Clinical implications of crown-rump length discordance at 11 to 14 weeks in dichorionic twins.

BACKGROUND: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. OBJECTIVE: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. STUDY DESIGN: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. RESULTS: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4-4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4-4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04-1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5-8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5-4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. CONCLUSION: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.

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

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

Copy number variants and fetal growth in stillbirths.

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

Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study.

BACKGROUND: Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE: This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13. STUDY DESIGN: This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. RESULTS: A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. CONCLUSION: Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: 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. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: 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. CONCLUSIONS: 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.

Fetomaternal hemorrhage: Evidence from a multihospital healthcare system that up to 40% of severe cases are missed.

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.

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

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

Social EEG: A novel neurodevelopmental approach to studying brain-behavior links and brain-to-brain synchrony during naturalistic toddler-parent interactions.

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.

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

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

Nonrapid eye movement sleep characteristics and relations with motor, memory, and cognitive ability from infancy to preadolescence.

Sleep plays a critical role in neural neurodevelopment. Hallmarks of sleep reflected in the electroencephalogram during nonrapid 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.

High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.

Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles.

Evaluation of stillbirth.

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.

Genetic Causes of Recurrent Pregnancy Loss.

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.

The risk of stillbirth and infant death by each additional week of expectant management in twin pregnancies.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

The risk of fetal death in nonanomalous pregnancies affected by polyhydramnios.

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.

A novel inhibitor of dengue virus replication that targets the capsid protein.

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.

The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age.

OBJECTIVE: The objective of the study was to examine fetal/infant mortality by gestational age at term stratified by maternal age. STUDY DESIGN: A retrospective cohort study was conducted using 2005 US national birth certificate data. For each week of term gestation, the risk of mortality associated with delivery was compared with composite mortality risk of expectant management. The expectant management measure included stillbirth and infant death. This expectant management risk was calculated to estimate the composite mortality risk with remaining pregnant an additional week by combining the risk of stillbirth during the additional week of pregnancy and infant death risk following delivery at the next week. Maternal age was stratified by 35 years or more compared with women younger than 35 years as well as subgroup analyses of younger than 20, 20-34, 35-39, or 40 years old or older. RESULTS: The fetal/infant mortality risk of expectant management is greater than the risk of infant death at 39 weeks' gestation in women 35 years old or older (15.2 vs 10.9 of 10,000, P < .05). In women younger than 35 years old, the risk of expectant management also exceeded that of infant death at 39 weeks (21.3 vs 18.8 of 10,000, P < .05). For women younger than 35 years old, the overall expectant management risk is influenced by higher infant death risk and does not rise significantly until 41 weeks compared with women 35 years old or older in which it increased at 40 weeks. CONCLUSION: Risk varies by maternal age, and delivery at 39 weeks minimizes fetal/infant mortality for both groups, although the magnitude of the risk reduction is greater in older women.

Gaps in Parental Understanding of Sleep Disturbances During Maintenance Therapy for Pediatric Acute Lymphoblastic Leukemia.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, with survival rates approaching 90%. Sleep disturbance is common among ALL patients, often developing during the initial stages of chemotherapy treatment. While there have been significant efforts to understand and intervene in this issue during survivorship, there is far less research on children who are actively receiving treatment. In the current study, we sought to better understand the parent's experience in the sleep domain during maintenance therapy, including their perceptions of how their child's medical team had managed sleep disturbances, and recommendations for how to improve sleep management. Method: Fifteen parents of pediatric ALL patients (aged 4-12 years) completed semistructured interviews. Interview content was analyzed using a multistage thematic analysis. Results: Parents consistently expressed feeling unprepared to manage the sleep disruptions that arose during treatment, often reporting that they did not recall being told this would be a side effect. They were enthusiastic about learning how to improve their child's sleep, though they did not want pharmacotherapeutic interventions or additional medical/psychosocial appointments to address this. Conclusion: Despite consistent provider communication on sleep, parents report limited knowledge of the issue. This provides an obvious intervention target to improve treatment-related sleep disturbances. Clear messaging may help direct parents' attention and expectations regarding their child's treatment and potential for disturbed sleep, possibly in the form of a behavioral intervention that empowers parents with information about how to support their child's sleep health while they are undergoing treatment for ALL.

Placental abruption and neonatal anemia.

OBJECTIVE: Placental abruption can cause maternal blood loss and maternal anemia. It is less certain whether abruption can cause fetal blood loss and neonatal anemia. STUDY DESIGN: Retrospective multi-hospital 24-month analysis of women with placental abruption and their neonates. RESULTS: Of 55,111 births, 678 (1.2%) had confirmed abruption; 83% of these neonates (564) had one or more hemoglobins recorded in the first day. Four-hundred-seventy (83.3%) had a normal hemoglobin (≥5th% reference interval) while 94 (16.7%) had anemia, relative risk 3.26 (95% CI, 2.66-4.01) vs. >360,000 neonates from previous reference interval reports. The relative risk of severe anemia (<1st% interval) was 4.96 (3.44-7.16). When the obstetrician identified the abruption as "small" or "marginal" the risk of anemia was insignificant. CONCLUSIONS: Most abruptions do not cause neonatal anemia but approximately 16% do. If an abruption is not documented as small, it is important to surveille the neonate for anemia.

Neonatal subgaleal hemorrhage: twenty years of trends in incidence, associations, and outcomes.

BACKGROUND: In 2011, we reported 38 neonates with subgaleal hemorrhage (SH), relating an increasing incidence. It is unclear whether the incidence in our hospitals continued to rise and which risk factors and outcomes are associated with this condition. DESIGN: We retrospectively analyzed every recognized case of SH in our hospitals from the end of our previous report (2010) to the present (2022). We redescribed the incidence, scored severity, tabulated blood products transfused, and recorded outcomes. RESULTS: Across 141 months, 191 neonates were diagnosed with SH; 30 after vacuum or forceps. The incidence (one/1815 births) was higher than in our 2011 report (one/7124 births). Also, severe SH (requiring transfusion) was more common (one/10,033 births vs. one/20,950 births previously). Four died (all with severe SH) and 12 had neurodevelopmental impairment. CONCLUSION: Recognized cases of SH are increasing in our system without a clear explanation. Adverse outcomes are rare but continue to occur.