Neurodevelopmental Complications Research Articles

A - 44 Value of Repeat Neuropsychological Assessments in Children with Complex Birth and Neurological Injuries

Abstract Objective Extremely low birth weight, in-utero insult, and PVL are associated with an array of neurodevelopmental complications. PVL is most common in very premature. Associated complications in this case study include diffuse demyelination, cerebellar atrophy, and arthrogryposis. Data from serial assessments reveal preservation of intelligence, decoding, and social skills. Implications for the role of repeat assessments in guiding education and intervention are discussed. Method The subject was an 18-year-old male with extremely low birth weight, in-utero insult, PVL, cerebellar atrophy, delayed myelination, and arthrogryposis. His presentation also included craniosynostosis. Three outpatient neuropsychological assessments were completed over eight years. Assessments included measures of intellectual, academic, neurocognitive, and emotional functions. Results Despite multiple physical and neurological impairments, assessments revealed preserved verbal and nonverbal intelligence, phonemic awareness, computation skills, and social cognition. Deficits were evident in processing speed, rapid naming, math fluency, word fluency, working memory, and executive functions. Academic strengths were evident in reading and written expression. Checklists revealed inattention and impulsivity with strengths in social cognition (See data tables). Conclusions This study demonstrates both variability in outcome following a complex birth history and neurological history and the value of repeat neuropsychological assessments. Assessment data was used to identify and build upon preserved skills and focus intervention strategies. Maintained verbal and nonverbal reasoning skills, in the context of strong social cognition, significantly contributed to progress, self-esteem, and future goals. Repeat neuropsychological assessment is well-suited for such cases. Access to such assessments is critical and should be regarded as medically necessary to guide intervention and promote positive outcomes.

A Systematic Review of the Relationship Between Neonatal Hypoxic-Ischemic Encephalopathy and Long-Term Cognitive Outcomes: Where Do We Stand?

This study aims to systematically review the existing literature on long-term cognitive outcomes in neonates with hypoxic-ischemic encephalopathy (HIE). A thorough search of PubMed, MEDLINE, and Embase was conducted to find studies that satisfied the inclusion requirements. Rayyan (Qatar Computing Research Institute, Doha, Qatar) was utilized during the whole operation.Our results included seven studies with a total of 521 patients and 247 (47.4%) were females. All of the included participants were assessed for the incidence of cognitive functions following hypothermia therapy. Newborns with significant HIE are at high risk for neurodevelopmental complications even in the absence of magnetic resonance imagining (MRI) abnormalities, such as poor performance score and hearing-language score, functional status, delayed language skills, emotional processing, sensory movement, learning, and memory.Independent of motor deficits, participants with a history of HIE are susceptible to issues with cognition and executive function during late childhood and adolescence. It is crucial to keep an eye on their intellectual development after infancy since cognitive dysfunction and memory problems might manifest subtly or not at all in the early years of life, but they can cause problems in later childhood and adolescence. Long-term follow-up research is also required to ascertain whether the enhanced cognitive outcomes will continue throughout adolescence. Even in cases where overt neuromotor abnormalities are not evident, children with watershed injuries on brain MRIs should be closely monitored to evaluate cognitive function, particularly language development.

Diagnostic options, physiopathology, risk factors and genetic causes of permanent congenital hypothyroidism: A narrative review.

In Permanent congenital hypothyroidism (PCH) is a lifelong condition characterized by a deficiency in thyroid hormone, leading to various neurodevelopmental complications. Early clinical signs are often nonspecific and easily overlooked, but newborn screening programs have improved early detection. This narrative review aims to provide insights comparatively transient and permanent PCH and also the diagnosis, risk factors, underlying pathophysiology, and genetic causes associated with PCH. Relevant studies were identified through a comprehensive search using the term 'Permanent congenital hypothyroidism' (Mesh) across scientific databases of electronic databases such as PubMed, Scopus, and Web of Science. Prompt initiation of thyroid hormone replacement therapy, particularly within the initial two weeks postpartum, crucially enhances neurocognitive development outcomes. Multiple predictive approaches, encompassing screening TSH levels, maternal thyroid history, and levothyroxine dosage per kilogram assessment, aid in identifying PCH. Recent studies have demonstrated a mounting prevalence of PCH, contributing significantly to the overall rise in CH incidence. Genetic factors, primarily DUOX2 and DUOXA2 mutations, alongside environmental influences such as post-term birth, low birth weight, and macrosomia, may induce PCH. Nonetheless, reliable markers for early PCH prediction upon diagnosis remain elusive, leading to delayed recognition post-ceasing levothyroxine treatment around age 3. Recent studies have observed an increased incidence of PCH, contributing substantially to the overall rise in cases of congenital hypothyroidism. Understanding the diagnostic options and genetic etiologies associated with PCH is crucial for the early identification and appropriate management.

