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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.). [ABSTRACT FROM AUTHOR]

Objective: Suboptimal prenatal care is linked to increased risk of stillbirth, but this association is not well-understood. The study objective was to evaluate the relationship between prenatal visit adherence and cause of death in stillbirths., Study Design: This is a secondary analysis from the Stillbirth Collaborative Research Network of data with complete cause of death evaluation. Appropriateness of prenatal visit frequency was determined per American College of Obstetricians and Gynecologists/American Academy of Pediatrics (ACOG/AAP) recommendations and the novel Michigan Plan for Appropriately Tailored Healthcare in Pregnancy (MiPATH) guidelines. Multivariate regression controlled for differences between groups., Results: Among 451 stillbirths included, 63.6% and 55.9% were non-adherent to ACOG/AAP and MiPATH recommendations, respectively. Non-adherent parturients according to the Michigan plan were more likely to have a stillbirth due to hypertensive disorders of pregnancy., Conclusion: Non-adherence to prenatal visit guidelines is associated with higher risk of stillbirth due to hypertensive disorders of pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective:  Adverse pregnancy outcomes, including preterm birth and preeclampsia, are associated with worse cardiovascular outcomes for offspring. Examination of the placenta is important for understanding how the prenatal period shapes long-term cardiovascular health. We sought to investigate the association between placental vascular malperfusion and fetal cardiac structure., Study Design:  Data obtained from the Stillbirth Collaborative Research Network included stillbirths with placental pathology and autopsy. Stillbirths were classified in two ways: based on the severity of placental maternal vascular malperfusion (MVM) and based on the cause of death (MVM, fetal vascular malperfusion [FVM], or acute infection/controls). Organ weight and heart measures were standardized by gestational age (GA) and compared across groups., Results:  We included 329 stillbirths in the analysis by MVM severity and 76 in the analysis by cause of death (COD). While z -scores for most organ weights/heart measures were smaller when COD was attributed to MVM as compared with FVM or controls, heart weight and brain weight z -scores did not differ by COD ( p  > 0.05). In analyses accounting for body size, the difference between heart and body weight z-score was -0.05 (standard deviation [SD]: 0.53) among those with MVM as a COD and -0.20 (SD: 0.95) among those with severe MVM. Right and left ventricle thicknesses and tricuspid, pulmonary, mitral, and aortic valve circumferences were consistently as expected or larger than expected for GA and body weight. In the analysis investigating the severity of MVM, those with the most severe MVM had heart measures that were as expected or larger than expected for body weight while those with only mild to moderate MVM had heart measures that were generally small relative to body weight., Conclusion:  When assessed as COD or based on severity, MVM was associated with heart measures that were as expected or larger than expected for GA and body weight, indicating possible heart sparing., Key Points: · Fetal deaths with MVM show smaller organ weights.. · Heart weight sparing is seen with fetal death attributed to MVM.. · Heart weight sparing is more pronounced with severe MVM.., Competing Interests: None declared., (Thieme. All rights reserved.)

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 [28-33 6/7  weeks], late PTSB [34-36 6/7  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., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2023 John Wiley & Sons Ltd.)

Background: Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR)., Methods: Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF)., Results: 𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7-0.85 ng/mL (p = 0.005, 95% CI 0.635, 3.636; predicting CPR of 88.9%). The optimal range for peak P in regard to pregnancy outcome was 0.15-1.349 ng/mL (p = 0.01; 95% CI for coefficient in model 0.48-3.570). A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P (p = 0.010, 95% CI 0.035, 0.256) and smallest 𝚫P (p = 0.012, 95% CI 0.030, 0.243) during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3-0.4 [75.6% vs. 62.5% within and outside of the range, respectively, (p = 0.023, 95% CI 0.119, 1.618)]. Highest LBRs were seen within the range of 0.3-0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% (p = 0.010, 95% CI 0.176, 1.311)]., Conclusions: Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles., (© 2023. The Author(s).)

