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1.  Small for Gestational Age and Higher Birth Weight Predict Childhood Obesity in Preterm Infants 
American journal of perinatology  2010;27(9):721-730.
We sought to determine the association between small for gestational age (SGA), birth weight, and childhood obesity within preterm polysubstance exposed children. We sampled 312 preterm children with 11-year body mass index (BMI; age- and sex-specific) data from the Maternal Lifestyle Study (51% girls, 21.5% SGA, 46% prenatal cocaine, and 55% tobacco exposed). Multinomial regression analyzed the association between 11-year obesity (OBE) and overweight (OW) and SGA, birth weight, first-year growth velocity, diet, and physical activity variables. Overall, 24% were OBE (BMI for age ≥95th percentile) and 16.7% were OW (BMI ≥85th and <95th percentiles). In adjusted analyses, SGA was associated with OW (odds ratio [OR]=3.4, confidence interval [CI] 1.5 to 7.5). Higher birth weight was associated with OBE (OR = 1.8, CI 1.3 to 2.4) and OW (OR=1.4, CI 1.1 to 2.0). Growth velocity was associated with OBE (OR=2.7, CI 1.8 to 4.0) and OW (OR=1.6, CI 1.1 to 2.4). Low exercise was associated with OBE (OR=2.1, CI 1.0 to 4.4) and OW (OR=2.1, CI 1.0 to 4.5). There was no effect of substance exposure on obesity outcomes. Many (41%) of these high-risk preterm 11-year-olds were obese/overweight. Multiple growth-related processes may be involved in obesity risk for preterm children, including fetal programming as indicated by the SGA effect.
doi:10.1055/s-0030-1253555
PMCID: PMC2949419  PMID: 20408111
Childhood obesity; premature birth; infant SGA; birth weight; exercise; prenatal drug exposure
2.  Prenatal cocaine exposure: An examination of childhood externalizing and internalizing behavior problems at age 7 years 
SUMMARY
Aim
This study examines the relationship between prenatal cocaine exposure and parent-reported child behavior problems at age 7 years.
Methods
Data are from 407 African-American children (210 cocaine-exposed, 197 non-cocaine-exposed) enrolled prospectively at birth in a longitudinal study on the neurodevelopmental consequences of in utero exposure to cocaine. Prenatal cocaine exposure was assessed at delivery through maternal self-report and bioassays (maternal and infant urine and infant meconium). The Achenbach Child Behavior Checklist (CBCL), a measure of childhood externalizing and internalizing behavior problems, was completed by the child’s current primary caregiver during an assessment visit scheduled when the child was seven years old.
Results
Structural equation and GLM/GEE models disclosed no association linking prenatal cocaine exposure status or level of cocaine exposure to child behavior (CBCL Externalizing and Internalizing scores or the eight CBCL sub-scale scores).
Conclusions
This evidence, based on standardized ratings by the current primary caregiver, fails to support hypothesized cocaine-associated behavioral problems in school-aged children with in utero cocaine exposure. A next step in this line of research is to secure standardized ratings from other informants (e.g., teachers, youth self-report).
PMCID: PMC2641031  PMID: 16584100
cocaine; prenatal exposure; child behavior
3.  Prenatal Cocaine Exposure and Body Mass Index and Blood Pressure at 9 Years of Age 
Journal of hypertension  2010;28(6):1166-1175.
Background
Prenatal cocaine exposure has been linked to intrauterine growth retardation and poor birth outcomes; little is known about the effects on longer-term medical outcomes, such as overweight status and hypertension in childhood. Our objective was to examine the association between prenatal cocaine exposure and body mass index and blood pressure at 9 years of age among children followed prospectively in a multi-site longitudinal study evaluating the impact of maternal lifestyle during pregnancy on childhood outcome.
Design/Methods
This analysis includes 880 children (277 cocaine exposed and 603 with no cocaine exposure) with blood pressure, height, and weight measurements at 9 years of age. Regression analyses were conducted to explore the relationship between prenatal cocaine exposure and body mass index and blood pressure at 9 years of age after controlling for demographics, other drug exposure, birth weight, maternal weight, infant postnatal weight gain, and childhood television viewing, exercise and dietary habits at 9 years. Path analyses were used to further explore these relationships.
Results
At 9 years of age, 15% of the children were pre-hypertensive and 19% were hypertensive; 16% were at risk for overweight status and 21% were overweight. A small percentage of women were exposed to high levels of prenatal cocaine throughout pregnancy. Among children born to these women, a higher body mass index was noted. Path analysis suggested that high cocaine exposure has an indirect effect on systolic and diastolic blood pressure that is mediated through its effect on body mass index.
