Clinical exome sequencing uncovers genetic disorders in neonates with suspected hypoxic-ischemic encephalopathy: A retrospective analysis.

Hypoxic-ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014-2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic-ischemic injury. Of 24 patients meeting inclusion criteria, six (25%) were diagnosed with a genetic condition. Four neonates had variants at loci linked to conditions with phenotypic features resembling HIE, including KIF1A, GBE1, ACTA1, and a 15q13.3 deletion. Two additional neonates had variants in genes not previously associated with encephalopathy, including DUOX2 and PTPN11. Of the six neonates with a molecular diagnosis, two had isolated HIE without apparent comorbidities to suggest a genetic disorder. Genetic diagnoses were identified among neonates with and without sentinel labor events, abnormal umbilical cord gasses, and low Apgar scores. These results suggest that genetic evaluation is clinically relevant for patients with perinatal HIE.

Limited Role of MSAFP Screening for Prenatal Omphalocele Detection.

OBJECTIVES: Although serum screening for aneuploidies has become less prevalent, maternal-serum alpha-fetoprotein (MSAFP) screening for body-wall defects remains widespread. We explored whether MSAFP screening is associated with earlier omphalocele detection than ultrasound alone. METHODS: This is a retrospective cohort study of prenatally detected omphalocele cases at our center from 2007 to 2023. We explored the association between MSAFP screening, gestational age at omphalocele detection, and clinical outcomes. RESULTS: Among 101 pregnancies with prenatally diagnosed omphalocele, 27 (26.7%) had MSAFP screening. The median gestational age at MSAFP screening was 17 weeks 4 days. Of those who received MSAFP screening, 11 (41%) had values ≥2.5 multiples of the median (MoM) and 16 (59%) were not elevated. MSAFP results did not correlate with omphalocele size and were not associated with prenatal or postnatal outcomes. MSAFP screening did not result in earlier suspicion for or confirmation of omphalocele (P = .97 and P = .87, respectively). In contrast, first-trimester ultrasound screening was associated with earlier suspicion for and confirmation of omphalocele (P < .01 and P = .01, respectively). There were no clinical or demographic differences between those who received MSAFP screening and those who did not (including body mass index or commute distance to an urban center). CONCLUSION: MSAFP screening is not associated with earlier omphalocele detection. Furthermore, in pregnancies with prenatally diagnosed omphalocele, the results of MSAFP screening are not predictive of clinical outcomes.

Using micro-computed tomography to examine the larynx in cases of suspected strangulation-a comparison of case findings and control images.

The examination of strangulation is one of the most challenging causes of death diagnoses encountered in forensic pathology. The injuries are often subtle and difficult to detect, especially in cases that lack superficial marks. Fractures of the laryngeal skeleton are commonly regarded as evidence of strangulation but these can be too subtle to be detected during autopsy. Micro-CT is a novel imaging technique that achieves a spatial resolution 1 µm or less which lends itself to the examination of small and delicate structures such as the larynx. However, there is little information to date regarding the appearance of the larynx at this scale, thus complicating the interpretation of the micro-CT images. This study therefore uses micro-CT to examine ten larynges from strangulation deaths and to compare them to nineteen samples from donor individuals in order to distinguish between naturally occurring features and actual trauma. It was found that there are several features which mimic damage in the donor group. Using associated case information, initial trends and patterns of different strangulation methods were established.

Prenatal Prognosis of Omphalocele Using Magnetic Resonance Imaging Measurement of Fetal Lung Volumes.

BACKGROUND: Omphalocele is a congenital midline abdominal wall defect resulting in herniation of viscera into a membrane-covered sac. Pulmonary complications, including pulmonary hypoplasia, pulmonary hypertension, and prolonged respiratory support are a leading cause of neonatal morbidity and mortality. OBJECTIVE(S): This study aimed to assess the role of fetal MRI-derived lung volumes and omphalocele defect size as clinical tools to prognosticate postnatal pulmonary morbidity and neonatal mortality in those with a prenatally diagnosed omphalocele (PDO). STUDY DESIGN: This was a retrospective cohort study of all pregnancies with PDO at our fetal center from 2007-2023. Pregnancies with aneuploidy or concurrent life-limiting fetal anomalies were excluded. Using fetal MRI, observed-to-expected total fetal lung volume (O/E TLV) ratios were determined by a previously published method. The transverse diameter of the abdominal defect was also measured. The O/E TLV ratios and abdominal defect measurements were compared with postnatal outcomes. The primary outcome was death at any time. Secondary outcomes included death in the first 30 days of life or before discharge from birth hospitalization, the requirement of respiratory support with intubation and mechanical ventilation, or development of pulmonary hypertension. RESULTS: Of 101 pregnancies with a PDO, 54 pregnancies (53.5%) with prenatally diagnosed omphalocele met inclusion criteria. There was a significant increase in the rate of death when compared between the three O/E TLV classifications: 1/36 (2.8%) in the O/E≥50% group, 3/14 (21.4%) in the O/E 25%-49.9% group, and 4/4 (100%) in the O/E<25% group (P<.001). The rate of intubation increased with the severity of O/E TLV classification, with 27.8% in the O/E≥50% group, 64.3% in the O/E 25%-49.9% group, and 100% in the O/E<25% group (P=.003). The rate of pulmonary hypertension was also higher in the O/E 25%-49.9% (50.0%) and the O/E<25% (50.0%) groups compared to the O/E≥50% group (8.3%, P=.002). There was no association between the transverse diameter of the abdominal wall defect and the primary outcome of death (OR=1.08 95% CI=[0.65-1.78], P=.77). CONCLUSIONS: In our cohort of patients with PDO, O/E TLV<50% is associated with death, need for intubation, prolonged intubation, and pulmonary hypertension. In contrast, omphalocele size demonstrated no prognostic value for these outcomes. The strong association between low fetal lung volume on MRI and poor neonatal outcomes highlights the utility of fetal MRI for estimating postnatal prognosis. Clinicians can utilize fetal lung volumes to direct perinatal counseling and optimize the plan of care.

