by which the maternal gastrointestinal microbiota contributes to fetal growth and neonatal birth weight is currently unknown. The purpose of this study was to explore how the composition of the maternal microbiome in varying pre-gravid body mass index (BMI) groups are associated with neonatal birth weight adjusted for gestational age. METHODS: Retrospective, cross-sectional metagenomic analysis of bio-banked fecal swab biospecimens (n = 102) self-collected by participants in the late second trimester of pregnancy. RESULTS: Through high-dimensional regression analysis using principal components (PC) of the microbiome, we found that the best performing multivariate model explained 22.9% of the variation in neonatal weight adjusted for gestational age. Pre-gravid BMI (p = 0.05), PC3 (p = 0.03), and the interaction of the maternal microbiome with maternal blood glucose on the glucose challenge test (p = 0.01) were significant predictors of neonatal birth weight after adjusting for potential confounders including maternal antibiotic use during gestation and total gestational weight gain. CONCLUSIONS: Our results indicate a significant association between the maternal gastrointestinal microbiome in the late second trimester and neonatal birth weight adjusted for gestational age. Moderated by blood glucose at the time of the universal glucose screening, the gastrointestinal microbiome may have a role in the regulation of fetal growth. IMPACT: Maternal blood glucose in the late second trimester significantly moderates the relationship between the maternal gastrointestinal microbiome and neonatal size adjusted for gestational age. Our findings provide preliminary evidence for fetal programming of neonatal birth weight through the maternal gastrointestinal microbiome during pregnancy.

Comparative Diagnostic Performance of Estimated Fetal Weight and Isolated Abdominal Circumference for the Detection of Fetal Growth Restriction.

OBJECTIVES: To describe the comparative incidence, detection of small-for-gestational age (SGA), and composite perinatal morbidity (CPM) associated with diagnostic criteria of fetal growth restriction (FGR) by estimated fetal weight (EFW) <10% with those with isolated abdominal circumference (AC) measurements <10%. METHODS: We performed a retrospective cohort study of 1587 patients receiving prenatal care and delivery at our institution. We included all patients with ultrasounds and delivery outcomes available, and excluded terminations, second trimester losses, and pregnancies without ultrasounds. EFW was calculated from Hadlock and use of the Duryea centiles, and AC from Hadlock's reference curves. We determined SGA at birth and defined CPM as birthweight less than 3% or birthweight less than 10% with neonatal morbidity. RESULTS: Of 1587 patients, 28 (1.8%) were classified as FGR by EFW <10%. Three of 12 patients with isolated AC <10% developed EFW <10% later in pregnancy (25%). The performance of each diagnostic criteria were comparable for the outcomes of SGA and CPM, with similar sensitivities, but with decreased specificity for SGA outcome, and an increased false positive rate for patients classified as FGR by isolated AC <10, with a tradeoff of decreased false negatives. CONCLUSIONS: Broadening the diagnosis of FGR to include patients with isolated AC <10 did not significantly increase the detection of pregnancies at risk for SGA or CPM. Our conclusions may be limited by a lack of statistical power given a low frequency of SGA and CPM.

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

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

Assessing Intrauterine Retention according to Microscopic Stillbirth Features: A Cluster Analysis Approach.

Background: Previous studies identified microscopic changes associated with intrauterine retention of stillbirths based on clinical time of death. The objective of this study was to utilize unsupervised machine learning (not reliant on subjective measures) to identify features associated with time from death to delivery. Methods: Data were derived from the Stillbirth Collaborative Research Network. Features were chosen a priori for entry into hierarchical cluster analysis, including fetal and placental changes. Results: A four-cluster solution (coefficient = 0.983) correlated with relative time periods of "no retention," "mild retention," "moderate retention," and "severe retention." Loss of nuclear basophilia within fetal organs were found at varying rates among these clusters. Conclusions: Hierarchical cluster analysis is able to classify stillbirths based on histopathological changes, roughly correlating to length of intrauterine retention. Such clusters, which rely solely on objective fetal and placental findings, can help clinicians more accurately assess the interval from death to delivery.

Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study.

BACKGROUND: Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. METHODS: This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341). RESULTS: Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001). CONCLUSIONS: Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Maternal Marijuana Exposure, Feto-Placental Weight Ratio, and Placental Histology.

OBJECTIVE: Marijuana use is associated with placenta-mediated adverse pregnancy outcomes including fetal growth restriction, but the mechanism remains uncertain. The objective was to evaluate the association between maternal marijuana use and the feto-placental weight ratio (FPR). Secondarily, we aimed to compare placental histology of women who used marijuana to those who did not. STUDY DESIGN: This was a secondary analysis of singleton pregnancies enrolled in a multicenter and case-control stillbirth study. Prior marijuana use was detected by electronic medical record abstraction or cord homogenate positive for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. Prior tobacco use was detected by self-report or presence of maternal serum cotinine. Stillbirths and live births were considered separately. The primary outcome was FPR. Association of marijuana use with FPR was estimated with multivariable linear modeling adjusted for fetal sex, preterm birth, and tobacco use. Comparisons between groups for placental histology were made using Chi-square and stratified by live birth and stillbirth, term and preterm deliveries, and fetal sex. RESULTS: Of 1,027 participants, 224 were stillbirths and 803 were live births. Overall, 41 (4%) women used marijuana during the pregnancy. The FPR ratio was lower among exposed offspring but reached statistical significance only for term stillbirths (mean 6.84 with marijuana use vs. mean 7.8 without use, p < 0.001). In multivariable modeling, marijuana use was not significantly associated with FPR (p = 0.09). There were no differences in histologic placental features among those with and without marijuana use overall or in stratified analyses. CONCLUSION: Exposure to marijuana may not be associated with FPR. Similarly, there were no placental histologic features associated with marijuana exposure. Further study of the influence of maternal marijuana use on placental development and function is warranted to better understand the association between prenatal marijuana use and poor fetal growth. KEY POINTS: · Maternal marijuana exposure was not associated with the feto-placental weight ratio.. · Marijuana exposure was not associated with differences in placental histology.. · Concerning trend toward lower feto-placental weight ratios among marijuana-exposed stillbirths..

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

OBJECTIVE: To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death. STUDY DESIGN: This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes (n = 11) and demographic and clinical factors (n = 10) evident by the time of discharge among surviving infants (n = 1889) and the primary outcome of death or moderate/severe CP at age 2 (n = 73) was estimated, and a prediction model was created. RESULTS: Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants. CONCLUSION: IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae. KEY POINTS: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..

DLK1: A Novel Biomarker of Placental Insufficiency in Stillbirth and Live Birth.

OBJECTIVE: Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency. STUDY DESIGN: A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB). SB and LB were stratified as placental insufficiency cases (small for gestational age <5% or circulatory lesions on placental histopathology) or normal placenta controls (appropriate for gestational age and no circulatory lesions). Enzyme-linked immunosorbent assay (ELISA) was used to measure DLK1. The mean difference in DLK1 was compared on the log scale in an adjusted linear regression model with pairwise differences, stratified by term/preterm deliveries among DLK1 results in the quantifiable range. In exploratory analysis, geometric means were compared among all data and the proportion of "low DLK1" (less than the median value for gestational age) was compared between groups and modeled using linear and logistic regression, respectively. RESULTS: Overall, 234 SB and 234 LB were analyzed; 246 DLK1 values were quantifiable within the standard curve. Pairwise comparisons of case and control DLK1 geometric means showed no significant differences between groups. In exploratory analysis of all data, adjusted analysis revealed a significant difference for the LB comparison only (SB: 71.9 vs. 99.1 pg/mL, p = 0.097; LB: 37.6 vs. 98.1 pg/mL, p = 0.005). In exploratory analysis of "low DLK1," there was a significant difference between the odds ratio of having "low DLK1" between preterm cases and controls for both SB and LB. There were no significant differences in geometric means nor "low DLK1" between SB and LB. CONCLUSION: In exploratory analysis, more placental insufficiency cases in preterm SB and LB had "low DLK1." However, low DLK1 levels were not associated with SB. KEY POINTS: · Maternally circulating DLK1 is correlated with placental insufficiency.. · Maternally circulating DLK1 is not correlated with SB.. · DLK1 is a promising marker for placental insufficiency..

