Associating neuromotor outcomes at 12 months with wearable sensor measures collected during early infancy in rural Guatemala.

BACKGROUND: Sensitive measures to predict neuromotor outcomes from data collected early in infancy are lacking. Measures derived from the recordings of infant movement using wearable sensors may be a useful new technique. METHODS: We collected full-day leg movement of 41 infants in rural Guatemala across 3 visits between birth and 6 months of age using wearable sensors. Average leg movement rate and fuzzy entropy, a measure to describe the complexity of signals, of the leg movements' peak acceleration time series and the time series itself were derived. We tested the three measures for the predictability of infants' developmental outcome, Bayley Scales of Infant and Toddler Development III motor, language, or cognitive composite score assessed at 12 months of age. We performed quantile regressions with clustered standard errors, accounting for the multiple visits for each infant. RESULTS: Fuzzy entropy was associated with the motor composite score at the 0.5 quantiles; this association was not found for the other two measures. Also, no leg movement characteristic was associated with language or cognitive composite scores. CONCLUSION: We propose that the entropy of leg movement associated peak accelerations calculated from the wearable sensor data collected for a full-day can be considered as one predictor for infants' motor developmental outcome assessed with Bayley Scales of Infant and Toddler Development III at 12 months of age.

Association between neonatal near miss and infant development: the Ribeirão Preto and São Luís birth cohorts (BRISA).

AIM: To analyze the association between neonatal near miss and infant development at two years. METHODS: Data from two birth cohorts, one conducted in Ribeirão Preto (RP)/São Paulo and the other in São Luís (SL)/Maranhão, were used. The cognitive, motor and communication development of children was evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). The following criteria were used for the definition of NNM: birth weight < 1,500 g, 5-min Apgar score < 7, gestational age < 32 weeks, and report of congenital malformations. The relationship between neonatal near miss and development was assessed using the weighted propensity score from the Inverse Probability of Treatment Weighting (IPTW). A directed acyclic graph was built to select the adjustment variables. RESULTS: A total of 1,050 mother-newborn dyads were evaluated in SL and 1,840 in RP. Regarding outcomes in SL and RP, respectively, 2.4% and 17.3% of the children were not competent in the cognitive domain, 12.1% and 13.3% in the receptive communication domain, 39.2% and 47.1% in the expressive communication domain, 20.7% and 12.6% in the fine motor domain, and 14.3% and 13.8% in the gross motor domain. The prevalence of neonatal near miss was 5.4% in SL and 4.3% in RP. Unadjusted analysis showed an association of neonatal near miss with fine motor development in SL and RP and with the cognitive, receptive communication, expressive communication, and gross motor domains only in RP. These associations remained after adjusted analysis. CONCLUSION: Neonatal near miss is a risk factor for developmental delays.

Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value (p = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities (p = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Nutritional, Socioeconomic, and Delivery Characteristics Are Associated with Neurodevelopment in Tanzanian Children.

OBJECTIVES: To evaluate the hypothesis that various maternal, socioeconomic, delivery, and infant nutritional characteristics are associated with early childhood development in young Tanzanian children. STUDY DESIGN: We performed a prospective cohort study among 206 HIV-exposed, uninfected and 247 HIV-unexposed Tanzanian infants who had been enrolled in 2 separate micronutrient trials (NCT00197730 and NCT00421668). Trained nurses administered culturally modified Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III), to evaluate cognitive, motor, and language development at 15 months of age. This analysis explored predictors of BSID-III z-scores using multivariable linear regression. RESULTS: Among maternal determinants, we found that low maternal height predicted all BSID-III domains in HIV-unexposed children; low maternal education predicted lower cognitive (standardized mean difference, -0.41; 95% CI, -0.74 to -0.08) and lower gross motor scores (standardized mean difference, -0.32; 95% CI, -0.61 to -0.04) in HIV-exposed children. Among delivery characteristics, facility delivery predicted higher cognitive scores (standardized mean difference, 1.36; 95% CI, 0.26-2.46); and oxytocin administration predicted lower fine motor scores (standardized mean difference, -0.48; 95% CI, -0.87 to -0.09) in HIV-exposed children. Higher length-for-age z-scores at 6 weeks of age predicted better cognitive (standardized mean difference, 0.15; 95% CI, 0.01-0.29) and expressive language scores (standardized mean difference, 0.16; 95% CI, 0.02-0.29) at 15 months in HIV-exposed infants. CONCLUSIONS: This hypothesis-generating study found significant associations between nutritional status and health of the mother and child, and maternal educational attainment, with direct measures of early childhood development at 15 months of age. In addition, several aspects of delivery (facility birth and oxytocin administration) were associated with early childhood development. Future intervention trials should focus on modifiable maternal, infant, and obstetric factors to strengthen the evidence base concerning early childhood development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730 and NCT00421668.