Prenatal nicotine exposure during pregnancy results in adverse neurodevelopmental alterations and neurobehavioral deficits.

Maternal tobacco use and nicotine exposure during pregnancy have been associated with adverse birth outcomes in infants and can lead to preventable pregnancy complications. Exposure to nicotine and other compounds in tobacco and electronic cigarettes (e-cigarettes) has been shown to increases the risk of miscarriage, prematurity, stillbirth, low birth weight, perinatal morbidity, and sudden infant death syndrome (SIDS). Additionally, recent data provided by clinical and pre-clinical research demonstrates that nicotine exposure during pregnancy may heighten the risk for adverse neurodevelopmental disorders such as Attention-Deficit Hyperactivity (ADHD), anxiety, and depression along with altering the infants underlying brain circuitry, response to neurotransmitters, and brain volume. In the United States, one in 14 women (7.2%) reported to have smoked cigarettes during their pregnancy with the global prevalence of smoking during pregnancy estimated to be 1.7%. Approximately 1.1% of women in the United States also reported to have used e-cigarettes during the last 3months of pregnancy. Due to the large percentage of women utilizing nicotine products during pregnancy in the United States and globally, this review seeks to centralize pre-clinical and clinical studies focused on the neurobehavioral and neurodevelopmental complications associated with prenatal nicotine exposure (PNE) such as alterations to the hypothalamic-pituitary-adrenal (HPA) axis and brain regions such as the prefrontal cortex (PFC), ventral tegmental area (VTA), nucleus accumbens (NA), hippocampus, and caudate as well as changes to nAChR and cholinergic receptor signaling, long-term drug seeking behavior following PNE, and other related developmental disorders. Current literature analyzing the association between PNE and the risk for offspring developing schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety, and obesity will also be discussed.

Prenatal exposure to phthalates and emotional/behavioral development in young children

IntroductionEndocrine disrupting chemicals (EDCs) such as phthalates, found in our daily environment, are nowadays suggested to be associated with adverse outcomes. Prenatal exposure was found associated with neurodevelopmental complications such as behavioral difficulties in school age children. AimTo explore the association between intrauterine exposure to phthalates and emotional/behavioral development of 24 months old toddlers. MethodsWomen were recruited at 11–18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Offspring were examined at 24 months of age, using standard maternal report, regarding developmental and behavioral problems (CBCL, ASQ-3, HOME questionnaires) (N = 158). To explore the associations between metabolite levels and developmental outcomes, multivariate GLM analysis (General Linear Model) was used according to tertiles and developmental scores on each developmental outcome. ResultsAssociations of Di-(2-ethylhexyl) phthalate (DEHP) maternal exposure with behavioral-developmental outcomes were found only in boys. Compared with boys with lower DEHP maternal exposure, boys with high DEHP maternal exposure had lower developmental score in personal social abilities in the ASQ-3 questionnaire (50.68 + 8.06 and 44.14 + 11.02, high and low DEHP, respectively, p = 0.03), and more internalizing problems (for example, emotionally reactive score in high and low DEHP: 53.77 + 7.41 and 50.50 + 1.19, respectively, p = 0.029; anxious or depressed score: 53.38 + 5.01 and 50.75 + 1.34, respectively, p = 0.009; and somatic complaints scores 64.03 + 10.1 and 55.84 + 7.84, respectively, p = 0.003), and externalizing problems (49.28 + 8.59 and 43.33 + 9.11, respectively, p = 0.039). No differences were found in the development and behavior problems between high and low DEHP maternal exposure level in girls. ConclusionMaternal DEHP metabolite concentrations measured in first trimester urine was associated with children’s emotional/behavioral developmental problems in 24-months old boys, supporting accumulating evidence of DEHP as a potentially harming chemical and call for environmental attention.