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.

In this study, 104 RIL (Recombinant Inbred Pepper Lines: F6) populations which generated by selfing Capsicum annuum (Long pepper) × Capsicum frutescens (PI281420) F6 population were characterized in terms of detailed bioactive properties, major phenolic composition, tocopherol and capsaicinoid profile. Total phenolics, flavonoid and total anthocyanin contents of the red pepper lines were in the range of 7.06-17.15 mg gallic acid equivalent (GAE)/g dw, 1.10-5.46 mg catechin equivalent (CE)/g dw and 7.9-516.6 mg/kg dw extract, respectively. Antiradical activity and antioxidant capacity values also ranged between 18.99 and 49.73% and 6.97-16.47 mg ascorbic acid equivalent (AAE)/kg dw, respectively. Capsaicin and dihydrocapsaicin levels showed a wide variance with the range of 27.9-1405.9 and 12.3-640.4 mg/100 g dw, respectively. Scoville heat unit revealed that the 95% of the peppers were highly pungent. The major tocopherol was alpha tocopherol for the pepper samples with the highest level of 1078.4 µg/g dw. The major phenolics were detected as p-coumaric acid, ferulic acid, myricetin, luteolin and quercetin. Pepper genotypes showed significant differences in terms of the characterized properties and principal component analysis was applied successfully to reveal the similar genotypes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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., Competing Interests: Declaration of competing interest The authors have no financial or other conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

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., (© 2022 John Wiley & Sons Ltd.)

Background: Zinc (Zn) deficiency is a widespread problem in reducing the yield and quality of crop plants worldwide. It is important to utilize molecular markers linked to Zn efficiency to develop high Zn efficient cultivars in pepper (Capsicum annuum L.)., Methods and Results: In present study, genetic map was constructed using a F 2 populations derived from C. annuum L. (Alata 21A) × C. frutescens L. (PI 281420) cross. The quantitative trait locus (QTLs) for Zn efficiency were mapped using F 2:3 population. A genetic map with 929.6 cM in length and 12 linkage groups were obtained using 62 markers (31 sequence-related amplified polymorphism (SRAP), 19 simple sequence repeat (SSR) and 11 random amplified polymorphic DNA (RAPD) markers). The 41 linked QTLs related with nine (9) Zn efficiency characters were mapped on linkage groups. Results suggest that selecting plants for tolerance to Zn deficiency are expected to be rather responsive among segregating populations for breeding and developing Zn efficient genotypes in pepper., Conclusions: The molecular markers are expected to aid selection and expedite breeding peppers resistant to Zn deficiency in soils low for available Zn contents., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

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.., Competing Interests: The authors do not have any conflicts of interest to report related to the submitted work. R.M.S. reports that he is a consultant to Gestvision. M.C.S. reports that she is a medical consultant to Gilead Science Inc. Each author has indicated that he/she has met the journal's requirements for authorship. M.C.S. reports personal fees from Gilead Science Inc, from null, outside the submitted work. R.M.S. reports personal fees from Gestvision, from null, outside the submitted work., (Thieme. All rights reserved.)

Objective: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth., Design: Secondary analysis of a case-control study., Setting: Multicentre study of five geographic catchment areas in the USA., Population: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls., Main Outcome Measures: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth., Results: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 μmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 μmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 μmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes., Conclusions: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth., Tweetable Abstract: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes., (© 2021 John Wiley & Sons Ltd.)

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., (© 2022. The Author(s).)

Objective: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth., Design: Secondary analysis of a prospective, case-control study., Setting: Multicentre, 59 hospitals in five regional catchment areas in the USA., Population or Sample: All stillbirths and representative live birth controls., Methods: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births., Main Outcome Measures: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent., Results: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems., Conclusions: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race., Tweetable Abstract: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen., (© 2020 John Wiley & Sons Ltd.)

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.

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.

