Robin Baker

Influence of Human Immunodeficiency Virus—Infected Maternal Environment on Development of Infant Interleukin-12 Production

Monocyte-derived cytokine production by cord blood mononuclear cells (CBMC) from infants born to human immunodeficiency virus (HIV)-positive and -negative women was measured to determine whether monocyte dysfunction could contribute to the accelerated HIV disease of pediatric patients. Production of interleukin (IL)-12, but not that of tumor necrosis factor-alpha and IL-10, was reduced, compared with adult peripheral blood mononuclear cells (PBMC). This deficiency was more pronounced in infants of HIV-positive women, whose IL-12 production was also deficient. CBMC IL-12 levels were increased by interferon-gamma and CD40 ligand but remained deficient, compared with PBMC. IL-12 production was undetectable in 7 of 8 HIV-positive infants, in contrast to 21 of 26 uninfected infants. Uninfected infants of infected women exhibited an intermediate profile. These findings suggest that the maternal environment and/or exposure in utero to HIV products influence the newborns immune response and that the differences between infants born to HIV-positive and -negative women may persist.

Visuospatial and verbal fluency relative deficits in 'complicated' late-preterm preschool children.

BACKGROUND Late-preterm children constitute a majority of all preterm deliveries (75%). Their immature brain development at birth has been associated with an increased risk for morbidities. Data have been sparse regarding neuropsychological outcomes in the preschool years. AIM To examine general cognition, attention/working memory, language, manual coordination/motor dexterity, visuomotor, visuospatial, and executive functions in preschoolers born late-preterm (LPT; 34-36 gestational weeks) who required NICU admission compared to term-born participants. DESIGN Single-center retrospective cohort study of 95 three-year-old children; 60 born LPT in 2004-2005 and admitted to the NICU compared to 35 healthy term-born participants born > or =37 gestational weeks and > or =2500 g. RESULTS LPT birth was associated with visuospatial (p=.005), visuomotor (p=.012), and executive function (noun [p=.018] and action-verb [p=.026] fluency) relative deficits, but not attention/working memory, receptive or expressive language, nonverbal reasoning, or manual coordination/dexterity deficit. CONCLUSIONS Late-preterm birth is likely to be associated with negative neuropsychological sequelae, although subtle and selective compared to effects reported for children born at an earlier gestational age. Visuospatial function appears to be especially vulnerable to disruption even at preschool age, and verbal fluency may be useful as an early predictor of executive dysfunction in childhood. Routine preschool neuropsychological evaluation is recommended to identify delay or deficit in LPT children preparing for school entry, and may highlight underlying vulnerable neural networks in LPT children.

Cognitive deficit in preschoolers born late-preterm

BACKGROUND late-preterm (LPT) birth accounts for a majority of preterm deliveries and until recently was considered low risk for poor cognitive outcome. Previously, we reported deficits in complicated LPT (cLPT) preschoolers (neonatal intensive care unit [NICU]-admitted). AIM to extend our prior study by comparing cognitive outcome in cLPT and uncomplicated LPT (uLPT; NICU non-admitted) preschoolers. STUDY DESIGN single center retrospective cohort study of 118 LPT children born in 2004-2006 at 35-36 weeks of gestation; 90 cLPT and 28 uLPT, compared with 100 term-born (≥ 37 weeks of gestation and ≥ 2500 g) participants. OUTCOME MEASURE a well-standardized measure of general conceptual ability (GCA), the Differential Ability Scales, Second Edition. RESULTS cLPT participants had average mean performances but significantly poorer GCA, Nonverbal Reasoning, and Spatial scores than term-born children, and higher rates of Nonverbal Reasoning and Spatial impairment; uLPT did not differ from TERM. Combined LPT males were at eightfold greater risk than term-born males for nonverbal deficit, and at sevenfold greater risk for GCA impairment than LPT females. CONCLUSIONS finding greater risk of cognitive deficit in those NICU-admitted due to clinical instability or birth weight < 2 kg compared with non-admitted preschoolers indicates that neonatal morbidities contribute to subtle cognitive deficits detectable at young age, with male gender an additive risk factor. LPT gestational age alone is an insufficient predictor of long-term neurocognitive outcome. Further study should elucidate salient etiologies for early emerging cognitive weaknesses and suggest appropriate interventions to prepare at-risk LPT preschoolers for elementary school entry.

Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates

Purpose:To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS).Methods:Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing.Results:NBS genes are generally well covered by WGS. There is a median of one (range: 0–6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%).Conclusion:WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.Genet Med 18 3, 221–230.

Neuropsychological and behavioral outcomes of extremely low birth weight at age three.

Preterm (PT) birth is an established risk factor for high mortality and morbidity rates. Infants and school-aged children have been well-studied, but few have described neuropsychological and behavioral outcomes at preschool age. We compared a 2004–2006 preterm/extremely low birth weight (ELBW) cohort (PT/ELBW; N = 60) born ≤33 weeks gestation and <1,000 g with term-born participants (N = 90) at age 3. PT/ELBW subgroups (<26 weeks; 26–33 weeks) performed more poorly than the term-born group on verbal, nonverbal, fine motor, visual-motor, visual attention, noun fluency, early number concepts, and functional communication measures prior to age correction; PT/ELBW children born <26 weeks additionally performed more poorly on action-verb fluency. Those born 26–33 weeks had executive and adaptive deficits on parental behavioral report. Age correction significantly improved preterm scores without masking relative verbal, nonverbal, motor, and behavioral weaknesses that may require early intervention. In conclusion, subtle delays in emergent neuropsychological and behavioral functions are measurable at age 3, and neurobiological immaturity remains a prepotent influence on outcome in the preschool years. Further study should enhance our understanding of the trajectory of brain development and the limits of neuroplasticity in these highly at-risk children.

Incorporation of zidovudine into cord blood DNA of infants and peripheral blood DNA of their HIV-1-positive mothers.

Abstract: The nucleoside analogue 3′‐azido‐3′‐deoxythymidine (AZT) is a weak carcinogen in adult female mice and a moderately strong carcinogen in the offspring of female mice given the drug during gestation. In addition, incorporation of AZT into DNA was observed in multiple organs of transplacentally exposed newborn mice. Here we investigate the incorporation of AZT into peripheral leukocyte DNA of HIV‐1‐positive adult pregnant women given AZT for variable times during gestation and cord blood of infants exposed to AZT in utero. The length of treatment varied between 10 days and 9 months. High molecular weight DNA was extracted from maternal peripheral blood mono‐nuclear cells (PBMC) and infant cord blood. A specific AZT‐DNA radioimmunoassay was used to determine the amount of AZT incorporated into leukocyte DNA. Incorporation of AZT into DNA ranged up to 183.3 and 344.5 molecules of AZT/106 nucleotides in the mothers and infants, respectively, and was detected in about 70% of samples. Therefore, AZT‐induced mutagenic events are possible in the majority of adults and infants. No correlation was found between level of incorporation and length of AZT treatment, suggesting that the differences observed among the individuals arise from variability in AZT metabolism. These data support previous observations that a high degree of inter‐individual variability in AZT phosphorylation occurs in primates.

Neuromotor outcomes at school age after extremely low birth weight: early detection of subtle signs.