Untreated Major Depression During Gestation: The Physical and Mental Implications in Women and Their Offspring

While postpartum depression has been extensively studied and is a concern surrounding major depression in women, the effects of major depression during pregnancy alone should also be considered. The purpose of this review article was to explore in longitudinal fashion, from neonate to adulthood, the lasting physical and mental implications that depression during gestation can present in offspring. Consideration of various sources pulled from the OVID Medline database yielded findings consistent with negative associations between gestational depression and offspring outcomes. In mothers, gestational depression presents with physical implications, such as preeclampsia and preterm delivery, leading to low birth weight and neurodevelopmental complications in neonates. As the children grow older, these complexities manifest as socioemotional, behavioral, and linguistic development delays presenting as increased incidence in attention-deficit/hyperactivity disorder diagnoses, parental attachment issues, and lower emotional and verbal IQ. Research regarding adolescents and adults is sparse in comparison with that of earlier stages, but there are studies that examine the developmental outcomes of certain mood disorders, such as generational depression, in the offspring of birthing parents with prenatal depression. This review presents an extended timeline of the effects of gestational major depression in offspring, and it provides suggestions for future research regarding underlying biological explanations and certain risk outcomes.

ILAE Genetic Literacy Series: Self-limited familial epilepsy syndromes with onset in neonatal age and infancy.

The self-limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal- or infantile-onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called "self-limited". A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self-limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.

EBNEO commentary: Oral versus intravenous sildenafil for pulmonary hypertension in neonates.

Chetan C, Suryawanshi P, Patnaik A, Soni SB, Rath C, Pareek P, Gupta B, Garergrat RR, Verma A, Singh, Y. Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomised trial. BMC Pediatr. 2022 May27; 22(1):311. DOI: 10.1186/s12887-022-03366-3. PMID: 35624452. Persistent pulmonary hypertension (PPHN) involves persistent pulmonary vascular resistance, which occurs in approximately 2 in every 1000 live infants.1 This is associated with sequelae, including chronic lung disease, neurodevelopmental complications, and death. The current well-understood management of PPHN includes inhaled nitric oxide (iNO), which is used as the first-line treatment of PPHN in higher-resourced countries.1 However, less-resourced countries have limited availability to iNO. There is some literature on other treatments, including sildenafil; however as recommended in the 2017 Cochrane review which evaluated five randomised clinical trials and several case reports that sildenafil has the potential to increase survival in neonates with PPHN, particularly in settings where iNO is not available.2 Subsequently, Chetan et al., at a single centre in a level III neonatal intensive care unit in an urban centre in India, developed an open labelled, parallel, randomised trial to determine if oral versus intravenous sildenafil have similar efficacy, safety, and response in the management of mild-to-moderate pulmonary hypertension in late preterm and term neonates. Pulmonary hypertension was defined as pulmonary arterial pressure (PAP) >25 mmHg on echocardiography within 72 h of birth. The primary outcome sought the time taken for PAP to <25 mmHg, comparing 6 hourly oral sildenafil 1 mg/kg/dose versus IV sildenafil given with a loading dose of 0.4 mg/kg of sildenafil over 3 h followed by continuous infusion of 1.6 mg/kg/day. Once treatment was started, echocardiograms were repeated every 12 h until PAP <25 mmHg and sildenafil were tapered within 4 days and stopped. Between February 2019 and December 2020, 40 infants were randomised in this study. Both groups had similar follow-up rates of 17/20 in the oral group and 15/20 in the IV group, and the sildenafil could be tapered after a median of 48 h in both groups. Complications of hypotension (n = 4) and reduced cardiac contractility (n = 1) were seen in the IV group requiring inotropes, compared to none in the oral group.3 Whilst there was no difference in the median time for sildenafil tapering between the two groups, this was in the context of 12 hourly echocardiograms. Perhaps, more frequent intervals of echocardiogram performed whilst on sildenafil may have found a difference between the two groups. This remains a small, unblinded trial with the clinicians managing the patients and performing the echocardiogram unblinded. Furthermore, the other limitations of this study were a small sample size of 40 babies which was not powered to detect a statistical or meaningful difference between the two preparations of sildenafil. Research directions could include a blinded, multicentre trial to increase further knowledge of the safety and efficacy of oral versus intravenous preparations of sildenafil in resource-limited settings. Whilst iNO will continue to be the first line, there may be scope to demonstrate sildenafil benefits as a dual therapy with iNO. Research performed in higher-resourced countries can lend further knowledge in this area. https://ebneo.org/ebneo-commentary-po-vs-iv-sildenafil-for-ph. AK receives funding from the Australian National Health and Medical Research Council (NHMRC) (APP1161379). The contents of this paper are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. The authors have no conflicts of interest to declare.

