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1.  Safety of Perinatal Exposure to Antiretroviral Medications: Developmental Outcomes in Infants 
This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants.
HIV-exposed, uninfected infants (age 9-15 months) enrolled in SMARTT, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development, and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class), and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates.
As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black, 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (PIs; 9% of PI-containing regimens also included non-nucleoside reverse transcriptase inhibitors [NNRTIs]), 5% to regimens containing NNRTIs (without PI), and 14% to regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen, or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (p=0.01).
These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.
PMCID: PMC3723344  PMID: 23340561
HIV; ARV; infant; neurodevelopment; developmental assessment
2.  Effect of ethnicity and race on cognitive and language testing at 18 – 22 months in extremely preterm infants 
The Journal of Pediatrics  2012;160(6):966-971.e2.
To evaluate the relationship of race/ethnicity to cognitive and language scores on the Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) in extremely preterm toddlers (<28+0 weeks’ estimated gestational age).
Study design
Extremely preterm toddlers at NICHD Neonatal Research Network Centers evaluated at 18–22 months adjusted age from 3 race/ethnic groups (White, Black, and Hispanic-White) were included in this cohort study. Multivariable regression modeling was used to identify race/ethnic differences adjusting for medical and psychosocial factors.
Children included 369 Whites, 352 Blacks and 144 Hispanic-Whites. Cognitive scores differed between groups in unadjusted analysis (p=<0.001), but not after adjusting for medical and psychosocial factors (p=0.13). Language scores differed in adjusted and unadjusted analyses. Whites scored higher than Blacks or Hispanic-Whites, and Blacks scored higher than Hispanic-Whites.
A combination of medical variables and primary caretaker education accounted for differences in BSID-III cognitive scores between groups. Black and Hispanic-White toddlers had lower language scores than Whites, even after adjustment. Early intervention should be targeted to these identified risk factors. Assessment of early language development among minority groups may be warranted.
PMCID: PMC3343209  PMID: 22269248
development; prematurity; Bayley Scales; BSID
3.  Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes 
The Journal of pediatrics  2012;161(2):222-8.e3.
To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development’s Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006–2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008–2011 (period 2).
Study design
Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.
Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).
Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.
PMCID: PMC3796892  PMID: 22421261
4.  Neurodevelopmental Effects of Low-level Prenatal Mercury Exposure From Maternal Fish Consumption in a Mediterranean Cohort: Study Rationale and Design 
Journal of Epidemiology  2013;23(2):146-152.
Mercury is a neurotoxic environmental pollutant. However, the literature on the neurodevelopmental effect of low-level prenatal mercury exposure from maternal fish intake is inconsistent. We assessed the association between prenatal mercury exposure and infant neurodevelopment in coastal areas of 4 Mediterranean countries.
This was a prospective cohort study that planned to enroll approximately 1700 mother–infant pairs. Pregnant women and their newborn children were recruited in selected hospitals of the study areas. Biological samples, including maternal hair and cord blood, were collected from mothers and children, and the concentrations of mercury and other elements were measured. Exposures to lifestyle, environmental, and social factors were assessed through questionnaires. The main outcome was child neurodevelopment at 18 months, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition.
This cohort has a number of strengths. First, mercury concentration was measured in several biological samples, which allows for a better understanding of mercury kinetics and is useful for sensitivity analyses. Therefore, we expect to be able to adjust for the potential confounding effects of lifestyle and social factors and for the effects of other elements that were measured in the biological samples. Finally, this is a multinational study and thus permits assessment of the relation between mercury and child neurodevelopment in different populations.
PMCID: PMC3700240  PMID: 23269124
cohort study; mercury; polyunsaturated fatty acids; nervous system development; fish
5.  Early Second Trimester Maternal Plasma Choline and Betaine Are Related to Measures of Early Cognitive Development in Term Infants 
PLoS ONE  2012;7(8):e43448.
The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age.
This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development–III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment.
The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78–8.03) and 9.40 (8.10–11.3) µmol/L, respectively. Estimated choline intakes were (mean ±SD) 383±98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142±70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B = 6.054, SE = 2.283, p = 0.009) and betaine (B = 7.350, SE = 1.933, p = 0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development.
We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women.
PMCID: PMC3423345  PMID: 22916264
6.  Impact of the HIV/AIDS Epidemic on the Neurodevelopment of Preschool-Aged Children in Kinshasa, Democratic Republic of the Congo 
Pediatrics  2008;122(1):e123-e128.