The root nodules are a unique environment formed on legume roots through a highly specific symbiotic relationship between leguminous plants and nodule-inducing bacteria. Previously, Rhizobia were presumed to be the only group of bacteria residing within nodules. However, recent studies discovered diverse groups of bacteria within the legume nodules. In this report soybean nodule-associated bacteria were studied in an effort to identify beneficial bacteria for plant disease control and growth promotion. Analysis of surface-sterilized single nodules showed bacterial diversity of the nodule microbiome. Five hundred non-rhizobial colonies from 10 nodules, 50 colonies per nodule, were tested individually against the tomato wilt causing bacterial pathogen Clavibacter michiganensis subsp. michiganensis (Cmm) for inhibition of pathogen growth. From the initial screening, 54 isolates were selected based on significant growth inhibition of Cmm. These isolates were further tested in vitro on another bacterial pathogen Pseudomonas syringae pv. tomato (Pst) and two fungal pathogens Rhizoctonia solani and Sclerotinia sclerotiorum . Bacterial metabolites were extracted from 15 selected isolates with ethanol and tested against pathogen Cmm and Pst. These isolates were identified by using MALDI-TOF mass spectrometry and 16S rRNA gene sequencing. Pseudomonas spp. were the dominant soybean nodule-associated non-rhizobial bacterial group. Several isolates imparted significant protection against pathogens and/or plant growth promotion on tomato seedlings. The most promising nodule-associated bacterial isolate that suppressed both Cmm and Pst in vitro and Pst in tomato seedlings was identified as a Proteus species. Isolation and identification of beneficial nodule-associated bacteria established the foundation for further exploration of potential nodule-associated bacteria for plant protection and growth promotion.

Uterine leiomyomas, also known as fibroids or myomas, are a common benign gynecologic tumor found in women of reproductive age. Though advances have been made in understanding leiomyomas, the etiology and pathogenesis of this disease are not fully characterized. Current evidence supports a role of putative human uterine stem/progenitor cells in the onset of uterine disease such as uterine myomas. In this study, we report that increased expression of CXCL12 in leiomyomas recruits bone marrow-derived cells (BMDCs) that may contribute to leiomyoma growth. Tissue was collected from leiomyomas or control myometrium from women with or without leiomyomas. qRT-PCR analysis showed increased expression of CXCL12 and decreased CXCR4 expression in the leiomyoma and myometrium of women with leiomyoma compared with normal myometrium. Increased CXCL12 protein secretion from cultured myoma cells was confirmed by ELISA. Further, we found that BMDCs migration was increased toward leiomyoma conditioned medium compared with conditioned medium from normal myometrium. CXCR4 antagonist AMD3100 completely blocked this migration. Engraftment of BMDCs significantly increased in myoma of mouse uteri treated with CXCL12 compared with placebo. We conclude that CXCL12 may play a role in leiomyomas growth by attracting bone marrow-derived cells to leiomyoma. Therefore, CXCL12 and its receptors are novel targets for leiomyoma therapy.

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., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.

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.

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., (© 2019 John Wiley & Sons Ltd.)