Placenta accreta spectrum care infrastructure: an evidence-based review of needed resources supporting placenta accreta spectrum care.

The incidence of placenta accreta spectrum, the deeply adherent placenta with associated increased risk of maternal morbidity and mortality, has seen a significant rise in recent years. Therefore, there has been a rise in clinical and research focus on this complex diagnosis. There is international consensus that a multidisciplinary coordinated approach optimizes outcomes. The composition of the team will vary from center to center; however, central themes of complex surgical experts, specialists in prenatal diagnosis, critical care specialists, neonatology specialists, obstetrics anesthesiology specialists, blood bank specialists, and dedicated mental health experts are universal throughout. Regionalization of care is a growing trend for complex medical needs, but the location of care alone is just a starting point. The goal of this article is to provide an evidence-based framework for the crucial infrastructure needed to address the unique antepartum, delivery, and postpartum needs of the patient with placenta accreta spectrum. Rather than a clinical checklist, we describe the personnel, clinical unit characteristics, and breadth of contributing clinical roles that make up a team. Screening protocols, diagnostic imaging, surgical and potential need for critical care, and trauma-informed interaction are the basis for comprehensive care. The vision from the author group is that this publication provides a semblance of infrastructure standardization as a means to ensure proper preparation and readiness.

Umbilical cord gas analysis: clinical implications of a comprehensive, contemporary determination of normal ranges.

BACKGROUND: Umbilical cord gases are often used to assess the impact of labor and delivery on the fetus. However, no large series exists that reflects contemporary obstetrical practice or that analyzed blood gas ranges by route of delivery. Baseline, prelabor acid-base status in the human fetus is also poorly defined, rendering the assessment of blood gas changes during labor difficult. OBJECTIVE: This study aimed to define normal umbilical cord gas and lactate values, stratified by mode of delivery, in a large contemporary series in which universal umbilical cord gas evaluation was dictated by protocol. STUDY DESIGN: This was a retrospective cohort study. We analyzed the umbilical cord gas and lactate data of an unselected population of infants born between March 2012 and April 2022 at a large teaching hospital. These values were then analyzed by mode of delivery and, for cesarean deliveries, by indication for cesarean delivery and type of anesthesia. Umbilical cord gas values from infants delivered by elective cesarean delivey under general anesthesia without labor were considered representative of baseline, prelabor values. RESULTS: Data were available for 45,475 infants. The median arterial pH values and interquartile ranges for vaginal births, elective cesarean deliveries without labor, and cesarean deliveries performed for fetal heart rate concerns were 7.27 (0.09), 7.27 (0.06), and 7.25 (0.09), respectively. Arterial lactate values for these same 3 groups were 4.1 (2.5), 2.5 (1.2), and 4.0 (2.8) mmoles/L, respectively. Because of the very large sample size, most comparisons yielded differences that were statistically significant, but clinically irrelevant. Of all the infants, 14% had an arterial pH <7.20; a pH value of 7.1 represents 2 standard deviations from the mean. CONCLUSION: This large, population-based study of umbilical cord gas and lactate levels in an unselected population, stratified by delivery mode, represents a previously unavailable benchmark for the evaluation of umbilical cord gases. Arterial umbilical cord pH values for infants delivered by elective caesarean delivery without labor (median pH 7.28) reflect a lower prelabor fetal pH baseline than previously assumed. This finding, coupled with our determination that a 2 standard deviation below normal pH limit of 7.1, instead of the historic arbitrary pH of 7.2 threshold, helps to explain the poor positive predictive value of electronic fetal heart rate monitoring, a test designed to detect arterial pH levels that have fallen from an assumed baseline near pH 7.4 to an assumed potentially injurious pH level of <7.2. Uncomplicated labor, even when prolonged, does not generally lead to a clinically significant cumulative hypoxic stress to the human fetus. These findings, along with our determination that there is no difference in the acid-base status among infants delivered by cesarean delivery for fetal heart rate concerns, help to explain the failure of current approaches in labor and delivery management to reduce the rates of neonatal hypoxic-ischemic encephalopathy and cerebral palsy, conditions that almost always reflect developmental events rather than the effects of labor on the fetus.

Novel application of three-dimensional technologies in a case of dismemberment.

This case study reports the novel application of three-dimensional technologies such as micro-CT and 3D printing to the forensic investigation of a complex case of dismemberment. Micro-CT was successfully employed to virtually align severed skeletal elements found in different locations, analyse tool marks created during the dismemberment process, and virtually dissect a charred piece of evidence. High resolution 3D prints of the burnt human bone contained within were created for physical visualisation to assist the investigation team. Micro-CT as a forensic radiological method provided vital information and the basis for visualisation both during the investigation and in the subsequent trial making it one of the first examples of such technology in a UK court.