Association of enlarged extra-axial spaces and subdural hemorrhage in preterm infants at term-equivalent age.

To determine the incidence of enlarged extra-axial space (EES) and its association with subdural hemorrhage (SDH) in a regional cohort of preterm infants. As part of a prospective cohort study of 395 preterm infants, brain magnetic resonance imaging (MRI) was collected on each infant at term-equivalent age. Six preterm infants showed evidence of SDH. We reviewed the MRIs to identify the incidence of EES in these 6 infants and the cohort broadly. We then completed a retrospective chart review of the 6 infants to identify any concerns for non-accidental trauma (NAT) since the MRI was obtained. The incidence of SDH in the cohort was 1.6%. The incidence of EES was 48.1% including all 6 infants with SDH. The incidence of SDH in infants with EES was 3.2%. The retrospective chart review of the 6 infants did not yield any evidence of NAT. The incidence of EES and SDH in our cohort was significantly higher than similar cohorts of term infants, demonstrating an increased risk in preterm infants. The incidence of SDH in infants with EES was greater than in the total cohort, suggesting that it is a risk factor for asymptomatic SDH in preterm infants.

Impact of Screening and Co-located Parent Coaching Within Pediatric Primary Care on Child Health Care Use: A Stepped Wedge Design.

Childhood adversity and toxic stress have been associated with poor mental and physical health. This study examined if Parent Connext, a program that integrates adversity screening and parent coaching by co-located specialists within pediatric primary care, had an impact on health care utilization. This stepped wedge cluster randomized controlled trial evaluated Parent Connext across six pediatric primary care practices. All practices (clusters) were in the control period during year 1. Three practices were randomized to begin the Parent Connext intervention in year 2, and three practices were randomized to begin in year 3. Medical records of all patients under age 8 treated at these practices during these 3 years were queried retrospectively for participant-level primary outcomes (sick visits, emergency department visits, hospitalizations) and secondary outcomes (well-child and immunization adherence, referrals). The study sample included 27,419 patients followed for an average 1.39 (SD = 0.66) years in the control period and 1.07 (SD = 0.60) years in the intervention period. During the intervention period, patients had significantly fewer sick visits (IRR = 0.91, p < 0.001) which aligned with our hypothesis, decreased odds of well-child visit adherence (OR = 0.88, p < 0.001) which was unexpected, and increased odds of receiving a referral (OR = 1.45, p < 0.001). The odds of an emergency department visit, hospitalization, and 2-year immunization adherence did not differ between periods. Parent Connext resulted in a significant reduction in child sick visits, highlighting the potential benefit of two-generation approaches to pediatric care for child health.

Identification of Initial and Subsequent Injury in Young Infants: Opportunities for Quality Improvement in the Evaluation of Child Abuse.

METHODS: Six children's hospitals identified infants with an initial injury and recurrent injury over a 1-year period using 2 methods: (1) diagnostic code method - infants 6 months or younger presenting with at least 1 diagnostic code for injury were tracked for 12 months to determine the frequency of recurrent injury, and (2) consult method - all available medical records of children 18 months or younger seen for an inpatient consultation for suspected child abuse were reviewed to identify history of a first injury at 6 months or younger. RESULTS: Using the diagnostic code method, 682 unique infants were identified with initial injuries, most commonly fractures (37.0%), bruising/ecchymosis (35.9%), and superficial injuries (28.3%). Forty-two infants (6.2%) returned with a second injury, and no demographic factors were significantly associated with the likelihood of a second injury. Using the consult method, 37 of 342 consults (10.8%) were identified as having a history of at least 1 initial injury. Of the initial injuries identified, the most common was bruising/ecchymosis (64.9%). The number of injuries identified with either method varied significantly across hospitals, as did completion of skeletal surveys for infants with bruising (range, 4.5%-71.1%; P < 0.001) and any injury (range, 4.4%-62.7%; P < 0.001). CONCLUSIONS: Our study demonstrates that young infants who experience 1 injury often experience a second injury. There exists significant variability in the identification of injury and the completion of skeletal surveys across a network of 6 children's hospitals. A standardized quality improvement approach may improve identification of injury and reduce the variability in practice observed.