Placental surface area is often estimated using diameter measurements. However, as many placentas are not elliptical, we were interested in the validity of these estimates. We compared placental surface area from images for 491 singletons from the Stillbirth Collaborative Research Network (SCRN) Study (416 live births, 75 stillbirths) to estimates obtained using diameter measurements. Placental images and diameters were obtained from pathologic assessments conducted for the SCRN Study and images were analyzed using ImageJ software. On average, diameter-based measures underestimated surface area by -5.58% (95% confidence interval: -30.23, 19.07); results were consistent for normal and abnormal shapes. The association between surface area and birthweight was similar for both measures. Thus, diameter-based surface area can be used to estimate placental surface area., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7-dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths., Study Design: Prospective, multicenter, population-based case-control study of all stillbirths and a representative sample of live births enrolled in five geographic areas. Cases with stillbirth due to obstetric complications, infection, or aneuploidy, and those with poor quality deoxyribonucleic acid (DNA) were excluded. DNA was extracted from placental tissue stored at -80°C, and exons 3 to 9 of the DCHR7 gene were amplified, purified, and subjected to bidirectional sequencing to identify mutations., Results: One-hundred forty four stillbirths were unexplained and had adequate DNA for analysis. Nine stillbirths of 139 (6.5%) had a single mutation in one allele in coding exons 3 to 9 of DHCR7 (Table 1). One case (0.7%) was a compound heterozygote for mutations in exons 3 to 9 of DHCR7; this fetus had no clinical or histologic features of SLOS., Conclusion: We detected SLOS mutations in only 0.7% of stillbirths. This does not support a strong association between unrecognized DHCR7 mutations and stillbirth., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Participation in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) has been associated with lower risk of stillbirth. We hypothesized that such an association would differ by race/ethnicity because of factors associated with WIC participation that confound the association., Methods: We conducted a secondary analysis of the Stillbirth Collaborative Research Network's population-based case-control study of stillbirths and live-born controls, enrolled at delivery between March 2006 and September 2008. Weighting accounted for study design and differential consent. Five nested models using multivariable logistic regression examined whether the WIC participation/stillbirth associations were attenuated after sequential adjustment for sociodemographic, health, healthcare, socioeconomic, and behavioral factors. Models also included an interaction term for race/ethnicity x WIC., Results: In the final model, WIC participation was associated with lower adjusted odds (aOR) of stillbirth among non-Hispanic Black women (aOR: 0.34; 95% CI 0.16, 0.72) but not among non-Hispanic White (aOR: 1.69; 95% CI: 0.89, 3.20) or Hispanic women (aOR: 0.91; 95% CI 0.52, 1.52)., Conclusions: Contrary to our hypotheses, control for potential confounding factors did not explain disparate findings by race/ethnicity. Rather, WIC may be most beneficial to women with the greatest risk factors for stillbirth. WIC-eligible, higher-risk women who do not participate may be missing the potential health associated benefits afforded by WIC.

Objective: To estimate the proportion of potentially preventable stillbirths in the United States., Methods: We conducted a secondary analysis of 512 stillbirths with complete evaluation enrolled in the Stillbirth Collaborative Research Network from 2006 to 2008. The Stillbirth Collaborative Research Network was a multisite, geographically, racially, and ethnically diverse, population-based case-control study of stillbirth in the United States. Cases of stillbirth underwent standard evaluation that included maternal interview, medical record abstraction, biospecimen collection, postmortem examination, placental pathology, and clinically recommended evaluation. Each stillbirth was assigned probable and possible causes of death using the Initial Causes of Fetal Death algorithm system. For this analysis, we defined potentially preventable stillbirths as those occurring in nonanomalous fetuses, 24 weeks of gestation or greater, and weighing 500 g or greater that were 1) intrapartum, 2) the result of medical complications, 3) the result of placental insufficiency, 4) multiple gestation (excluding twin-twin transfusion), 5) the result of spontaneous preterm birth, or 6) the result of hypertensive disorders of pregnancy., Results: Of the 512 stillbirths included in our cohort, causes of potentially preventable stillbirth included placental insufficiency (65 [12.7%]), medical complications of pregnancy (31 [6.1%]), hypertensive disorders of pregnancy (20 [3.9%]), preterm labor (16 [3.1%]), intrapartum (nine [1.8%]), and multiple gestations (four [0.8%]). Twenty-seven stillbirths fit two or more categories, leaving 114 (22.3%) potentially preventable stillbirths., Conclusion: Based on our definition, almost one fourth of stillbirths are potentially preventable. Given the predominance of placental insufficiency among stillbirths, identification and management of placental insufficiency may have the most immediate effect on stillbirth reduction.