Findings in Stillbirths Associated with Placental Disease.

OBJECTIVE: Placental disease is a leading cause of stillbirth. Our purpose was to characterize stillbirths associated with placental disease. STUDY DESIGN: The Stillbirth Collaborative Research Network conducted a prospective, case-control study of stillbirths and live births from 2006 to 2008. This analysis includes 512 stillbirths with cause of death assignment and a comparison group of live births. We compared exposures between women with stillbirth due to placental disease and those due to other causes as well as between women with term (≥ 37 weeks) stillbirth due to placental disease and term live births. RESULTS: A total of 121 (23.6%) out of 512 stillbirths had a probable or possible cause of death due to placental disease by Initial Causes of Fetal Death. Characteristics were similar between stillbirths due to placental disease and other stillbirths. When comparing term live births to stillbirths due to placental disease, women with non-Hispanic black race, Hispanic ethnicity, lack of insurance, or who were born outside of the United States had higher odds of stillbirth due to placental disease. Nulliparity and antenatal bleeding also increased risk of stillbirth due to placental disease. CONCLUSION: Multiple discrete exposures were associated with stillbirth caused by placental disease. The relationship between these factors and utility of surveillance warrants further study.

Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery.

OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10-4), accounted for linkage disequilibrium between markers. RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10-4) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant. CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.

Associations Between Features of Placental Morphology and Birth Weight in Dichorionic Twins.

Low birth weight is associated with perinatal and long-term morbidity and mortality, and may be a result of abnormal placental development and function. In studies of singletons, associations have been reported between features of placental morphology and birth weight. Evaluating similar associations within twin pairs offers a unique opportunity to control for key confounders shared within a twin pair, including gestational age, parental characteristics, and intrauterine environment. Data from 3 studies in the United States that were completed from 2012 to 2013, 2006 to 2008, and 1959 to 1966 were used in our analysis of 208 sets of dichorionic twins with unfused placentas. We used linear regression to model difference in birth weight within a twin pair as a function of differences in placental characteristics (i.e., thickness, 2-dimensional surface area, intraplacental difference in diameter). After controlling for sex discordance, a 75.3- cm2 difference in placental surface area, which reflects the interquartile range, was associated with a difference in birth weight of 142.1 g (95% confidence interval (CI): 62.9, 221.3). The magnitude of the association also may be larger for same-sex male pairs than same-sex female pairs (males: 265.8 g, 95% CI: 60.8, 470.8; females: 133.0 g, 95% CI: 15.7, 250.3). Strong associations between surface area and birth weight are consistent with reported results for singleton pregnancies.

The association of stillbirth with placental abnormalities in growth-restricted and normally grown fetuses.

