Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Lack of placental neurosteroid alters cortical development and female somatosensory function.

Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of neurodevelopmental processes via positive allosteric modulation of the GABAA receptor (GABAA-R). Using a mouse model (plKO) in which the gene encoding the ALLO synthesis enzyme is specifically deleted in trophoblasts, we previously showed that placental ALLO insufficiency alters cerebellar white matter development and leads to male-specific autistic-like behavior. We now demonstrate that the lack of placental ALLO causes female-predominant alterations of cortical development and function. Placental ALLO insufficiency disrupts cell proliferation in the primary somatosensory cortex (S1) in a sex-linked manner. Early changes are seen in plKO embryos of both sexes, but persist primarily in female offspring after birth. Adolescent plKO females show significant reduction in pyramidal neuron density, as well as somatosensory behavioral deficits as compared with plKO males and control littermates. Assessment of layer-specific markers in human postmortem cortices suggests that preterm infants may also have female-biased abnormalities in cortical layer specification as compared with term infants. This study establishes a novel and fundamental link between placental function and sex-linked long-term neurological outcomes, emphasizing the importance of the growing field of neuroplacentology.

Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.

Importance: Associations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown. Objective: To examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months. Design, Setting, and Participants: A cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses. Exposures: Maternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic. Main Outcomes and Measures: Outcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months. Results: Of 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267 = 12.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267 = 14.71; P < .005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267 = 6.37; P<.05) subdomains in fully adjusted models. Conclusions and Relevance: In this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.

High-Frequency Positive Pressure Ventilation as Primary Rescue Strategy for Patients with Congenital Diaphragmatic Hernia: A Comparison to High-Frequency Oscillatory Ventilation.

OBJECTIVE: The aim of this article was to evaluate high-frequency positive pressure ventilation (HFPPV) compared with high-frequency oscillatory ventilation (HFOV) as a rescue ventilation strategy for patients with congenital diaphragmatic hernia (CDH). HFPPV is a pressure-controlled conventional ventilation method utilizing high respiratory rate and low positive end-expiratory pressure. STUDY DESIGN: Seventy-seven patients diagnosed with CDH from January 2005 to September 2019 who were treated with stepwise progression from HFPPV to HFOV versus only HFOV were included. Fisher's exact test and the Kruskal-Wallis test were used to compare outcomes. RESULTS: Patients treated with HFPPV + HFOV had higher survival to discharge (80 vs. 50%, p = 0.007) and to surgical intervention (95.6 vs. 68.8%, p = 0.003), with average age at repair 2 days earlier (p = 0.004). Need for extracorporeal membrane oxygenation (p = 0.490), inhaled nitric oxide (p = 0.585), supplemental oxygen (p = 0.341), and pulmonary hypertension medications (p = 0.381) were similar. CONCLUSION: In CDH patients who fail respiratory support with conventional ventilation, HFPPV may be used as an intermediary mode of rescue ventilation prior to HFOV without adverse effects. KEY POINTS: · HFPPV may be used as an intermediary mode of rescue ventilation prior to HFOV without adverse effect.. · HFPPV is more widely available and can mitigate the limitations faced when using HFOV.. · HFPPV allows for intra- or interhospital transfer of neonates with CDH..

A new pipeline for clinico-pathological and molecular placental research utilizing FFPE tissues.

The placenta is at the core of many pregnancy pathologies, but we have limited knowledge about placental function because of two key research barriers: 1) lack of guidelines for sample collection and pathologic diagnosis; and 2) limited tools are available for molecular analysis of stored placental samples. We aimed to create a searchable, population-based placental database of pathologic diagnoses, and to validate molecular methods for gene expression studies of matching formalin fixed paraffin embedded (FFPE) placental blocks. Our database has over 1000 pregnancies coded for clinical diagnosis with corresponding FFPE blocks that are available for gene expression studies. RNA harvested from FFPE tissues is of sufficient quality for downstream applications. We successfully used this pipeline to identify FFPE placenta from term and preterm pregnancies, and compared their gene expression. The establishment of this platform, which links clinicopathological data and molecular gene expression, will increase our understanding of obstetrical diseases.

Placental endocrine function shapes cerebellar development and social behavior.