Predicting the future of mental health: (how) will in utero COVID-19 infection influence psychiatric illness in future generations?

Objectives: There is limited research on the potential future psychiatric effects of in utero COVID-19 infection. There is evidence that COVID-19 infection can lead to obstetric complications and adverse neonatal outcomes. Obstetric complications and neurodevelopmental insults such as viral infections have been implicated in the development of some mental disorders including schizophrenia (SZ). The aim was to address the possible mechanisms and influences related to in utero infection that could increase the risk of mental illness in the future. &#x0D; Methods: Searches were conducted in the databases PubMed, Embase, and PsycINFO for studies involving COVID-19 infection and pregnancy, obstetric complications, and psychiatric complications. Additionally, any external information outside of these search terms was sourced from these databases. &#x0D; Results: Several studies found evidence of significantly higher incidences of preterm delivery and cesarean section associated with maternal COVID-19 infection. Other noted adverse birth outcomes included fetal distress, stillbirth, low birth weight, neonatal asphyxia, and pre-eclampsia. These birth outcomes tend to occur in the third trimester, a crucial period for neurodevelopment. Additionally, there have been occurrences of vertical transmission of COVID-19. &#x0D; Conclusion: It is plausible that in utero COVID-19 infection could increase the risk of mental illness development in the offspring. The observed implications of COVID-19 along with known neurodevelopmental complications of in utero infection provide multiple processes that could impact the mental health of the offspring in the future. This increased risk could arise from neonatal outcomes associated with COVID-19 infection, the consequences of maternal infection on the fetus, or direct viral infection of the fetus and fetal brain. Due to its novel nature, more evidence is needed to determine the exact prevalence of adverse obstetric outcomes, vertical transmission, effects on neurodevelopment, and development of mental illness due to SARS-CoV-19.

Abstract 11531: Neurodevelopmental Outcomes After Neonatal Tetralogy of Fallot Repair or Palliation: Scope of The Problem and Does Treatment Strategy Matter

Introduction: Neonates with symptomatic tetralogy of Fallot (sTOF) require early intervention with either staged repair (SR; initial palliation with subsequent complete repair) or primary repair (PR). Implications of these neonatal management strategies on late outcomes are not well understood. Thus, we aimed to assess neurodevelopmental (ND) outcomes and identify risk factors for ND concerns. Methods: From 2005-2017, sTOF patients who underwent neonatal intervention across 9 centers were identified. To assess ND, all living patients were sent age-appropriate parent-rating scales of executive function (Behavior Rating Inventory of Executive Function - BRIEF) and psychosocial symptoms (The Behavior Assessment System for Children, 3rd Edition - BASC-3). The results were compared by primary treatment strategy (SR vs. PR) using multivariable models. Patient and clinical factors were compared between those with normal and clinically significant abnormal results (T-score ≥60). Results: Of 572 patients in the initial cohort, surveys were sent to 511 survivors and returned from 144 (28%, 53% male, age 3.2-15.9 years). Up to 37% of respondents had a clinically concerning score on ≥ 1 scales, including 36% with ≥1 abnormal scale present on the BRIEF and 30% with an abnormal scale on the BASC. Across SR and PR strategies, there was no difference in ND outcomes (BRIEF adjusted odds ratio (AOR) 1.55 (0.57, 4.21, p=0.39); BASC AOR 1.13 (0.43, 2.99, p=0.81)). Factors associated with clinically significant executive dysfunction included genetic syndrome (p=0.001), need for invasive ventilatory support (p=0.003) and inotropic support (p=0.01) prior to the index procedure. Only genetic syndrome (p=0.026) was associated with clinically significant psychosocial problems. Conclusions: Late ND abnormalities, specifically executive dysfunction and psychosocial concerns, are common in sTOF patients. While initial treatment strategy does not appear to have impact, intrinsic patient characteristics and pre-procedure measures of clinical severity may predict late ND outcomes and help target increased surveillance for ND complications. Forthcoming analyses will explore existing ND service utilization and parental concerns in the context of these findings.

A Review of Sensorineural Hearing Loss in Congenital Cytomegalovirus Infection.