Providers' Ability to Identify Sentinel Injuries Concerning for Physical Abuse in Infants.

OBJECTIVES: The objectives of this study were to assess the ability of pediatric health care providers and social workers to recognize sentinel injuries in infants under 6 months of age and to determine what factors influence their decision to evaluate for physical abuse. METHODS: A statewide collaborative focused on sentinel injuries administered a survey to pediatric health care providers and social workers in the emergency department, urgent care, and primary care. The survey contained 8 case scenarios of infants under 6 months of age with an injury, and respondents were asked if they would consider the injury to be a sentinel injury requiring a physical abuse evaluation. Respondents were then presented with several factors and asked how much each influences the decision to perform a physical abuse evaluation. RESULTS: A total of 565 providers completed the survey. Providers had moderate interrater reliability on their classification of the cases as sentinel injuries or not (κ = 0.57). Nearly all respondents (97%) recognized genital bruising as a sentinel injury, whereas 77% of respondents recognized intraoral injuries. Agreement was highest among social workers (κ = 0.76) and physicians with categorical pediatrics training and pediatric emergency medicine fellowship (κ = 0.63) and lowest among nurse practitioners (κ = 0.48) and residents (κ = 0.51). Concern over missing the diagnosis of abuse had the greatest influence on the decision to perform a physical abuse evaluation. CONCLUSIONS: Sentinel injuries are not uniformly recognized as potential signs of child abuse requiring further evaluation by pediatric health care providers. Additional evidence and education are needed regarding sentinel injuries.

Chlamydia Conjunctivitis in 2 Prepubertal Children: An Uncommon Presentation of Child Sexual Abuse.

Sexually transmitted infection as the result of child sexual abuse in prepubertal children is uncommon. Chlamydia trachomatis conjunctivitis is an even less common entity in prepubertal children outside the newborn period. This report details the presentation of 2 children with conjunctivitis who were subsequently diagnosed as having C. trachomatis conjunctivitis. One child was also diagnosed as having rectal and pharyngeal C. trachomatis infection, and the other also had genital C. trachomatis infection. Even with multisite C. trachomatis infection as an indication of sexual abuse, neither child gave a detailed disclosure of abuse to account for their infections. The absence of a clear disclosure is not uncommon. Previous literature reports that a disclosure in these circumstances occurs in less than half of cases. In this report, we review the recommendations for diagnosis of C. trachomatis using nucleic acid amplification testing and culture as well as treatment. Specific clinical features should alert the clinician to C. trachomatis conjunctivitis and lead to timely diagnosis and protection of the child from further sexual abuse.

Caution Is Required When Using Non-Food and Drug Administration-Cleared Assays to Diagnose Sexually Transmitted Infections in Children.

Nucleic acid amplification testing is the gold-standard for Chlamydia trachomatis and Neisseria gonorrhoeae testing in adults. We present 3 pediatric cases in which testing resulted in probable false-positive results. Clinicians should avoid tests without clearance from a regulatory agency and should maintain consistent communication with laboratories.

Parental Adverse Childhood Experiences and Pediatric Healthcare Use by 2 Years of Age.

OBJECTIVE: To determine whether maternal and paternal exposure to adverse childhood experiences (ACEs) has an association with offspring healthcare use by 2 years of age. STUDY DESIGN: A retrospective cohort study was performed on 454 patients at a large suburban pediatric primary care practice whose mother (n = 374) or father (n = 156) or both (n = 123) completed an ACE survey between October 2012 and June 2014. The association between self-reported parental ACEs and healthcare use by 2 years of age, including number of missed well-child visits, sick visits, and delayed or missed immunizations, was modeled using multivariable negative binomial regression. All analyses adjusted for child sex, payer source, and preterm birth. RESULTS: Maternal, but not paternal, ACE exposure was significantly associated with missed well-child visits by 2 years of age. For each additional maternal ACE, there was a significant 12% increase in the incidence rate of missed well-child visits (relative risk, 1.12; 95% CI, 1.03-1.22; P = .010). Maternal and paternal ACE scores were not significantly associated with increased sick visits or delayed or missed immunizations. CONCLUSIONS: The ACE exposure of mothers is negatively associated with adherence to preventive healthcare visits among their children early in life. Future research is needed to elucidate the mechanisms of this association and to develop and implement family-based intervention strategies.

Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys.

Whereas the ovary produces the majority of estradiol (E2) in mature female primates, extraovarian sources contribute to E2 synthesis and action, including the brain E2-regulating hypothalamic gonadotropin-releasing hormone. In ovary-intact female rodent models, aromatase inhibition (AI) induces a polycystic ovary syndrome-like hypergonadotropic hyperandrogenism due to absent E2-mediated negative feedback. To examine the role of extraovarian E2 on nonhuman primate gonadotropin regulation, the present study uses letrozole to elicit AI in adult female marmoset monkeys. Sixteen female marmosets (Callithrix jacchus; >2 yr) were randomly assigned to ovary-intact or ovariectomy (OVX) conditions and subsequently placed on a daily oral regimen of either ~200 µl vehicle alone (ovary-intact Control, n = 3; OVX, n = 3) or 1 mg ⋅ kg-1 ⋅ day-1 letrozole in vehicle (ovary-intact AI, n = 4; OVX + AI, n = 6). Blood samples were collected every 10 days, and plasma chorionic gonadotropin (CG) and steroid hormone levels were determined by validated radioimmunoassay and liquid chromatography/tandem mass spectrometry, respectively. Ovary-intact, AI-treated and OVX females exhibited elevated CG (P < 0.01, P = 0.004, respectively) compared with controls, and after 30 days, OVX + AI females exhibited a suprahypergonadotropic phenotype (P = 0.004) compared with ovary-intact + AI and OVX females. Androstenedione (P = 0.03) and testosterone (P = 0.05) were also elevated in ovary-intact, AI-treated females above all other groups. The current study thus confirms in a nonhuman primate that E2 depletion and diminished negative feedback in ovary-intact females engage hypergonadotropic hyperandrogenism. Additionally, we demonstrate that extraovarian estrogens, possibly neuroestrogens, contribute to female negative feedback regulation of gonadotropin release.

Maternal Interpersonal Trauma and Child Social-Emotional Development: An Intergenerational Effect.

BACKGROUND: Evidence suggests that maternal interpersonal trauma can adversely affect offspring health, but little is known about potential transmission pathways. We investigated whether interpersonal trauma exposure had direct and indirect associations with offspring social-emotional development at 12-months of age in an at-risk, home visited population. METHODS: A retrospective cohort study was conducted of 1172 mother-child dyads who participated in a multi-site, early childhood home visiting program. Children were born January 2007 to June 2010 and data were collected at enrolment (prenatal/birth) through 12-months of age. Multivariable path analyses were used to examine the relationship between maternal interpersonal trauma, subsequent psychosocial mediators (maternal depressive symptoms, social support, and home environment), and the outcome of child social-emotional development measured with the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE). Maternal interpersonal trauma was characterized as any previous exposure, the level of exposure, and type (e.g. abuse) of exposure. RESULTS: The prevalence of maternal interpersonal trauma exposure was 69.1%, and exposures ranged from 1 type (19.3%) to 7 types (2.3%). Interpersonal trauma was associated with a 3.6 point (95% confidence interval 1.8, 5.4) higher ASQ:SE score among offspring and indicated greater developmental risk. An estimated 23.4% of the total effect was mediated by increased maternal depressive symptoms and lower social support. Differential effects were observed by the level and type of interpersonal trauma exposure. CONCLUSION: Maternal interpersonal trauma exposures can negatively impact child social-emotional development, acting in part through maternal psychosocial factors. Future research is needed to further elucidate the mechanisms of intergenerational risk.

Co-located Parent Coaching Services Within Pediatric Primary Care: Feasibility and Acceptability.