Early motor development and cognitive abilities among Mexican preschoolers.

Psychomotricity plays a very important role in children's development, especially for learning involving reading-writing and mathematical calculations. Evaluate motor development in children 3 years old and its relationship with their cognitive abilities at the age of 5 years. Based on a cohort study, we analyzed the information about motor performance evaluated at 3 years old by Peabody Motor Scale and cognitive abilities at 5 years old. The association was estimated using linear regression models adjusted by mother's intelligence quotient, sex, Bayley mental development index at 18 months, and quality of the environment at home (HOME scale). 148 children whose motor performance was determined at age 3 and was evaluated later at age 5 to determine their cognitive abilities. Cognitive abilities (verbal, quantitative, and memory) measured by McCarthy Scales. Significant positive associations were observed between stationary balance at age 3 with verbal abilities (ß = 0.67, p = .04) and memory (ß = 0.81, p = .02) at 5 years. Grasping and visual-motor integration were significant and positively associated with quantitative abilities (ß = 0.74, p = .005; ß = 0.61, p = .01) and memory (ß = 2.11, p = .001; ß = 1.74, p = .004). The results suggest that early motor performance contributes to the establishment of cognitive abilities at 5 years. Evaluation and early motor stimulation before the child is faced with formal learning likely helps to create neuronal networks that facilitate the acquisition of academic knowledge.

Using Eye Movements to Assess Language Comprehension in Toddlers Born Preterm and Full Term.

OBJECTIVE: To assess language skills in children born preterm and full term by the use of a standardized language test and eye-tracking methods. STUDY DESIGN: Children born ≤32 weeks' gestation (n = 44) were matched on sex and socioeconomic status to children born full term (n = 44) and studied longitudinally. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) were administered at 18 months (corrected for prematurity as applicable). The Looking-While-Listening Task (LWL) simultaneously presents 2 pictures and an auditory stimulus that directs the child's attention to one image. The pattern of eye movements reflects visual processing and the efficiency of language comprehension. Children born preterm were evaluated on LWL 3 times between 18 and 24 months. Children born full term were evaluated at ages corresponding to chronological and corrected ages of their preterm match. Results were compared between groups for the BSID-III and 2 LWL measures: accuracy (proportion of time looking at target) and reaction time (latency to shift gaze from distracter to target). RESULTS: Children born preterm had lower BSID-III scores than children born full term. Children born preterm had poorer performance than children born full term on LWL measures for chronological age but similar performance for corrected age. Accuracy and reaction time at 18 months' corrected age displaced preterm-full term group membership as significant predictors of BSID-III scores. CONCLUSIONS: Performance and rate of change on language comprehension measures were similar in children born preterm and full term compared at corrected age. Individual variation in language comprehension efficiency was a robust predictor of scores on a standardized language assessment in both groups.

Manganese in teeth and neurodevelopment in young Mexican-American children.

INTRODUCTION: Manganese (Mn) is an essential nutrient but higher exposure has been associated with poorer neurodevelopment in children. METHODS: We measured Mn levels in prenatal (Mnpre) (n=197) and postnatal (Mnpost) dentin (n=193) from children's shed teeth using laser ablation inductively coupled plasma mass spectroscopy and examined the relationship with children's scores on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) on the Bayley Scales of Infant Development at 6, 12, and 24-months. We explored non-linear associations and interactions by sex, blood lead concentrations and maternal iron status during pregnancy. RESULTS: A two-fold increase of Mnpost levels in dentin was associated with small decreases in MDI at 6-months and 12-months of age. We also observed a non-linear relationship between Mnpost levels and PDI at 6-months. We found effect modification by sex for Mnpost levels and neurodevelopment at 6-months with stronger effects among girls for both MDI (-1.5 points; 95% Confidence Interval (CI): -2.4, -0.6) and PDI (-1.8 points; 95% CI: -3.3, -0.3). Girls whose mothers had lower hemoglobin levels experienced larger decreases in MDI and PDI associated with Mnpre levels than girls whose mothers had higher hemoglobin levels (pinteraction=0.007 and 0.09, respectively). We did not observe interactions with blood lead concentrations or any relationships with neurodevelopment at 24-months. CONCLUSIONS: Using Mn measurements in tooth dentin, a novel biomarker that provides prenatal and early postnatal levels, we observed negative transient associations between postnatal Mn levels and early neurodevelopment with effect modification by sex and interactions with prenatal hemoglobin.