Conclusion
High levels of in-utero cocaine exposure are a marker for elevated body mass index and blood pressure among children born full term.
PMCID: PMC2874425  PMID: 20486281
Prenatal cocaine exposure; Body mass index; Childhood hypertension; Overweight; Obesity
4.  Assessing Latent Effects of Prenatal Cocaine Exposure on Growth and Risk of Cardiometabolic Disease in Late Adolescence: Design and Methods 
Prenatal cocaine exposure has been linked to neurocognitive and developmental outcomes throughout childhood. The cardiovascular toxicity of cocaine is also markedly increased in pregnancy, but it is unknown whether this toxicity affects anthropometric growth and the development of cardiometabolic disease risk factors in the offspring across the lifespan. During the early 1990s, the Miami Prenatal Cocaine Study enrolled a cohort of 476 African American children (253 cocaine-exposed, 223 non-cocaine-exposed) and their biological mothers at delivery in a prospective, longitudinal study. The MPCS has collected 12 prior waves of multidomain data on over 400 infants and their mothers/alternate caregivers through mid-adolescence and is now embarking on an additional wave of data collection at ages 18-19 years. We describe here the analytical methods for examining the relationship between prenatal cocaine exposure, anthropometric growth, and cardiometabolic disease risk factors in late adolescence in this minority, urban cohort. Findings from this investigation should inform both the fields of substance use and cardiovascular research about subsequent risks of cocaine ingestion during pregnancy in offspring.
doi:10.1155/2012/467918
PMCID: PMC3529470  PMID: 23304172
5.  Pre-natal exposures to cocaine and alcohol and physical growth patterns to age 8 years 
Neurotoxicology and teratology  2007;29(4):446-457.
Two hundred and two primarily African American/Caribbean children (classified by maternal report and infant meconium as 38 heavier, 74 lighter and 89 not cocaine-exposed) were measured repeatedly from birth to age 8 years to assess whether there is an independent effect of prenatal cocaine exposure on physical growth patterns. Children with fetal alcohol syndrome identifiable at birth were excluded. At birth, cocaine and alcohol exposures were significantly and independently associated with lower weight, length and head circumference in cross-sectional multiple regression analyses. The relationship over time of pre-natal exposures to weight, height, and head circumference was then examined by multiple linear regression using mixed linear models including covariates: child’s gestational age, gender, ethnicity, age at assessment, current caregiver, birth mother’s use of alcohol, marijuana and tobacco during the pregnancy and pre-pregnancy weight (for child’s weight) and height (for child’s height and head circumference). The cocaine effects did not persist beyond infancy in piecewise linear mixed models, but a significant and independent negative effect of pre-natal alcohol exposure persisted for weight, height, and head circumference. Catch-up growth in cocaine-exposed infants occurred primarily by 6 months of age for all growth parameters, with some small fluctuations in growth rates in the preschool age range but no detectable differences between heavier versus unexposed nor lighter versus unexposed thereafter.
doi:10.1016/j.ntt.2007.02.004
PMCID: PMC2227319  PMID: 17412558
Cocaine; Alcohol; Pregnancy; Growth; Children
6.  Role of adiponectin and leptin on body development in infants during the first year of life 
Background
The control of growth and nutritional status in the foetus and neonate is a complex mechanism, in which also hormones produced by adipose tissue, such as adiponectin and leptin are involved. The aim of this study was to evaluate levels of adiponectin, leptin and insulin in appropriate (AGA) and small for gestational age (SGA) children during the 1st year of life and to correlate these with auxological parameters.
Methods
In 33 AGA and 29 SGA infants, weight, length, head circumference, glucose, insulin, adiponectin and leptin levels were evaluated at the second day of life, and at one, six and twelve months, during which a portion of SGA could show catch-up growth (rapid growth in infants born small for their gestational age).
Results
Both total and isoform adiponectin levels were comparable between AGA and SGA infants at birth and until age one year. These levels significantly increased from birth to the first month of life and then decreased to lower values at 1 year of age in all subjects. Circulating leptin concentrations were higher in AGA (2.1 ± 4.1 ng/ml) than in SGA neonates (0.88 ± 1.03 ng/ml, p < 0.05) at birth, then similar at the 1st and the 6th month of age, but they increased in SGA from six months to one year, when they showed catch-up growth. Circulating insulin levels were not statistically different in AGA and SGA neonates at any study time point. Insulin levels in both AGA and SGA infants increased over the study period, and were significantly lower at birth compared to one, six and 12 months of age.
