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To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees.State-wide matched case-control study.Utah, United States.Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019.Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models.Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models.We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value 0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively.We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

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 5 geographic regions in the USA. POPULATION: 387 stillbirth cases (2006–2008). METHODS: Using standard definitions, PPLs were categorized by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb 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-squared 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 compared with those with normal CNVs (81.7% vs. 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 compared to 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. Findings may provide insight on the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

Fetal growth restriction (FGR) is a common clinical manifestation of placental insufficiency. As such, FGR is a risk factor for stillbirth. This association has been demonstrated in numerous studies but is prone to overestimation because of the possibility of prolonged in utero retention before the recognition of the fetal death. Stillbirth risk reduction by optimizing maternal medical conditions and exposures and appropriate antenatal testing and delivery timing are essential to pregnancies affected by FGR. It is important to evaluate stillbirths with FGR with fetal autopsy, placental pathology, genetic testing, and assessment of antiphospholipid antibodies and fetal-maternal hemorrhage.

Fetal growth restriction (FGR) is a common obstetric complication that predisposes to mortality across the lifespan. Women with a prior pregnancy affected by FGR have a 20% to 30% risk of recurrence, but effective preventive strategies are lacking. Pharmacologic interventions to prevent FGR are lacking. Low-dose aspirin may be somewhat effective, but low-molecular-weight heparin and sildenafil are not. Surveillance in a subsequent pregnancy may consist of serial ultrasonography with timing and frequency determined by the clinical severity in the index pregnancy. Once FGR is diagnosed, the principal management strategy consists of close surveillance and carefully timed delivery.

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

A systematic, effective stillbirth evaluation is important for identification of potential causes of fetal death. Knowledge of potential causes of fetal death facilitates emotional closure for patients and informs recurrence risk as well as future pregnancy management. The highest-yield components of a stillbirth evaluation for finding a cause of fetal death are fetal autopsy, placental pathology, and genetic testing. All patients should be offered these tests following a stillbirth. A clear plan for postpartum follow-up should be made with the patient in order to ensure ongoing support through the grief and recovery process.

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.This study aimed to assess the relationship between abnormal copy number variants and fetal growth abnormalities in stillbirths using chromosomal microarray.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 birthweight10th percentile and greater than the 90th percentile for gestational age, respectively.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.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.

Background: Pregnancy loss is the most common obstetric complication occurring in almost 30% of conceptions overall and in 12–14% of clinically recognized pregnancies. Pregnancy loss has strong genetic underpinnings, and despite this consensus, our understanding of its genetic causes remains limited. We conducted a systematic review of genetic factors in pregnancy loss to identify strategies to guide future research.Methods: To synthesize data from population-based association studies on genetics of pregnancy loss, we searched PubMed for relevant articles published between 01/01/2000-01/01/2020. We excluded review articles, case studies, studies with limited sample sizes to detect associations (N < 4), descriptive studies, commentaries, and studies with non-genetic etiologies. Studies were classified based on developmental periods in gestation to synthesize data across various developmental epochs.Results: Our search yielded 580 potential titles with 107 (18%) eligible after title/abstract review. Of these, 54 (50%) were selected for systematic review after full-text review. These studies examined either early pregnancy loss (n = 9 [17%]), pregnancy loss >20 weeks' gestation (n = 10 [18%]), recurrent pregnancy loss (n = 32 [59%]), unclassified pregnancy loss (n = 3 [4%]) as their primary outcomes. Multiple genetic pathways that are essential for embryonic/fetal survival as well as human development were identified.Conclusion: Several genetic pathways may play a role in pregnancy loss across developmental periods in gestation. Systematic evaluation of pregnancy loss across developmental epochs, utilizing whole genome sequencing in families may further elucidate causal genetic mechanisms and identify other pathways critical for embryonic/fetal survival.

