Faculty Bibliography

Objectives:To examine the associations of antibiotic exposures during the first 2 years of life and the development of body mass over the first 7 years of life.Design:Longitudinal birth cohort study.Subjects:A total of 11 532 children born at >/=2500 g in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based study of children born in Avon, UK in 1991-1992.Measurements:Exposures to antibiotics during three different early-life time windows (<6 months, 6-14 months, 15-23 months), and indices of body mass at five time points (6 weeks, 10 months, 20 months, 38 months and 7 years).Results:Antibiotic exposure during the earliest time window (<6 months) was consistently associated with increased body mass (+0.105 and +0.083 s.d. unit, increase in weight-for-length Z-scores at 10 and 20 months, P<0.001 and P=0.001, respectively; body mass index (BMI) Z-score at 38 months +0.067 s.d. units, P=0.009; overweight OR 1.22 at 38 months, P=0.029) in multivariable, mixed-effect models controlling for known social and behavioral obesity risk factors. Exposure from 6 to 14 months showed no association with body mass, while exposure from 15 to 23 months was significantly associated with increased BMI Z-score at 7 years (+0.049 s.d. units, P=0.050). Exposures to non-antibiotic medications were not associated with body mass.Conclusions:Exposure to antibiotics during the first 6 months of life is associated with consistent increases in body mass from 10 to 38 months. Exposures later in infancy (6-14 months, 15-23 months) are not consistently associated with increased body mass. Although effects of early exposures are modest at the individual level, they could have substantial consequences for population health. Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and define life-course implications for body mass and cardiovascular risks.

BACKGROUND: Neuroimaging findings have provided evidence for a relation between variations in brain structures and attention deficit/hyperactivity disorder (ADHD). However, longitudinal neuroimaging studies are typically confined to children who have already been diagnosed with ADHD. In a population-based study, we aimed to characterize the prospective association between brain structures measured during infancy and executive function and attention deficit/hyperactivity problems assessed at preschool age. METHODS: In the Generation R Study, the corpus callosum length, the gangliothalamic ovoid diameter (encompassing the basal ganglia and thalamus), and the ventricular volume were measured in 784 6-week-old children using cranial postnatal ultrasounds. Parents rated executive functioning at 4 years using the behavior rating inventory of executive function-preschool version in five dimensions: inhibition, shifting, emotional control, working memory, and planning/organizing. Attention deficit/hyperactivity problems were assessed at ages 3 and 5 years using the child behavior checklist. RESULTS: A smaller corpus callosum length during infancy was associated with greater deficits in executive functioning at 4 years. This was accounted for by higher problem scores on inhibition and emotional control. The corpus callosum length during infancy did not predict attention deficit/hyperactivity problem at 3 and 5 years, when controlling for the confounders. We did not find any relation between gangliothalamic ovoid diameter and executive function or Attention deficit/hyperactivity problem. CONCLUSIONS: Variations in brain structures detectible in infants predicted subtle impairments in inhibition and emotional control. However, in this population-based study, we could not demonstrate that early structural brain variations precede symptoms of ADHD.

Context: Bisphenol A (BPA) is an environmental endocrine disruptor that has been linked to many reproductive disorders in animal models and humans. One such disorder is polycystic ovary syndrome (PCOS), which has been correlated with increased BPA levels in adult women. However, little is known about the role of serum BPA in adolescents with PCOS and its correlation with the metabolic profile. Objectives: To measure BPA levels in adolescent with PCOS as compared to a body mass index (BMI)-matched control group. To correlate serum BPA levels with disease severity, as measured by biochemical and radiologic features. Design: A retrospective chart review of clinical, biochemical, and ultrasonographic data in adolescents with PCOS and controls. Serum BPA was measured and compared between groups and correlated with biochemical (testosterone, insulin resistance) and ovarian ultrasound findings. Setting: Urban tertiary academic medical center. Participants: Study groups included 15 overweight/obese adolescent females with PCOS (mean age 15.27 years, mean BMI 32.84) and 14 BMI-matched female controls (mean age 14.1 years, mean BMI 31). Results: Biochemical data showed a mean free testosterone of 7.06 pg/mL and mean LH:FSH ratio of 1.93 in the PCOS group as compared to mean testosterone of 4.51 pg/mL and mean LH:FSH ratio of 1.12 in the control group (P=0.08 and 0.012, respectively). The index of insulin resistance (HOMA-IR) was 1.65 in the PCOS group and 1.82 in the control group (P=0.75). Serum BPA levels were 0.624 +/-1.29 ng/mL in the PCOS group versus 0.28 +/-0.11 ng/mL in controls (P=0.325). No correlation was found between serum BPA levels and biochemical and radiologic markers of PCOS severity. Conclusions: The results of this exploratory study pose many interesting questions about BPA exposure in adolescents. Although the results are not statistically significant, both adult studies and animal models have shown a strong correlation between serum BPA and severity of PCOS. The weaker relationship in adolescents may be explained in part by shorter duration of exposure to BPA in years. Further studies are warranted to clarify the correlation of PCOS and the endocrine disruptor BPA in a larger setting

OBJECTIVE:To assess the association of the severity of obesity with diagnosis and health education, and to identify any differences within demographic or other subgroups.DESIGN:Clinician visits for 2-18 year olds from the 2005-2008 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey were combined. Descriptive, bivariate and multivariate analyses were used to compare diagnosis of obesity and health education (nutrition, exercise and weight reduction) across elevated body mass index (BMI) groups (overweight, obese and extreme or very obese, defined as >120% of the 95th percentile for age and gender), patient socio-demographic characteristics, physician specialty and type of visit (well child visits (WCV) versus non-well child visits (non-WCV).RESULTS:A total of 17 808 visits had a calculated BMI, of which 5.8% were extremely obese, 13% were obese and 15.2% were overweight, with the highest percentages among older children, blacks and Hispanics. Diagnosis and weight reduction education were higher among children with an extreme BMI. Nutrition and exercise education were not correlated with severity of obesity. Race, ethnicity or gender biases were not identified. Severity of obesity was significantly associated with presentation to a non-WCV rather than a WCV. CONCLUSION:Extremely obese children have higher, but still insufficient, rates of diagnosis and health education. Nutrition and exercise education are not prevalent throughout all age groups. Providers may be relying inconsistently and insufficiently on visual cues to drive their obesity prevention practices. Furthermore, lower rates of diagnosis and education at non-WCV may result in a missed opportunity to prevent comorbidities. This is of particular concern as overweight children are less likely to be seen at WCV than non-WCV.