The intrauterine transmission of the TORCH group (toxoplasmosis, rubella cytomegalovirus (CMV), herpes simplex, and HIV) produces severe complications in the fetus, leading to major life challenges for the newborns. CMV is considered one of the leading causes of congenital hearing loss in babies born to infected mothers. The majority of the cases are asymptomatic but a certain proportion show symptoms, which may not be present until later. The human cytomegalovirus (HCMV) infection can also be transferred to the baby postnatally through breastfeeding. Mothers facing primary infection from the CMV have a greater tendency to transmit the infection to the fetus, whereas secondary infection due to reactivation of the virus in females who were affected before pregnancy, delivers asymptomatic babies in most cases. Vertical transmission of HCMV,that is via the placenta from infected mother to fetus, is one of the leading causes of congenital sensorineural hearing loss (SNHL) and neurodevelopmental complications in newborns. It accounts for up to 10% of SNHL cases in newborns, of both unilateral and bilateral types. Antiviral therapy is helpful in such cases if administered within the first month of life, and for hearing impairment, cochlear implants have been used to treat children who develop profound hearing loss. The child can present with hearing loss at birth or it may be late in onset and of progressive type. Suspected children should be evaluated regularly for the early detection of hearing loss and to provide the appropriate treatment.

Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study

PurposeDysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants. MethodsA multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained. ResultsThe overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity. ConclusionMolecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.

EP136: An exploration of the impact of Hormonal Replacement Therapy (HRT) upon vocabulary skills in males with 49,XXXXY

49,XXXXY is a rare variant of 47,XXY, Klinefelter syndrome, that occurs in approximately 1 in 100,000 live male births. It is the most uncommon and complex X and Y chromosomal variation consisting of neurodevelopmental, physical, and medical complications. These boys are at an increased risk for musculoskeletal abnormalities and health difficulties. Intellectual disability, motor deficits, and severe speech dysfunction are common to this population. Specifically, receptive language skills are typically more advanced than expressive language skills, with some individuals being nonverbal. Childhood Apraxia of Speech (CAS) is thought to be the origin of speech and expressive language dysfunction in these boys suggesting that the core challenge is rooted in motor planning deficiency. Challenges in expressive language typically affect all aspects of daily life for males with 49,XXXXY, as it is difficult for them to convey their thoughts and feelings. This often leads to difficulties expressing themselves, social communication challenges, and peer isolation. Males with 49,XXXXY have androgen deficiency that benefits from hormonal replacement therapy (HRT). HRT has been found to have positive effects on neurodevelopmental capabilities in males with 49, XXXXY. Specifically, treated individuals have been found to have improved neurodevelopmental function than the untreated and may therefore have a potential beneficial impact on social skills. Two types of HRT are common during infancy and the childhood years: early hormonal treatment (EHT) and hormonal booster therapy (HBT). EHT is often administered during the “mini-puberty” period, ideally given at 4, 5, and 6 months old, but can be given up until 2 years of age. HBT may be recommended during the school-aged population, often beginning around 5 years old and given up until 11years old. The current study explores the effect of HRT upon expressive and receptive vocabulary skills in males with 49,XXXXY. One hundred and one participants with a diagnosis of 49,XXXXY were evaluated for this study (CA: 88.9 months). Participants completed the Expressive One-Word Picture Vocabulary Test 4th Edition (EOWPVT-4) and the Receptive One-Word Picture Vocabulary Test 4th Edition (ROWPVT-4). Subjects were segregated into four different groups according to their HRT status: no-T, EHT, HBT, and EHT&HBT. EHT consisted of 3 intramuscular injections of 25 mg of testosterone enanthate, once monthly, for three months given between 4 and 24 months of age. HBT consisted of 3 intramuscular injections of 50 mg of testosterone enanthate, once monthly for three months administered between the ages of 5 and 11. Two-tailed t-tests were completed to assess the differences within HRT groups between performance on the EOWPVT-4 and ROWPVT-4. The no-T group (CA: 90.3 months, N = 20) showed a significant difference between EOWPVT-4 and ROWPVT-4 scores (p = .00888) with receptive capabilities being higher than their expressive skills. The EHT group (CA: 79.3 months, N = 44) approached significance with greater skills on the ROWPVT-4 in comparison to the EOWPVT-4 (p = .0556). Finally, the HBT (CA: 104.5 months, N = 8) and EHT&HBT groups (CA: 98.1 months, N = 29) showed no differences between their receptive and expressive capabilities (p = .532; p = .700). The current study expands on the neurocognitive profile of boys with 49,XXXXY and the impact of HRT on their expressive and receptive vocabulary skills. Individuals with 49,XXXXY typically present with severely depressed expressive capabilities in comparison to their receptive skills. The no-T group had this typical presentation with higher receptive language abilities in comparison to expressive capabilities while the EHT, HBT, and EHT&HBT groups showed no differences between receptive and expressive vocabulary skills. Participants who received EHT, HBT, or a combination performed higher on the EOWPVT-4 and presented with commensurate and higher receptive and expressive vocabulary skills than those who had not been treated. These results suggest a positive treatment effect of both EHT and HBT on expressive vocabulary capabilities in boys with 49,XXXXY.