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

Placental response to maternal SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic affected people at all ages. Whereas pregnant women seemed to have a worse course of disease than age-matched non-pregnant women, the risk of feto-placental infection is low. Using a cohort of 66 COVID-19-positive women in late pregnancy, we correlated clinical parameters with disease severity, placental histopathology, and the expression of viral entry and Interferon-induced transmembrane (IFITM) antiviral transcripts. All newborns were negative for SARS-CoV-2. None of the demographic parameters or placental histopathological characteristics were associated with disease severity. The fetal-maternal transfer ratio for IgG against the N or S viral proteins was commonly less than one, as recently reported. We found that the expression level of placental ACE2, but not TMPRSS2 or Furin, was higher in women with severe COVID-19. Placental expression of IFITM1 and IFITM3, which have been implicated in antiviral response, was higher in participants with severe disease. We also showed that IFITM3 protein expression, which localized to early and late endosomes, was enhanced in severe COVID-19. Our data suggest an association between disease severity and placental SARS-CoV-2 processing and antiviral pathways, implying a role for these proteins in placental response to SARS-CoV-2.

Placental pathology and intraventricular hemorrhage in preterm and small for gestational age infants.

OBJECTIVE: The aim of this study was to examine the relationship between chorioamnionitis and vascular malperfusion on placental pathology and intraventricular hemorrhage (IVH) in premature and small for gestational age (SGA) infants. STUDY DESIGN: A retrospective analysis of 263 infants ≤34 weeks gestation or ≤1800 g and their mothers was conducted by chart review for placental pathology and clinical data from 2014 to 2018. Unadjusted and adjusted odds ratios (OR) for the association of placental pathology with IVH were calculated. RESULT: Unadjusted OR showed an association between acute chorioamnionitis and IVH, but logistic regression analysis showed a non-significant adjusted OR between acute or chronic chorioamnionitis with IVH. Maternal vascular malperfusion was significantly associated with increased IVH when controlling for confounders. CONCLUSION: Placental maternal vascular malperfusion is associated with the development of IVH in premature and SGA infants when controlling for other confounders.

The utility of the fronto-temporal horn ratio on cranial ultrasound in premature newborns: a ventriculomegaly marker.

BACKGROUND: The aims of this study were to find the normal value of fronto-temporal horn ratio (FTHR) as a marker of ventriculomegaly on cranial ultrasound (CUS) in premature newborns and the relation to white matter injury (WMI) and cerebral palsy (CP). METHODS: This is a retrospective study of newborns admitted between 2011 and 2014. Inclusion criteria were: (1) gestation <29 weeks, (2) birth weight ≤1500 g, (3) referred within 7 days of life, (4) at least two CUS preformed, (5) brain magnetic resonance imaging (MRI) at term age-equivalent. Intraventricular hemorrhage (IVH) grade was identified and FTHR was measured on all CUS. WMI on MRI was evaluated through (1) injury score (Kidokoro 2013) and (2) fractional anisotropy (FA) on the MRI diffusion tensor imaging. CP was estimated using the gross motor function classification system (GMFCS). RESULTS: One hundred neonates met the inclusion criteria: 37 with no IVH, 36 with IVH grade 1-2, and 27 with IVH grade 3-4. The FTHR cut-point of 0.51 had the highest sensitivity and specificity for moderate-to-severe WMI. In the IVH grade 3-4 group, the elevated FTHR correlated with lower FA and higher GMFCS. CONCLUSIONS: FTHR is a useful quantitative biomarker of ventriculomegaly in preterm newborns. It may help standardize ventricular measurement and direct intervention. IMPACT: The fronto-temporal horn ratio has the potential to become a standardized tool that can provide an actionable measure to direct intervention for post-hemorrhagic ventricular dilation. This current study will provide the basis of a future clinical trial to optimize intervention timing to decrease the risk of white matter injury in this vulnerable population.

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex.

Developmental changes in GABAergic and glutamatergic systems during frontal lobe development have been hypothesized to play a key role in neurodevelopmental disorders seen in children born very preterm or at/with low birth weight, but the associated cellular changes have not yet been identified. Here we studied the molecular development of the GABAergic system specifically in the dorsolateral prefrontal cortex, a region that has been implicated in neurodevelopmental and psychiatric disorders. The maturation state of the GABAergic system in this region was assessed in human post-mortem brain samples, from term infants ranging in age from 0 to 8 months (n = 17 male, 9 female). Gene expression was measured for 47 GABAergic genes and used to calculate a maturation index. This maturation index was significantly more dynamic in male than female infants. To evaluate the impact of premature birth on the GABAergic system development, samples from 1-month-old term (n = 9 male, 4 female) and 1-month corrected-age very preterm (n = 8 male, 6 female) infants, were compared using the same gene list and methodology. The maturation index for the GABAergic system was significantly lower (-50%, p < 0.05) in male preterm infants, with major alterations in genes linked to GABAergic function in astrocytes, suggesting astrocytic GABAergic developmental changes as a new cellular mechanism underlying preterm brain injury.

