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.

Copy number variants and fetal structural abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. SETTING: Multicenter, 59 hospitals in five geographic regions in the USA. POPULATION: 388 stillbirth cases of the SCRN study (2006-2008). METHODS: Fetal structural malformations were grouped by anatomic system and specific malformation type (e.g. central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNVs >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-square test. RESULTS: The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs than among those with normal CNVs (47.5 versus 19.1%; P-value <0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by hydrops, craniofacial defects and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g. CHD1L) and a duplication of 21q22.13 involving four genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. CONCLUSION: Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counselling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Macroscopic lesions of maternal and fetal vascular malperfusion in stillborn placentas: Diagnosis in the absence of microscopic histopathological examination.

INTRODUCTION: Lesions of maternal vascular malperfusion (MVM) and fetal vascular malperfusion (FVM) are common in placentas associated with both stillbirth and live birth. The objective of this study was to identify lesions present more commonly in stillborn placentas and those most indicative of MVM and FVM without microscopic pathologic evaluation. METHODS: Data were derived from the Stillbirth Collaborative Research Network. Lesions were identified according to standard protocols published previously and categorized as either MVM or FVM according to the Amsterdam Placental Workshop Group Consensus Statement and macroscopic "umbilical cord at risk" findings. Multivariate logistic regression was used to determine the odds of stillbirth with macroscopic findings of MVM or FVM. RESULTS: 595 stillbirths and 1,305 live births were analyzed. FVM lesions (85.2%) were marginally more common (though not statistically different) in stillbirths compared to MVM lesions (81.3%). Macroscopic findings of both MVM and FVM were more common in stillbirths versus livebirths (p < 0.001). Odds ratios of macroscopic MVM and FVM lesions for stillbirth, adjusted for gestational age at delivery, maternal race (minority), ethnicity (Hispanic), age, and history of hypertension or diabetes, were 1.48 (95% CI 1.30-1.69) and 1.34 (95% CI 1.18-1.53), respectively. DISCUSSION: Macroscopic features of MVM and FVM are associated with higher odds of stillbirth versus live birth even when controlled for gestational age and maternal factors, which may be a useful clue in determining the pathophysiology of these events. This information is also useful for pathologists when microscopic examination is not available.

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.

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.

Placental lesions associated with stillbirth by gestational age, according to feature importance: Results from the stillbirth collaborative research network.

INTRODUCTION: Previous studies have identified lesions commonly found in placentas associated with stillbirth but have not distinguished across a range of gestational ages (GAs). The objective of this study was to identify lesions associated with stillbirths at different GAs by adapting methods from the chemical machine learning field to assign lesion importance based on correlation with GA. METHODS: Placentas from the Stillbirth Collaborative Research Network were examined according to standard protocols. GAs at stillbirth were categorized as: <28 weeks (extreme preterm stillbirth [PTSB]), 28-33'6 weeks (early PTSB), 34-36'6 weeks (late PTSB), ≥37 weeks (term stillbirth). We identified and ranked the most discriminating placental features, as well as those that were similar across GA ranges, using Kernel Principal Covariates Regression (KPCovR). RESULTS: These analyses included 210 (47.2%) extreme PTSB, 85 (19.1%) early PTSB, 62 (13.9%) late PTSB, and 88 (19.8%) term stillbirths. When we compute the KPCovR, the first principal covariate indicates that there are four lesions (acute funisitis & nucleated fetal red blood cells found in extreme PTSB; multifocal reactive amniocytes & multifocal meconium found in term stillbirth) that distinguish GA ranges among all stillbirths. DISCUSSION: There are distinct placental lesions present across GA ranges in stillbirths; these lesions are identifiable using sophisticated feature selection. Further investigation may identify histologic changes across gestations that relate to fetal mortality.

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.

Ipsilateral chondral lesions worsen the long-term prognosis following arthroscopic partial medial meniscectomy.

