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• The placenta is the first organ to form in mammals and is required for establishment of a maternal–fetal vascular interface capable of supplying the bioenergetic needs of the developing conceptus. • Multiple placental cell types engage in highly varied functions, from attachment, invasion, and vascular remodeling to cell fusion, hormone production, and nutrient transport. • Multiple mechanisms allow transport of waste and nutrients across the placenta, including diffusion, transporter protein-mediated (facilitated diffusion and active transporters), and receptor-mediated mechanisms. • The placenta is not an inert transport interface. It consumes 40%–60% of the oxygen and glucose delivered to the uterus at term. Thus conditions that alter placental metabolism can indirectly affect nutrient transport to the fetus. • Maternal and fetal health alter placental function, which in turn influences fetal adaptations and contributes to in utero fetal programming. • Abnormal placentation and placental infections can lead to preeclampsia (PE), fetal growth retardation, or preterm birth, which can have lifelong bearing on health. • In the United States, iatrogenic delivery is responsible for almost half the births that occur between 28 and 37 weeks of gestation, primarily caused by placental pathologies such as PE or intrauterine growth restriction. • Efforts to standardize placental examination after delivery are in progress so that connections between specific placental problems and poor outcomes can be better defined. In parallel, new advanced imaging techniques and biomarkers for placental function are being developed.

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 dysfunction has been implicated in abnormal neurodevelopment. Vacher et al. found that loss of a neuroactive hormone from the placenta alters brain development in a regional and sex-linked manner, resulting in autism-like behaviors in male offspring.

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

ImportanceAssociations 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.ObjectiveTo 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 ParticipantsThis 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.ExposuresMaternal symptomatic or asymptomatic SARS-CoV-2 infection.Main Outcomes and MeasuresInfant 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.ResultsAmong 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 (β = 0.31; 95% CI, −2.97 to 3.58), gross motor (β = 0.82; 95% CI, −1.34 to 2.99), fine motor (β = 0.36; 95% CI, −0.74 to 1.47), expressive language (β = −1.00; 95% CI, −4.02 to 2.02), or receptive language (β = 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 RelevanceIn 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.

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; F(1,267) = 12.63; P

ispartof: J Neonatal Perinatal Med vol:15 issue:2 pages:411-426 ispartof: location:Netherlands status: published

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.

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.

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.

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).This is a retrospective study of newborns admitted between 2011 and 2014. Inclusion criteria were: (1) gestation29 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).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.FTHR is a useful quantitative biomarker of ventriculomegaly in preterm newborns. It may help standardize ventricular measurement and direct intervention.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.

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.

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.

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). This is a retrospective study of newborns (gestational age

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders 1,2. The placenta is the first functional foetal endocrine organ, but the direct impact of placental hormone loss on foetal brain in late gestation has not been empirically tested. Allopregnanolone (ALLO) is a non-glucocorticoid, progesterone derivative that acts as a positive modulator of GABA-A receptor activity3 with the potential to alter critical GABA-mediated developmental processes 4,5. To directly test the role of placental ALLO, we generated a novel mouse model in which the gene encoding the synthetic enzyme for ALLO (Akr1c14) is specifically deleted in trophoblasts using a tissue-specific Cre-Lox strategy. ALLO concentrations are significantly decreased in late gestation in placenta and brain when placental Akr1c14 is removed, indicating placenta as the primary gestational ALLO source. We now demonstrate that targeted placental ALLO loss leads to permanent changes in brain development in a sex- and regionally-specific manner. Placental ALLO insufficiency led to male-specific cerebellar white matter (WM) abnormalities characterized by excess myelination with increased myelin protein expression, similar to changes reported in boys with autism spectrum disorders (ASD)6,7. Behavioural testing of these mice revealed increased repetitive behaviour and sociability deficits, two hallmarks of ASD, only in male offspring with placental ALLO insufficiency. Notably, a strong positive correlation was seen between the cerebellar contents of myelin basic protein (MBP) and the severity of ASD-like behaviours. A single injection of ALLO during gestation was sufficient to rescue both cerebellar MBP levels and aberrant behaviours. This study reveals a new role for a placental hormone in shaping specific brain structures and behaviours, and suggests that identifying placental hormone insufficiency or preterm loss may offer novel therapeutic opportunities to prevent later neurobehavioural disorders.