INTRODUCTION: This project assessed the feasibility and acceptability of Parent Connext, a positive parenting program that integrates screening and co-located parent coaching within pediatric primary care. METHOD: Eleven practices implemented Parent Connext in phases between November 1, 2016, and July 31, 2019. Screening and surveillance for parenting and family psychosocial concerns were performed during patient visits. Providers responded with brief motivational interviewing and referral. Parenting Specialists provided individualized parent coaching to referred caregivers. RESULTS: Screens were completed at 13,346 (65%) targeted visits, with 26% positive for concerns. Parent coaching was provided to 1,301 of 2,711 (48%) referred families (average 2.2 sessions per family). Providers and staff felt significantly more supported, confident, and knowledgeable about addressing parenting and family psychosocial concerns after implementing Parent Connext and felt the program improved their relationships with families and quality of care. DISCUSSION: Co-located parent coaching was found to be a feasible and worthwhile addition to pediatric primary care.

Integration of the Safe Environment for Every Kid (SEEK) Model Across Primary Care Settings.

This project sought to assess the generalizability, barriers, and facilitators of implementing the Safe Environment for Every Kid (SEEK) model for addressing psychosocial risk factors for maltreatment across multiple primary care settings, including a pediatric practice, federally qualified health center, and family medicine practice. The SEEK model includes screening caregivers for psychosocial risk factors at well-child visits age 0 to 5 years, brief intervention incorporating principles of motivational interviewing to engage caregivers, and referral to treatment. All practices successfully implemented SEEK, with screening completion rates from 75% to 93% and brief intervention rates from 61% to 81%. Major parental stress (14%) and food insecurity (11%) were the most common risk factors. Providers found SEEK worthwhile for improving their knowledge, skills, and ability to address psychosocial concerns and provide whole person care. Barriers included limited time and resources, incomplete resource knowledge, and lack of follow-up. Facilitators included on-site support staff to assist with communication and referrals.

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes.

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

Has this prepubertal girl been sexually abused?

CONTEXT: The legal and social sequelae of interpreting genital findings as indicative of sexual abuse are significant. While the absence of genital trauma does not rule out sexual abuse, the physical examination can identify genital findings compatible with sexual abuse. OBJECTIVES: To determine the diagnostic utility of the genital examination in prepubertal girls for identifying nonacute sexual abuse. DATA SOURCES: Published articles (1966-October 2008) that appeared in the MEDLINE database and were indexed under the search terms of child abuse, sexual or child abuse and either physical examination; genitalia; female, diagnosis; or sensitivity and specificity; and bibliographies of retrieved articles and textbooks. STUDY SELECTION: Three of the authors independently reviewed titles of articles obtained from MEDLINE and selected articles for full-text review. DATA EXTRACTION: Two authors independently abstracted data to calculate sensitivity, specificity, and likelihood ratios for the diagnosis of nonacute genital trauma caused by sexual abuse in prepubertal girls. RESULTS: Data were not pooled due to study heterogeneity. The presence of vaginal discharge (positive likelihood ratio, 2.7; 95% confidence interval, 1.2-6.0) indicates an increased likelihood of sexual abuse. In the posterior hymen, hymenal transections, deep notches, and perforations prompt concerns for genital trauma from sexual abuse, but the sensitivity is unknown. Without a history of genital trauma from sexual abuse, the majority of prepubertal girls will not have a hymenal transection (specificity close to 100%). CONCLUSIONS: Vaginal discharge as well as posterior hymenal transections, deep notches, and perforations raise the suspicion for sexual abuse in a prepubertal girl, but the findings do not independently confirm the diagnosis. Given the broad 95% confidence intervals around the likelihood ratios for the presence of findings along with the low or unknown sensitivity of all physical examination findings evaluated, the physical examination cannot independently confirm or exclude nonacute sexual abuse as the cause of genital trauma in prepubertal girls.

Parental Adverse Childhood Experiences and Offspring Development at 2 Years of Age.