Despite increasing emphasis on emergent brain-behavior patterns supporting language, cognitive, and socioemotional development in toddlerhood, methodologic challenges impede their characterization. Toddlers are notoriously difficult to engage in brain research, leaving a developmental window in which neural processes are understudied. Further, electroencephalography (EEG) and event-related potential paradigms at this age typically employ structured, experimental tasks that rarely reflect formative naturalistic interactions with caregivers. Here, we introduce and provide proof of concept for a new "Social EEG" paradigm, in which parent-toddler dyads interact naturally during EEG recording. Parents and toddlers sit at a table together and engage in different activities, such as book sharing or watching a movie. EEG is time locked to the video recording of their interaction. Offline, behavioral data are microcoded with mutually exclusive engagement state codes. From 216 sessions to date with 2- and 3-year-old toddlers and their parents, 72% of dyads successfully completed the full Social EEG paradigm, suggesting that it is possible to collect dual EEG from parents and toddlers during naturalistic interactions. In addition to providing naturalistic information about child neural development within the caregiving context, this paradigm holds promise for examination of emerging constructs such as brain-to-brain synchrony in parents and children.

Background We previously reported fetomaternal hemorrhage (FMH) in 1/9160 births, and only one neonatal death from FMH among 219,853 births. Recent reports indicate FMH is not uncommon among stillbirths. Consequently, we speculated we were missing cases among early neonatal deaths. We began a new FMH initiative to determine the current incidence. Methods We analyzed births from 2011 to 2020 where FMH was diagnosed. We also evaluated potential cases among neonates receiving an emergent transfusion just after birth, whose mothers were not tested for FMH. Results Among 297,403 births, 1375 mothers were tested for FMH (1/216 births). Fourteen percent tested positive (1/1599 births). Of those, we found 25 with clinical and laboratory evidence of FMH adversely affecting the neonate. Twenty-one received one or more emergency transfusions on the day of birth; all but two lived. We found 17 others who received an emergency transfusion on the day of birth where FMH was not tested for, but was likely; eight of those died. The 42 severe (proven + probable) cases equate to 1/7081 births. We judged that 10 of the 42 had an acute FMH, and in the others it likely had more than a day before birth. Conclusions We estimate that we fail to diagnose >40% of our severe FMH cases. Needed improvements include (1) education to request maternal FMH testing when neonates are born anemic, (2) education on false-negative FMH tests, and (3) improved FMH communications between neonatology, obstetrics, and blood bank.

Sleep plays a critical role in neural neurodevelopment. Hallmarks of sleep reflected in the electroencephalogram (EEG) during non-rapid eye movement (NREM) sleep are associated with learning processes, cognitive ability, memory, and motor functioning. Research in adults is well-established; however, the role of NREM sleep in childhood is less clear. Growing evidence suggests the importance of two NREM sleep features: slow wave activity and sleep spindles. These features may be critical for understanding maturational change and the functional role of sleep during development. Here, we review the literature on NREM sleep from infancy to preadolescence to provide insight into the network dynamics of the developing brain. The reviewed findings show distinct relations between topographical and maturational aspects of slow waves and sleep spindles; however, the direction and consistency of these relationships vary, and associations with cognitive ability remain unclear. Future research investigating the role of NREM sleep and development would benefit from longitudinal approaches, increased control for circadian and homeostatic influences, and in early childhood, studies recording daytime naps and overnight sleep to yield increased precision for detecting age-related change. Such evidence could help explicate the role of NREM sleep and provide putative physiological markers of neurodevelopment.

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

The placenta is a remarkable organ that coordinates and regulates maternal-fetal interactions during pregnancy to optimize fetal development. A host of obstetric complications are associated with placental dysfunction, and existing methods for evaluating in vivo placental function fail to reliably detect at-risk pregnancies prior to maternal or fetal morbidity. Although routinely used as a monitoring tool, the predictive power of ultrasound for identifying compromised pregnancies is poor. Recent preclinical studies performed in our laboratory, using blood oxygen-level dependent magnetic resonance imaging (BOLD-MRI) in the pregnant nonhuman primate (NHP), established a strong correlation between placental T2* values and maternal-fetal oxygen transport. Here we extend this work to a large, longitudinal, two-site study of quantitative in vivo T2* mapping in human pregnancies across 11 to 38 weeks of gestation to characterize the evolution of placental oxygenation in uncomplicated pregnancies and to elucidate the relationship between aberrant placental T2* and adverse obstetric outcomes attributable to placental dysfunction. This methodology has high discriminatory power and strong potential diagnostic utility.