Pediatric HIV infection is a growing problem in most regions of the world. Data on the effects of HIV on the neurodevelopment of children in resource-poor settings are scarce but necessary to guide interventions. The purpose of this study was to compare the neurodevelopment of preschool-aged HIV-infected, HIV-affected (HIV-uninfected AIDS orphans and HIV-uninfected children whose mother had symptomatic AIDS), and healthy control children in Kinshasa, Democratic Republic of Congo.
Thirty-five HIV-infected, 35 HIV-affected, and 90 control children aged 18 to 72 months were assessed by using the Bayley Scales of Infant Development II, Peabody Developmental Motor Scales, Snijders-Oomen Nonverbal Intelligence Test, and Rossetti Infant-Toddler Language Scale, as appropriate for age.
Overall, 60% of HIV-infected children had severe delay in cognitive function, 29% had severe delay in motor skills, 85% had delays in language expression, and 77% had delays in language comprehension, all significantly higher rates as compared with control children. Young HIV-infected children (aged 18–29 months) performed worse, with 91% and 82% demonstrating severe mental and motor delay, respectively, compared with 46% and 4% in older HIV-infected children (aged 30–72 months). HIV-affected children had significantly more motor and language expression delay than control children.
The impact of the HIV pandemic on children’s neurodevelopment extends beyond the direct effect of the HIV virus on the central nervous system. AIDS orphans and HIV-negative children whose mothers had AIDS demonstrated significant delays in their neurodevelopment, although to a lesser degree and in fewer developmental domains than HIV-infected children. Young HIV-infected children were the most severely afflicted group, indicating the need for early interventions. Older children performed better as a result of a “survival effect,” with only those children with less aggressive disease surviving.
PMCID: PMC2900927  PMID: 18595957
HIV; AIDS; neurodevelopment; child; Africa
7.  Duration of Exposure to Cranial Vault Surgery: Associations with Neurodevelopment among Children with Single-Suture Craniosynostosis 
Paediatric anaesthesia  2012;10.1111/j.1460-9592.2012.03843.x.
To evaluate associations between neurodevelopment and exposure to surgery and anesthetic agents in children with single-suture craniosynostosis (SSC).
Young children with SSC have unexplained neurodevelopmental delays. The possible contributions of factors related to cranial vault surgery--including anesthesia--have not been previously examined.
Two anesthesiologists reviewed the surgical records of 89 infants (70 had complete data). Primary exposures were duration of surgery and anesthesia and total duration of inhaled anesthesia (at age 6 months on average). Outcomes were the cognitive and motor scores from the Bayley Scales of Infant Development-II and language scores from the Preschool Language Scale, 3rd edition, given at age 36 months. Linear regression using robust standard error estimates was performed, adjusting for age at surgery and suture site.
Anesthesia duration ranged from 155 to 547 minutes. For every 30-minute increase in anesthesia duration, the estimated average decrease in developmental test scores ranged from 1.1 to 2.9 (p ranged from <0.001 to 0.30). Similar, but weaker findings were observed with surgery duration and total duration of inhaled anesthesia. Inverse relations between exposure amounts and neurodevelopment were stronger in children with non-sagittal synostosis.
Average neurodevelopmental scores were lower among children experiencing longer surgeries and higher exposures to inhaled anesthesia. These associations may be due to anesthesia exposure, nonspecific effects of surgery, or unmeasured variables that correlate with surgery duration. Further study of potential causal mechanisms is warranted.
PMCID: PMC3404221  PMID: 22502768
8.  Effects of Periodontal Therapy on Rate of Preterm Delivery A Randomized Controlled Trial 
Obstetrics and gynecology  2009;114(3):551-559.
To test the effects of maternal periodontal disease treatment on the incidence of preterm birth (delivery before 37 weeks of gestation).
The Maternal Oral Therapy to Reduce Obstetric Risk Study was a randomized, treatment-masked, controlled clinical trial of pregnant women with periodontal disease who were receiving standard obstetric care. Participants were assigned to either a periodontal treatment arm, consisting of scaling and root planing early in the second trimester, or a delayed treatment arm that provided periodontal care after delivery. Pregnancy and maternal periodontal status were followed to delivery and neonatal outcomes until discharge. The primary outcome (gestational age less than 37 weeks) and the secondary outcome (gestational age less than 35 weeks) were analyzed using a χ2 test of equality of two proportions.