A major goal of neonatal medicine is to identify neonates at highest risk for morbidity and mortality. Previously, we developed PhysiScore (Saria et al., 2010), a novel tool for preterm morbidity risk prediction. We now further define links between overall individual morbidity risk, specific neonatal morbidities, and placental pathologies.102 placentas, including 38 from multiple gestations, were available from the previously defined PhysiScore cohort (gestational age ≤ 34 weeks and birth weight ≤ 2000 g). Placentas were analyzed for gross and histologic variables including maternal malperfusion, amniotic fluid infection sequence, chronic inflammation, and fetal vascular obstruction. Risk as determined by PhysiScore and recorded neonatal morbidities were tested for statistical association with placental findings.In pair-wise correlations, respiratory distress syndrome, bronchopulmonary dysplasia, acute hemodynamic instability, post-hemorrhagic hydrocephalus, culture-positive sepsis, and necrotizing enterocolitis each significantly correlated with at least one placenta histology variable. Amniotic fluid infection sequence (p = 0.039), specifically the fetal inflammatory response (p = 0.017), correlated with higher PhysiScores (greater morbidity) but was not independent of gestational age and birth weight. In multivariate analyses correlating variables with all nine morbidities, gestational age (p 0.001), placental size10th percentile (p = 0.031), full thickness perivillous fibrin deposition (p = 0.001), and amniotic fluid infection sequence (umbilical arteritis, p = 0.031; ≥2 chorionic plate vessels with vasculitis, p = 0.0125), each were significant associations.Amniotic fluid infection sequence plays a significant role in neonatal morbidity. Less neonatal morbidity was observed in older and heavier infants and those with small placental size and full thickness perivillous fibrin deposition. The combined assessment of placental gross and histologic findings together with physiologic risk evaluation may allow more precise prediction of neonatal morbidity risk soon after delivery.

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.

Background Extreme variation in provider nutritional practices in the NICU leads to poor growth of premature infants. Standardization of current feeding practices through quality improvement may improve growth trajectory and developmental outcomes. Objectives Increase the mean delta Z score for weight (difference in z-score between birth weight and discharge weight) from −1.8 to −1 within 6 months and sustain for 1 year, for neonates with birth weight (BW) Methods A multidisciplinary team evaluated nutrition practices for VLBW infants and key drivers were determined (figure 1). Re-education around our current feeding protocol and intolerance decision aid, sharing growth information during rounds using an in-house assessment tool (figure 2), increased accessibility to breast pump rentals, standardization of lactation consultation ordering, and development of an infographic to assist mothers in choosing breast milk over formula (figure 3) were interventions tested using the IHI Model for Improvement. Mean delta Z score for weight (primary outcome measure) and number of lactation consultation orders per week (process measure) were recorded and analyzed. Results Mean delta weight Z-score increased from −1.8 to −1.08 (figure 4) following the implementation of all of the noted interventions with centerline shift that has lasted for 8 months (40% improvement). Mean number of lactation consults ordered per week increased from 1 to 4. Conclusions Reducing nutrition practice variation shows marked improvements in infant nutrition status. We continue to test other interventions with the hope of further decreasing growth failure.

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.

Premature neonates with intraventricular hemorrhage (IVH) followed by post hemorrhagic hydrocephalus (PHH) are at high risk for brain injury. Cranial ultrasound (CUS) is used for monitoring of premature neonates during the first weeks after birth to identify IVH and follow the progression to PHH. However, the lack of a standardized method for CUS evaluation has led to significant variability in decision making regarding treatment. We propose a quantitative imaging tool for the evaluation of PHH on CUS for premature neonates based on morphological features of the cerebral ventricles. We retrospectively studied 64 extremely premature neonates born less than 29 weeks gestational age, less than 1,500 grams weight at birth, admitted to our center within two weeks of life, and diagnosed with different grades of IVH. We extracted morphological features of the lateral ventricles from CUS imaging using image analysis techniques to compare neonates who needed a temporizing intervention to treat PHH to the ones who did not. From the original set of features, an optimal ranking was obtained based on linear support vector machine. A subset of features was subsequently selected that maximizes the overall accuracy level. Regarding whether or not there was a need for temporizing intervention, we predicted the outcome of PHH with an improved accuracy level of 84%, compared to the 76% rate obtained by linear manual measurement. The proposed imaging tool allowed us to establish a quantitative method for PHH evaluation on CUS in extremely premature neonates with IVH. Further studies will help standardize the evaluation of CUS in those neonates to institute treatments earlier and improve outcomes.