Conclusions
During the first year of life, in both AGA and SGA infants a progressive decrease in adiponectin levels was observed, while a difference in leptin values was correlated with the nutritional status.
doi:10.1186/1824-7288-36-26
PMCID: PMC2851707  PMID: 20298581
7.  Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants 
AIDS (London, England)  2012;26(9):1151-1159.
Objective
To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants.
Design
US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure.
Methods
We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5kg); weight-for-age z-scores (WAZ), length-forage z-scores (LAZ) and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age one year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ and HCAZ by TDF exposure.
Results
Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with versus without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age one year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, p=0.04; HCAZ: 0.17 vs. 0.42, p=0.02).
Conclusions
TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age one year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.
doi:10.1097/QAD.0b013e328352d135
PMCID: PMC3476702  PMID: 22382151
Tenofovir disoproxil fumarate; perinatal HIV exposure; infant growth; antiretroviral drugs; pregnancy
8.  Expressive and Receptive Language Functioning in Preschool Children With Prenatal Cocaine Exposure 
Journal of pediatric psychology  2004;29(7):543-554.
Objective
To estimate the relationship between severity of prenatal cocaine exposure and expressive and receptive language skills in full-term, African American children at age 3 years.
Methods
Language was assessed at age 3 using the Clinical Evaluation of Language Fundamentals–Preschool (CELF-P). The sample included 424 children (226 cocaine exposed, 198 non–cocaine exposed) who received preschool language assessments at age 3, drawn from a cohort of 476 children enrolled prospectively at birth.
Results
Structural equation modeling was used to regress expressive and receptive language as intercorrelated response variables on level of prenatal cocaine exposure, measured by a latent construct including maternal self-report of cocaine use and maternal/infant urine toxicology assays and infant meconium. Results indicated a .168 SD decrease in expressive language functioning for every unit increase in exposure level (95% CI = −.320, −.015; p = .031) after consideration for fetal growth and gestational age as correlated response variables. Receptive language was more modestly related to prenatal cocaine exposure and was not statistically significant. Results for expressive language remained stable with inclusion of the McCarthy general cognitive index as a response variable (expressive language β = −.173, 95% CI = −.330, −.016; p = .031), and with adjustment for maternal age and prenatal exposures to alcohol, tobacco, and marijuana (expressive language β = −.175, 95% CI = −.347, −.003; p = .046). Additional child and caregiver environmental variables assessed at age 3 were also evaluated in varying statistical models with similar results.
Conclusion
The evidence from this study supports a gradient relationship between increased level of prenatal cocaine exposure and decreased expressive language functioning in preschool-aged cocaine-exposed children.
doi:10.1093/jpepsy/jsh056
PMCID: PMC2653083  PMID: 15347702
prenatal cocaine exposure; language functioning; preschool children; CELF-P
9.  Influence of Prenatal Cocaine Exposure on Early Language Development: Longitudinal Findings from Four Months to Three Years of Age 
The influence of prenatal cocaine exposure on children's language functioning was evaluated longitudinally at six time points from 4 months to 3 years of age. The Miami Prenatal Cocaine Study prospectively enrolled 476 full-term African-American infants at birth, categorized as cocaine-exposed (n = 253) or non-cocaine-exposed (n = 223) by maternal self-report and bioassays (maternal/infant urine, meconium). The Bayley Scales of Infant Development, scored using the Kent Scoring Adaptation for language, was administered at 4, 8, 12, 18, and 24 months. The Clinical Evaluation of Language Fundamentals-Preschool was administered at 3 years. In longitudinal analyses using Generalized Estimating Equations, cocaine-exposed children had lower overall language skills than non-cocaine-exposed children (D = -0.151; 95% CI = -0.269, -0.033; p = .012). Longitudinal findings remained stable after evaluation of potential confounding influences including other prenatal substance exposures and sociodemographic factors. Preliminary evidence also indicated possible mediation through an intermediary effect involving cocaine-associated deficits in fetal growth.
PMCID: PMC2641033  PMID: 12584484
10.  Severity of Prenatal Cocaine Exposure and Child Language Functioning Through Age Seven Years: A Longitudinal Latent Growth Curve Analysis 
Substance use & misuse  2004;39(1):25-59.