The study randomized 1,806 patients at three performance sites and completed 1,760 evaluable patients. At baseline, there were no differences comparing the treatment and control arms for any of the periodontal or obstetric measures. The rate of preterm delivery for the treatment group was 13.1% and 11.5% for the control group (P=.316). There were no significant differences when comparing women in the treatment group with those in the control group with regard to the adverse event rate or the major obstetric and neonatal outcomes.
Periodontal therapy did not reduce the incidence of preterm delivery.
PMCID: PMC2917914  PMID: 19701034
9.  Effects of Gender on the Health and Development of Medically At-Risk Infants 
To examine gender-differentiated health and cognitive/motor/language developmental outcomes among medically at-risk infants.
Longitudinal descriptive and comparative secondary analysis.
Neonatal intensive care unit, intermediate care unit, and infectious disease clinic of the tertiary medical centers in the Southeast and East United States.
One hundred eight (108) premature infants, 67 medically fragile infants, and 83 infants seropositive for HIV.
Neonatal and later health variables were obtained from the medical record to determine the technology dependence scores and frequency of common health problems. Data for physical growth and cognitive/motor/language development were obtained through the physical measurement, including the Bayley Scales of Infant Development–Second Edition, the Vineland Adaptive Behavior Scale, the Toll Control Developmental Checklist, and the Preschool Language Scale–3 during home visits between 6 to 27 months corrected ages.
Fewer effects on health and developmental outcomes related to gender were observed with medically fragile infants than the other two groups of infants. The cognitive/motor/language scores were decreased with increasing age of the infants in all groups.
Male gender can be considered a significant biological risk factor for infants' cognitive and motor development, especially for premature infants. Because of their increased risk, it is recommended that male infants who are born prematurely or seropositive for HIV have early and advanced developmental screening tests by trained personnel through periodic pediatric clinic.
PMCID: PMC2951302  PMID: 20920000
Gender; Health and Development; Premature Infants; Medically Fragile Infants; Infants Seropositive for HIV
10.  Maternal depression and perceived social support as predictors of cognitive function trajectories during the first 3 years of life for preterm infants in Wisconsin 
Child  2011;38(3):425-434.
Among families of infants born preterm, the association between postnatal depression and children’s cognitive function is not well understood, but thought to be compromised. The purpose of this study is to investigate maternal depressive symptoms and perceived social support as predictors of children’s cognitive function trajectories.
This is a longitudinal study of a sample of infants born preterm (less than 37 weeks) in Wisconsin. This study includes 130 infants who were hospitalized in one of three Wisconsin neonatal intensive care units in 2002–2005 and followed until 36 months of age. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Social support was measured using the Maternal Support scale. Children’s cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition, and the Stanford-Binet Intelligence scale, 5th edition.
Children’s cognitive function trajectories declined initially and then increased. Being female [coefficient=5.14, s.e.=1.89] and non-poor [coefficient =11.26 s.e=5.78], and having a mother who has a graduate degree [coefficient =7.67, s.e.=3.37)] was associated with higher levels of cognition initially. Being white was associated with a more optimal cognitive trajectory. Although depression did not predict children’s cognitive trajectories, the presence of clinically-elevated depressive symptoms at 9 months postterm was associated with lower cognitive functioning at 16 months when mothers reported low social support.
Postnatal depressive symptoms appear to have a meaningful, dynamic influence on the cognitive outcomes of children born preterm, above and beyond family socio-demographic risk when the presence and timing of perceived social support is considered. Interventions to ameliorate developmental risk associated with preterm birth should include repeated assessments of maternal social support and postnatal depression and be targeted toward socially disadvantaged families.
PMCID: PMC3191240  PMID: 21651608
preterm birth; cognitive function; maternal depression; social support
11.  In-utero exposure to DDT and cognitive development among infants and school-aged children 
Epidemiology (Cambridge, Mass.)  2012;23(5):689-698.
Dichlorodiphenyltrichloroethane (DDT) continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and dichlorodiphenyldichloroethylene (DDE) has been associated with developmental and cognitive impairment among children. We examined this association in an historical cohort in which the level of exposure was greater than in previous studies.
The association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in approximately 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the U.S. from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years using the Wechsler Intelligence Scale for Children.