To elucidate and categorize the murine placental hormones expressed across gestation, including the expression of hormones with previously undescribed roles.Expression levels of all genes with known or predicted hormone activity expressed in two separate tissues, the placenta and maternal decidua, were assessed across a timecourse spanning the full lifetime of the placenta. Novel expression patterns were confirmed by in situ hybridization and protein level measurements.A combination of temporal and spatial information defines five groups that can accurately predict the patterns of uncharacterized hormones. Our analysis identified Secretin, a novel placental hormone that is expressed specifically by the trophoblast at levels many times greater than in any other tissue.The characteristics of Secretin fit the paradigm of known placental hormones and suggest that it may play an important role during pregnancy.

Male sex is an independent risk factor for long-term neurologic deficits in human preterm infants. Using a chronic, sublethal hypoxia (CSH) mouse model of preterm brain injury, we recently demonstrated acute brain volume loss with an increased male susceptibility to hippocampal volume loss and hypomyelination. We now characterize the long-term, sex-specific effects of CSH on cognition and brain growth. Neonatal mice were treated with CSH for 8 d, raised in normoxia thereafter and underwent behavioral testing at 6 wk of age. Behavioral assays sensitive to hippocampal function were chosen. CSH-treated males had impairments in associative learning, spatial memory, and long-term social memory compared with control males. In contrast, CSH-treated females were less impaired. Persistent reductions in hippocampal and cerebellar volumes were found in adult CSH-treated males, whereas regional brain volumes in adult CSH-treated females were indistinguishable from controls. Similar to human preterm infants, males exposed to hypoxia are especially vulnerable to short-term and long-term deficits in cognition and brain growth.

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.

In adults and in very preterm neonates, systemic infection is a well-recognised cause of encephalopathy. Although the manifestations of encephalopathy are very similar in the fetal inflammatory response and in acute hypoxic-ischaemic events, neonatal encephalopathy (NE) in term infants is more often attributed primarily to hypoxia-ischaemia rather than to infection. Is systemic infection an important etiological factor in NE in term and late preterm infants? A striking 1999 case report1 showed that placental infection with group B streptococcus can cause NE and that the clinical picture can closely mimic both immediate and later signs commonly assumed to indicate birth asphyxia. Many other reports describe associations of placental infections with encephalopathy in term neonates, suggesting that infection, or the resulting inflammation, can indeed underlie NE without an associated sentinel event causing asphyxia. This brief discussion considers the evidence of an infection-NE association, the difficulty of distinguishing infectious from non-infectious inflammation and the way forward. Most of the evidence relating infection to NE has concerned infections identified during the admission for delivery, usually defined histologically in the placenta, or clinically. Histological evidence includes chorioamnionitis, which is inflammation on the maternal side of the placenta and funisitis on the fetal side, with infiltration of the umbilical cord with inflammatory cells. Clinical evidence of infection includes maternal fever in labour, uterine tenderness, purulent discharge or fetal tachycardia. A third approach to identifying placental infection is by microbiological evaluation. Unfortunately, results of these approaches are often not in agreement,2 ,3 and multiple identification methods are rarely used in the same study. McDonald et al 4 compared placentas of 93 infants with NE with placentas of normal term controls (n=816) and of random controls (n=387), finding funisitis in 31.2% of NE placentas versus 5.4% and 4.4% of controls (p=0.002). Chorioamnionitis and villitis were …