OBJECTIVES: The study objective was to determine if maternal and paternal exposure to adverse childhood experiences (ACEs) have a significant association with negative offspring development at 24 months of age in a suburban pediatric primary care population. METHODS: A retrospective cohort study was conducted of 311 mother-child and 122 father-child dyads who attended a large pediatric primary care practice. Children were born from October 2012 to June 2014, and data were collected at the 2-, 4-, and 24-month well-child visits. Multivariable Poisson regression with robust error variance was used to model the relationship between self-reported parental ACEs and the outcomes of suspected developmental delay at 24 months and eligibility for early intervention services. RESULTS: For each additional maternal ACE, there was an 18% increase in the risk for a suspected developmental delay (relative risk: 1.18, 95% confidence interval: 1.08-1.29). A similar trend was observed for paternal ACEs (relative risk: 1.34, 95% confidence interval: 1.07-1.67). Three or more maternal ACEs (versus <3 ACEs) was associated with a significantly increased risk for a suspected developmental delay that affected multiple domains. Similar effects were observed for early intervention services. CONCLUSIONS: Parental ACE exposures can negatively impact child development in multiple domains, including problem solving, communication, personal-social, and motor skills. Research is needed to elucidate the psychosocial and biological mechanisms of intergenerational risk. This research has implications for the value of parental ACE screening in the context of pediatric primary care.

Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin.

Neurodevelopmental changes induced by environmental stress exposure play a significant but poorly defined role in the etiology of schizophrenia. Exposure of pregnant female rats to a series of unpredictable stresses during the final week of pregnancy generates behavioral deficits and molecular changes in the offspring similar to those observed in schizophrenic individuals. We used this rat prenatal stress preparation to investigate social withdrawal behaviors that may have relevance to the negative symptoms of schizophrenia. The cumulative time adult male offspring of stress-exposed pregnant female rats actively interacted with a weight-matched, same-sex peer was decreased approximately 76% relative to non-stress exposed control rats. Prenatal stress exposure also diminished the quality of the social interaction behavior indicative of reduced social drive. Analysis of the oxytocinergic system in the prenatally stressed male rats revealed significantly less oxytocin mRNA in the paraventricular nucleus and increased oxytocin receptor binding in the central amygdala. Moreover, oxytocin, but not vasopressin, administration into the central amygdala reversed the social incompetence of the prenatally stressed rats without increasing behavior in non-stressed control animals. In addition, cross-fostering pups from prenatally stressed mothers to non-stressed mothers failed to improve the social deficit of the prenatally stressed male offspring. Two behavioral assays designed to measure anxiety did not differentiate the prenatally stressed rats from non-stressed controls. These data indicate that prenatal stress may be an etiologically appropriate animal model for some aspects of schizophrenic social withdrawal. Furthermore, unpredictable prenatal stress exposure selectively degrades social interaction behaviors without increasing anxiety measures.

Guidelines for medical care of children who may have been sexually abused.

BACKGROUND: Children who may have been sexually abused are examined in many different settings by medical providers with variable levels of education and experience in this special area of practice. Therefore, there is a need for a consistent evidence-based approach that is agreed upon by medical experts. OBJECTIVES: To develop and provide guidelines and recommendations for performing and interpreting findings of the medical evaluation of children referred for sexual abuse medical evaluations, and to provide guidelines for the education, oversight, and peer review process for clinicians who provide assessments for suspected child sexual abuse. METHODS: Participation from medical providers was solicited through postings on the Internet list-serves administered by Cornell University (Special Interest Group in Child Abuse), and by the Ray E. Helfer Society, an honorary society for physician specialists in child abuse diagnosis and treatment. The guidelines were developed through review and critique of published research studies, discussions in focus group meetings at child abuse medical conferences, and ongoing communication leading to revision of draft documents. RESULTS: Groups of 10 to 40 physician experts met at child abuse conferences between January 2002 and January 2005 to revise the table summarizing the interpretation of physical and laboratory findings in suspected child sexual abuse and to develop guidelines for medical care for sexually abused children. Between January and December 2005, the guidelines were expanded and revised. CONCLUSIONS: The guidelines presented here reflect the current knowledge, recommended clinical approaches, and required competencies in the field of child sexual abuse medical evaluation.

Hospital-based multidisciplinary teams can prevent unnecessary child abuse reports and out-of-home placements.