Although levels of both DDT and DDE were relatively high in this population (median DDT concentration, 8.9 µg/L; DDE, 24.5 µg/L), neither was related to Mental or Psychomotor Development scores on the Bayley Scales or to Full-Scale IQ at 7 years of age. Categorical analyses showed no evidence of dose-response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0.
Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years of age in this cohort.
PMCID: PMC3415569  PMID: 22766752
12.  Effects of Prenatal Exposure to Polychlorinated Biphenyls and Dioxins on Mental and Motor Development in Japanese Children at 6 Months of Age 
Environmental Health Perspectives  2005;114(5):773-778.
Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children’s Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0–51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.
PMCID: PMC1459935  PMID: 16675436
dioxins; infant development; maternal blood; polychlorinated biphenyls (PCBs); prenatal exposure
13.  Presurgical and postsurgical assessment of the neurodevelopment of infants with single-suture craniosynostosis: comparison with controls 
Journal of neurosurgery  2007;107(2 Suppl):103-110.
Although most infants with single-suture craniosynostosis (SSC) appear to have neurodevelopmental test scores in the average range, SSC has been associated with cognitive and motor delays during infancy. Whether and when surgery improves such deficits are not yet known. The authors aimed to compare the pre- and postsurgical neurodevelopmental status of patients with SSC with those of control infants without craniosynostosis.
The authors conducted a large, multicenter, longitudinal study of 168 infants with craniosynostosis and 115 controls without synostosis who were of similar age, race, sex, and socioeconomic status. The authors assessed participants by using the Bayley Scales of Infant Development, Second Edition (BSID-II) and the Preschool Language Scale, Third Edition (PLS-3) at enrollment, before patients’ intracranial surgery, and when participants were 18 months of age (after surgery for patients).
After adjusting for potential confounding factors in linear regression analyses, the authors found a tendency for patients to perform similarly to or slightly worse than controls on neurodevelopmental examinations at both visits. After surgery, the patients’ mean scores were 0.6 to three points lower than those of controls on the five BSID-II and PLS-3 scales (p = 0.02–0.07). Compared with controls, patients had 2.3 and 1.9 times the adjusted odds of scoring in the delayed range on either BSID-II scale (Mental Development Index and Psychomotor Development Index) for the first and second visits, respectively (p = 0.001 and p = 0.015, respectively). The patients’ mean adjusted test scores were nearly unrelated to the timing of their surgery.
These findings support recommendations for neurodevelopmental screening in infants with SSC. Longer follow-up, as is being conducted with the patients in the present study, will be critical for identifying the potential longer-term correlates of SSC and its surgical correction.
PMCID: PMC3417768  PMID: 18459881
cranioplasty; neurodevelopment; pediatric neurosurgery; single-suture craniosynostosis
14.  Maternal Vitamin D Status and Infant Outcomes in Rural Vietnam: A Prospective Cohort Study 
PLoS ONE  2014;9(6):e99005.
Vitamin D deficiency affects 1 billion people globally. It has an important role in bone homeostasis, brain development and modulation of the immune system and yet the impact of antenatal vitamin D deficiency on infant outcomes is poorly understood. We assessed the association of 25- hydroxyvitamin D levels (25-OHD) in late pregnancy and early infant growth and developmental outcomes in rural Vietnam.
Design and Methods
A prospective cohort study of 960 women who had previously participated in a double-blind cluster randomized controlled trial of antenatal micronutrient supplementation in rural Vietnam was undertaken. Maternal 25-OHD concentration was measured at 32 weeks gestation, and infants were followed until 6 months of age. Main outcome measures were cognitive, motor, socio-emotional and language scores using the Bayley Scales of Infant Development, 3rd edition, and infant length-for-age z scores at 6 months of age.
60% (582/960) of women had 25-OHD levels <75 nmol/L at 32 weeks gestation. Infants born to women with 25-OHD deficiency (<37.5 nmol/L) had reduced developmental language scores compared to those born to women who were vitamin D replete (≥75 nmol/L) (Mean Difference (MD) −3.48, 95% Confidence Interval (CI) −5.67 to −1.28). For every 25 nmol increase in 25-OHD concentration in late pregnancy, infant length-for-age z scores at 6 months of age decreased by 0.08 (95% CI −0.15 to −0.02).