Severe Retinopathy of Prematurity Associated With Neurodevelopmental Disorder in Children.

ObjectiveThis study aimed to investigate whether severe retinopathy of prematurity (ROP) could be an association factor for neurodevelopmental disorders in premature infants without other risk factors—such as congenital anomalies, birth injuries, and neurological diseases—that may cause developmental delay.MethodsWe used health claims data recorded between 2007 and 2018 in the Korean National Health Insurance Service (KNHIS) database. We recruited a total of 18,256 premature infant born between 2007 and 2008 without congenital anomaly or birth injury (with ROP 6,995, without ROP 11,261) and divided them into four groups as follows: Group A, 209 extremely premature infants [gestational age (GA) < 28] with mild ROP; Group B, 75 extremely premature infants (GA < 28) with severe ROP; Group C, 6,510 other premature infants (28 ≤ GA <37)with mild ROP; and Group D, 201 other premature infants (28 ≤ GA < 37) with severe ROP. Using regression analysis, we analyzed whether there was a correlation between ROP prevalence, severity, and developmental delay in premature infants without other risk factors.ResultsThe prevalence of developmental delay, according to GA and ROP severity, was higher in patients with severe ROP than in the other patients. The prevalence gradually decreased after birth. Among extremely premature infants with ROP, those with severe ROP had a 3.082-fold higher association with neurodevelopmental complications than those with mild ROP (p < 0.001). Compared with other premature infants with ROP, those with severe ROP had a 3.269-fold higher association with neurodevelopmental complications than those with mild ROP.ConclusionThe severity of ROP may be associated with neurodevelopmental disorders in premature infants.

Prenatal inflammation causes obesity and abnormal lipid metabolism via impaired energy expenditure in male offspring

IntroductionObesity has becoming a global health issue. Fetus exposed to adversity in the uterine are susceptible to unhealth stimulus in adulthood. Prenatal inflammation is related to poor neonatal outcomes like neurodevelopmental impairments and respiratory complications. Recent studies suggested prenatal lipopolysaccharide (LPS) exposure could result in metabolic disorders. Thus, we hypothesized that offspring exposed to prenatal inflammation could develop into metabolic disorder.MethodsThe pregnant C57BL/6J mice were intraperitoneally injected with 50 μg/kg LPS or saline only once at GD15. The male offspring were weighted weekly until sacrificed. Indirect calorimetry and body composition were both performed at 9 and 18 weeks old. At 20 weeks old, mice were fasted overnight before collecting blood samples and liver for metabolomics analysis and RNA sequencing, respectively. Differentially expressed genes were further verified by RT-qPCR and western blotting.ResultsPrenatal inflammation resulted in obesity with increased fat percentage and decreased energy expenditure in middle-age male offspring. Abnormal lipid accumulation, changes of gene expression profile and upregulation of multi-component mechanistic target of rapamycin complex 1 (mTOR)/Peroxisome proliferator-activated receptor-γ pathway was observed in liver, accompanied with decreased bile acids level, unsaturated fatty acids androgens and prostaglandins in serum. Indirect calorimetry showed increased respiratory exchange rate and deceased spontaneous activity at 9 weeks in LPS group. Impaired energy expenditure was also observed at 18 weeks in LPS group.ConclusionPrenatal LPS exposure led to obesity and abnormal lipid metabolism through impaired energy expenditure.