The effect of deworming on early childhood development in Peru: A randomized controlled trial.

BACKGROUND: There is a knowledge gap on the effect of early childhood deworming on development in low- and middle-income countries. This evidence is important in the critical window of growth and development before two years of age. METHODS: A randomized controlled trial of the benefit, and optimal timing and frequency, of deworming on development was conducted in Iquitos, Peru. Children were enrolled during routine 12-month growth and development visits and randomly allocated to: (1) deworming at the 12-month visit and placebo at the 18-month visit; (2) placebo at the 12-month visit and deworming at the 18-month visit; (3) deworming at the 12 and 18-month visits; or (4) placebo at the 12 and 18-month visits. The Bayley Scales of Infant Development III was used to assess cognitive, language and motor skills at the 12 and 24-month visits. One-way ANOVA analyses used an intention-to-treat approach. RESULTS: Between September 2011 and June 2012, 1760 children were enrolled. Attendance at the 24-month visit was 88.8% (n=1563). Raw scores on all subtests increased over 12 months; however, cognitive and expressive language scaled scores decreased. There was no statistically significant benefit of deworming, or effect of timing or frequency, on any of the development scores. Baseline height and weight and maternal education were associated with development scores at 24 months. CONCLUSIONS: After 12 months of follow-up, an overall benefit of deworming on cognition, language or fine motor development was not detected. Additional integrated child and maternal interventions should be considered to prevent developmental deficits in this critical period.

Prenatal molybdenum exposure and infant neurodevelopment in Mexican children.

OBJECTIVE: To evaluate the association between prenatal exposure to molybdenum (Mo) and infant neurodevelopment during the first 30 months of life. METHODS: We selected a random sample of 147 children who participated in a prospective cohort study in four municipalities in the State of Morelos, Mexico. The children were the products of uncomplicated pregnancies with no perinatal asphyxia, with a weight of ≥2 kg at birth, and whose mothers had no history of chronic illnesses. These women were monitored before, during, and after the pregnancy. For each of these children a maternal urine sample was available for at least one trimester of pregnancy, and urine Mo levels were determined by electrothermal atomic absorption spectrometry. Neurodevelopment was evaluated using the psychomotor (PDI) and mental development indices (MDI) of the Bayley scale. Association between prenatal exposure to Mo and infant neurodevelopment was estimated using generalized mixed effect models. RESULTS: The average urinary concentrations of Mo adjusted for creatinine varied between 45.6 and 54.0 µg/g of creatinine at first and third trimester, respectively. For each doubling increase of Mo (µg/g creatinine) during the third trimester of pregnancy, we observed a significant reduction on PDI (ß = -0.57 points; P = 0.03), and no effect on MDI (ß = 0.07 points; P = 0.66). DISCUSSION: As this is the first study that suggests a potential negative association between prenatal Mo exposure and infant neurodevelopment, these results require further confirmation.

Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments.

OBJECTIVE: To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology, and brain structure at hospital discharge; and developmental outcomes at 2 years of age. STUDY DESIGN: In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at 2 years of age (n = 86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were: (1) medical factors throughout the hospitalization; (2) neurobehavior; and (3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). RESULTS: At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores (P = .02; ß = -0.52 [CI -0.95, -0.10]). At age 2 years, infants from private rooms had lower language scores (P = .006; ß = -8.3 [CI -14.2, -2.4]) and a trend toward lower motor scores (P = .02; ß = -6.3 [CI -11.7, -0.99]), which persisted after adjustment for potential confounders. CONCLUSION: These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment.

Evaluation of early childhood social-communication difficulties in children born preterm using the Quantitative Checklist for Autism in Toddlers.