Low maternal 25- hydroxyvitamin D levels during late pregnancy are of concern in rural Vietnam, and are associated with reduced language developmental outcomes at 6 months of age. Our findings strengthen the evidence for giving vitamin D supplementation during pregnancy.
PMCID: PMC4072587  PMID: 24967813
15.  Concurrent Validity of the TIMP and the Bayley III Scales at 6 Weeks Corrected Age 
Examine agreement between the Test of Infant Motor Performance (TIMP) and the Bayley III.
One-hundred, forty-five infants born at 29-34 weeks gestation with socioenvironmental risk factors were tested on the TIMP and Bayley III at 6 weeks corrected age (CA). Scores were correlated to assess convergence/divergence of content. Decision analysis using a cutoff of the mean on the Bayley Motor Composite and -.5 and -1 SD from the mean on the TIMP assessed agreement on delay/non-delay.
The TIMP-Bayley Motor Composite correlation was .546, with Cognitive was .310, and with Language was .281. 9% of infants scored below −1.0 SD on the TIMP while no child performed below -1 SD on the Bayley Motor scale (sensitivity 31%).
Convergent validity between the TIMP and the Bayley Motor scale was demonstrated, but no infant showed delay on any Bayley scale. The TIMP is preferred for early assessment of infants.
PMCID: PMC3788354  PMID: 24081011
developmental disabilities/diagnosis; infant/premature; infant, newborn; motor skills disorders/diagnosis; neuropsychological tests; predictive value of tests; reproducibility of results; risk; socioeconomic factors
16.  Parent-child interaction, maternal depressive symptoms and preterm infant cognitive function 
Infant behavior & development  2012;35(3):489-498.
Preterm infants are at risk for cognitive difficulties due to infant neurological immaturity and family social disadvantage, and this may be exacerbated by maternal depressive symptoms. This longitudinal study of infants born preterm (<35 weeks) or low birth weight (<2500 grams) (n=137) tests if maternal depressive symptoms at 4 months is associated with preterm children’s cognitive function at 16 months. Additionally, we test if this association is mediated by the quality of parent-child interaction at 9 months, and if these associations differ by levels of maternal social support. Children’s cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Perceived social support was measured using the Maternal Support scale. The quality of parent-child interaction was measured using the Parent-Child Early Relational Assessment. Linear regression and structural equation modeling were used to test the research questions. Postnatal depression at 4 months is associated with lower cognitive function (mean difference=−5.22, 95% CI:[−10.19, −0.25]) at 16 months controlling for a host of socioeconomic characteristics. For mothers with fewer depressive symptoms, bolstering effects of maternal supports on children’s cognitive function were evident. We find no evidence for effect mediation by quality of parent-child interaction. Early exposure to maternal depressive symptoms appears to have a negative influence on preterm children’s later cognitive function. These findings suggest important policy and programmatic implications for early detection and intervention for families of preterm infants.
PMCID: PMC3409313  PMID: 22721747
postnatal depression; parent-child interaction; preterm birth; cognitive function
17.  Associations of Prenatal Mercury Exposure From Maternal Fish Consumption and Polyunsaturated Fatty Acids With Child Neurodevelopment: A Prospective Cohort Study in Italy 
Journal of Epidemiology  2013;23(5):360-370.
Mercury is a neurotoxin, and limited prenatal exposure to it can affect long-term child neurodevelopment. However, results of epidemiologic studies of such exposure have been inconsistent. We examined the association of prenatal mercury exposure from maternal fish consumption with child neurodevelopment in northern Italy.
A population-based cohort of 606 children and their mothers was studied from pregnancy to age 18 months. Mercury levels were measured in maternal hair and blood during pregnancy and in umbilical cord blood and breast milk. Levels of polyunsaturated fatty acids (PUFAs) were measured in maternal serum. Maternal and child intakes of fish were assessed by using a food frequency questionnaire. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was used to evaluate child neurodevelopment. Multivariate linear regression was used to examine the association of mercury exposure with BSID-III scores, after controlling for maternal fish intake, PUFAs during pregnancy, and several other confounders.
Mean weekly fish intake during pregnancy was less than 2 servings. Mercury concentrations in biological samples were low (mean, 1061 ng/g in hair) and moderately correlated with fish intake, particularly of carnivorous species. Maternal ω-3 PUFA concentrations were poorly correlated with fish intake. Maternal intelligence quotient (IQ) and child intake of fish were significantly associated with neurodevelopment scores. In multivariate models, the level of Hg exposure was not associated with neurodevelopmental performance at 18 months.