ImportancePregnant people are at high risk for severe COVID-19 but were excluded from mRNA vaccine trials; data on COVID-19 vaccine effectiveness (VE) are needed.ObjectiveTo evaluate the estimated effectiveness of mRNA vaccination against medically attended COVID-19 among pregnant people during Delta and Omicron predominance.Design, Setting, and ParticipantsThis test-negative, case-control study was conducted from June 2021 to June 2022 in a network of 306 hospitals and 164 emergency department and urgent care (ED/UC) facilities across 10 US states, including 4517 ED/UC encounters and 975 hospitalizations among pregnant people with COVID-19–like illness (CLI) who underwent SARS-CoV-2 molecular testing.ExposuresTwo doses (14-149 and ≥150 days prior) and 3 doses (7-119 and ≥120 days prior) of COVID-19 mRNA vaccine (≥1 dose received during pregnancy) vs unvaccinated.Main Outcomes and MeasuresEstimated VE against laboratory-confirmed COVID-19–associated ED/UC encounter or hospitalization, based on the adjusted odds ratio (aOR) for prior vaccination; VE was calculated as (1 − aOR) × 100%.ResultsAmong 4517 eligible CLI-associated ED/UC encounters and 975 hospitalizations, 885 (19.6%) and 334 (34.3%) were SARS-CoV-2 positive, respectively; the median (IQR) patient age was 28 (24-32) years and 31 (26-35) years, 537 (12.0%) and 118 (12.0%) were non-Hispanic Black and 1189 (26.0%) and 240 (25.0%) were Hispanic. During Delta predominance, the estimated VE against COVID-19–associated ED/UC encounters was 84% (95% CI, 69% to 92%) for 2 doses within 14 to 149 days, 75% (95% CI, 5% to 93%) for 2 doses 150 or more days prior, and 81% (95% CI, 30% to 95%) for 3 doses 7 to 119 days prior; estimated VE against COVID-19–associated hospitalization was 99% (95% CI, 96% to 100%), 96% (95% CI, 86% to 99%), and 97% (95% CI, 79% to 100%), respectively. During Omicron predominance, for ED/UC encounters, the estimated VE of 2 doses within 14 to 149 days, 2 doses 150 or more days, 3 doses within 7 to 119 days, and 3 doses 120 or more days prior was 3% (95% CI, −49% to 37%), 42% (95% CI, −16% to 72%), 79% (95% CI, 59% to 89%), and −124% (95% CI, −414% to 2%), respectively; for hospitalization, estimated VE was 86% (95% CI, 41% to 97%), 64% (95% CI, −102% to 93%), 86% (95% CI, 28% to 97%), and −53% (95% CI, −1254% to 83%), respectively.Conclusions and RelevanceIn this study, maternal mRNA COVID-19 vaccination, including booster dose, was associated with protection against medically attended COVID-19. VE estimates were higher against COVID-19–associated hospitalization than ED/UC visits and lower against the Omicron variant than the Delta variant. Protection waned over time, particularly during Omicron predominance.

A systematic, effective stillbirth evaluation is important for identification of potential causes of fetal death. Knowledge of potential causes of fetal death facilitates emotional closure for patients and informs recurrence risk as well as future pregnancy management. The highest-yield components of a stillbirth evaluation for finding a cause of fetal death are fetal autopsy, placental pathology, and genetic testing. All patients should be offered these tests following a stillbirth. A clear plan for postpartum follow-up should be made with the patient in order to ensure ongoing support through the grief and recovery process.

Genetic abnormalities, whether occurring in the conceptus or the parents, can predispose to sporadic or recurrent pregnancy loss (RPL). Abnormalities in the conceptus include aneuploidy, copy number changes, skewed X inactivation, and single gene disorders or mutations. Among parents who suffer RPL, the best studied genetic cause is balanced chromosomal translocations. For evaluation of genetic abnormalities in cases of pregnancy loss, chromosomal microarray is more likely to yield interpretable results than karyotype due to cell culture failure. For parents, karyotype remains the standard since microarray may not detect truly balanced translocations. For those with an identified underlying genetic abnormality, preimplantation genetic testing has been proposed to optimize the live birth rate. This approach shows promise, but currently lacks supporting evidence. In summary, various genetic causes for recurrent pregnancy loss are known, but when such a cause is identified, the implications for management remain unclear.

