Brain MRI segmentation of Zika-Exposed normocephalic infants shows smaller amygdala volumes.

BACKGROUND: Infants with congenital Zika syndrome (CZS) are known to exhibit characteristic brain abnormalities. However, the brain anatomy of Zika virus (ZIKV)-exposed infants, born to ZIKV-positive pregnant mothers, who have normal-appearing head characteristics at birth, has not been evaluated in detail. The aim of this prospective study is, therefore, to compare the cortical and subcortical brain structural volume measures of ZIKV-exposed normocephalic infants to age-matched healthy controls. METHODS AND FINDINGS: We acquired T2-MRI of the whole brain of 18 ZIKV-exposed infants and 8 normal controls on a 3T MRI scanner. The MR images were auto-segmented into eight tissue types and anatomical regions including the white matter, cortical grey matter, deep nuclear grey matter, corticospinal fluid, amygdala, hippocampus, cerebellum, and brainstem. We determined the volumes of these regions and calculated the total intracranial volume (TICV) and head circumference (HC). We compared these measurements between the two groups, controlling for infant age at scan, by first comparing results for all subjects in each group and secondly performing a subgroup analysis for subjects below 8 weeks of postnatal age at scan. ZIKV-exposed infants demonstrated a significant decrease in amygdala volume compared to the control group in both the group and subgroup comparisons (p<0.05, corrected for multiple comparisons using FDR). No significant volume differences were observed in TICV, HC, or any specific brain tissue structures or regions. Study limitations include small sample size, which was due to abrupt cessation of extramural funding as the ZIKV epidemic waned. CONCLUSION: ZIKV-exposed infants exhibited smaller volumes in the amygdala, a brain region primarily involved in emotional and behavioral processing. This brain MRI finding may lead to poorer behavioral outcomes and warrants long-term monitoring of pediatric cases of infants with gestational exposure to Zika virus as well as other neurotropic viruses.

Case report: Fatal lung hyperinflammation in a preterm newborn with SARS-CoV-2 infection.

Vertical transmission of SARS-CoV-2 from mother to fetus is widely accepted. Whereas most infected neonates present with mild symptoms or are asymptomatic, respiratory distress syndrome (RDS) and abnormal lung images are significantly more frequent in COVID-19 positive neonates than in non-infected newborns. Fatality is rare and discordant meta-analyses of case reports and series relating perinatal maternal COVID-19 status to neonatal disease severity complicate their extrapolation as prognostic indicators. A larger database of detailed case reports from more extreme cases will be required to establish therapeutic guidelines and allow informed decision making. Here we report an unusual case of a 28 weeks' gestation infant with perinatally acquired SARS-CoV-2, who developed severe protracted respiratory failure. Despite intensive care from birth with first line anti-viral and anti-inflammatory therapy, respiratory failure persisted, and death ensued at 5 months. Lung histopathology showed severe diffuse bronchopneumonia, and heart and lung immunohistochemistry confirmed macrophage infiltration, platelet activation and neutrophil extracellular trap formation consistent with late multisystem inflammation. To our knowledge, this is the first report of SARS CoV-2 pulmonary hyperinflammation in a preterm newborn with fatal outcome.

Maternal SARS-CoV-2, Placental Changes and Brain Injury in 2 Neonates.