OBJECTIVE: To determine how often and for what reasons a hospital-based multidisciplinary child abuse team concluded that a report of alleged or suspected child abuse was unnecessary in young children with fractures. METHODS: A retrospective review was completed of all children less than 12 months of age who, because of fractures, were referred to the hospital multidisciplinary child abuse team for consultation regarding the need to consider child abuse. RESULTS: The team received 99 consultations, reported 92 (93%) children as alleged or possible victims of physical abuse, and did not report 7 (7%). Age at presentation of those who were reported was 4.2 months compared to 3.0 months in the non-reported group. The average number of fractures in the reported group was 2.9 (SD 3.53) compared to 3.4 (SD 4.6) in the non-reported group. Factors that led to cases not being reported included: (a) a trauma history consistent with the fracture (n=4), (b) a diagnosis of bone fragility secondary to genetic, nutritional or medical therapy etiologies (n=2), and (c) iatrogenic fracture (n=1). CONCLUSIONS: Seven percent of the children less than 12 months of age and with at least one fracture referred to the multidisciplinary team for evaluation of possible child abuse were not reported as alleged or suspected physical abuse. The involvement of the hospital multidisciplinary child abuse team may have prevented unnecessary investigation by the county social services agency and/or police, and possible out-of-home temporary placement.

Estradiol reduces nonclassical transcription at cyclic adenosine 3',5'-monophosphate response elements in glioma cells expressing estrogen receptor alpha.

Estradiol can protect the brain from a variety of insults by activating membrane-initiated signaling pathways, and thereby modulate gene expression and lead to functional changes in neurons. These direct neuronal effects of the hormone have been well documented; however, it is less understood what effects estradiol may have on nonneuronal cells of the central nervous system. There is evidence that estradiol levels can induce the release of glial-derived growth factors and other cytokines, suggesting that estradiol may both directly and indirectly protect neurons. To determine whether 17beta-estradiol (E2) can activate rapid signaling and modulate nonclassical transcription in astrocytes, we stably transfected the C6 rat glioblastoma cell line with human estrogen receptor (ER) alpha (C6ERalpha) or rat ERbeta (C6ERbeta). Introduction of a cAMP response element-luciferase reporter gene into C6, C6ERalpha, and C6ERbeta cells leads to the observation that E2 treatment reduced isoproterenol-stimulated luciferase activity by 35% in C6ERalpha but had no effect on reporter gene expression in C6ERbeta or untransfected C6 cells. A similar effect was seen with a membrane-impermeable estrogen (E2-BSA), suggesting the modulation of nonclassical transcription by estradiol treatment is mediated by the activation of a membrane-initiated signaling pathway. Furthermore, pretreatment with wortmannin (phosphatidylinsositol 3-kinase) or U73122 (phospholipase C) attenuated the E2-induced reduction in nonclassical transcription. We conclude that E2 treatment reduces cAMP response element-mediated transcription in glioma cells expressing ERalpha and that this reduction is dependent on the activation of membrane-initiated signaling. These findings suggest a novel model of estrogen rapid signaling in astrocytes that leads to modulation of nonclassical transcription.

ERα Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy(1,2,3).

Male neonate brains are more susceptible to the effects of perinatal asphyxia resulting in hypoxia and ischemia (HI)-related brain injury. The relative resistance of female neonatal brains to adverse consequences of HI suggests that there are sex-specific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI. We hypothesized that HI preferentially induces estrogen receptor α (ERα) expression in female neonatal hippocampi and that ERα is coupled to Src family kinase (SFK) activation that in turn augments phosphorylation of the TrkB and thereby results in decreased apoptosis. After inducing the Vannucci's HI model on P9 (C57BL/6J) mice, female and male ERα wild-type (ERα(+/+)) or ERα null mutant (ERα(-/-)) mice received vehicle control or the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF). Hippocampi were collected for analysis of mRNA of ERα and BDNF, protein levels of ERα, p-TrkB, p-src, and cleaved caspase 3 (c-caspase-3) post-HI. Our results demonstrate that: (1) HI differentially induces ERα expression in the hippocampus of the female versus male neonate, (2) src and TrkB phosphorylation post-HI is greater in females than in males after 7,8-DHF therapy, (3) src and TrkB phosphorylation post-HI depend on the presence of ERα, and (4) TrkB agonist therapy decreases the c-caspase-3 only in ERα(+/+) female mice hippocampus. Together, these observations provide evidence that female-specific induction of ERα expression confers neuroprotection with TrkB agonist therapy via SFK activation and account for improved functional outcomes in female neonates post-HI.