Background: Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth., Methods and Findings: Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births., Conclusions: The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

Pregnancy results in alterations in coagulation processes, which may increase the risk of thrombosis. Inherited thrombophilia mutations may further increase this risk, possibly through alterations in the placenta, which may result in pregnancy complications such as poor fetal growth. The purpose of our study is to evaluate the association of fetal growth, approximated by birth weight for gestational age percentile, with genetic markers of thrombophilia and placental characteristics related to vascular malperfusion. We analyzed data from the Stillbirth Collaborative Research Network's population-based case-control study conducted in 2006-2008. Study recruitment occurred in five states: Rhode Island and counties in Massachusetts, Georgia, Texas, and Utah. The analysis was restricted to singleton, nonanomalous live births ≤42 weeks' gestation with a complete placental examination and successful testing for ≥1 thrombophilia marker (858 mothers, 902 infants). Data were weighted to account for oversampling, differential consent, and availability of placental examination. We evaluated five thrombophilia markers: factor V Leiden, factor II prothrombin, methylenetetrahydrofolate reductase A1298C and C677T, and plasminogen activator inhibitor type 1 in both maternal blood and placenta/cord blood. We modeled maternal and fetal thrombophilia markers separately using linear regression. Maternal factor V Leiden mutation was associated with a 13.16-point decrease in adjusted birth weight percentile (95% confidence interval: -25.50, -0.82). Adjustment for placental abnormalities related to vascular malperfusion did not affect the observed association. No other maternal or fetal thrombophilia markers were significantly associated with birth weight percentile. Maternal factor V Leiden may be associated with fetal growth independent of placental characteristics.

Objective: To estimate the usefulness of each diagnostic test in the work-up for potential causes of stillbirth., Methods: A secondary analysis of 512 stillbirths enrolled in the Stillbirth Collaborative Research Network from 2006 to 2008 was performed. The Stillbirth Collaborative Research Network was a multisite, geographically, racially, and ethnically diverse, population-based study of stillbirth in the United States. Participants underwent standardized evaluations that included maternal interview, medical record abstraction, biospecimen collection, fetal autopsy, and placental pathology. Also, most participants had a clinical work-up that included karyotype, toxicology screen, syphilis serology, antibody screen, fetal-maternal hemorrhage testing, and testing for antiphospholipid antibodies as well as testing performed on biospecimens for research purposes. Previously, each participant had been assigned probable and possible causes of death using the Initial Causes of Fetal Death classification system. In this analysis, tests were considered useful if a positive result established (or helped to establish) this cause of death or a negative result excluded a cause of death that was suspected based on the clinical history or other results., Results: The usefulness of each test was as follows: placental pathology 64.6% (95% confidence interval [CI] 57.9-72.0), fetal autopsy 42.4% (95% CI 36.9-48.4), genetic testing 11.9% (95% CI 9.1-15.3), testing for antiphospholipid antibodies 11.1% (95% CI 8.4-14.4), fetal-maternal hemorrhage 6.4% (95% CI 4.4-9.1), glucose screen 1.6% (95% CI 0.7-3.1), parvovirus 0.4% (95% CI 0.0-1.4), and syphilis 0.2% (95% CI 0.0-1.1). The utility of the tests varied by clinical presentation, suggesting a customized approach for each patient., Conclusion: The most useful tests were placental pathology and fetal autopsy followed by genetic testing and testing for antiphospholipid antibodies.