PURPOSE: The effect of knee cartilage defects that are detected during partial meniscectomy remains controversial in terms of the long-term prognosis on knee function. This study aimed to investigate the effect of concurrent medial compartment focal cartilage lesions on the long-term prognosis of knee function in patients who underwent arthroscopic partial medial meniscectomy for traumatic medial meniscal tears. METHODS: This retrospective study analyzed 46 patients who underwent arthroscopic partial medial meniscectomy between 1991 and 2008 by a single surgeon. Twenty-one patients who underwent arthroscopic partial medial meniscectomy due to traumatic meniscal tear had focal chondral lesions only at the medial compartment, and these patients were assigned to group A. Twenty-five patients who had no cartilage lesions in any compartments were assigned to group B. The age, sex, body mass index (BMI), follow-up time, age at the time of surgery, clinical and radiological scores, and perioperative arthroscopy findings were analyzed. RESULTS: The mean follow-up time was 20 ± 3.7 years. No significant difference was found in the demographic data, and the average age of the patients at the time of operation was 35 ± 9.5 years. Both groups had improved Lysholm score at the last follow-up. Although no difference was found between the groups during the preoperative period, group B had a higher Lysholm score at the last follow-up than group A. The mean International Knee Documentation Committee (IKDC) and Knee injury and Osteoarthritis Outcome Score (KOOS) scores at the last follow-up were significantly higher in group B. The mean Kellgren-Lawrence grades in the operated knees of group A were higher than those of group B. In group A, a negative correlation was found between the BMI and postoperative Lysholm (r = - 0.461, p = 0.03) IKDC (r = - 0.433, p = 0.05) and KOOS (r = - 0.565, p = 0.008) scores. In group B, no correlation was found between BMI and any score. CONCLUSION: Among patients who underwent arthroscopic partial medial meniscectomy with an average follow-up of 20 years, those with concurrent focal cartilage defect in the medial compartment had clinically and radiologically worse outcomes than patients without any cartilage defect. Therefore, orthopedic surgeons should be meticulous before performing any arthroscopic partial medial meniscectomy in case of concurrent cartilage lesion. LEVEL OF EVIDENCE: Level III.

Intrauterine Fetal Demise Associated with Vascular Malperfusion and Multiple Uterine Leiomyomata: A Report of Two Cases.

BACKGROUND: Uterine leiomyomata have been loosely associated with intrauterine fetal demise (IUFD), largely attributed to fetal growth restriction from cavitary distortion. We present two cases of IUFD in patients with non-distorting leiomyomata and pathologic placental findings of maternal vascular malperfusion (MVM) and fetal vascular malperfusion (FVM). CASE REPORT: Case 1 details a 28w3d IUFD associated with large leiomyomata (largest 11.9 × 7.6 × 9.7 cm), post-partum deep vein thrombosis, and severe pre-eclampsia histologic features. Case 2 details a 25w2d IUFD associated with smaller leiomyomata (largest 3.1 × 3.0 × 3.3 cm). Both placentas demonstrated MVM, including parenchymal thrombi and accelerated villous maturity, and FVM, including avascular stem villi. DISCUSSION: As the placentas in both cases demonstrated findings consistent with altered placental perfusion, we posit that leiomyomata in these cases may have been associated with both maternal and fetal vascular malperfusion, ultimately contributing to fetal demise.

Holding a baby after stillbirth: the impact of fetal congenital and structural abnormalities.

OBJECTIVE: Stillbirth can result in numerous adverse psychosocial sequelae. Recommendations vary with regard to holding the baby after a stillbirth. Few studies have addressed the impact of fetal abnormalities on these outcomes. STUDY DESIGN: Analyses of singleton stillbirths within the Stillbirth Collaborative Research Network were conducted. Patient and stillbirth characteristics were compared between those who did and did not hold their baby. Results from psychometric surveys were compared between cases with and without visible fetal anomalies. RESULT: There were no significant differences between those who held and those who did not hold in any patient or stillborn characteristics. Visible fetal abnormalities were not associated with adverse psychological outcomes. CONCLUSION: Fetal abnormalities, including congenital and post-demise changes, do not differ between those who held and did not hold their baby after stillbirth. This suggests that patients should not be discouraged from holding their stillborn infant in the presence of visible abnormalities.

Copy number variants and placental abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of fetal/placental DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in pregnancies complicated by stillbirth. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. SETTING: Multicenter, 59 hospitals in five geographical regions in the USA. POPULATION: 387 stillbirth cases (2006-2008). METHODS: Using standard definitions, PPLs were categorised by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNV >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs compared between stillbirth cases with and without PPLs using the Wald Chi-square test. RESULTS: Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs than in those with normal CNVs (81.7% versus 64.2%; P = 0.008). The proportions of fetal vascular, maternal/fetal inflammatory and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs and those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several known genes. CONCLUSIONS: Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillbirth cases. The findings may provide insight into the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

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..

Heterotopic Nodules in the Placenta, an Immunohistochemical Re-evaluation of the Diagnosis of Adrenocortical Heterotopia.