Outcomes of Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection at a Large Medical Center in New York City.

Importance: Limited data on vertical and perinatal transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and health outcomes of neonates born to mothers with symptomatic or asymptomatic coronavirus disease 2019 (COVID-19) are available. Studies are needed to inform evidence-based infection prevention and control (IP&C) policies. Objective: To describe the outcomes of neonates born to mothers with perinatal SARS-CoV-2 infection and the IP&C practices associated with these outcomes. Design, Setting, and Participants: This retrospective cohort analysis reviewed the medical records for maternal and newborn data for all 101 neonates born to 100 mothers positive for or with suspected SARS-CoV-2 infection from March 13 to April 24, 2020. Testing for SARS-CoV-2 was performed using Cobas (Roche Diagnostics) or Xpert Xpress (Cepheid) assays. Newborns were admitted to well-baby nurseries (WBNs) (82 infants) and neonatal intensive care units (NICUs) (19 infants) in 2 affiliate hospitals at a large academic medical center in New York, New York. Newborns from the WBNs roomed-in with their mothers, who were required to wear masks. Direct breastfeeding after appropriate hygiene was encouraged. Exposures: Perinatal exposure to maternal asymptomatic/mild vs severe/critical COVID-19. Main Outcomes and Measures: The primary outcome was newborn SARS-CoV-2 testing results. Maternal COVID-19 status was classified as asymptomatic/mildly symptomatic vs severe/critical. Newborn characteristics and clinical courses were compared across maternal COVID-19 severity. Results: In total, 141 tests were obtained from 101 newborns (54 girls [53.5%]) on 0 to 25 days of life (DOL-0 to DOL-25) (median, DOL-1; interquartile range [IQR], DOL-1 to DOL-3). Two newborns had indeterminate test results, indicative of low viral load (2.0%; 95% CI, 0.2%-7.0%); 1 newborn never underwent retesting but remained well on follow-up, and the other had negative results on retesting. Maternal severe/critical COVID-19 was associated with newborns born approximately 1 week earlier (median gestational age, 37.9 [IQR, 37.1-38.4] vs 39.1 [IQR, 38.3-40.2] weeks; P = .02) and at increased risk of requiring phototherapy (3 of 10 [30.0%] vs 6 of 91 [7.0%]; P = .04) compared with newborns of mothers with asymptomatic/mild COVID-19. Fifty-five newborns were followed up in a new COVID-19 Newborn Follow-up Clinic at DOL-3 to DOL-10 and remained well. Twenty of these newborns plus 3 newborns followed up elsewhere had 32 nonroutine encounters documented at DOL-3 to DOL-25, and none had evidence of SARS-CoV-2 infection, including 6 with negative retesting results. Conclusions and Relevance: No clinical evidence of vertical transmission was identified in 101 newborns of mothers positive for or with suspected SARS-CoV-2 infection, despite most newborns rooming-in and direct breastfeeding practices.

Infection prevention and control for labor and delivery, well baby nurseries, and neonatal intensive care units.

During the early months of the COVID-19 pandemic, infection prevention and control (IP&C) for women in labor and mothers and newborns during delivery and receiving post-partum care was quite challenging for staff, patients, and support persons due to a relative lack of evidence-based practices, high rates of community transmission, and shortages of personal protective equipment (PPE). We present our IP&C policies and procedures for the obstetrical population developed from mid-March to mid-May 2020 when New York City served as the epicenter of the pandemic in the U.S. For patients, we describe screening for COVID-19, testing for SARS-CoV-2, and clearing patients from COVID-19 precautions. For staff, we address self-monitoring for symptoms, PPE in different clinical scenarios, and reducing staff exposures to SARS-CoV-2. For visitors/support persons, we address limiting them in labor and delivery, the postpartum units, and the NICU to promote staff and patient safety. We describe management of SARS-CoV-2-positive mothers and their newborns in both the well-baby nursery and in the neonatal ICU. Notably, in the well-baby nursery we do not separate SARS-CoV-2-positive mothers from their newborns, but emphasize maternal mask use and social distancing by placing newborns in isolates and asking mothers to remain 6 feet away unless feeding or changing their newborn. We also encourage direct breastfeeding and do not advocate early bathing. Newborns of SARS-CoV-2-positive mothers are considered persons under investigation (PUIs) until 14 days of life, the duration of the incubation period for SARS-CoV-2. We share two models of community-based care for PUI neonates. Finally, we provide our strategies for enhancing communication and education during the early months of the pandemic.