BACKGROUND: Stillbirth, defined as foetal death ≥20 weeks' gestation, is associated with poor foetal growth and is often attributed to placental abnormalities, which are also associated with poor foetal growth. Evaluating inter-relationships between placental abnormalities, poor foetal growth, and stillbirth may improve our understanding of the underlying mechanisms for some causes of stillbirth. OBJECTIVE: Our primary objective was to determine whether poor foetal growth, operationalised as small for gestational age (SGA), mediates the relationship between placental abnormalities and stillbirth. METHODS: We used data from the Stillbirth Collaborative Research Network study, a population-based case-control study conducted from 2006-2008. Our analysis included 266 stillbirths and 1135 livebirths. We evaluated associations of stillbirth with five types of placental characteristics (developmental disorders, maternal and foetal inflammatory responses, and maternal and foetal circulatory disorders) and examined mediation of these relationships by SGA. We also assessed exposure-mediator interaction. Models were adjusted for maternal age, race/ethnicity, education, body mass index, parity, and smoking status. RESULTS: All five placental abnormalities were more prevalent in cases than controls. After adjustment for potential confounders, maternal inflammatory response (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.77, 3.75), maternal circulatory disorders OR 4.14, 95% CI 2.93, 5.84, and foetal circulatory disorders OR 4.58, 95% CI 3.11, 6.74 were strongly associated with stillbirth, and the relationships did not appear to be mediated by SGA status. Associations for developmental disorders and foetal inflammatory response diverged for SGA and non-SGA births, and strong associations were only observed when SGA was not present. CONCLUSIONS: Foetal growth did not mediate the relationships between placental abnormalities and stillbirth. The relationships of stillbirth with maternal and foetal circulatory disorders and maternal inflammatory response appear to be independent of poor foetal growth, while developmental disorders and foetal inflammatory response likely interact with foetal growth to affect stillbirth risk.

Associations Between the Features of Gross Placental Morphology and Birthweight.

The placenta plays a critical role in regulating fetal growth. Recent studies suggest that there may be sex-specific differences in placental development. The purpose of our study was to evaluate the associations between birthweight and placental morphology in models adjusted for covariates and to assess sex-specific differences in these associations. We analyzed data from the Stillbirth Collaborative Research Network's population-based case-control study conducted between 2006 and 2008, which recruited cases of stillbirth and population-based controls in 5 states. Our analysis was restricted to singleton live births with a placental examination (n = 1229). Characteristics of placental morphology evaluated include thickness, surface area, difference in diameters, shape, and umbilical cord insertion site. We used linear regression to model birthweight as a function of placental morphology and covariates. Surface area had the greatest association with birthweight; a reduction in surface area of 83 cm2, which reflects the interquartile range, is associated with a 260.2-g reduction in birthweight (95% confidence interval, -299.9 to -220.6), after adjustment for other features of placental morphology and covariates. Reduced placental thickness was also associated with lower birthweight. These associations did not differ between males and females. Our results suggest that reduced placental thickness and surface area are independently associated with lower birthweight and that these relationships are not related to sex.

The association between gestational weight gain z-score and stillbirth: a case-control study.

BACKGROUND: There is limited information on potentially modifiable risk factors for stillbirth, such as gestational weight gain (GWG). Our purpose was to explore the association between GWG and stillbirth using the GWG z-score. METHODS: We analyzed 479 stillbirths and 1601 live births from the Stillbirth Collaborative Research Network case-control study. Women with triplets or monochorionic twins were excluded from analysis. We evaluated the association between GWG z-score (modeled as a restricted cubic spline with knots at the 5th, 50th, and 95th percentiles) and stillbirth using multivariable logistic regression with generalized estimating equations, adjusting for pre - pregnancy body mass index (BMI) and other confounders. In addition, we conducted analyses stratified by pre - pregnancy BMI category (normal weight, overweight, obese). RESULTS: Mean GWG was 18.95 (SD 17.6) lb. among mothers of stillbirths and 30.89 (SD 13.3) lb. among mothers of live births; mean GWG z-score was - 0.39 (SD 1.5) among mothers of cases and - 0.17 (SD 0.9) among control mothers. In adjusted analyses, the odds of stillbirth were elevated for women with very low GWG z-scores (e.g., adjusted odds ratio (aOR) and 95% Confidence Interval (CI) for z-score - 1.5 SD versus 0 SD: 1.52 (1.30, 1.78); aOR (95% CI) for z-score - 2.5 SD versus 0 SD: 2.36 (1.74, 3.20)). Results differed slightly by pre - pregnancy BMI. The odds of stillbirth were slightly elevated among women with overweight BMI and GWG z-scores ≥1 SD (e.g., aOR (95% CI) for z-score of 1.5 SD versus 0 SD: 1.84 (0.97, 3.50)). CONCLUSIONS: GWG z-scores below - 1.5 SD are associated with increased odds of stillbirth.