Characterization of Neurological Complications Among Children with Sickle Cell Disease in the United States: Findings from the 2007-2018 National Health Interview Survey (NHIS)

Background: In the United States , sickle cell disease (SCD), affects about 100,000 individuals, with roughly 2,000 babies born annually with SCD. African Americans are disproportionately affected by SCD. In addition to medical conditions, psychosocial and affective comorbidities are also observed in relation to the frequency and intensity of pain crises. Evidence also suggests robust academic challenges that begin in elementary school and persist until high school. It is estimated that about 25% to 33% of children with SCD experience neurodevelopmental complications. Neurological complications lead to cognitive deficits and educational challenges. African Americans and those with low socioeconomic status are affected the most by neurological complications. Among Children with SCD, data suggest that specialized school service utilization rates are about 37%, and grade retention ranges from 28% to 40%. We used the 2007-2018 NHIS to describe additional neurocognitive impairments and health services used among Black children aged 0-17 years with SCD and place findings into context.Methods: Data was acquired from the NHIS database. The study included an unweighted sample of 133,542 children, with 68,745 male children and 64,797 female children. Questionnaires were answered by a parent/guardian on behalf of the child. We examined (1) the prevalence of neurological conditions; (2) indicators of functional status and perceived health status; (3) use of healthcare and special educational services; (4) barriers to accessing healthcare services for a national sample of children with SCD; (5) Association of the comorbidities with the utilization of care. We hypothesized that black children with SCD would have higher levels of disease-related complications and comorbidities, as well as healthcare utilization than their counterparts without SCD. We used logistic regression to compare the associations between SCD and No SCD on various neurological conditions for all races and for Black children only groups.Results: Of the 133,542 children, 215 have SCD (.16%). Among the SCD children, 51.1% are male, 170 (79.1%) are Black, 16 (7.44%) are White, 1(.47%) are American Indian, 2 (.93%) are Asian, 21 (9.77%) are other races, and 5 (2.33%) are of Multiple Races. Among all races, Black children had a higher prevalence of SCD than other races. Black children with SCD had a higher predominance of girls than did those without SCD. They were also more likely than their counterparts without SCD to have a household income < 1% of the federal poverty levels. After applying the appropriate weights to each of the demographics, Children with SCD had higher odds of having a developmental condition such as: learning disability (Adjusted odds ratio -AOR 1.5; CI: .7, 3.5: p=0.311), intellectual disability (AOR 4.2; CI: 1.3, 13.3: p=0.014), trouble hearing (AOR 2.6; CI: 1.1, 6.1: p=0.026), trouble seeing (AOR 2.3; CI: 1.0, 5.3: p=0.061) and another developmental delay (AOR .8; CI: .1, 6.2: p=0.838). We see similar results in the Black children only sample where Black children with SCD were more likely to have a learning disability (AOR 1.3; CI: .5, 3.2; p=0.590), intellectual disability (AOR 2.4; CI: .6, 10.2: p=0.236), trouble hearing (AOR 1.6; CI: .6, 4.1: p=0.310) or trouble seeing (AOR 2.3; CI: 1.0, 5.4; p=0.048). They also exhibit other developmental delays (AOR 1.9; CI: .2, 22.4: p=0.625), although not statistically significant.Conclusion: In this study sample, it is clear that children with SCD had higher odds of having a developmental condition and in addition Black children with SCD also have a comparable odd of developing neurological complications compared to children with SCD of other races. A similar pattern was identified that Black children with SCD reported increased utilization of healthcare and special education services in the past 12 months. This creates the urgency to address the health burden for Black children with SCD that has been exaggerated by barriers to accessing comprehensive health care. Studies that further assess Black children's health burden with SCD, its neurocognitive impairment and healthcare utilization is crucial. DisclosuresNo relevant conflicts of interest to declare.

Association Between Prenatal Exposure to Antipsychotics and Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Preterm Birth, and Small for Gestational Age