Care of the COVID-19 exposed complex newborn infant.

As we confront COVID-19, the global public health emergency of our times, new knowledge is emerging that, combined with information from prior epidemics, can provide insights on how to manage this threat in specific patient populations. Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), both caused by coronaviruses, caused serious respiratory illness in pregnant women that resulted in adverse perinatal outcomes. Thus far, COVID-19 appears to follow a mild course in the vast majority of pregnant women. A significant proportion of pregnant women appear to be asymptomatic carriers of SARS-CoV-2. However, there is limited information on how COVID-19 impacts the fetus and whether vertical transmission occurs. While these knowledge gaps are addressed, it is important to recognize the highly efficient transmission characteristics of SARS-C0V-2 and its potential for causing serious disease in vulnerable individuals, including health care workers. This review provides perspectives from a single center in New York City, the epicenter of the pandemic within the United States. It offers an overview of the preparations required for deliveries of newborns of mothers with COVID-19 and the management of neonates with particular emphasis on those born with complex issues.

A review of newborn outcomes during the COVID-19 pandemic.

As the COVID-19 pandemic continues to spread worldwide, it is crucial that we determine populations that are at-risk and develop appropriate clinical care policies to protect them. While several respiratory illnesses are known to seriously impact pregnant women and newborns, preliminary data on the novel SARS-CoV-2 Coronavirus suggest that these groups are no more at-risk than the general population. Here, we review the available literature on newborns born to infected mothers and show that newborns of mothers with positive/suspected SARS-CoV-2 infection rarely acquire the disease or show adverse clinical outcomes. With this evidence in mind, it appears that strict postnatal care policies, including separating mothers and newborns, discouraging breastfeeding, and performing early bathing, may be more likely to adversely impact newborns than they are to reduce the low risk of maternal transmission of SARS-CoV-2 or the even lower risk of severe COVID-19 disease in otherwise healthy newborns.

Ultrasound-Based Phenotyping of Lateral Ventricles to Predict Hydrocephalus Outcome in Premature Neonates.

OBJECTIVE: Prediction of post-hemorrhagic hydrocephalus (PHH) outcome-i.e., whether it requires intervention or not-in premature neonates using cranial ultrasound (CUS) images is challenging. In this paper, we present a novel fully-automatic method to perform phenotyping of the brain lateral ventricles and predict PHH outcome from CUS. METHODS: Our method consists of two parts: ventricle quantification followed by prediction of PHH outcome. First, cranial bounding box and brain interhemispheric fissure are detected to determine the anatomical position of ventricles and correct the cranium rotation. Then, lateral ventricles are extracted using a new deep learning-based method by incorporating the convolutional neural network into a probabilistic atlas-based weighted loss function and an image-specific adaption. PHH outcome is predicted using a support vector machine classifier trained using ventricular morphological phenotypes and clinical information. RESULTS: Experiments demonstrated that our method achieves accurate ventricle segmentation results with an average Dice similarity coefficient of 0.86, as well as very good PHH outcome prediction with accuracy of 0.91. CONCLUSION: Automatic CUS-based ventricular phenotyping in premature newborns could objectively and accurately predict the progression to severe PHH. SIGNIFICANCE: Early prediction of severe PHH development in premature newborns could potentially advance criteria for diagnosis and offer an opportunity for early interventions to improve outcome.

Placental programming of neuropsychiatric disease.

The placenta is vital for fetal growth, and compromised function is associated with abnormal development, especially of the brain. Linking placental function to brain development is a new field we have dubbed neuroplacentology. Approximately 380,000 infants in the United States each year abruptly lose placental support upon premature birth, and more than 10% of pregnancies are affected by more insidious placental dysfunction such as preeclampsia or infection. Abnormal fetal brain development or injury can lead to life-long neurological impairments, including psychiatric disorders. The majority of research connecting placental compromise to fetal brain injury has focused on gas exchange or nutritional programming, neglecting the placenta's essential neuroendocrine role. We will review the current evidence that placental dysfunction, particularly endocrine dysfunction, secretion of pro-inflammatory cytokines, or barrier breakdown may place many thousands of fetuses at risk for life-long neurodevelopmental impairments each year. Understanding how specific placental factors shape brain development and increase the risk for later psychiatric disorders, including autism, attention deficit disorder, and schizophrenia, paves the way for novel treatment strategies to maintain the normal developmental milieu and protect from further injury.