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.

Objective Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that emerges in the beginning years of life (12–48 months). Yet, an early diagnosis of ASD is challenging as it relies on the consistent presence of behavioral symptomatology, and thus, many children are diagnosed later in development, which prevents early interventions that could benefit cognitive and social outcomes. As a result, there is growing interest in detecting early brain markers of ASD, such as in the electroencephalogram (EEG) to elucidate divergence in early development. Here, we examine the EEG of nonrapid eye movement (NREM) sleep in the transition from infancy to toddlerhood, a period of rapid development and pronounced changes in early brain function. NREM features exhibit clear developmental trajectories, are related to social and cognitive development, and may be altered in neurodevelopmental disorders. Yet, spectral features of NREM sleep are poorly understood in infants/toddlers with or at high risk for ASD. Methods The present pilot study is the first to examine NREM sleep in 13‐ to 30‐month‐olds with ASD in comparison with age‐matched healthy controls (TD). EEG was recorded during a daytime nap with high‐density array EEG. Results We found topographically distinct decreased fast theta oscillations (5–7.25 Hz), decreased fast sigma (15–16 Hz), and increased beta oscillations (20–25 Hz) in ASD compared to TD. Conclusion These findings suggest a possible functional role of NREM sleep during this important developmental period and provide support for NREM sleep to be a potential early marker for ASD., Brain and Behavior, 10 (3), ISSN:2162-3279

Objective: To compare fetal/infant mortality risk associated with each additional week of expectant management with the infant mortality risk of immediate delivery in growth-restricted pregnancies. Methods: A retrospective cohort study was conducted of singleton, nonanomalous pregnancies from the 2005–2008 California Birth Registry comparing pregnancies affected and unaffected by growth restriction, defined using birth weights as a proxy for fetal growth restriction (FGR). Birth weights were subdivided as greater than the 90th percentile, between the 10th percentile and 90th percentile, and less than the 10th percentile. Cases greater than the 90th percentile were excluded from analysis. Cases less than the 10th percentile were considered to have FGR and were further subcategorized into Results: We identified 1,641,000 births, of which 110,748 (6.7%) were less than 10th percentile. The risk of stillbirth increased with gestational age with the risk of stillbirth at each week of gestation inversely proportional to growth percentile. The risks of fetal and infant mortality with expectant management outweighed the risk of infant death for all FGR categories analyzed beginning at 38 weeks. However, the absolute risks differed by growth percentiles, with the highest risks of infant death and stillbirth in the Conclusion: At 38 weeks, the mortality risk of expectant management for one additional week exceeds the risk of delivery across all growth-restricted cohorts, despite variation in absolute risk by degree of growth restriction.

OBJECTIVE: To better characterize infection stillbirth in terms of pathogenesis and microbiology. METHODS: We conducted a secondary analysis of 512 stillbirths in a prospective, multisite, geographically, racially and ethnically diverse, population-based study of stillbirth in the United States. Cases underwent evaluation that included maternal interview, chart abstraction, biospecimen collection, fetal autopsy, and placental pathology. Recommended evaluations included syphilis and parvovirus serology. Each case was assigned probable and possible causes of death using the INCODE Stillbirth Classification System. Cases where infection was assigned as a probable or possible cause of death were reviewed. For these cases, clinical scenario, autopsy, maternal serology, culture results and placental pathology were evaluated. RESULTS: For 66 (12.9%) cases of stillbirth, infection was identified as a probable or possible cause of death. Of these, 36% (95% CI 35% - 38%) were categorized as a probable and 64% (95% CI 62% - 65%) as a possible cause of death. Infection-related stillbirth occurred earlier than non-infection related stillbirth (median gestational age 22 weeks vs 28 weeks, p= 0.001). Fetal bacterial culture results were available in 47 cases (71%), of which 35 (53%) grew identifiable organisms. The predominant species were Escherichia coli (19; 29%), group B streptococcus (8; 12%), and enterococcus (8; 12%). Placental pathology revealed chorioamnionitis in 50 (76%), funisitis in 27 (41%), villitis in 11 (17%), deciduitis in 35 (53%), necrosis in 27 (41%), and viral staining in 7 (11%) cases. Placental pathology found inflammation or evidence of infection in 65 (99%) cases and fetal autopsy in 26 (39%) cases. In infection stillbirth cases, the likely causative non-bacterial organisms identified were parvovirus in 2 (3%) cases, syphilis in 1 (2%) case, cytomegalovirus in 5 (8%) cases and herpes in 1 (2%) case. CONCLUSIONS: Of infection-related stillbirth cases in a large U.S. cohort, E. coli, group B streptococcus and enterococcus were the most common bacterial pathogens and cytomegalovirus the most common viral pathogen.