The current study estimates the longitudinal effects of severity of prenatal cocaine exposure on language functioning in an urban sample of full-term African-American children (200 cocaine-exposed, 176 noncocaine-exposed) through age 7 years. The Miami Prenatal Cocaine Study sample was enrolled prospectively at birth, with documentation of prenatal drug exposure status through maternal interview and toxicology assays of maternal and infant urine and infant meconium. Language functioning was measured at ages 3 and 5 years using the Clinical Evaluation of Language Fundamentals–Preschool (CELF-P) and at age 7 years using the Core Language Domain of the NEPSY: A Developmental Neuropsychological Assessment. Longitudinal latent growth curve analyses were used to examine two components of language functioning, a more stable aptitude for language performance and a time-varying trajectory of language development, across the three time points and their relationship to varying levels of prenatal cocaine exposure. Severity of prenatal cocaine exposure was characterized using a latent construct combining maternal self-report of cocaine use during pregnancy by trimesters and maternal and infant bioassays, allowing all available information to be taken into account. The association between severity of exposure and language functioning was examined within a model including factors for fetal growth, gestational age, and IQ as intercorrelated response variables and child’s age, gender, and prenatal alcohol, tobacco, and marijuana exposure as covariates. Results indicated that greater severity of prenatal cocaine exposure was associated with greater deficits within the more stable aptitude for language performance (D = −0.071, 95% CI = −0.133, −0.009; p = 0.026). There was no relationship between severity of prenatal cocaine exposure and the time-varying trajectory of language development. The observed cocaine-associated deficit was independent of multiple alternative suspected sources of variation in language performance, including other potential responses to prenatal cocaine exposure, such as child’s intellectual functioning, and other birth and postnatal influences, including language stimulation in the home environment.
doi:10.1081/JA-120027765
PMCID: PMC2634602  PMID: 15002943
Prenatal cocaine exposure; Language performance
11.  Impact of Prenatal Cocaine Exposure on Attention and Response Inhibition as Assessed by Continuous Performance Tests 
Objective
This study examined the influence of prenatal cocaine exposure on attention and response inhibition measured by continuous performance tests (CPTs) at ages 5 and 7 years.
Methods
The baseline sample consisted of 253 cocaine-exposed and 223 non–cocaine-exposed children enrolled prospectively at birth and assessed comprehensively through age 7 years in the longitudinal Miami Prenatal Cocaine Study. This report includes a subsample of 415 children (219 cocaine-exposed, 196 non–cocaine-exposed) who completed at least one CPT assessment at ages 5 and/or 7 years. Prenatal cocaine exposure was measured by maternal self-report and maternal and infant bioassays. Deficits in attention and response inhibition are estimated in relation to prenatal cocaine exposure using generalized estimating equations within the general linear model.
Results
Results indicate cocaine-associated increases in omission errors at ages 5 and 7 as well as increases in response times for target tasks (i.e., slower reaction times) and decreased consistency in performance at age 7. There were no demonstrable cocaine-associated deficits in commission errors. Estimates did not change markedly with statistical adjustment for selected prenatal and postnatal covariates.
Conclusion
Evidence supports cocaine-associated deficits in attention processing through age 7 years.
doi:10.1097/01.DBP.0000268560.72580.f9
PMCID: PMC2760335  PMID: 17565286
prenatal cocaine exposure; sustained attention; response inhibition; continuous performance test
12.  The Auxological and Biochemical Continuum of Short Children Born Small for Gestational Age (SGA) or with Normal Birth Size (Idiopathic Short Stature) 
Objective. Retrospective single-centre analysis of growth characteristics in 182 healthy short children born small for gestational age (SGA) or appropriate for gestational age (idiopathic short stature, ISS). Methods. Birth size references from the USA and Sweden were compared, and for the classification as SGA or ISS the Swedish reference was chosen. Height, target height (TH), bone age (BA), predicted adult height (PAH), IGF-I and IGFBP-3 values were compared between SGA and ISS. Results. In the combined group, birth weight and length showed a symmetric Gaussian distribution. The American reference overestimates the percentage of short birth length and underestimates that of low birth weight. In childhood, SGA children were shorter than ISS (−3.1 versus −2.6 SDS, P < .001), also in comparison to TH (−2.6 versus −1.9 SDS, P < .001). TH, height SDS change over time, BA delay, and PAH were similar. IGF-I and IGFBP-3 were lower in ISS (P = .03 and .09). Conclusions. SGA children represent the left tail of the Gaussian distribution of birth size in short children. The distinction between SGA and ISS depends on birth size reference. Childhood height of SGA is lower than of ISS, but the other auxological features are similar.
doi:10.1155/2010/852967
PMCID: PMC2872754  PMID: 20490349
13.  Elevated Plasma Norepinephrine After In Utero Exposure to Cocaine and Marijuana 
Pediatrics  1997;99(4):555-559.