OBJECTIVES: To characterize early childhood social-communication skills and autistic traits in children born very preterm using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) and explore neonatal and sociodemographic factors associated with Q-CHAT scores. STUDY DESIGN: Parents of children born before 30 weeks gestation and enrolled in a study evaluating routinely collected neurodevelopmental data between the post-menstrual ages of 20 and 28 months were invited to complete the Q-CHAT questionnaire. Children with severe neurosensory disabilities and cerebral palsy were excluded. Participants received neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Q-CHAT scores of this preterm cohort were compared with published general population scores. The association between Bayley-III cognitive and language scores and neonatal and sociodemographic factors with Q-CHAT scores were examined. RESULTS: Q-CHAT questionnaires were completed from 141 participants. At a mean post-menstrual age of 24 months, the Q-CHAT scores of the preterm cohort (mean 33.7, SD 8.3) were significantly higher than published general population scores (mean 26.7; SD 7.8), indicating greater social-communication difficulty and autistic behavior. Preterm children received higher scores, particularly in the categories of restricted, repetitive, stereotyped behavior, communication, and sensory abnormalities. Lower Bayley-III language scores and non-white ethnicity were associated with higher Q-CHAT scores. CONCLUSIONS: Preterm children display greater social-communication difficulty and autistic behavior than the general population in early childhood as assessed by the Q-CHAT. The implications for longer-term outcome will be important to assess.

Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial.

OBJECTIVE: To compare the effect of 2.5 vs 4 g/kg/d of amino acid (AA) in parenteral nutrition of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment. STUDY DESIGN: One hundred thirty-one infants with birth weight between 500 and 1249 g were randomized to 2.5 (standard AA [SAA] group) or 4 (high AA [HAA] group) g/kg/d AA intake, with equal nonprotein energy. The primary outcome was body size at 36 weeks. RESULTS: One hundred thirty-one patients were randomized and 114 analyzed (58 SAA group and 56 HAA group). Study groups had similar demographics and clinical characteristics. Elevated blood urea (BU >70 mg/dL = BU nitrogen >32.6 mg/dL) occurred in 24% vs 59% (P = .000) and hyperglycemia (>175 mg/dL) in 34% vs 11% (P = .003) of the SAA and HAA patients, respectively. Body weight, length, and head circumference at 36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 ± 13 in the SAA group and 97 ± 15 in the HAA group (P = .35). CONCLUSIONS: The HAA group had higher BU levels and better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment.

Factors associated with permanent hearing impairment in infants treated with therapeutic hypothermia.

OBJECTIVE: To define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants subjected to therapeutic hypothermia for moderate or severe neonatal encephalopathy. STUDY DESIGN: Data were collected prospectively in a regional center providing therapeutic hypothermia. Cooled infants at ≥ 36 weeks gestation with moderate or severe neonatal encephalopathy were analyzed if a full dataset was available (n = 108), including clinical variables and gentamicin trough levels. Infants with hearing impairment were identified, and survivors were followed up with neurodevelopmental evaluation at age 18 months. Stepwise logistic regression identified factors associated with hearing impairment. RESULTS: Nine infants died, and among the survivors, 10.1% developed a permanent hearing impairment. The trough gentamicin level was above the recommended cutoff of 2 mg/L in 37% of the infants in the entire cohort and in 90% of the infants with hearing impairment. Logistic regression analysis identified high trough gentamicin level, low cord pH, and hypoglycemia (<46.8 mg/dL) in the first postnatal hour as significantly associated with hearing impairment. The need for inotropic support was close to significant (P = .055). CONCLUSION: Hearing impairment was a common finding among cooled infants. Plasma gentamicin levels were commonly >2 mg/L. Based on these findings, we propose changes in gentamicin dosing interval and trough level monitoring to minimize the risk of potentially toxic levels in cooled newborns.

Neurodevelopmental outcome of extremely low birth weight infants with Candida infection.

OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age.

BACKGROUND: Previous studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life. OBJECTIVES: To evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24-36 months of age. METHODS: This analysis was conducted on the first three years of life among a subsample of 136 mother-child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di-2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36 months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level. RESULTS: No significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (ß=-2.11 [95% CI: -3.73, -0.49]), MEHHP (ß=-1.89 [95% CI: -3.64, -0.15]), MEOHP (ß=-1.80 [95% CI: -3.58, -0.03]) MECPP (ß=-2.52 [95% CI: -4.44, -0.61]), and ΣDEHP (ß=-3.41 [95% CI: -5.26, -1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (ß=1.79 [95% CI: 0.14, 3.45]) and MCPP (ß=1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls. CONCLUSION: This study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment.

Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants.