Pregnancy loss is one of the most common obstetric complications, affecting over 30% of conceptions. A considerable proportion of losses are due to genetic abnormalities. Indeed, over 50% of early pregnancy losses have been associated with chromosomal abnormalities. Most are due to de novo nondisjunctional events but balanced parental translocations are responsible for a small but important percentage of genetic abnormalities in couples with recurrent pregnancy loss. In the past, assessment of genetic abnormalities was limited to karyotype performed on placental or fetal tissue. However, advances in molecular genetic technology now provide rich genetic information about additional genetic causes of and risk factors for pregnancy loss. In addition, the use of preimplantation genetic testing in couples undergoing in vitro fertilization has the potential to decrease the risk of pregnancy loss from genetic abnormalities. To date, efficacy is uncertain but considerable potential remains. This chapter will review what is known about genetic causes of recurrent pregnancy loss with a focus on novel causes and potential treatments. Remaining knowledge gaps will be highlighted.

Widespread change in behavior and the underlying brain network substrate is a hallmark of early development. Sleep plays a fundamental role in this process. Both slow waves and spindles are key features of nonrapid eye movement sleep (NREM) that exhibit pronounced developmental trajectories from infancy to adulthood. Yet, these prominent features of NREM sleep are poorly understood in infants and toddlers in the age range of 12 to 30 months. Moreover, it is unknown how network dynamics of NREM sleep are associated with outcomes of early development. Addressing this gap in our understanding of sleep during development will enable the subsequent study of pathological changes in neurodevelopmental disorders. The aim of the current study was to characterize the sleep topography with high-density electroencephalography in this age group. We found that δ, θ, and β oscillations and sleep spindles exhibited clear developmental changes. Low δ and high θ oscillations correlated with motor, language, and social skills, independent of age. These findings suggest an important role of network dynamics of NREM sleep in cortical maturation and the associated development of skills during this important developmental period.

Objective To evaluate the gestational age (GA) at which perinatal mortality risk is minimized for fetuses with Down syndrome (DS). Methods Retrospective cohort of singleton pregnancies delivered between 24 and 41 weeks, using 2005-2006 United States linked birth and death certificate data. Among fetal DS cases, prospective risk of intrauterine fetal demise (IUFD) and risk of infant death were calculated for each week, and composite risk of fetal/infant mortality with expectant management was compared to delivery. Results Of 3,113,098 pregnancies, 1766 had fetal DS (0.06%). IUFD occurred in 7.4% with DS, and infant death in 6.5%. Prospective risk of IUFD increased from 37 weeks onward to reach 50.7 per 1000 pregnancies (95% CI 33.2-68.3) at 42 weeks. Comparing mortality with expectant management to delivery, expectant management carried increasing risk from 38 (RR 1.18; 95% CI 1.05-1.33) to 41 weeks (RR 1.84; 95% CI 1.66-2.05). Further, number needed to deliver to avoid one excess death decreased from 38 (109.17; 95% CI 64.52-344.83) to 41 weeks (24.08; 95% CI 20.59-29.04). Conclusions Although further research is needed to clarify risk factors for fetal and neonatal death in cases of DS, risk of perinatal mortality appears to be minimized with delivery at 38 weeks.

Purpose of review To review current evidence regarding the most useful tests for evaluation of potential causes of stillbirth. Recent findings Stillbirth remains one of the most devastating obstetric complications. Recent advances include work investigating the highest yield diagnostic tests for determining a cause of death in stillbirths. Placental pathology and fetal autopsy improve the diagnostic yield when combined with maternal clinical history. Additional tools include genetic evaluation, and testing for antiphospholipid antibodies and fetal-maternal hemorrhage based on the clinical scenario. However, routine testing for heritable thrombophilias or infection has not proven to be useful. In cases in which fetal autopsy is not acceptable to patients or possible for logistical reasons, alternative forms of fetal evaluation should be considered. Summary A systematic approach to stillbirth evaluation is useful in identifying a potential cause of death. This should incorporate clinical information as well as placental pathology and fetal autopsy. Based on clinical characteristics further testing may be indicated.