Long-term neurodevelopmental sequelae are a potential concern in neonates following in utero exposure to severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2). We report 2 neonates born to SARS-CoV-2 positive mothers, who displayed early-onset (day 1) seizures, acquired microcephaly, and significant developmental delay over time. Sequential MRI showed severe parenchymal atrophy and cystic encephalomalacia. At birth, neither infant was SARS-CoV-2 positive (nasopharyngeal swab, reverse transcription polymerase chain reaction), but both had detectable SARS-CoV-2 antibodies and increased blood inflammatory markers. Placentas from both mothers showed SARS-CoV-2-nucleocapsid protein and spike glycoprotein 1 in the syncytiotrophoblast, fetal vascular malperfusion, and significantly increased inflammatory and oxidative stress markers pyrin domain containing 1 protein, macrophage inflammatory protein 1 ßη, stromal cell-derived factor 1, interleukin 13, and interleukin 10, whereas human chorionic gonadotropin was markedly decreased. One infant (case 1) experienced sudden unexpected infant death at 13 months of age. The deceased infant's brain showed evidence of SARS-CoV-2 by immunofluorescence, with colocalization of the nucleocapsid protein and spike glycoprotein around the nucleus as well as within the cytoplasm. The constellation of clinical findings, placental pathology, and immunohistochemical changes strongly suggests that second-trimester maternal SARS-CoV-2 infection with placentitis triggered an inflammatory response and oxidative stress injury to the fetoplacental unit that affected the fetal brain. The demonstration of SARS-CoV-2 in the deceased infant's brain also raises the possibility that SARS-CoV-2 infection of the fetal brain directly contributed to ongoing brain injury. In both infants, the neurologic findings at birth mimicked the presentation of hypoxic-ischemic encephalopathy of newborn and neurologic sequelae progressed well beyond the neonatal period.

First Locally Acquired Congenital Zika Syndrome Case in the United States: Neonatal Clinical Manifestations.

In the spring of 2017, a full-term infant with microcephaly was delivered in South Florida. During first trimester, the mother presented with fever, nausea, and vomiting. She reported no foreign travel for herself or her partner. The infant's neurologic, ophthalmologic, neuroradiologic, and audiologic findings were highly suggestive of congenital Zika syndrome (CZS), confirmed by IgM antibodies and plaque reduction neutralization test. New observations, including peripheral temporal retinal avascularity and peripapillary retinal nerve fiber layer thinning, are presented from this first known case of non-travel-associated CZS in the United States. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e93-e98.].

Zika Virus: An Emerging Global Health Threat.

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease.

Scalp congenital hemangioma with associated high-output cardiac failure in a premature infant: Case report and review of literature.

Introduction Scalp congenital hemangiomas (CHs) are rare vascular malformations among infants; they can be associated with an array of complications, including cardiac and cosmetic issues. Here, we report the endovascular treatment of a premature infant with a suspected large right parietal scalp hemangioma and associated high-output cardiac failure. Case description A two-day-old female premature infant (29 weeks gestational age; 1330 g birth weight) was referred by the neonatologists to our department for consultation and potential treatment of a large right parietal CH causing abrupt hypotension and high-output cardiac failure. Doppler ultrasound imaging at bedside revealed areas of arterial-venous shunting from the scalp and the presence of a superior sagittal sinus waveform, consistent with intracranial venous drainage. To alleviate cardiac dysfunction secondary to this lesion, trans-arterial embolization via n-butyl cyanoacrylate (nBCA) glue and deployment of detachable coils was performed via umbilical artery to occlude the right superficial temporal and occipital artery branches supplying the CH. Following treatment, the infant continued to require ventilator management, vasopressor support, and correction of coagulopathy, but by post-operative day two, her condition improved remarkably and the mass size began decreasing. The patient was discharged after a relatively uncomplicated subsequent 2½-month course in the neonatal intensive care unit. Conclusion Endovascular therapy proved effective and safe in treating cardiac failure associated with scalp CH, despite potential complications associated with neuro-interventional surgery in premature infants. Appropriate consideration in this patient population should be given to factors including blood loss, contrast use, radiation exposure, operative time, and possible intra-/post-operative complications.

Prenatal Cocaine Exposure and Cardiometabolic Disease Risk Factors in 18- to 20-Year-Old African Americans.