Impaired Interneuron Development in a Novel Model of Neonatal Brain Injury.

Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism and schizophrenia. A common feature of these psychiatric disorders is prefrontal cortex (PFC) inhibitory circuit disruption due to GABAergic interneuron alteration. Cortical interneurons are generated and migrate throughout late gestation and early infancy, making them highly susceptible to perinatal insults such as preterm birth. Term and preterm PFC pathology specimens were assessed using immunohistochemical markers for interneurons. Based on the changes seen, a new preterm encephalopathy mouse model was developed to produce similar PFC interneuron loss. Maternal immune activation (MIA; modeling chorioamnionitis, associated with 85% of extremely preterm births) was combined with chronic sublethal hypoxia (CSH; modeling preterm respiratory failure), with offspring of both sexes assessed anatomically, molecularly and neurobehaviorally. In the PFC examined from the human preterm samples compared to matched term samples at corrected age, a decrease in somatostatin (SST) and calbindin (CLB) interneurons was seen in upper cortical layers. This pattern of interneuron loss in upper cortical layers was mimicked in the mouse PFC following the combination of MIA and CSH, but not after either insult alone. This persistent interneuron loss is associated with postnatal microglial activation that occurs during CSH only after MIA. The combined insults lead to long-term neurobehavioral deficits which parallel human psychopathologies that may be seen after extremely preterm birth. This new preclinical model supports a paradigm in which specific cellular alterations seen in preterm encephalopathy can be linked with a risk of neuropsychiatric sequela. Specific interneuron subtypes may provide therapeutic targets to prevent or ameliorate these neurodevelopmental risks.

Ventricular shape evaluation on early ultrasound predicts post-hemorrhagic hydrocephalus.

BACKGROUND: To compare the ability of ventricular morphology on cranial ultrasound (CUS) versus standard clinical variables to predict the need for temporizing cerebrospinal fluid drainage in newborns with intraventricular hemorrhage (IVH). METHOD: This is a retrospective study of newborns (gestational age <29 weeks) diagnosed with IVH. Clinical variables known to increase the risk for post-hemorrhagic hydrocephalus were collected. The first CUS with IVH was identified and a slice in the coronal plane was selected. The frontal horns of the lateral ventricles were manually segmented. Automated quantitative morphological features were extracted from both lateral ventricles. Predictive models of the need of temporizing intervention were compared. RESULTS: Sixty-two newborns met inclusion criteria. Fifteen out of the 62 had a temporizing intervention. The morphological features had a better accuracy predicting temporizing interventions when compared to clinical variables: 0.94 versus 0.85, respectively; p < 0.01 for both. By considering both morphological and clinical variables, our method predicts the need of temporizing intervention with positive and negative predictive values of 0.83 and 1, respectively, and accuracy of 0.97. CONCLUSION: Early cranial ultrasound-based quantitative ventricular evaluation in premature newborns can predict the eventual use of a temporizing intervention to treat post-hemorrhagic hydrocephalus. This may be helpful for early monitoring and treatment.

Automatic Segmentation of Neonatal Ventricles from Cranial Ultrasound for Prediction of Intraventricular Hemorrhage Outcome.

Intraventricular hemorrhage (IVH) followed by post hemorrhagic hydrocephalus (PHH) in premature neonates is one of the recognized reasons of brain injury in newborns. Cranial ultrasound (CUS) is a noninvasive imaging tool that has been used widely to diagnose and monitor neonates with IVH. In our previous work, we showed the potential of quantitative morphological analysis of lateral ventricles from early CUS to predict the PHH outcome in neonates with IVH. In this paper, we first present a new automatic method for ventricle segmentation in 2D CUS images. We detect the brain bounding box and brain mid-line to estimate the anatomical positions of ventricles and correct the brain rotation. The ventricles are segmented using a combination of fuzzy c-means, phase congruency, and active contour algorithms. Finally, we compare this fully automated approach with our previous work for the prediction of the outcome of PHH on a set of 2D CUS images taken from 60 premature neonates with different IVH grades. Experimental results showed that our method could segment ventricles with an average Dice similarity coefficient of 0.8 ± 0.12. In addition, our fully automated method could predict the outcome of PHH based on the extracted ventricle regions with similar accuracy to our previous semi-automated approach (83% vs. 84%, respectively, p-value = 0.8). This method has the potential to standardize the evaluation of CUS images and can be a helpful clinical tool for early monitoring and treatment of IVH and PHH.