BACKGROUND: Rare nodules of heterotopic adrenocortical and hepatic tissue are reported in the placenta. A mechanism for adrenocortical tissue in the placenta has been perplexing, while hepatic tissue is generally considered related to yolk sac primordia. The clear cell morphology of these nodules is similar to the adrenal cortex of the adult; however, the fetal adrenal gland does not usually display clear cells. METHODS: We stained 9 placental nodules, histologically identical to "adrenocortical" heterotopia of the placenta, to determine whether adrenocortical differentiation could be confirmed. These cases include 3 archival cases initially diagnosed as "adrenocortical" heterotopia. RESULTS: Immunohistochemical staining with steroid factor-1 (SF-1), HepPar-1, and Arginase-1 showed that these nodules of clear cells are actually hepatic (SF-1 negative, HepPar-1, and Arginase-1 positive). PAS staining suggests that glycogen accumulation is responsible for the clear cytoplasm. In contrast, a nodule of adrenocortical heterotopia near the testis and the adrenal gland from a 38-week-old neonatal autopsy case confirm SF-1 reactivity as expected. CONCLUSION: We propose that adrenocortical heterotopia in the placenta is a misnomer, and that these subchorionic nodules of clear cells demonstrate hepatic differentiation.

Characteristics of Stillbirths Associated With Diabetes in a Diverse U.S. Cohort.

OBJECTIVE: To characterize stillbirths associated with pregestational diabetes and gestational diabetes mellitus (GDM) in a large, prospective, U.S. case-control study. METHODS: A secondary analysis of stillbirths among patients enrolled in a prospective; multisite; geographically, racially, and ethnically diverse case-control study in the United States was performed. Singleton gestations with complete information regarding diabetes status and with a complete postmortem evaluation were included. A standard evaluation protocol for stillbirth cases included postmortem evaluation, placental pathology, clinical testing as performed at the discretion of the health care professional, and a recommended panel of tests. A potential cause of death was assigned to stillbirth cases using a standardized classification tool. Demographic and delivery characteristics among women with pregestational diabetes and GDM were compared with characteristics of women with no diabetes in pairwise comparisons using χ or two-sample t tests as appropriate. Sensitivity analysis was performed excluding pregnancies with genetic conditions or major fetal malformations. RESULTS: Of 455 stillbirth cases included in the primary analysis, women with stillbirth and diabetes were more likely to be older than 35 years and have a higher body mass index. They were also more likely to have a gestational hypertensive disorder than women without diabetes (28% vs 9.1%; P<.001). Women with pregestational diabetes had more large-for-gestational-age (LGA) neonates (26% vs 3.4%; P<.001). Stillbirths occurred more often at term in women with pregestational diabetes (36%) and those with GDM (52%). Maternal medical complications, including pregestational diabetes and others, were more often identified as a probable or possible cause of death among stillbirths with maternal diabetes (43% vs 4%, P<.001) as compared with stillbirths without diabetes. CONCLUSION: Compared with stillbirths in women with no diabetes, stillbirths among women with pregestational diabetes and GDM occur later in pregnancy and are associated with hypertensive disorders of pregnancy, maternal medical complications, and LGA.

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.).

Umbilical Cord Abnormalities and Stillbirth.

OBJECTIVE: Umbilical cord abnormalities are commonly cited as a cause of stillbirth, but details regarding these stillbirths are rare. Our objective was to characterize stillbirths associated with umbilical cord abnormalities using rigorous criteria and to examine associated risk factors. METHODS: The Stillbirth Collaborative Research Network conducted a case-control study of stillbirth and live births from 2006 to 2008. We analyzed stillbirths that underwent complete fetal and placental evaluations and cause of death analysis using the INCODE (Initial Causes of Fetal Death) classification system. Umbilical cord abnormality was defined as cord entrapment (defined as nuchal, body, shoulder cord accompanied by evidence of cord occlusion on pathologic examination); knots, torsions, or strictures with thrombi, or other obstruction by pathologic examination; cord prolapse; vasa previa; and compromised fetal microcirculation, which is defined as a histopathologic finding that represents objective evidence of vascular obstruction and can be used to indirectly confirm umbilical cord abnormalities when suspected as a cause for stillbirth. We compared demographic and clinical factors between women with stillbirths associated with umbilical cord abnormalities and those associated with other causes, as well as with live births. Secondarily, we analyzed the subset of pregnancies with a low umbilical cord index. RESULTS: Of 496 stillbirths with complete cause of death analysis by INCODE, 94 (19%, 95% CI 16-23%) were associated with umbilical cord abnormality. Forty-five (48%) had compromised fetal microcirculation, 27 (29%) had cord entrapment, 26 (27%) knots, torsions, or stricture, and five (5%) had cord prolapse. No cases of vasa previa occurred. With few exceptions, maternal characteristics were similar between umbilical cord abnormality stillbirths and non-umbilical cord abnormality stillbirths and between umbilical cord abnormality stillbirths and live births, including among a subanalysis of those with hypo-coiled umbilical cords. CONCLUSION: Umbilical cord abnormalities are an important risk factor for stillbirth, accounting for 19% of cases, even when using rigorous criteria. Few specific maternal and clinical characteristics were associated with risk.