Aim: Flow diverter (FD) stents have been used in the treatment of unruptured intracranial aneurysms. There are a few studies that report the use of these devices in ruptured blister-like aneurysms. We present 5 consecutive patients, who had ruptured intracranial wide necked or side branch close to the neck of saccular aneurysms, with no other treatment options, treated with FD stents and coil embolization., Material and Methods: Between September 2012 and April 2015, 139 ruptured aneurysms of 133 consequent patients were treated. Of these, 48 were surgically treated aneurysms. Five of the remaining 85 aneurysms treated with FD stents. Three aneurysms were in the posterior communicating artery, and 2 were in the supraclinoid internal carotid artery (ICA). Partial coil embolization was performed in addition to FD stents in three patients. All patients were treated in the first 3 days after bleeding., Results: Technical success was 100%. Inappropriate deployment of silk stent and partial thrombus formation occurred in one patient due to the jailed micro-catheter. Inappropriate apposition of stent was corrected with a balloon, and the thrombus resolved with tirofiban, tissue plasminogen activator (t-PA) injections. No other complication or death occurred related to the procedure. One patient who had a giant ICA aneurysm and Fisher grade 4 bleeding died due to vasospasm, cerebral edema and sepsis on the postoperative 13 < sup > th < /sup > day. The other patients were followed-up uneventfully with computed tomography angiography (CTA) at 6th month and digital subtraction angiography (DSA) at 12 < sup > th < /sup > month., Conclusion: FD stents can be used in the treatment of ruptured large wide necked or side branch close to the neck of saccular aneurysms when other treatment options can not be used.

Introduction . To investigate whether maternal oral flora might be involved in intrauterine infection and subsequent stillbirth or neonatal death and could therefore be detected in fetal and neonatal postmortem bacterial cultures. Methods . This retrospective study of postmortem examinations from 1/1/2000 to 12/31/2010 was searched for bacterial cultures positive for common oral flora from heart blood or lung tissue. Maternal age, gestational age, age at neonatal death, and placental and fetal/neonatal histopathological findings were collected. Results . During the study period 1197 postmortem examinations (861 stillbirths and 336 neonatal deaths) were performed in our hospital with gestational ages ranging from 13 to 40+ weeks. Cultures positive for oral flora were identified in 24 autopsies including 20 pure and 8 mixed growths (26/227, 11.5%), found in 16 stillbirths and 8 neonates. Microscopic examinations of these 16 stillbirths revealed 8 with features of infection and inflammation in fetus and placenta. The 7 neonatal deaths within 72 hours after birth grew 6 pure isolates and 1 mixed, and 6 correlated with fetal and placental inflammation. Conclusions . Pure isolates of oral flora with histological evidence of inflammation/infection in the placenta and fetus or infant suggest a strong association between maternal periodontal conditions and perinatal death., Competing Interests: The authors report no conflict of interests.

Aim: The brain venous drainage dominance is generally divided into three groups; right or left dominance and co-dominance. There is no study in the literature examining the link between brain venous drainage and aneurysm formation or rupture. Our aim was to evaluate the association between venous dominancy, aneurysm formation and rupture., Material and Methods: Eighty-six patients, who underwent cerebral digital subtraction angiography and who had cerebral aneurysms, were included in the study. The angiographic images, patient charts, and tomography images were scanned retrospectively. We recorded the aneurysm"s location, size, dome to neck ratio (D/N); the patient"s gender, age, whether there was a ruptured aneurysm, smoking history, and/or hypertension; dominance of venous drainage, aneurysm side, Fisher scores and the World Federation of Neurosurgical Societies (WFNS) Grading System for Subarachnoid Hemorrhage scores for patients who had a ruptured aneurysm. We assessed whether or not venous drainage was associated with rupture of the aneurysm and if venous dominance was a predisposing factor for aneurysm formation like location, size, and hypertension., Results: There was a statistically significant association between venous dominance and side of aneurysm; and also a statistically significant association between venous dominance and rupture. There was a positive correlation between hypertension and rupture. The most common aneurysm location was the anterior communicating artery, followed by the middle cerebral artery., Conclusion: Brain venous drainage dominance may be a predisposing factor for aneurysm formation and it can be predictive for rupture.