We evaluated the impact of uteroplacental insufficiency (UPI), and subsequent intrauterine growth restriction (IUGR), on serum testosterone and hippocampal expression of Cyp19a1 variants and aromatase in rats. Additionally, we determined UPI induced histone modification of the promoter regions of Cyp19a1 variants using chromatin immunoprecipitation. Cyp19a1 is the gene encoding the protein aromatase, that catalyzes the biosynthesis of estrogens from androgens and is necessary for masculinization of the brain. IUGR was induced via bilateral uterine artery. UPI increased serum testosterone in day of life 0 (D(0)) and day of life 21 (D(21)) IUGR males to 224% and 299% of control values, respectively. While there was no significant impact of UPI on testosterone in D(0) females, testosterone in D(21) IUGR females was 187% of controls. Cyp19a1 variant 1.f and variant II are expressed in the rat hippocampus at D(0) and D(21). UPI significantly reduced expression of Cyp19a1 variant 1.f in D(0) males, with no impact in females. Similarly at D(0), UPI reduced expression of aromatase, the protein encoded by Cyp19a1, in males. Dimethylation of H3K4 was increased in the promoter region of variant 1.f (P1.f) and trimethylation of H3K4 was decreased in the promoter region of variant II (PII). At D(21), dimethylation of H3K4 is significantly reduced in PII of IUGR males. We conclude that UPI increases serum testosterone and reduces Cyp19a1 variant 1.f expression in the hippocampus of D(0) IUGR males. Additionally, UPI alters the chromatin structure of CYP19a1 at both D(0) and D(21).

The placenta long has been underappreciated and understudied by the scientific community. Improper function of this critical organ causes fetal abnormalities, preterm labor, and the most common disease of pregnancy, preeclampsia. Despite the importance of the placenta, understanding of its role in fetal development, especially at a molecular level, is crude. Sadly, understanding of placental function may be compared with the knowledge of kidney function 50 years ago in that researchers can describe the anatomy but not the biology. As an endocrine organ, the placenta produces a wide array of hormones that affect both mother and fetus as well as the development of the placenta itself. Most research on placental endocrinology has focused either on parameters of fetal growth or placentally induced changes in maternal physiology that support pregnancy. The possibility that placental hormones may have direct effects on the developing fetus deserves increased attention. Placental endocrine function can be disrupted by abnormal gene expression, infection, or prematurity, resulting in long-term damage from loss of the normal hormonal milieu. In this review, we focus on placental endocrine function related to fetal well-being, particularly neurodevelopment. Better understanding of this function may open new avenues to therapeutic treatments to improve developmental outcome in fetuses and infants at high risk of developmental brain damage.

Male sex is a well-established risk factor for poor neurodevelopmental outcome after premature birth. The mechanisms behind this sex-related difference are unknown. The damage associated with prematurity can be mimicked in rodents by prolonged exposure to sublethal postnatal hypoxia. This chronic hypoxia leads to anatomical changes in mice that strongly resemble the loss of volume, decreased myelination, and ventriculomegaly seen in preterm newborns. However, no sex differences have been previously noted in this rodent model. We hypothesized that sex comparisons in hypoxic mice would show sex-related differences in brain volume and white matter loss in response to the same degree of hypoxic insult. Mice were placed in chronic sublethal hypoxia from postnatal day 3-11. Cortical, hippocampal, and cerebellar volumes and myelination indices were measured. We found that the male hippocampus, normally larger than the female, undergoes a greater volume loss compared with females (p < 0.05). Myelination, generally greater in males, was significantly disrupted by hypoxia in neonatal male forebrain. These results support the use of this rodent model to investigate the basis of sex-related susceptibility to brain damage and develop new sex-based neuroprotective strategies.

Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N = 20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r = 0.73, p = 0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r = 0.75, p = 0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

When contacts are first forming in the developing nervous system, many neurons generate spontaneous activity that has been hypothesized to shape appropriately patterned connections. In Mustela putorius furo , monocular intraocular blockade of spontaneous retinal waves of action potentials by cholinergic agents altered the subsequent eye-specific lamination pattern of the lateral geniculate nucleus (LGN). The projection from the active retina was greatly expanded into territory normally belonging to the other eye, and the projection from the inactive retina was substantially reduced. Thus, interocular competition driven by endogenous retinal activity determines the pattern of eye-specific connections from retina to LGN, demonstrating that spontaneous activity can produce highly stereotyped patterns of connections before the onset of visual experience.