Objective
To compare plasma catecholamine concentrations between cocaine-exposed and unexposed term newborns and to determine the relationship between plasma catecholamines and newborn behavior.
Methods
Forty-six newborn infants participating in a prospective study of the neonatal and long-term effects of prenatal cocaine exposure were studied. Based on maternal self-report, maternal urine screening, and infant meconium analysis, 24 infants were classified as cocaine-exposed and 22 as unexposed. Between 24 and 72 hours postpartum, plasma samples for norepinephrine (NE), epinephrine, dopamine, and dihydroxyphenylalanine analysis were obtained. The Neonatal Behavioral Assessment Scale was administered at 1 to 3 days of age and at 2 weeks of age by examiners masked to the drug exposure status of the newborns.
Results
The cocaine-exposed newborns had increased plasma NE concentrations when compared to the unexposed infants (geometric mean, 923 pg/mL vs 667 pg/mL). There were no significant differences in plasma epinephrine, dopamine, or dihydroxyphenylalanine concentrations. Analysis for the effect of potential confounding variables revealed that maternal marijuana use was also associated with increased plasma NE, although birth weight, gender, and maternal use of alcohol or cigarettes were not. Geometric mean plasma NE was 1164 pg/mL in those infants with in utero exposure to both cocaine and marijuana compared to 812 pg/mL in those exposed to only cocaine and 667 pg/mL in those exposed to neither. Among the cocaine-exposed infants, plasma NE concentration correlated with an increased score for the depressed cluster (r = .53) and a decreased score for the orientation cluster (r = −.43) of the Neonatal Behavioral Assessment Scale administered at 1 to 3 days of age. Adjusting for marijuana exposure had no effect on these relationships between plasma NE and the depressed and orientation clusters.
Conclusion
Plasma NE is increased in newborns exposed to cocaine and marijuana. Increased plasma NE is associated with selected neurobehavioral disturbances among cocaine exposed infants at 1 to 3 days of life but not at 2 weeks.
doi:10.1542/peds.99.4.555
PMCID: PMC2365460  PMID: 9093298
14.  Methylphenidate and the Response to Growth Hormone Treatment in Short Children Born Small for Gestational Age 
PLoS ONE  2012;7(12):e53164.
Background
Growth hormone (GH) treatment has become a frequently applied growth promoting therapy in short children born small for gestational age (SGA). Children born SGA have a higher risk of developing attention deficit hyperactivity disorder (ADHD). Treatment of ADHD with methylphenidate (MP) has greatly increased in recent years, therefore more children are being treated with GH and MP simultaneously. Some studies have found an association between MP treatment and growth deceleration, but data are contradictory.
Objective
To explore the effects of MP treatment on growth in GH-treated short SGA children
Methods
Anthropometric measurements were performed in 78 GH-treated short SGA children (mean age 10.6 yr), 39 of whom were also treated with MP (SGA-GH/MP). The SGA-GH/MP group was compared to 39 SGA-GH treated subjects. They were matched for sex, age and height at start of GH, height SDS at start of MP treatment and target height SDS. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were yearly determined. Growth, serum IGF-I and IGFBP-3 levels during the first three years of treatment were analyzed using repeated measures regression analysis.
Results
The SGA-GH/MP group had a lower height gain during the first 3 years than the SGA-GH subjects, only significant between 6 and 12 months of MP treatment. After 3 years of MP treatment, the height gain was 0.2 SDS (±0.1 SD) lower in the SGA-GH/MP group (P = 0.17). Adult height was not significantly different between the SGA-GH/MP and SGA-GH group (−1.9 SDS and −1.9 SDS respectively, P = 0.46). Moreover, during the first 3 years of MP treatment IGF-I and IGFBP-3 measurements were similar in both groups.
Conclusion
MP has some negative effect on growth during the first years in short SGA children treated with GH, but adult height is not affected.
doi:10.1371/journal.pone.0053164
PMCID: PMC3531371  PMID: 23300884
15.  Effects of prenatal cocaine exposure on infant reactivity and regulation 
Neurotoxicology and teratology  2008;31(1):60-68.