In this Italian population, neurodevelopment at 18 months was associated with child intake of fresh fish and maternal IQ rather than with mercury exposure. The expected beneficial effect of maternal fish intake (from maternal ω-3 PUFAs) was not found.
PMCID: PMC3775530  PMID: 23933621
mercury; polyunsaturated fatty acids; nervous system development; fish; Bayley Scales of Infant and Toddler Development
18.  Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns 
Pediatrics  2012;129(3):494-502.
Extremely low gestational age neonates are more likely than term infants to develop cognitive impairment. Few studies have addressed antenatal risk factors of this condition. We identified antenatal antecedents of cognitive impairment determined by the Mental Development Index (MDI) portion of the Bayley Scales of Infant Development, Second Edition (BSID-II), at 24 months corrected age.
We studied a multicenter cohort of 921 infants born before 28 weeks of gestation during 2002 to 2004 and assessed their placentas for histologic characteristics and microorganisms. The mother was interviewed and her medical record was reviewed. At 24 months adjusted age, children were assessed with BSID-II. Multinomial logistic models were used to estimate odds ratios.
A total of 103 infants (11%) had an MDI <55, and 99 infants (11%) had an MDI between 55 and 69. No associations were identified between organisms recovered from the placenta and developmental delay. Factors most strongly associated with MDI <55 were thrombosis of fetal vessels (OR 3.1; 95% confidence interval [CI] 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), maternal education ≤12 years (OR 3.4; 95% CI 1.9, 6.2), nonwhite race (OR 2.2; 95% CI 1.3, 3.8), birth weight z score < −2 (OR 2.8; 95% CI 1.1, 6.9), and male gender (OR 2.7; 95% CI 1.6, 4.5).
Antenatal factors, including thrombosis of fetal vessels in the placenta, severe fetal growth restriction, and maternal obesity, convey information about the risk of cognitive impairment among extremely premature newborns.
PMCID: PMC3289523  PMID: 22331342
prematurity; placenta; chorioamnionitis; fetal growth restriction; mental development
19.  The results of early physiotherapy on a child with incontinentia pigmenti with encephalocele 
BMJ Case Reports  2010;2010:bcr0320102814.
This study aimed to exhibit the effects of early physiotherapy and discusses post-treatment results on a patient with incontinentia pigmenti (IP) with encephalocele. Physiotherapy evaluations of the child included cognitive, fine and gross motor development assessed with the Bayley Scales of Infant and Toddler Development – Third Edition (Bayley-III), disability level with the gross motor function classification system, gross motor function with the gross motor function measurement (GMFM), and tonus evaluation with the Modified Ashworth Scale. The child was included in a physiotherapy and rehabilitation programme based on neurodevelopmental treatment three times a week. Although cognitive and motor development according to Bayley-III improved in the present case, motor and cognitive retardation became more apparent with growth. GMFM results indicated a large improvement from 5.88% to 47.73%. Presentation of this case shows the significance of early physiotherapy in this first study on physiotherapy for IP during the early rehabilitation process.
PMCID: PMC3029085  PMID: 22767665
20.  Little Evidence of Association Between Severity of Trigonocephaly and Cognitive Development in Infants With Single-Suture Metopic Synostosis 
Neurosurgery  2010;67(2):408-416.
To measure severity of trigonocephaly among infants with single-suture metopic craniosynostosis by using a novel shape descriptor, the trigonocephaly severity index (TSI), and to evaluate whether degree of trigonocephaly correlates with their neurodevelopmental test scores.
We conducted a multicenter cross-sectional and longitudinal study, identifying and recruiting 65 infants with metopic synostosis before their corrective surgery. We obtained computed tomography images for 49 infants and measured the presurgical TSI, a 3-dimensional outline-based cranial shape descriptor. We evaluated neurodevelopment by administering the Bayley Scales of Infant Development, Second Edition, and the Preschool Language Scale, Third Edition, before surgery and at 18 and 36 months of age. We fit linear regression models to estimate associations between test scores and TSI values adjusted for age at testing and race/ethnicity. We fit logistic regression models to estimate whether the odds of developmental delay were increased among children with more severe trigonocephaly.