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.

Stillbirth is one of the most distressing complications of pregnancy and still occurs far too frequently. The rate of stillbirth has been decreasing worldwide but room for improvement remains even in high-income countries. Risk factors for stillbirth have been identified in an effort to detect those women at increased risk. However, risk factors are non-specific and do not identify most stillbirths. Strategies employed to screen the general population such as assessment of fetal activity, fetal growth screening and biomarkers have also been used to identify increased risk for stillbirth. As with clinical risk factors, these methods are non-specific. Interventions to prevent stillbirth include antenatal testing of high-risk women, ultrasonographic assessments of fetal growth and Doppler velocimetry as well as iatrogenic preterm or term delivery. Additional research into the role of these interventions and better identification of those at high risk for stillbirth will help to achieve further stillbirth reduction.

Dengue viruses (DENV) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. This mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. While there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. Here, we describe a novel small-molecule compound, ST-148, that is a potent inhibitor of all four serotypes of DENV in vitro . ST-148 significantly reduced viremia and viral load in vital organs and tended to lower cytokine levels in the plasma in a nonlethal model of DENV infection in AG129 mice. Compound resistance mapped to the DENV capsid (C) gene, and a direct interaction of ST-148 with C protein is suggested by alterations of the intrinsic fluorescence of the protein in the presence of compound. Thus, ST-148 appears to interact with the DENV C protein and inhibits a distinct step(s) of the viral replication cycle.

Background Prior studies have evaluated the overall risk of stillbirth in pregnancies with fetal gastroschisis. However, the gestational age at which mortality is minimized, balancing the risk of stillbirth against neonatal mortality, remains unclear. Objective We sought to evaluate the gestational age at which prenatal and postnatal mortality risk is minimized for fetuses with gastroschisis. Study Design This was a retrospective cohort study of singleton pregnancies delivered between 24 0/7 and 39 6/7 weeks, using 2005 through 2006 US national linked birth and death certificate data. Among pregnancies with fetal gastroschisis, prospective risk of stillbirth and risk of infant death were determined for each gestational age week. Risk of infant death with delivery was further compared to composite fetal/infant mortality risk with expectant management for 1 additional week. Results Among 2,119,049 pregnancies, 860 cases (0.04%) of gastroschisis were identified. The overall stillbirth rate among gastroschisis cases was 4.8%, and infant death occurred in 8.3%. Prospective risk of stillbirth became more consistently elevated beginning at 35 weeks, rising to 13.9 per 1000 pregnancies (95% confidence interval, 10.8–17.1) at 39 weeks. Risk of infant death concurrently nadired in the third trimester, ranging between 62.4-66.8 per 1000 live births between 32-39 weeks. Comparing mortality with expectant management vs delivery, relative risk was significantly greater with expectant management between 37-39 weeks, reaching 1.90 (95% confidence interval, 1.73–2.08) at 39 weeks with a number needed to deliver of 17.49 (95% confidence interval, 15.34–20.32) to avoid 1 excess death. Conclusion Risk of prenatal and postnatal mortality for fetuses with gastroschisis may be minimized with delivery as early as 37 weeks.