OBJECTIVE: The long-term effects of prenatal cocaine exposure (PCE) on physical health are largely unknown. No human studies support or refute a relationship between PCE and the long-term risk for cardiovascular and/or metabolic disease. We investigated the association of PCE on primary cardiometabolic disease risk factors in African Americans (AA) aged 18 to 20 years. DESIGN: Cohort, longitudinal, prospective. SETTING: Miami-Dade County, Florida, and the University of Miami Miller School of Medicine/Jackson Memorial Medical Center. PARTICIPANTS: Healthy full-term inner-city AA adolescents (aged 18 to 20 years, n=350) previously enrolled at birth from 1990-1993. MAIN OUTCOME MEASURES: Fasting serum insulin, glucose, lipids, and high-sensitivity C-reactive protein; systolic and diastolic blood pressures; and the components and prevalence of the metabolic syndrome. RESULTS: There were no PCE-associated differences in cardiometabolic disease risk factors including the metabolic syndrome and its individual components in AAs aged 18 to 20 years. CONCLUSIONS: The results of our study do not support an association between PCE and increased cardiometabolic disease risk in AAs aged 18 to 20 years. Whether PCE is associated with cardiovascular or metabolic disease in adulthood would require further investigation.

Perinatal Factors Associated with Cardiovascular Disease Risk among Preschool-Age Children in the United States: An Analysis of 1999-2008 NHANES Data.

We examined the relationships between selected perinatal and early infancy factors (maternal smoking during pregnancy, infant low birthweight, breastfeeding, and early introduction of solid foods [<6 months of age] and increased BMI [≥85th, ≥95th percentiles for age, sex]), waist circumference (WC), C-reactive protein (CRP), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, and decreased HDL cholesterol during early childhood. The population-based sample included 3,644 3-to-6-year-old Non-Hispanic White (NHW), Hispanic, and Non-Hispanic Black (NHB) children who participated in the 1999-2008 National Health and Nutrition Examination Surveys. Analysis showed that breastfeeding was significantly protective against early childhood obesity (OR 0.43, 95% CI, 0.27-0.69) and the highest quintile for WC (OR 0.58, 95% CI, 0.37-0.32) among NHW, and against the highest quintile of non-HDL cholesterol among NHB (OR 0.56, 95% CI, 0.32-0.98). Additionally, NHW children were significantly more likely to be obese (OR 2.22, 95% CI 1.30-3.78) and have higher CRP levels (OR 1.63, 95% CI, 1.05-2.51) if their mothers smoked during pregnancy. These results support the observation that breastfeeding may be protective against early childhood obesity while maternal smoking during pregnancy is a risk factor for obesity and increased CRP levels among NHW young children.

Longitudinal effects of prenatal cocaine use on mother-child interactions at ages 3 and 5 years.

OBJECTIVE: To assess the effect of maternal prenatal and past-year cocaine use on mother-child interactions across preschool years. METHODS: The sample is drawn from the Miami Prenatal Cocaine Study, a longitudinal follow-up of prenatal cocaine exposure (PCE) in a large cohort of African-American infants prospectively enrolled at birth. Analyses are based on the 366 children (168 PCE and 198 non-cocaine-exposed) in the care of their biological mothers and with completed mother-child interaction measures at the 3- and/or 5-year assessments. Videotaped interactions were coded using a modified Egeland Teaching Task scheme. Generalized linear models with a generalized estimating equations approach were used to evaluate the effect of PCE on the overall quality of maternal-child interaction, measured by the Egeland total score at both study visits, and on the individual Egeland subscales at the 5-year visit, while adjusting for other suspected influences on interactions. RESULTS: PCE dyads demonstrated less optimal overall mother-child interactions compared with non-cocaine-exposed dyads. The estimated PCE-associated difference did not shift appreciably with statistical adjustment for child sex, child age at examination, or other birth covariates. PCE dyads with past-year maternal cocaine use had significantly lower Egeland summary scores compared with children with neither exposure. In subscale analyses, PCE was most strongly associated with greater maternal intrusiveness and boundary dissolution at the 5-year visit. CONCLUSIONS: Prenatal and past-year maternal cocaine use seems to be associated with poorer quality in mother-child interaction during early childhood. These dynamics should be considered when examining the association between PCE and child cognitive, behavioral, and academic outcomes.