The purpose of this study was to examine the role of prenatal cocaine exposure and associated risk factors on infant reactivity and regulation at 7 months of infant age. Participants consisted of 167 mother-infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure, who completed the arm-restraint procedure at the 7-month assessment (87 cocaine exposed, 80 non-cocaine exposed). We hypothesized that cocaine exposed infants would display higher arousal or reactivity and lower regulation during a procedure designed to arouse anger/frustration. Results indicated that cocaine exposed infants were more reactive to increases in the level of stress from trial 1 to trial 2 but exhibited no change in the number of regulatory strategies as stress increased, unlike the control group infants. Infant birth weight moderated the association between cocaine exposure and infant regulation. Among cocaine exposed infants, those with lower birth weight displayed higher reactivity compared to those with higher birth weight. Contrary to expectations, there were no indirect effects between cocaine exposure and infant reactivity/regulation via environmental risk, parenting, or birth weight. Results are supportive of a teratological model of prenatal cocaine exposure for infant reactivity/regulation in infancy.
doi:10.1016/j.ntt.2008.08.005
PMCID: PMC2631277  PMID: 18822371
Infant Regulation; Cocaine exposure; infant arousal
16.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
Background
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
Aims
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
Results
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Conclusions
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
doi:10.1016/j.earlhumdev.2012.04.004
PMCID: PMC3694609  PMID: 22732241
17.  Cocaine Exposure and Children's Self-Regulation: Indirect Association via Maternal Harshness 
Objectives: This study examined the association between prenatal cocaine exposure and children’s self-regulation at 3 years of child age. In addition to direct effects of prenatal cocaine exposure on children’s self-regulation, we hypothesized there would be indirect associations between cocaine exposure and self-regulation via higher maternal harshness and poor autonomic regulation in infancy. Methods: The sample consisted of 216 mother–infant dyads recruited at delivery from local area hospitals (116 cocaine-exposed, 100 non-exposed). Infant autonomic regulation was measured at 7 months of age during an anger/frustration task, maternal harshness was coded from observations of mother–toddler interactions at 2 years of age, and children’s self-regulation was measured at 3 years of age using several laboratory paradigms. Results: Contrary to hypotheses, there were no direct associations between maternal cocaine use during pregnancy and children’s self-regulation. However, results from testing our conceptual model including the indirect effects via maternal harshness or infant parasympathetic regulation indicated that this model fit the data well, χ2 (23) = 34.36, p > 0.05, Comparative Fit Index = 0.95, RMSEA = 0.05. Cocaine using mothers displayed higher intensity of harshness toward their toddlers during lab interactions across a variety of tasks at 2 years of age (β = 0.23, p < 0.05), and higher intensity of harshness at 2 years was predictive of lower self-regulation at 3 years (β = −0.36, p < 0.01). Maternal cocaine use was also predictive of a non-adaptive increase in respiratory sinus arrhythmia (RSA) from baseline to the negative affect task, but RSA change in infancy was not predictive of self-regulation at 3 years. Conclusion: Results are supportive of animal models indicating higher aggression among cocaine treated dams, and indicate that higher maternal harshness among cocaine using mothers is predictive of child self-regulatory outcomes in the preschool period.
doi:10.3389/fpsyt.2011.00031
PMCID: PMC3115536  PMID: 21716637
cocaine exposure; self-regulation; maternal harshness; autonomic regulation
18.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
International journal of epidemiology  2013;42(5):10.1093/ije/dyt109.
Background
Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods
Using extant longitudinal birth cohorts (n = 19) with data on birth-weight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results
We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions
This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
doi:10.1093/ije/dyt109
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood
19.  Physiological Regulation in Cigarette Exposed Infants: An Examination of Potential Moderators 
Neurotoxicology and teratology  2011;33(5):567-574.