Background: An evaluation for heritable thrombophilias is recommended in the evaluation of stillbirth. However, the association between thrombophilias and stillbirth remains uncertain., Objective: We sought to assess the association between maternal and fetal/placental heritable thrombophilias and stillbirth in a population-based, case-control study in a geographically, racially, and ethnically diverse population., Study Design: We conducted secondary analysis of data from the Stillbirth Collaborative Research Network, a population-based case-control study of stillbirth. Testing for factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase C677T and A1298C, and plasminogen activating inhibitor (PAI)-1 4G/5G mutations was done on maternal and fetal (or placental) DNA from singleton pregnancies. Data analyses were weighted for oversampling and other aspects of the design. Odds ratios (OR) were generated from univariate models regressing stillbirth/live birth status on each thrombophilia marker., Results: Results were available for ≥1 marker in 488 stillbirths and 1342 live birth mothers and 405 stillbirths and 990 live birth fetuses. There was an increased odds of stillbirth for maternal homozygous factor V Leiden mutation (2/488; 0.4% vs 1/1380; 0.0046%; OR, 87.44; 95% confidence interval, 7.88-970.92). However, there were no significant differences in the odds of stillbirth for any other maternal thrombophilia, even after stratified analyses. Fetal 4G/4G PAI-1 (OR, 0.63; 95% confidence interval, 0.43-0.91) was associated with decreased odds of stillbirth. Other fetal thrombophilias were similar among groups., Conclusion: Most maternal and fetal thrombophilias were not associated with stillbirth. Maternal factor V Leiden was weakly associated with stillbirth, and the fetal PAI-1 4G/4G polymorphism was associated with live birth. Our data do not support routine testing for heritable thrombophilias as part of an evaluation for possible causes of stillbirth., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Stillbirth, preeclampsia, and gestational hypertension (PE/GH) have similar clinical risk factors and redundant placental pathology. We aim to discern if stillbirth with PE/GH has a particular phenotype by comparing stillbirths with and without PE/GH., Methods: Secondary analysis of the Stillbirth Collaborative Research Network, a population-based cohort study of all stillbirths and a sample of live births from 2006 to 2008 in five catchment areas. We compared placental pathology between stillbirths and with and without PE/GH, stratified by term or preterm. We also compared placental pathology between stillbirths and live births with PE/GH., Results: 79/518 stillbirths and 140/1200 live births had PE/GH. Amongst preterm stillbirths, there was higher feto-placental ratio in PE/GH pregnancies (OR 1.24 [1.11, 1.37] per unit increase), and there were more parenchymal infarctions (OR 5.77 [3.18, 10.47]). Among PE/GH pregnancies, stillbirths had increased maternal and fetal vascular lesions, including retroplacental hematoma, parenchymal infarction, fibrin deposition, fetal vascular thrombi, and avascular villi., Discussion: Stillbirth pregnancies are overwhelmingly associated with placental lesions. Parenchymal infarctions are more common in PE/GH preterm stillbirths, but there is significant overlap in lesions found in stillbirths and PE/GH., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose of Review: The objectives of the present review are to discuss the role of endometrial polyps in infertility and to analyze the evidence for hysteroscopic polypectomy prior to IVF., Recent Findings: Endometrial polyps are frequently found during routine workup for infertility and are known to negatively impact endometrial receptivity through various mechanisms. Overall, most studies to date point to a favorable effect of hysteroscopic polypectomy on subsequent fertility. A recent meta-analysis showed a four-fold increase in expected pregnancy rates following hysteroscopic polypectomy in women planning to undergo intrauterine insemination, and although there are no randomized controlled trials specifically addressing hysteroscopic polypectomy prior to IVF, several large studies suggest a beneficial effect of hysteroscopy both prior to initial IVF and after failed IVF as intrauterine abnormalities, mostly endometrial polyps, are found in a significant proportion of the infertile population. There may be an added benefit of hysteroscopy itself in facilitating subsequent embryo transfer via dilation of the cervix or by increasing endometrial receptivity through endometrial injury., Summary: Hysteroscopic polypectomy is a minimally invasive procedure with little risk of complication and therefore should be performed prior to IVF to optimize chances for successful implantation.