We observed little adjusted association between neurodevelopmental test scores and TSI values, and no associations that persisted at 3 years. Trigonocephaly was less severe among children referred at older ages.
We observed little evidence of an association between the severity of trigonocephaly among metopic synostosis patients and their neurodevelopmental test scores. Detecting such a relationship with precision may require larger sample sizes or alternative phenotypic quantifiers. Until studies are conducted to explore these possibilities, it appears that although associated with the presence of metopic synostosis, the risk of developmental delays in young children is unrelated to further variation in trigonocephalic shape.
PMCID: PMC3417772  PMID: 20644427
Child development; Congenital abnormalities; Cranial shape; Craniosynostosis; Metopic suture; Premature suture fusion
21.  Development in Toddlers With and Without Deformational Plagiocephaly 
To determine whether the heightened risk of developmental delays seen in infancy in patients with deformational plagiocephaly (DP) continues into the toddler years.
Longitudinal study comparing the development of children with and without DP, with assessments in infancy (mean age, 7 months) and at age 18 months.
Infants with DP were recruited from a large craniofacial center, and unaffected infants were recruited from a research registry.
The study included 227 children with DP and 232 children without previously diagnosed DP.
Main Exposure
Diagnosis of DP by a craniofacial specialist.
Main Outcome Measures
Bayley Scales of Infant and Toddler Development, Third Edition, scores.
Toddlers with DP scored lower than did unaffected children on all the scales of the Bayley Scales of Infant and Toddler Development, Third Edition. Motor score differences were smaller and cognitive and language score differences were greater than those observed in infancy.
Toddlers with DP continue to exhibit evidence of developmental delays relative to toddlers without DP. These findings do not necessarily imply a causal relationship between DP and development because children with delays may be more likely to develop DP. Nonetheless, it seems that increased developmental surveillance is warranted in this population.
PMCID: PMC3393044  PMID: 21727278
22.  Impact of Prenatal Exposure to Piperonyl Butoxide and Permethrin on 36-Month Neurodevelopment 
Pediatrics  2011;127(3):e699-e706.
Recent pesticide-monitoring results suggest that a shift in residential pesticide exposure from organophosphorus insecticides to pyrethroid insecticides has occurred. Pyrethroid insecticides are potential neurodevelopmental toxicants and have not been evaluated for developmental toxicity. Our objective was to explore the association between prenatal exposure to permethrin (a common pyrethroid) and piperonyl butoxide (a pyrethroid synergist) and 36-month neurodevelopment.
Participants is this study were part of a prospective cohort of black and Dominican mothers and newborns living in low-income neighborhoods in New York City. We examined 36-month cognitive and motor development (using the Bayley Scales of Infant Development, second edition) as a function of permethrin levels measured in maternal and umbilical cord plasma collected on delivery and permethrin and piperonyl butoxide levels measured in personal air collected during pregnancy. All models were controlled for gender, gestational age, ethnicity, maternal education, maternal intelligence, quality of the home environment, and prenatal exposure to environmental tobacco smoke and chlorpyrifos.
Prenatal exposure to permethrin in personal air and/or plasma was not associated with performance scores for the Bayley Mental Developmental Index or the Psychomotor Developmental Index. After data adjustment, children more highly exposed to piperonyl butoxide in personal air samples (>4.34 ng/m3) scored 3.9 points lower on the Mental Developmental Index than those with lower exposures (95% confidence interval: −0.25 to −7.49).
Prenatal exposure to piperonyl butoxide was negatively associated with 36-month neurodevelopment.
PMCID: PMC3065142  PMID: 21300677
prenatal pesticide exposure; neurodevelopment
23.  Effect of Arsenic Exposure during Pregnancy on Infant Development at 7 Months in Rural Matlab, Bangladesh 
Environmental Health Perspectives  2008;117(2):288-293.
Exposure to arsenic-contaminated drinking water during pregnancy is associated with low birth weight and fetal loss, and there is concern that the infants’ development may be affected.
We assessed the effects of in utero arsenic exposure during pregnancy on infants’ problem-solving ability and motor development.
We conducted a large population-based study of nutritional supplementation with 4,436 pregnant women in Matlab, Bangladesh, an area of high-arsenic–contaminated tube wells. We measured arsenic concentration in spot urine specimens at 8 and 30 weeks of pregnancy. We assessed a subsample of 1,799 infants, born to these mothers, at 7 months of age on two problem-solving tests (PSTs), the motor scale of the Bayley Scales of Infant Development–II, and behavior ratings.
