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.

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.

Second-Trimester Uterine Model for Teaching Ultrasound-Guided Obstetric Procedures.

The declining number of ultrasound-guided obstetric procedures in clinical practice mandates a shift toward simulation-based teaching. Current uterine simulation aids are animal tissue-sourced or expensive, and improvement is needed. We describe a low-cost reusable uterine model with "fetus," cord and skin, constructed from synthetic gel and silicone rubber. Ultrasound appearance and tactile feedback approximate clinical use, and all parts of the model are portable, durable, and shelf-stable. Those made of ballistics gel can be recycled numerous times without noticeable effect. This appears to be ideal for proctored learning and independent practice within an ultrasound procedural curriculum.

Major trauma in pregnancy: prediction of maternal and perinatal adverse outcomes.

BACKGROUND: Trauma, largely the consequence of motor vehicle crashes, is the leading cause of pregnancy-associated maternal mortality. Prediction of adverse outcomes has been difficult in pregnancy given the infrequent occurrence of traumatic events and anatomic considerations unique to pregnancy. The injury severity score, an anatomic scoring system with weighting dependent on severity and anatomic region of injury, is used in the prediction of adverse outcomes in the nonpregnant population but has yet to be validated in pregnancy. OBJECTIVE: This study aimed to estimate the associations between risk factors and adverse pregnancy outcomes after major trauma in pregnancy and to develop a clinical prediction model for adverse maternal and perinatal outcomes. STUDY DESIGN: This was a retrospective analysis of a cohort of pregnant patients who sustained major trauma and who were admitted to 1 of 2 level 1 trauma centers. Three composite adverse pregnancy outcomes were evaluated, namely adverse maternal outcomes and short- and long-term adverse perinatal outcomes, defined as outcomes occurring within the first 72 hours of the traumatic event or encompassing the entire pregnancy. Bivariate analyses were performed to estimate the associations between clinical or trauma-related variables and adverse pregnancy outcomes. Multivariable logistic regression analyses were performed to predict each adverse pregnancy outcome. The predictive performance of each model was estimated using receiver operating characteristic curve analyses. RESULTS: A total of 119 pregnant trauma patients were included, 26.1% of whom met the severe adverse maternal pregnancy outcome criteria, 29.4% of whom met the severe short-term adverse perinatal pregnancy outcome definition, and 51.3% of whom met the severe long-term adverse perinatal pregnancy outcome definition. Injury severity score and gestational age were associated with the composite short-term adverse perinatal pregnancy outcome with an adjusted odds ratio of 1.20 (95% confidence interval, 1.11-1.30). The injury severity score was solely predictive of the adverse maternal and long-term adverse perinatal pregnancy outcomes with odds ratios of 1.65 (95% confidence interval, 1.31-2.09) and 1.14 (95% confidence interval, 1.07-1.23), respectively. An injury severity score ≥8 was the best cutoff for predicting adverse maternal outcomes with 96.8% sensitivity and 92.0% specificity (area under the receiver operating characteristic curve, 0.990±0.006). An injury severity score ≥3 was the best cutoff for the short-term adverse perinatal outcomes, which correlates with a 68.6% sensitivity and 65.1% specificity (area under the receiver operating characteristic curve, 0.755±0.055). An injury severity score ≥2 was the best cutoff for the long-term adverse perinatal outcomes, yielding a 68.3% sensitivity and 72.4% specificity (area under the receiver operating characteristic curve, 0.763±0.042). CONCLUSION: For pregnant trauma patients, an injury severity score of ≥8 was predictive of severe adverse maternal outcomes. Minor trauma in pregnancy, defined in this study as an injury severity score <2, was not associated with maternal or perinatal morbidity or mortality. These data can guide management decisions for pregnant patients who present after trauma.

Accuracy and utilization patterns of intraabdominal imaging for major trauma in pregnancy.