Assessing latent effects of prenatal cocaine exposure on growth and risk of cardiometabolic disease in late adolescence: design and methods.

Prenatal cocaine exposure has been linked to neurocognitive and developmental outcomes throughout childhood. The cardiovascular toxicity of cocaine is also markedly increased in pregnancy, but it is unknown whether this toxicity affects anthropometric growth and the development of cardiometabolic disease risk factors in the offspring across the lifespan. During the early 1990s, the Miami Prenatal Cocaine Study enrolled a cohort of 476 African American children (253 cocaine-exposed, 223 non-cocaine-exposed) and their biological mothers at delivery in a prospective, longitudinal study. The MPCS has collected 12 prior waves of multidomain data on over 400 infants and their mothers/alternate caregivers through mid-adolescence and is now embarking on an additional wave of data collection at ages 18-19 years. We describe here the analytical methods for examining the relationship between prenatal cocaine exposure, anthropometric growth, and cardiometabolic disease risk factors in late adolescence in this minority, urban cohort. Findings from this investigation should inform both the fields of substance use and cardiovascular research about subsequent risks of cocaine ingestion during pregnancy in offspring.

Estimated effect of prenatal cocaine exposure on examiner-rated behavior at age 7 years.

UNLABELLED: Prenatal cocaine exposure has been linked to increased child behavior difficulties in some studies but not others. OBJECTIVE: The primary aim was to estimate the relationship between in utero cocaine exposure and child behavioral functioning at age 7 years with ratings made by blinded examiners during a structured testing session. A second aim was to examine whether caregiver drug use and psychological problems might mediate suspected relationships between prenatal cocaine exposure and aspects of examiner-rated behavior. METHODS: 407 children (212 cocaine-exposed, 195 non-exposed) participating in the longitudinal Miami Prenatal Cocaine Study (MPCS) were rated with regard to their behavior during a neuropsychological assessment conducted at age 7 years. Raters were trained research psychometricians blinded to drug exposure status. Individual behavioral items were summarized and the cocaine-behavior relationship was estimated within the context of latent variable modeling, using Mplus software. RESULTS: Two latent variables, Behavioral Regulation and Sociability, were derived via exploratory latent structure analysis with promax rotation. Prenatal cocaine exposure, statistically controlling for child sex, test age, and prenatal exposure to alcohol, tobacco, and marijuana, was associated with Behavioral Regulation (estimated slope ß=-0.25; 95% CI=-0.48, -0.02; p=0.04) but not Sociability (estimated slope ß=-0.03; 95% CI=-0.26, 0.20; p=0.79). Neither postnatal drug use by caregivers nor the severity of their psychological problems at age 5 follow-up predicted levels of child Behavioral Regulation or Sociability at age 7 years (p>0.10). CONCLUSIONS: Examiner ratings of child behavior at age 7 revealed less optimal behavioral regulation for prenatally cocaine-exposed compared to non-exposed children, in contrast with what had been previously found from parent-report data. This evidence highlights the potential value of trained observers in assessing behavioral outcomes of children exposed in utero to drugs and other toxicants.

Potential latent effects of prenatal cocaine exposure on growth and the risk of cardiovascular and metabolic disease in childhood.