OBJECTIVE: To test the hypothesis that increasing severity of the fetal inflammatory response (FIR) would have a dose-dependent relationship with severe neurodevelopmental impairment or death in extremely preterm infants. STUDY DESIGN: We report 347 infants of 23-28 weeks gestational age admitted to a tertiary neonatal intensive care unit between 2006 and 2008. The primary outcome was death or neurodevelopmental impairment at the 18- to 22-month follow-up. Exposure status was defined by increasing stage of funisitis (stage 1, phlebitis; stage 2, arteritis with or without phlebitis; stage 3, subacute necrotizing funisitis) and severity of chorionic plate vasculitis (inflammation with or without thrombosis). RESULTS: A FIR was detected in 110 placentas (32%). The rate of severe neurodevelopmental impairment/death was higher in infants with subacute necrotizing funisitis compared with infants without placental/umbilical cord inflammation (60% vs 35%; P < .05). Among infants with stage 1 or 2 funisitis, the presence of any chorionic vasculitis was associated with a higher rate of severe neurodevelopmental impairment/death (47% vs 23%; P < .05). After adjustment for confounding factors, only subacute necrotizing funisitis (risk ratio, 1.87; 95% CI, 1.04-3.35; P = .04) and chorionic plate vasculitis with thrombosis (risk ratio, 2.21; 95% CI, 1.10-4.46; P = .03) were associated with severe neurodevelopmental impairment/death. CONCLUSION: Severe FIR, characterized by subacute necrotizing funisitis and severe chorionic plate vasculitis with thrombosis, is associated with severe neurodevelopmental impairment/death in preterm infants.

Association between feeding difficulties and language delay in preterm infants using Bayley Scales of Infant Development-Third Edition.

OBJECTIVE: To evaluate the relationship between abnormal feeding patterns and language performance on the Bayley Scales of Infant Development-Third Edition at 18-22 months adjusted age among a cohort of extremely premature infants. STUDY DESIGN: This is a descriptive analysis of 1477 preterm infants born ≤ 26 weeks gestation or enrolled in a clinical trial between January 1, 2006 and March 18, 2008 at a National Institute of Child Health and Human Development Neonatal Research Network center who completed the 18-month neurodevelopmental follow-up assessment. At 18-22 months adjusted age, a comprehensive neurodevelopmental evaluation was performed by certified examiners including the Receptive and Expressive Language Subscales of the Bayley Scales of Infant Development-Third Edition and a standardized adjusted age feeding behaviors and nutritional intake. Data were analyzed using bivariate and multilevel linear and logistic regression modeling. RESULTS: Abnormal feeding behaviors were reported in 193 (13%) of these infants at 18-22 months adjusted age. Abnormal feeding patterns, days of mechanical ventilation, hearing impairment, and Gross Motor Functional Classification System level ≥ 2 each independently predicted lower composite language scores. CONCLUSIONS: At 18 months adjusted age, premature infants with a history of feeding difficulties are more likely to have language delay. Neuromotor impairment and days of mechanical ventilation are both important risk factors associated with these outcomes.

Clinical, biochemical, and neuroimaging findings predict long-term neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To evaluate clinical, biochemical, and neuroimaging findings as predictors of neurodevelopmental outcome in patients with symptomatic congenital cytomegalovirus (CMV). STUDY DESIGN: The study cohort comprised 26 patients with symptomatic congenital CMV born between 1993 and 2009 in a single center. Absolute and weight deficit-adjusted head circumference were considered. Cerebrospinal fluid (CSF) investigations included standard cytochemical analysis, determination of beta2-microglobulin (ß2-m), neuron-specific enolase, and CMV DNA detection. Neuroimaging was classified according to a validated scoring system comprising calcifications, ventriculomegaly, and atrophy, with findings graded from 0 to 3. Systematic long-term neurodevelopmental assessment included motor function, cognition, behavior, hearing, vision, and epilepsy. Sequelae were graded as mild/absent, moderate, or severe; adverse outcome was defined as death or moderate to severe disability. RESULTS: Three children died. The mean age at follow-up of the survivors was 8.7 ± 5.3 years (range, 19 months to 18.0 years). Neonatal findings showing a significant association with adverse outcome were relative microcephaly, CSF ß2-m concentrations, and grade 2-3 neuroimaging abnormalities (P < .05). Receiver operator characteristic curve analysis indicated that the most accurate single factor for predicting unfavorable outcome was CSF ß2-m >7.9 mg/L (area under the curve, 0.84 ± 0.08; sensitivity, 69%; specificity, 100%). The combination of CSF ß2-m >7.9 mg/L and moderate-severe neuroimaging alterations improved predictive ability (area under the curve, 0.92 ± 0.06; sensitivity, 87%; specificity, 100%). CONCLUSION: Adjusted head circumference, CSF ß2-m level, and neuroimaging studies have prognostic significance for neurodevelopmental outcome in newborns with congenital CMV. A combination of early findings improves the predictive value.