OBJECTIVE Motor impairments are prevalent in children born at extremely low birth weight (ELBW; <1,000 g). Rarely studied are subtle motor deficits that indicate dysfunction or delay in neural systems critical for optimal cognitive, academic, and behavioral function. We aimed to examine quantifiable signs of subtle neuromotor dysfunction in an early school-aged ELBW cohort that coincidentally had age-appropriate cognition and design copying. METHOD We studied 97 participants born between 1998 and 2001; 74 ELBW (6.7 years ± 0.75) compared with 23 term-born (6.6 years ± 0.29). Neuromotor outcomes were assessed using the Physical and Neurological Examination of Subtle Signs-Revised, and measures of dexterity/coordination and visual-motor integration. RESULTS ELBW participants performed worse than term-born on design-copying and dexterity, were age-appropriate compared to normative data, and had slower timed movements and more subtle overflow movements. Those ELBW born <26 weeks performed most poorly compared with those born 26-34 weeks and term-born. CONCLUSION Subtle motor dysfunctions are detectable and quantifiable in ELBW children by school age, even in the presence of average cognition. Early age assessment of incoordination, motor speed, and overflow movements should aid initiation of timely therapies to prepare at-risk ELBW children for subsequent school entry and facilitate design of optimal early treatment strategies.

Subtle adverse effects of late preterm birth: a cautionary note.

OBJECTIVE Late preterm birth increases risk of perinatal health complications that typically resolve in the short term. Thus, early elective delivery is thought to have no long-term effects. Whether there is increased risk of adverse psychological outcomes that emerge in early childhood remains uncertain. METHOD The authors compared intellectual, neuropsychological, and behavioral outcomes in 278 late preterm (35-36 weeks) and 192 term (37-41 weeks) participants at age 3 years recruited from a single center, using analysis of variance, analysis of covariance, and regression analyses. Late-preterm participants were further subgrouped by admission to the neonatal intensive care unit (NICU; n = 202) or a well-baby unit (n = 76). Analyses included 132 additional participants born at 34 weeks. RESULTS Late preterm participants had lower general conceptual ability (GCA; i.e., IQ); lower verbal, nonverbal, spatial, visuomotor, and dexterity scores; and poorer adaptability than term participants (p < .01; -0.271 to -0.511 SDs). Gestational age was the most important predictor of these subtle outcomes, not neonatal medical variables; no differences were found between NICU admitted and nonadmitted late-preterm groups. A 1-week increase in gestational age resulted in a 1.941 increase in GCA (d = 0.127). CONCLUSION Gestation is a developmental continuum best not interrupted during its natural course. Our data showing subtle but appreciable effects have important implications for obstetric practice and parental decision making regarding early elective delivery in the absence of maternal or fetal adverse indications.

Neonatal Respiratory Distress Secondary to an Obstructing Nasopharyngeal Dermoid

A case presentation of a newborn infant with intermittent, complete airway obstruction secondary to a pedunculated nasopharyngeal dermoid is presented. The differential diagnosis of obstructing nasopharyngeal lesions of the neonatal period is discussed, and an organized management strategy is proposed.

Comparison of Infant Gut and Skin Microbiota, Resistome and Virulome Between Neonatal Intensive Care Unit (NICU) Environments

Background: There is a growing move to provide care for premature infants in a single family, private room neonatal intensive care unit (NICU) in place of the traditional shared space, open bay NICU. The resultant effect on the developing neonatal microbiota is unknown. Study Design: Stool and groin skin swabs were collected from infants in a shared-space NICU (old NICU) and a single-family room NICU (new NICU) on the same hospital campus. Metagenomic sequencing was performed and data analyzed by CosmosID bioinformatics software package. Results: There were no significant differences between the cohorts in gestational age, length of stay, and delivery mode; infants in the old NICU received significantly more antibiotics (p = 0.03). Differentially abundant antimicrobial resistance genes and virulence associated genes were found between the cohorts in stool and skin, with more differentially abundant antimicrobial resistance genes in the new NICU. The entire bacterial microbiota analyzed to the genus level significantly differed between cohorts in skin (p = 0.0001) but not in stool samples. There was no difference in alpha diversity between the two cohorts. DNA viruses and fungi were detected but did not differ between cohorts. Conclusion: Differences were seen in the resistome and virulome between the two cohorts with more differentially abundant antimicrobial resistance genes in the new NICU. This highlights the influence that different NICU environments can have on the neonatal microbiota. Whether the differences were due to the new NICU being a single-family NICU or located in a newly constructed building warrants exploration. Long term health outcomes from the differences observed must be followed longitudinally.