The literature strongly suggests that prenatal exposure to certain medications and substances does not cause major malformations in early childhood. However, these exposures may have far-reaching latent health effects, such as restricted growth, hypertension, and cardiovascular events in adulthood. We reviewed the literature to identify the effects of prenatal cocaine exposure on growth and the risk of cardiovascular and metabolic disease in late adolescence and early adulthood by examining studies that were published in peer-reviewed English-language journals from 1990 through 2009 and indexed in MEDLINE. We found that animal and clinical studies of the influence of prenatal cocaine exposure on child and adolescent growth and the subsequent development of myocardial and cardiometabolic disease risk factors are few and inconclusive. Studies support the hypothesis that vascular and hemodynamic functions are partially programmed in early life and thus substantially influence vascular aging and arterial stiffening in later life. Sub-optimal fetal nutrition and growth may increase blood pressure and the development of cardiovascular and metabolic disease in late life. How prenatal cocaine and other drug exposure effects this relationship is currently unknown. Despite high rates of cocaine and other drug use during pregnancy (up to 18% in some studies), little is known about the health effects of prenatal cocaine exposure in adolescence and early adulthood. The few studies of early growth deficits persisting into adolescence are inconclusive. The literature provides little information on how exposed children grow into adulthood and about their subsequent risk of cardiometabolic and vascular disease.

Estimated effects of in utero cocaine exposure on language development through early adolescence.

The potential longitudinal effects of prenatal cocaine exposure (PCE) on language functioning were estimated from early childhood through early adolescence in a large, well-retained urban sample of 451 full-term children (242 cocaine-exposed, 209 non-cocaine-exposed) participating in the Miami Prenatal Cocaine Study (MPCS). The sample was enrolled prospectively at birth, with documentation of prenatal drug exposure status through maternal interview, and toxicology assays of maternal and infant urine, and infant meconium. Age-appropriate versions of the Clinical Evaluation of Language Fundamentals (CELF) were used to measure total, expressive, and receptive language at ages 3, 5, and 12years. Longitudinal latent growth curve (LLGC) modeling of the data revealed an association between PCE (measured dichotomously as yes/no) and lower functioning in expressive and total language scores, after considering other sources of variation including child's age at testing, sex, prenatal exposure to alcohol, marijuana, and tobacco, and additional medical and social-demographic covariates. Analyses of level of PCE showed a gradient, i.e. dose-dependent, relationship between PCE level and expressive, receptive, and total language scores in the models controlling for age, child's sex, and other prenatal drug exposures. With additional covariate control these findings were most stable for the total language score. The evidence supports an inference about an enduring stable cocaine-specific effect on children's language abilities, with no effect on language growth over time in the longitudinal trajectory of language development.

Prenatal drug exposure: infant and toddler outcomes.

This manuscript provides an overview of the current scientific literature on the impact of maternal drug use, specifically opioids and cocaine, during pregnancy on the acute and long-term outcomes of infants and toddlers from birth through age 3 years. Emphasis with regard to opioids is placed on heroin and opioid substitutes used to treat opioid addiction, including methadone, which has long been regarded as the standard of care in pregnancy, and buprenorphine, which is increasingly being investigated and prescribed as an alternative to methadone. Controlled studies comparing methadone at high and low doses, as well as those comparing methadone with buprenorphine, are highlighted and the diagnosis and management of neonatal abstinence syndrome is discussed. Over the past two decades, attention of the scientific and lay communities has also been focused on the potential adverse effects of cocaine and crack cocaine, especially during the height of the cocaine epidemic in the United States. Herein, the findings are summarized from prospective studies comparing cocaine-exposed with non-cocaine-exposed infants and toddlers with respect to anthropometric growth, infant neurobehavior, visual and auditory function, and cognitive, motor, and language development. The potentially stigmatizing label of the so-called "crack baby" preceded the evidence now accumulating from well-designed prospective investigations that have revealed less severe sequelae in the majority of prenatally exposed infants than originally anticipated. In contrast to opioids, which may produce neonatal abstinence syndrome and infant neurobehavioral deficits, prenatal cocaine exposure appears to be associated with what has been described as statistically significant but subtle decrements in neurobehavioral, cognitive, and language function, especially when viewed in the context of other exposures and the caregiving environment which may mediate or moderate the effects. Whether these early findings may herald more significant learning and behavioral problems during school-age and adolescence when the child is inevitably confronted with increasing social and academic challenges is the subject of ongoing longitudinal research.

Estimated Risk of Developing Selected DSM-IV Disorders Among 5-Year-Old Children with Prenatal Cocaine Exposure.