The primary purpose of this study was to examine pathways from prenatal cigarette exposure to physiological regulation at 2 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by fetal growth, prenatal or postnatal environmental tobacco smoke (ETS) exposure or maternal depressive symptomatology during pregnancy. We evaluated whether exposed infants who were also exposed to ETS after birth, were small for gestational age (SGA) or had mothers with higher depressive symptoms during pregnancy had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 234 (166 exposed and 68 nonexposed) infants during sleep. As expected, cigarette-exposed infants had significantly lower RSA than nonexposed infants. This association was not moderated by prenatal or postnatal ETS exposure, or maternal depressive symptomatology during pregnancy. However, small for gestational age status did moderate this association such that nonexposed infants who were not small for gestational age had a significantly higher RSA than nonexposed small for gestational age infants and exposed infants. These findings provide additional evidence that prenatal cigarette exposure is directly associated with dysregulation during infancy.
doi:10.1016/j.ntt.2011.07.004
PMCID: PMC3183283  PMID: 21798345
Physiological Regulation; Prenatal Cigarette Exposure
20.  Level of In Utero Cocaine Exposure and Neonatal Ultrasound Findings 
Pediatrics  1999;104(5 Pt 1):1101-1105.
Objective
To assess whether there is an association between the level of in utero cocaine exposure and findings on neonatal cranial ultrasound, controlling for potentially confounding variables.
Study Design
In a prospective longitudinal study, three cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (>75th percentile self-reported days of use or of meconium benzoylecogonine concentration) or lighter cocaine exposure (all others). Neonatal ultrasounds from 241 well, term infants were read by a single radiologist who was masked to the exposure group.
Results
Infants with lighter cocaine exposure did not differ from the unexposed infants on any ultrasound findings. After controlling for infant gender, gestational age, and birth weight z scores and for maternal parity, blood pressure in labor, ethnicity, and use of cigarettes, alcohol, and marijuana during pregnancy, the more heavily cocaine-exposed infants were more likely than the unexposed infants to show subependymal hemorrhage in the caudothalamic groove (covariate adjusted odds ratio: 3.88; 95% confidence interval: 1.45, 10.35).
Conclusions
This is the first study to demonstrate that ultrasound findings suggestive of vascular injury to the neonatal central nervous system are related to the level of prenatal cocaine exposure. Inconsistency in previous research in identifying an association between prenatal cocaine exposure and neonatal cranial ultrasound findings may reflect failure to consider dose effects.
doi:10.1542/peds.104.5.1101
PMCID: PMC2365465  PMID: 10545554
21.  A comparison of the socio-economic determinants of growth retardation in South African and Filipino infants 
Public health nutrition  2008;11(12):1220-1228.
Objective
To examine the association between household socio-economic status (SES) at birth and poor infant growth such as small for gestational age (SGA) and stunting across two different socio-cultural settings: South Africa and the Philippines.
Design
Data were from two longitudinal birth cohorts, the Birth to Twenty (Bt20) study in South Africa and the Cebu Longitudinal Health and Nutrition Survey (CLHNS) in the Philippines.
Subjects
Bt20 infants (n 2293 total; reduced to 758 (SGA), 450 (stunting 1 year) and 401 (stunting 2 years)) and CLHNS infants (n 2513 total; reduced to 2161 (SGA), 1820 (stunting 1 year) and 1710 (stunting 2 years)).
Results
CLHNS infants were significantly more likely to be born SGA (20·9 v. 11·7%) and be stunted at 1 year (32·6 v. 8·7%) and 2 years (48·9 v. 21·1%) compared with Bt20 infants. Logistic regression analyses showed that SES (index) was a significant predictor of stunting at 1 and 2 years of age in the CLHNS cohort. SES (index or individual variables) was not a significant predictor of SGA in either cohort, or of stunting in the Bt20 cohort. Maternal education, ownership of a television and toilet facilities were all independent predictors of stunting in the CLHNS cohort.
Conclusions
The social and economic milieu within the Philippines appears to place CLHNS infants at greater risk of being born SGA and being stunted compared with Bt20 infants. The present research highlights the importance of investigating the individual SES variables that predict infantile growth faltering, to identify the key areas for context-specific policy development and intervention.
doi:10.1017/S1368980008002498
PMCID: PMC2939971  PMID: 18462561
Stunting; Small for gestational age; Socio-economic status; Socio-economic index; South Africa; Philippines
22.  Growth and adrenal androgen status at 7 years in very low birth weight survivors with and without bronchopulmonary dysplasia 
Archives of Disease in Childhood  2004;89(4):320-324.
Aims: To evaluate whether 7 year old VLBW (very low birth weight, <1500 g) survivors with and without bronchopulmonary dysplasia (BPD) evince similar growth status and higher adrenal androgen (AA) levels than term controls, and whether AA levels are higher in VLBW children born small for gestational age (SGA) than in non-SGA cases.
Methods: Assessment of height standard deviation score (SDs), body mass index (BMI), and serum androstenedione and dehydroepiandrostenedione sulphate levels in 31 VLBW children with BPD, 33 without BPD (no-BPD group), and 33 term controls.