Objective The objective of the study was to evaluate the ongoing risk of intrauterine fetal demise (IUFD) in nonanomalous pregnancies affected by polyhydramnios. Study Design We analyzed a retrospective cohort of all singleton, nonanomalous births in California between 2005 and 2008 as recorded in a statewide birth certificate registry. We included all births between 24+0 and 41+6 weeks' gestational age, excluding multiple gestations, major congenital anomalies, and pregnancies affected by oligohydramnios. Polyhydramnios was identified by International Classification of Diseases , ninth revision, codes. χ 2 tests were used to compare the dichotomous outcomes, and multivariable logistic regression analyses were then performed to control for potential confounders. We analyzed the data for pregnancies affected and unaffected by polyhydramnios. The IUFD risk was expressed as a rate per 10,000. Results The risk of IUFD in pregnancies affected by polyhydramnios was greater at every gestational age compared with unaffected pregnancies. The IUFD risk in pregnancies affected by polyhydramnios was more than 7 times higher than unaffected pregnancies at 37 weeks at a rate of 18.0 (95% confidence interval [CI], 9.0–32.6) vs 2.4 (95% CI, 2.0–2.5) and was 11-fold higher by 40 weeks' gestational age at a rate of 66.3 (95% CI, 10.8–68.6) vs 6.0 (95% CI, 5.1–6.3) in unaffected pregnancies. When adjusted for multiple confounding variables, the presence of polyhydramnios remained associated with an increased odds of IUFD in nonanomalous singleton pregnancies, with an adjusted odds ratio of 5.5 (95% CI, 4.1–7.6). Conclusion Ongoing risk of IUFD is greater in low-risk pregnancies affected by polyhydramnios at all gestational ages compared with unaffected pregnancies with the greatest increase in risk at term. Although further study is needed to explore the underlying etiology of polyhydramnios in these cases, the identification of polyhydramnios alone may warrant increased antenatal surveillance.

The objective of the study was to compare the fetal/infant mortality risk associated with each additional week of expectant management with the mortality risk of immediate delivery in women with twin gestations.A retrospective cohort study was performed utilizing 2006-2008 National linked birth certificate and death certificate data. The incidence of stillbirth and infant death were determined for each week of pregnancy from 32 0/7 weeks' through 40 6/7 weeks' gestation. Pregnancies complicated by fetal anomalies were excluded. These measures were combined to estimate the theoretic risk of remaining pregnant an additional week by adding the risk of stillbirth during the extra week of pregnancy with the risk of infant death encountered with delivery during the following week. This composite fetal/infant mortality risk was compared with the risk of infant death associated with delivery at the corresponding gestational age.The risk of stillbirth increased with increasing gestational age, for example, between 37 and 38 weeks' gestation (12.5 per 10,000 vs 22.5 per 10,000; P.05). As expected, the risk of infant death following delivery gradually decreased as pregnancies approached term gestation. Week-by-week differences were statistically significant (P.05) between 32 and 36 weeks with decreasing risk of infant death at advancing gestational ages. The composite risk of stillbirth and infant death associated with an additional week of pregnancy had a significant increase from 37 to 38 weeks' gestation (43.9 per 10,000 vs 59.2 per 10,000; P.05). At 37 weeks' gestation, the relative risk of mortality was statistically significantly lower with immediate delivery as compared with expectant management (relative risk, 0.87; 95% confidence interval, 0.77-0.99).Our results suggest that fetal/infant death risk is minimized at 37 weeks' gestation; however, individual maternal and fetal characteristics must also be taken into account when determining the optimal timing of delivery for twin pregnancies.

Although previous studies have demonstrated that a variety of local anesthetics are effective to decrease pain associated with tenaculum placement, no studies directly compare an injection with a topical anesthetic. The objective of this study was therefore to compare mean pain scores with tenaculum placement after an intracervical lidocaine injection or topical lidocaine gel.A randomized, single-blinded trial of women presenting for office gynecologic procedures that required a tenaculum. Women aged 18 years or older were randomized to receive either a 1% lidocaine intracervical injection or topical application of 2% lidocaine gel to the cervix immediately prior to tenaculum placement. The primary outcome was pain at the time of tenaculum placement, measured on a 100 mm Visual Analog Scale. Secondary outcomes included pain with the intervention and satisfaction with tenaculum placement.Seventy-four women were enrolled and randomized; 35 subjects in each group met criteria for analysis. The two groups had similar socio-demographic characteristics. Women who received the injection had lower mean pain levels at tenaculum placement [12.3 mm (S.D. 17.4 mm) versus 36.6 mm (S.D. 23.0 mm), p.001] but higher mean pain levels with study drug application [20.4 mm (S.D. 19.4 mm) versus 5.9 mm (S.D. 8.6 mm), p.001]. Satisfaction with tenaculum placement was similar for the two groups.Mean pain with tenaculum placement is lower after receiving a lidocaine injection than after receiving a topical lidocaine gel. Satisfaction with tenaculum placement is similar with both interventions.