BACKGROUND: Imaging protocols for major maternal trauma during pregnancy are not standardized, and it is uncertain whether focused assessment with sonography for trauma or computed tomography of the abdomen/pelvis is preferred for detecting intraabdominal hemorrhage. OBJECTIVE: This study aimed to estimate the accuracy of focused assessment with sonography for trauma compared with computed tomography of the abdomen/pelvis, validate imaging accuracy with clinical outcomes, and describe clinical factors associated with each imaging mode. STUDY DESIGN: A retrospective cohort study of pregnant patients evaluated for major trauma at one of two Level 1 trauma centers between 2003 and 2019. We identified 4 imaging groups: no intraabdominal imaging, focused assessment with sonography for trauma only, computed tomography of the abdomen/pelvis only, and both focused assessment with sonography for trauma and computed tomography of the abdomen/pelvis. The primary outcome was a composite maternal severe adverse pregnancy outcome, including death and intensive care unit admission. We estimated sensitivity, specificity, and positive and negative predictive values of focused assessment with sonography for trauma for hemorrhage with computed tomography of the abdomen/pelvis as the reference standard. We performed analysis of variance and chi-square tests to compare clinical factors and outcomes across imaging groups. Multinomial logistic regression was used to estimate associations between selected imaging mode and clinical factors. RESULTS: Of 119 pregnant trauma patients, 31 (26.1%) experienced a maternal severe adverse pregnancy outcome. Intraabdominal imaging modes included none in 37.0%, focused assessment with sonography for trauma only in 21.0%, computed tomography of the abdomen/pelvis only in 25.2%, and both modes in 16.8%. With computed tomography of the abdomen/pelvis as the reference, focused assessment with sonography for trauma had sensitivity, specificity, positive predictive value, and negative predictive value of 11%, 91%, 50%, and 55%, respectively. One patient had a maternal severe adverse pregnancy outcome with a positive focused assessment with sonography for trauma and negative computed tomography of the abdomen/pelvis, and 2 patients with a positive computed tomography of the abdomen/pelvis did not have an adverse outcome. Use of computed tomography of the abdomen/pelvis with or without focused assessment with sonography for trauma was associated with a higher injury severity score, lower systolic blood pressure nadir, higher motor vehicle collision speed, and higher rates of hypotension, tachycardia, bone fracture, maternal severe adverse pregnancy outcome, and fetal demise. The association of computed tomography of the abdomen/pelvis use with higher injury severity score, tachycardia, and lower systolic blood pressure nadir persisted in multivariable analysis. With each 1-point increase in the injury severity score, there was an 11% higher likelihood of using computed tomography of the abdomen/pelvis over focused assessment with sonography for trauma for intraabdominal imaging. CONCLUSION: The sensitivity of focused assessment with sonography for trauma in detecting intraabdominal hemorrhage in pregnant trauma patients is poor, and computed tomography of the abdomen/pelvis has a low false-negative rate. Providers seem to prefer computed tomography of the abdomen/pelvis to focused assessment with sonography for trauma in patients with the most severe trauma. Computed tomography of the abdomen/pelvis with or without focused assessment with sonography for trauma is more accurate than focused assessment with sonography for trauma alone.

The Prenatal Hormone Milieu in Autism Spectrum Disorder.

Though the etiology of autism spectrum disorder (ASD) remains largely unknown, recent findings suggest that hormone dysregulation within the prenatal environment, in conjunction with genetic factors, may alter fetal neurodevelopment. Early emphasis has been placed on the potential role of in utero exposure to androgens, particularly testosterone, to theorize ASD as the manifestation of an "extreme male brain." The relationship between autism risk and obstetric conditions associated with inflammation and steroid dysregulation merits a much broader understanding of the in utero steroid environment and its potential influence on fetal neuroendocrine development. The exploration of hormone dysregulation in the prenatal environment and ASD development builds upon prior research publishing associations with obstetric conditions and ASD risk. The insight gained may be applied to the development of chronic adult metabolic diseases that share prenatal risk factors with ASD. Future research directions will also be discussed.

Opioid use in pregnant women and the increase in neonatal abstinence syndrome: what is the cost?

OBJECTIVES: To investigate the length of stay for observation and treatment of neonatal abstinence syndrome (NAS), as well as the hospital costs associated with the medical care of affected newborns. METHODS: A retrospective chart review was conducted at Shands Hospital at the University of Florida, Gainesville, Florida. Data were collected for newborns diagnosed with NAS, including their hospital length of stay and the associated hospital charges, from December 1, 2008, to November 30, 2011. RESULTS: One hundred-sixty eligible newborns were included in the study. During the 3-year study period, hospital charges related to the diagnosis and treatment of NAS increased from $1.1 million per year to $1.8 million per year. Compared with the cost of caring for newborns without the risk of NAS, an additional $4.1 million was spent in the medical care of these newborns. CONCLUSIONS: The costs associated with treating newborns with NAS are exponentially higher than the costs associated with newborns not affected with NAS. The societal costs associated with treatment of newborns with NAS, as well as infant symptomatology experienced with NAS, can be reduced by encouraging physicians to be proactive in screening for drug use, urging women who use chronic opioids to actively engage in family planning and contraception, and encouraging pregnant women who use opioids to seek substance treatment.