Results: Lower median (range) height SDs was found in BPD (-1.0 (-3.4 to 1.4) SD) and no-BPD (-0.9 (-2.9 to 2.2) SD) children than in term controls (0.3 (-1.5 to 1.9) SD). Low BMI (below 10th centile) was more common in both the BPD (18 (58%)) and no-BPD (16 (49%)) children compared to term cases (3 (9%)). The median (range) androstenedione levels tended to be higher in the BPD (0.8 (0 to 2.8) nmol/l) and no-BPD (0.8 (0 to 2.3) nmol/l) groups than in term controls (0.6 (0 to 1.8)). Higher median (range) dehydroepiandrostenedione sulphate levels were detected in the no-BPD compared to the term group (0.9 (0 to 4.1) v 0.3 (0 to 2.3) µmol/l). VLBW children born SGA had higher AA levels compared to non-SGA cases.
Conclusions: At 7 years of age, VLBW children are shorter and tend to have higher AA levels than term controls, but VLBW children with and without BPD do not differ from each other in growth or AA status. Those born SGA have higher AA levels compared to non-SGA cases. The consequences of these findings to final height and to later metabolic and vascular health remain to be determined.
doi:10.1136/adc.2002.022699
PMCID: PMC1719878  PMID: 15033838
23.  The Effects of Prenatal Cocaine-Exposure on Problem Behavior in Children 4-10 Years 
Neurotoxicology and teratology  2010;32(4):443-451.
Background
Children prenatally exposed to cocaine may be at increased risk for behavioral problems due to disruptions of monaminergically regulated arousal systems and/or environmental conditions.
Objective
To assess behavioral outcomes of cocaine (CE) and non-cocaine exposed (NCE) children, 4 through 10 years old, controlling for other prenatal drug exposures and environmental factors.
Methods
Low socioeconomic status (SES), primarily African-American children (n = 381 (193 (CE), 188 (NCE)) were recruited from birth. Generalized Estimating Equation (GEE) analyses were used to assess the predictive relationship of prenatal cocaine exposure to odds of caregiver reported clinically elevated behavioral problems at 4, 6, 9 and 10 years of age, controlling for confounders.
Results
Prenatal cocaine exposure was associated with increased rates of caregiver reported delinquency (OR=1.93, CI: 1.09-3.42, p<.02). A significant prenatal cocaine exposure by sex interaction was found for delinquency indicating that only females were affected (OR=3.57, CI: 1.67-7.60, p<.001). There was no effect of cocaine on increased odds of other CBCL subscales. Higher prenatal tobacco exposure was associated with increased odds of externalizing symptoms at 4, 9 and 10 years of age. For CE children, those in foster or adoptive care were rated as having more behavior problems than those in biologic mother or relative care. Greater caregiver psychological distress was associated with increased behavioral problems. There were no independent effects of elevated blood lead level on increased behavior problems after control for prenatal drug exposure and other environmental conditions.
Conclusion
Prenatal cocaine and tobacco exposure were associated with greater externalizing behavior after control for multiple prenatal drug exposures, other environmental and caregiving factors and lead exposure from 4 through 10 years of age. Greater caregiver psychological distress negatively affected caregiver ratings of all CBCL domains. Since cocaine and tobacco use during pregnancy and maternal psychological distress have the potential to be altered through prenatal educational, drug treatment and and mental health interventions, they warrant attention in efforts to reduce rates of problem behaviors in children.
doi:10.1016/j.ntt.2010.03.005
PMCID: PMC3586186  PMID: 20227491
behavior; delinquency; prenatal cocaine-exposure; lead exposure; longitudinal
24.  Preterm Birth, Fetal Growth, and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES) 
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95%CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31,1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95%CI=0.97, 2.03) than defined as <= 11 years (OR=1.16; 95%CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
doi:10.1016/j.reprotox.2010.11.006
PMCID: PMC3057340  PMID: 21130156
diethylstilbestrol; early life factors; birth weight; small for gestational age; gestational length; menarche; endocrine disruptors
25.  Reduced genetic influence on childhood obesity in small for gestational age children 
BMC Medical Genetics  2013;14:10.
Background
Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative.
Methods
A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate.
Results
SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA.
Conclusions
Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA.
doi:10.1186/1471-2350-14-10
PMCID: PMC3556300  PMID: 23339409
BMI; Childhood obesity; AGA children; SGA children

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