Arsenic concentrations in maternal urine were high, with a median (interquartile range) of 81 μg/L (37–207 μg/L) at 8 weeks of gestation and of 84 μg/L (42–230 μg/L) at 30 weeks. Arsenic exposure was related to many poor socioeconomic conditions that also correlated with child development measures. Multiple regressions of children’s motor and PST scores and behavior ratings, controlling for socioeconomic background variables, age, and sex, showed no significant effect of urinary arsenic concentration on any developmental outcome.
We detected no significant effect of arsenic exposure during pregnancy on infant development. However, it is possible that other effects are as yet unmeasured or that effects will become apparent at a later age.
PMCID: PMC2649233  PMID: 19270801
Bangladesh cognitive function; infants; motor development; problem-solving tests; urinary arsenic
24.  Early childhood development when second-trimester ultrasound dating disagrees with last menstrual period: a prospective cohort study 
When an ultrasound-based estimate of gestational age (GA) is less (greater) than an estimate based on a definite last menstrual period, the fetus may grow slower (faster) than average. While the association between these discrepancies in GA estimates and adverse perinatal outcomes has been examined extensively, there is scant evidence about long-term effects, such as child neurodevelopment.
Using data from a prospective cohort study titled, NICHD Study of Successive Small-for-Gestational Age Births, we examined if GA discrepancies in early second trimester of pregnancy (17 weeks’ gestation) are associated with: (1) impaired motor and mental function at 13 months (measured using Bayley Scales of Infant Development (Bayley)), and (2) impaired cognitive development at five years (assessed by Wechsler Preschool and Primary Scale of Intelligence – Revised Intelligence Quotient (WPPSI-R)) in the infant. The study population consisted of 572 (30% of the overall sample of 1,945) women who presented for prenatal care in Norway and Sweden between 1986 and 1988.
Our results showed that GA discrepancies in early second trimester are significantly associated with birthweight. We found no significant relationship, however, with the Bayley development scores at 13 months and with the WPPSI-R IQ measures at five years.
GA discrepancies at 17 weeks’ gestation are not associated child neurodevelopment. These discrepancies do, however, relate to birthweights, providing a basis for detecting fetal growth patterns early in the second trimester of pregnancy. Our study, however, was unable to evaluate the impact of first-trimester discrepancies on impaired neurodevelopment in the infant.
PMCID: PMC3495038  PMID: 22545943
Gestational age discrepancy; Childhood development; Cognitive functioning; LMP
25.  Impact on Infants’ Cognitive Development of Antenatal Exposure to Iron Deficiency Disorder and Common Mental Disorders 
PLoS ONE  2013;8(9):e74876.
The aim of this study was to examine the effects of antenatal exposure to iron deficiency anemia (IDA) and common mental disorders (CMD) on cognitive development of 6 months old infants in a developing country.
A prospective population-based study in a rural province in Vietnam, which enrolled pregnant women at 12–20 weeks gestation and followed them up with their infants until six months postpartum. Criteria for IDA were Hb <11 g/dL and serum ferritin <15 ng/mL. CMD symptoms were assessed by the Edinburgh Postnatal Depression Scale-Vietnam validation. Infant cognitive development was assessed by Bayley Scales of Infant and Toddler Development, 3rd Ed. Path analyses were performed to determine the direct and indirect, partly or fully mediated, causal effects of the antenatal exposures.
A total of 497 pregnant women were recruited, of those 378 women provided complete data which were included in the analyses. Statistically significant direct adverse effects of persistent antenatal IDA (estimated difference of −11.62 points; 95% CI −23.01 to −0.22) and antenatal CMD (−4.80 points; 95% CI: −9.40 to −0.20) on infant Bayley cognitive scores at six months were found. Higher birthweight, household wealth, and self-rated sufficient supply of breastmilk were associated with higher cognitive scores. Maternal age >30 years and primiparity had an indirect adverse effect on infants’ Bayley cognitive scores.
These findings suggest that antenatal IDA and CMD both have adverse effects on child cognitive development, which if unrecognized and unaddressed are likely to be lasting. It is crucial that both these risks are considered by policy makers, clinicians, and researchers seeking to improve child cognitive function in developing countries.
PMCID: PMC3781140  PMID: 24086390

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