The rare but deleterious effects of severe iodine deficiency during pregnancy on cognitive functioning of children are well known. Reports on possible associations between mild-to-moderate maternal iodine deficiency and child development, however, are scarce. In a population-based cohort we examined the association between maternal urinary iodine during early pregnancy and executive functioning in children at 4 y of age. In addition, we investigated the modification of this association by maternal diet and thyroid function. During pregnancy, we measured urinary iodine and thyroid hormone concentrations in 1156 women. In 692 of their children impairment of executive functioning was assessed by the Behavior Rating Inventory of Executive Function. Five hundred mothers of Dutch national origin completed an FFQ. Analyses were performed by using regression models. The children of mothers with low urinary iodine showed higher scores on the problem scales of inhibition [beta = 0.05 (95% CI: 0.01, 0.10), P = 0.03] and working memory [beta = 0.07 (95% CI: 0.02, 0.12), P = 0.003]. Although maternal dietary intake and thyroid hormone concentration did not significantly modify these associations, the associations between urinary iodine and problems of inhibition were attenuated after adjustment for maternal psychological symptoms. In addition, the consumption of bread [beta = 0.61 (95% CI: 0.27, 0.95), P < 0.001] and eggs (beta = 1.87 (95% CI: 0.13, 3.62), P = 0.04] was associated with higher urinary iodine. Thus, low maternal urinary iodine during pregnancy is associated with impaired executive functioning in children. Because these symptoms were subclinical and occurred at an early age, future studies are needed to show whether these children are more vulnerable to develop later clinical disorders.

Severe maternal thyroid dysfunction during pregnancy affects fetal brain growth and corticogenesis. This study focused on the effect of maternal hypothyroxinemia during early pregnancy on growth of the fetal and infant head. In a population-based birth cohort, we assessed thyroid status in early pregnancy (median 13.4, 90% range 10.8-17.2), in 4894 women, and measured the prenatal and postnatal head size of their children at 5 time points. Hypothyroxinemia was defined as normal thyroid-stimulating hormone levels and free thyroxine-4 concentrations below the 10th percentile. Statistical analysis was performed using linear generalized estimating equation. Maternal hypothyroxinemia was associated with larger fetal and infant head size (overall estimate beta: 1.38, 95% confidence interval 0.56; 2.19, P = .001). In conclusion, in the general population, even small variations in maternal thyroid function during pregnancy may affect the developing head of the young child.

During the past decades, observational studies have demonstrated a relationship between thyroid dysfunction in pregnancy and a range of adverse outcomes in both mother and offspring. However, results from the few randomized trials of screening for thyroid dysfunction in pregnant women have not shown any benefit for women or their children. Before implementing screening in pregnant women at population level, randomized trials are needed to show that screening with subsequent intervention is effective for mothers or children. Here, we review the literature and argue that the findings from existing trials are not conclusive. Until such conclusive evidence from randomized trials is available, the best advice to the clinician is to screen only high-risk pregnant women. Such women, for example those with symptoms or a history of thyroid problems, should be screened using trimester-specific reference ranges for thyroid stimulating hormone (TSH) levels. We recommend new prospective randomized trials that combine different thyroid parameters as the screening tool, apply trimester-specific ranges for thyroid hormones and examine whether screening and intervention during the first trimester of pregnancy will improve neuropsychological outcomes in the offspring.

OBJECTIVE: To determine clinical characteristics, demographics and short-term outcomes of neonates diagnosed with fetomaternal haemorrhage (FMH). DESIGN: The authors analysed the Nationwide Inpatient Sample, 1993 to 2008. Singleton births diagnosed with FMH were identified by International Classification of Diseases (ICD-9) code 762.3. Descriptive, univariate and multivariable regression analyses were performed to determine the national annual incidence of FMH over time as well as demographics and clinical characteristics of neonates with FMH. RESULTS: FMH was identified in 12 116 singleton births. Newborns with FMH required high intensity of care: 26.3% received mechanical ventilation, 22.4% received blood product transfusion and 27.8% underwent central line placement. Preterm birth (OR 3.7), placental abruption (OR 9.8) and umbilical cord anomaly (OR 11.4) were risk factors for FMH. Higher patient income was associated with increased likelihood of FMH diagnosis (OR 1.2), and Whites were more likely to be diagnosed than ethnic minorities (OR 1.9). There was reduced frequency of diagnosis in the Southern USA (OR 0.8 vs the Northeastern USA). CONCLUSIONS: Diagnosis of FMH is associated with significant morbidity as well as regional, socioeconomic and racial disparity. Further study is needed to distinguish between diagnostic coding bias and true epidemiology of the disease. This is the first report of socioeconomic and racial/ethnic disparities in FMH, which may represent disparities in detection that require national attention.

AIM: General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. METHOD: This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3 years. At the age of 3 years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4 years old. Final analyses were based on 3157 children. RESULTS: No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94]). INTERPRETATION: Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development.