Endometriosis is a common gynecologic disorder that persists throughout the reproductive years. Although endometriosis is a surgical diagnosis, medical management with ovarian suppression remains the mainstay of long-term management with superimposed surgical intervention when needed. The goal of surgery should be excision or ablation of all visible disease to minimize risk of recurrence and need for repeat surgeries. When infertility is the presenting symptom, surgical therapy in addition to assisted reproductive technology can improve chances of conception; however, the treatment approach depends on stage of disease and other patient characteristics that affect fecundity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Virus diseases are among the key limiting factors that cause significant yield loss and continuously threaten crop production. Resistant cultivars coupled with pesticide application are commonly used to circumvent these threats. One of the limitations of the reliance on resistant cultivars is the inevitable breakdown of resistance due to the multitude of variable virus populations. Similarly, chemical applications to control virus transmitting insect vectors are costly to the farmers, cause adverse health and environmental consequences, and often result in the emergence of resistant vector strains. Thus, exploiting strategies that provide durable and broad-spectrum resistance over diverse environments are of paramount importance. The development of plant gene transfer systems has allowed for the introgression of alien genes into plant genomes for novel disease control strategies, thus providing a mechanism for broadening the genetic resources available to plant breeders. Genetic engineering offers various options for introducing transgenic virus resistance into crop plants to provide a wide range of resistance to viral pathogens. This review examines the current strategies of developing virus resistant transgenic plants., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Monochorionic-diamniotic twins are usually monozygotic twins and known to be associated with adverse obstetric and perinatal outcomes. Cases of discordant karyotype of monozygotic twins are rare and most involves sex chromosomes. We present the first case of monochorionic twins with discordant karyotype manifested as mosaic trisomy 14 in one twin (B) and a normal karyotype in the other (A). We describe the postmortem pathological and imaging findings of the trisomic twin and for the first time neuropathological findings of this entity. Metaphase chromosome analysis of twin B using fetal tissue showed a 47,XX, +14 karyotype. Chromosomal microarray analysis (CMA) using fetal tissue revealed 38% mosaicism. CMA with placental tissue from both sides demonstrated normal karyotype and confirmed monozygosity, highlighting the value of array based testing on diagnosing mosaicism and zygosity., (© 2014 Wiley Periodicals, Inc.)

Objective: We sought to compare bile acids in women with and without stillbirth in a population-based study., Study Design: The Stillbirth Collaborative Research Network conducted a multisite, population-based case-control study of stillbirth (fetal deaths ≥20 weeks). Maternal sera were obtained at the time of enrollment and frozen at -80°C until assay for bile acids., Results: Assays were performed in 581 women with stillbirth and 1546 women with live births. Bile acid levels were slightly higher in women with stillbirth (geometric mean [95% confidence interval {CI}] = 3.2 [3.0-3.5]) compared to live births (2.9 [2.7-3.1], P = .0327). However, the difference was not significant after adjustment for baseline risk factors for stillbirth. The proportion of women with elevated levels (≥10 or ≥40 μmol/L) was similar in stillbirths and live births. Results were similar when the analysis was limited to subsets of stillbirths and live births. In women with stillbirths not associated with fetal anomalies or obstetric complications bile acid levels were higher than in women with term live births (geometric mean [95% CI] = 3.4 [3.0-3.8] vs 2.9 [2.7-3.0], P = .0152, unadjusted; P = .06, adjusted). However, a similar proportion of women in both groups had levels ≥10 μmol/L (10.7 vs 7.2%; odds ratio [OR], 1.54; 95% CI, 0.97-2.44; adjusted OR, 1.29; 95% CI, 0.78-2.15) and ≥40 μmol/L (1.7 vs 0.7%; OR, 2.58; 95% CI, 0.85-7.84; adjusted OR, 2.28; 95% CI, 0.79-6.56)., Conclusion: Our data do not support testing for bile acids in cases of stillbirth in the absence of clinical evidence of intrahepatic cholestasis of pregnancy., (Copyright © 2014. Published by Mosby, Inc.)