Oxytocin (OT) has been linked to social behavior in rodents, non-human primates, and adult humans, but almost nothing is known about brain OT activity in human newborns or its impact on social development. To better understand the role of OT biology in human social functioning, a multi-disciplinary, longitudinal study was conducted. Cerebral spinal fluid (CSF) OT levels from 18 human neonates were evaluated and examined in relationship to social-seeking behavior at term, at 3 months, and at 6 months of age. Higher neonatal CSF OT levels were consistently associated with solicitation of parental soothing and interest in social engagement with others. This is the first study to link CSF OT levels to normative human social functioning. Research is now required to test whether early OT levels serve as a biomarker for subsequent social abnormalities.

Before vision, retinal ganglion cells produce spontaneous waves of action potentials. A crucial question is whether this spontaneous activity is transmitted to lateral geniculate nucleus (LGN) neurons. Using a novel in vitro preparation, we report that LGN neurons receive periodic barrages of postsynaptic currents from the retina that drive them to fire bursts of action potentials. Groups of LGN neurons are highly correlated in their firing. Experiments in wild-type and NMDAR1 knockout mice show that NMDA receptor activation is not necessary for firing. The transmission of the highly correlated retinal activity to the LGN supports the hypothesis that retinal waves drive retinogeniculate synaptic remodeling. Because LGN neurons are driven to fire action potentials, this spontaneous activity could also act more centrally to influence synaptic modification within the developing visual cortex.

Neonatal jaundice can represent a benign physiologic process or be the harbinger of serious illness with associated severe neurotoxicity. The neurological manifestations of kernicterus, a condition resulting from the deposition of unconjugated bilirubin in the central nervous system, are rarely seen in modern neonatal care, but jaundice, which reflects elevated serum bilirubin levels, is one of the most common findings in the neonatal period.1 More than half of all term infants will develop some neonatal jaundice and at least 6% will have a serum bilirubin concentration above 12.9 mg/dL.2 The appropriate treatment of hyperbilirubinemia is currently a topic of much debate in pediatrics, particularly treatment of full term infants without risk factors for hemolytic disease.3,4

Integrating easy-to-extract structured information such as medication and treatments into current natural language processing based systems can significantly boost coding performance; in this paper, we present a system that rigorously attempts to validate this intuitive idea. Based on recent i2b2 challenge winners, we derive a strong language model baseline that extracts patient outcomes from discharge summaries. Upon incorporating additional clinical cues into this language model, we see a significant boost in performance to F1 of 88.3 and a corresponding reduction in error of 23.52%.

Physiological data are routinely recorded in intensive care, but their use for rapid assessment of illness severity or long-term morbidity prediction has been limited. We developed a physiological assessment score for preterm newborns, akin to an electronic Apgar score, based on standard signals recorded noninvasively on admission to a neonatal intensive care unit. We were able to accurately and reliably estimate the probability of an individual preterm infant's risk of severe morbidity on the basis of noninvasive measurements. This prediction algorithm was developed with electronically captured physiological time series data from the first 3 hours of life in preterm infants (or =34 weeks gestation, birth weightor =2000 g). Extraction and integration of the data with state-of-the-art machine learning methods produced a probability score for illness severity, the PhysiScore. PhysiScore was validated on 138 infants with the leave-one-out method to prospectively identify infants at risk of short- and long-term morbidity. PhysiScore provided higher accuracy prediction of overall morbidity (86% sensitive at 96% specificity) than other neonatal scoring systems, including the standard Apgar score. PhysiScore was particularly accurate at identifying infants with high morbidity related to specific complications (infection: 90% at 100%; cardiopulmonary: 96% at 100%). Physiological parameters, particularly short-term variability in respiratory and heart rates, contributed more to morbidity prediction than invasive laboratory studies. Our flexible methodology of individual risk prediction based on automated, rapid, noninvasive measurements can be easily applied to a range of prediction tasks to improve patient care and resource allocation.