This study estimated childhood risk of developing selected DSM-IV Disorders, including Attention-Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Separation Anxiety Disorder (SAD), in children with prenatal cocaine exposure (PCE). Children were enrolled prospectively at birth (n=476) with prenatal drug exposures documented by maternal interview, urine and meconium assays. Study participants included 400 African-American children from the birth cohort, 208 cocaine-exposed (CE) and 192 non-cocaine-exposed (NCE) who attended a 5-year follow-up assessment and whose caregiver completed the Computerized Diagnostic Interview Schedule for Children. Under a generalized linear model (logistic link), Fisher's exact methods were used to estimate the CE-associated relative risk (RR) of these disorders. Results indicated a modest but statistically robust elevation of ADHD risk associated with increasing levels of PCE (p<0.05). Binary comparison of CE versus NCE children indicated no CE-associated RR. Estimated cumulative incidence proportions among CE children were 2.9% for ADHD (vs 3.1% NCE); 1.4% for SAD (vs 1.6% NCE); and 4.3% for ODD (vs 6.8% NCE). Findings offer suggestive evidence of increased risk of ADHD (but not ODD or SAD) in relation to an increasing gradient of PCE during gestation.

Impact of prenatal cocaine exposure on attention and response inhibition as assessed by continuous performance tests.

OBJECTIVE: This study examined the influence of prenatal cocaine exposure on attention and response inhibition measured by continuous performance tests (CPTs) at ages 5 and 7 years. METHODS: The baseline sample consisted of 253 cocaine-exposed and 223 non-cocaine-exposed children enrolled prospectively at birth and assessed comprehensively through age 7 years in the longitudinal Miami Prenatal Cocaine Study. This report includes a subsample of 415 children (219 cocaine-exposed, 196 non-cocaine-exposed) who completed at least one CPT assessment at ages 5 and/or 7 years. Prenatal cocaine exposure was measured by maternal self-report and maternal and infant bioassays. Deficits in attention and response inhibition are estimated in relation to prenatal cocaine exposure using generalized estimating equations within the general linear model. RESULTS: Results indicate cocaine-associated increases in omission errors at ages 5 and 7 as well as increases in response times for target tasks (i.e., slower reaction times) and decreased consistency in performance at age 7. There were no demonstrable cocaine-associated deficits in commission errors. Estimates did not change markedly with statistical adjustment for selected prenatal and postnatal covariates. CONCLUSION: Evidence supports cocaine-associated deficits in attention processing through age 7 years.

Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure.

Risk for developing a learning disability (LD) or impaired intellectual functioning by age 7 was assessed in full-term children with prenatal cocaine exposure drawn from a cohort of 476 children born full term and enrolled prospectively at birth. Intellectual functioning was assessed using the Wechsler Intelligence Scale for Children-Third Edition (Wechsler, 1991) short form, and academic functioning was assessed using the Wechsler Individual Achievement Test (WIAT; Wechsler, 1993) Screener by examiners blind to exposure status. LDs were categorized based on ability-achievement discrepancy scores, using the regression-based predicted achievement method described in the WIAT manual. The sample in this report included 409 children (212 cocaine-exposed, 197 non-cocaine-exposed) from the birth cohort with available data. Cumulative incidence proportions and relative risk values were estimated using STATA software (Statacorp, 2003). No differences were found in the estimate of relative risk for impaired intellectual functioning (IQ below 70) between children with and without prenatal cocaine exposure (estimated relative risk = .95; 95% confidence interval [CI] = 0.65, 1.39; p = .79). The cocaine-exposed children had 2.8 times greater risk of developing a LD by age 7 than non-cocaine-exposed children (95% CI = 1.05, 7.67; p = .038; IQ >/= 70 cutoff). Results remained stable with adjustment for multiple child and caregiver covariates, suggesting that children with prenatal cocaine exposure are at increased risk for developing a learning disability by age 7 when compared to their non-cocaine-exposed peers.