Leaf development in Lolium temulentum L.: characterization of a slow-to-green mutant.

A nuclear-gene mutation of the C3 grass Lolium temulentum L., which arose following cell suspension culture and plant regeneration, is manifested as delayed and incomplete greening, which occurs from the leaf tip downwards. Many plastids in the mutant exhibit abnormal morphology when examined by transmission electron microscopy; the plastid outer envelope lacks integrity and thylakoids, while still stacked, are spread over a wide area surrounded by diffuse stromal contents. These aberrant plastids can coexist with apparently normal chloroplasts in the same cell of mutant plants. Levels of chlorophyll a and b, and carotenoids, are all lower in the mutants than in normal Lolium temulentum. Leaf length, absolute growth rate, and number of cells per unit length at the leaf base, are greatly reduced (20-30% the normal values) in slow-to-green plants, but relative growth rate, duration of leaf growth, length of cell division zone and proportion of cells dividing are little affected. This novel mutant is a potentially valuable resource for studying interrelationships between photosynthetic function and leaf extension growth in grasses.

Two Rab2 interactors regulate dense-core vesicle maturation.

Peptide neuromodulators are released from a unique organelle: the dense-core vesicle. Dense-core vesicles are generated at the trans-Golgi and then sort cargo during maturation before being secreted. To identify proteins that act in this pathway, we performed a genetic screen in Caenorhabditis elegans for mutants defective in dense-core vesicle function. We identified two conserved Rab2-binding proteins: RUND-1, a RUN domain protein, and CCCP-1, a coiled-coil protein. RUND-1 and CCCP-1 colocalize with RAB-2 at the Golgi, and rab-2, rund-1, and cccp-1 mutants have similar defects in sorting soluble and transmembrane dense-core vesicle cargos. RUND-1 also interacts with the Rab2 GAP protein TBC-8 and the BAR domain protein RIC-19, a RAB-2 effector. In summary, a pathway of conserved proteins controls the maturation of dense-core vesicles at the trans-Golgi network.

Accuracy of the contrast sensitivity card test for infants: retest variability and prediction of spatial resolution.

PURPOSE: We assessed the retest variability of a new contrast sensitivity (CS) card procedure and its ability to predict spatial resolution. METHODS: Twenty-four 3-month-olds were tested twice with the CS cards and once with the Teller acuity cards (TAC) within a single session. RESULTS: Coefficient of repeatability (COR) analysis revealed that retest variability of the new cards is superior to that of an earlier prototype at low to mid spatial frequencies. Furthermore, retest variability is comparable to that of infant visual evoked potential studies and the Vistech 6500, a chart commonly used to measure CS in adults. Finally, estimates of visual acuity based on the CS cards were consistent with those provided by the TAC (although CS-based estimates were generally lower overall). CONCLUSIONS: Given its reliability and accuracy, the new CS card procedure has good potential as a clinical tool for assessing spatial vision in infants and toddlers.

Testing young infants with the Welch Allyn suresight non-cycloplegic autorefractor.

Both eyes of 74 healthy 2-12-month-old human infants were refracted twice with the new Welch Allyn SureSight non-cycloplegic autorefractor. At least one reliable estimate of sphere and cylinder was obtained from both eyes of all babies attempted, and 88% of infants contributed two estimates from each eye. These measurements were collected in less than 2 min. Although spherical estimates changed little over the first year (mean = +1.78 D), cylindrical error appeared to decrease from a mean of about 1.4 D (at 6 months) to 0.9 D (at 12 months). Refractive estimates and variability agreed well with published infant data obtained with traditional cycloplegic retinoscopy. Repeatability was excellent for measurement of cylinder but for sphere, 17% of infants' estimates differed by at least 1.0 D between tests. However, given its simplicity and time-efficiency, the SureSight should be a good candidate for the relatively easy screening of significant refractive error in non-verbal paediatric patients.