The risk of birth and neurodevelopmental complications with prenatal exposure to antipsychotics is unclear. To evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems. This population-based cohort study included children born between January 2001 and January 2015 with follow-up to December 2019 who were identified by the Hong Kong Clinical Data Analysis and Reporting System. Pregnancies with maternal antidepressant/lithium exposure were removed. Primary analyses compared gestationally exposed and gestationally nonexposed individuals with propensity score fine stratification. Additional analyses included gestationally exposed individuals vs those with past exposure and a sibling-matched analysis to evaluate the effect of confounding by indication. Prenatal antipsychotic exposure. Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 standard deviations below the mean for gestational age), and first diagnosis of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children. The cohorts included 333 749 mother-child pairs for ADHD (mean [SD] maternal age at delivery, 31.46 [5.03] years) and 411 251 pairs for ASD, preterm birth, and small for gestational age analyses (mean [SD] maternal age at delivery, 31.56 [5.01] years). There were 13 196 children (3.95%) with a diagnosis of ADHD, 8715 (2.12%) with ASD, 33 891 (8.24%) preterm, and 7009 (1.70%) who were small for gestational age. The weighted hazard ratio (wHR) was 1.16 (95% CI, 0.83-1.61) for ADHD and 1.06 (95% CI, 0.70-1.60) for ASD, while the weighted odds ratio (wOR) was 1.40 (95% CI, 1.13-1.75) for preterm birth and 1.36 (95% CI, 0.86-2.14) for small for gestational age when comparing gestationally exposed with gestationally nonexposed individuals. Additional analyses showed no association when comparing gestationally exposed individuals with those with past exposure (ADHD: wHR, 0.99; 95% CI, 0.60-1.61; ASD: wHR, 1.10; 95% CI, 0.58-2.08; preterm birth: wOR, 0.93; 95% CI, 0.70-1.24; small for gestational age: wOR, 1.21; 95% CI, 0.66-2.20) and in a sibling-matched analysis (ADHD: wHR, 0.41; 95% CI, 0.04-4.93; ASD: wHR, 0.90; 95% CI, 0.40-2.01; preterm birth: wOR, 1.25; 95% CI, 0.85-1.82; small for gestational age: wOR, 0.86, 95% CI, 0.32-2.31). In this cohort study, the findings did not suggest that prenatal antipsychotics exposure increased the risk of ADHD, ASD, or small for gestational age. In the primary analysis, there was a small increased risk of preterm birth, but additional analyses comparing gestationally exposed individuals with those with past exposure and comparing gestationally exposed with gestationally nonexposed siblings did not support an increased risk. Given the benefits of treating psychosis during pregnancy, our findings do not support a recommendation for women to discontinue receipt of their regular antipsychotic treatment during pregnancy.

Neurodevelopmental outcomes in congenital heart disease through the lens of single ventricle patients.

This review aims to summarize and organize the current body of literature on this contemporary topic, alongside a more general discussion of neurodevelopmental complications of congenital heart disease. It is theorized that the causes of the neurodevelopment disabilities are multifactorial resulting from structural central nervous system abnormalities, haemodynamic alterations and/or biochemical changes. It is therefore imperative that all patients with single ventricle anatomy and physiology receive long-term neurologic and developmental assessments in addition to their cardiac monitoring. Advancements in surgical techniques and medical management have improved survivorship of these medically complex patients. Neurodevelopmental sequelae are one of the most common comorbidities affecting this patient population leading to long-term challenges in motor, language, social and cognitive skills.

Label-free screening of brain tissue myelin content using phase imaging with computational specificity (PICS).

Inadequate myelination in the central nervous system is associated with neurodevelopmental complications. Thus, quantitative, high spatial resolution measurements of myelin levels are highly desirable. We used spatial light interference microcopy (SLIM), a highly sensitive quantitative phase imaging (QPI) technique, to correlate the dry mass content of myelin in piglet brain tissue with dietary changes and gestational size. We combined SLIM micrographs with an artificial intelligence (AI) classifying model that allows us to discern subtle disparities in myelin distributions with high accuracy. This concept of combining QPI label-free data with AI for the purpose of extracting molecular specificity has recently been introduced by our laboratory as phase imaging with computational specificity. Training on 8000 SLIM images of piglet brain tissue with the 71-layer transfer learning model Xception, we created a two-parameter classification to differentiate gestational size and diet type with an accuracy of 82% and 80%, respectively. To our knowledge, this type of evaluation is impossible to perform by an expert pathologist or other techniques.

A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development.

Coronavirus disease 2019 (COVID-19) is a devastating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The incidence and mortality of COVID-19 patients have been increasing at an alarming rate. The mortality is much higher in older individuals, especially the ones suffering from respiratory distress, cardiac abnormalities, renal diseases, diabetes, and hypertension. Existing evidence demonstrated that SARS-CoV-2 makes its entry into human cells through angiotensin-converting enzyme 2 (ACE-2) followed by the uptake of virions through cathepsin L or transmembrane protease serine 2 (TMPRSS2). SARS-CoV-2-mediated abnormalities in particular cardiovascular and neurological ones and the damaged coagulation systems require extensive research to develop better therapeutic modalities. As SARS-CoV-2 uses its S-protein to enter into the host cells of several organs, the S-protein of the virus is considered as the ideal target to develop a potential vaccine. In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.