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Objective: To examine neighborhood effects on academic achievement of children with extremely low birth weight (ELBW <1000 g) and normal birth weight (NBW) controls., Methods: The study included 183 8-year-old children with ELBW born during 1992-1995 and 176 sociodemographically similar NBW controls. Academic achievement was measured via The Woodcock-Johnson III Academic Skills Cluster., Results: Children with ELBW had significantly lower achievement scores (89 +/- 16 vs. 97 +/- 13). A multilevel estimation of predictors of academic achievement revealed that neighborhood poverty was significantly associated with lower achievement (beta = -.17; 95% CI -.3, -.05; p < .01). Additional correlates included birth weight status, male sex, and parent ratings of attention deficit hyperactivity disorder symptoms. Family characteristics included maternal education and parent protection., Conclusions: Neighborhood characteristics affect academic achievement of both children with ELBW and NBW controls, over and above individual and family influences. Interventions designed to address family and neighborhood factors may potentially improve these outcomes.

Objective: To describe the prevalence of behavioral problems and symptomatology suggestive of Autism and Asperger's disorders at age 8 years among extremely low birth weight (ELBW, <1 kg) children, born 1992 through 1995., Method: Parent reports of the behavior of 219 ELBW (mean birth weight, 810 g; gestational age 26 weeks) were compared with 176 normal birth weight children of similar maternal sociodemographic status, sex, and age. Behavior was assessed via the Child Symptom Inventory that includes both Symptom Severity Scores and scores meeting DSM-IV criteria for disorders., Results: ELBW compared with normal birth weight children had significantly higher mean Symptom Severity Scores for the inattentive, hyperactive, and combined types of attention-deficit hyperactivity disorder (all p < .001) as well as higher scores for Generalized Anxiety (p < .01) and Autistic (p < .001) and Asperger's (p < .01) disorders. When DSM-IV criteria were considered, ELBW children also had significantly higher rates of attention-deficit hyperactivity disorder of the inattentive (10% vs 3%, p < .01) and combined (5% vs 0.6%, p < .05) types., Conclusions: Attention-deficit hyperactivity disorder, mainly the inattentive type is prevalent among ELBW children. Our findings of an increase in symptoms pertaining to Autistic and Asperger's disorders at school age agree with recent reports of others during early childhood. Early identification and intervention for these problems might improve child functioning and ameliorate parent and child distress.

Background: The primary determinant of reproductive age in women is the number of ovarian non-growing (primordial, intermediate and primary) follicles (NGFs). To better characterize the decline in NGF number associated with aging, we have employed modern stereology techniques to determine NGF number in women from birth to menopause., Methods: Normal human ovaries were collected from 122 women (aged 0-51 years) undergoing elective oophorectomy, organ donation or autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. Models to describe the resulting decay curve were constructed and evaluated., Results: NGF decay was best described by a simple power function: log (y) = ax(b) + c, where a, b and c are constants and y = NGF count at age x (R(2) = 0.84, Sums of Squares Error = 28.18 on 119 degrees of freedom). This model implies that follicles decay faster with increasing age., Conclusions: Unlike previous models of ovarian follicle depletion, our model predicts no sudden change in decay rate, but rather a constantly increasing rate. The model not only agrees well with observed ages of menopause in women, but also is more biologically plausible than previous models. Although the model represents a significant improvement compared with earlier attempts, a considerable percentage of the variation in NGF number between women cannot be explained by age alone.

Objective: To examine the self-perceived health of very low birth weight (VLBW; <1.5 kg) infants during young adulthood., Study Design: The population included 241 VLBW and 232 normal birth weight (NBW) controls who completed the Child Health and Illness Profile: Adolescent Edition (CHIP-AE) at 20 years of age. The CHIP-AE includes six domains: Satisfaction, Comfort, Resilience, Achievement, Risk Avoidance, and Disorders, and 13 profiles that characterize patterns of health. Results were compared between VLBW and NBW subjects adjusting for sex and sociodemographic status., Results: VLBW subjects did not differ from NBW controls in the domains of Satisfaction or Comfort but reported less Resilience (effect size [ES] -0.19, P < .05), specifically in physical activity and family involvement. They reported better Achievement, specifically in work performance (ES 0.28, P < .05), more Risk Avoidance (ES 0.43, P < .001), and significantly more long-term medical, surgical, and psychosocial disorders. Similar proportions of VLBW and NBW subjects reported Excellent (15% vs 11%), Average (27% vs 34%), and Poor (12% vs 13%) profiles of health., Conclusions: VLBW subjects report similar health, well-being, and functioning compared with NBW controls and greater risk avoidance. However, we are concerned that their lesser resilience may prove detrimental to their future adult health.

BACKGROUND Previous published reports on the number of non-growing follicles (NGFs) in the human ovary have employed model-based methods for number estimates. These methods are time-intensive, and require correction factors and assumptions that ultimately limit their accuracy. Here, we describe the modification, application and validation of a modern fractionator/optical disector technique for the estimation of human ovarian NGF number. METHODS Forty-eight pairs of normal human ovaries were collected from women (age 8-51 years) undergoing elective bilateral oophorectomy, organ donation, or from autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. The precision of individual NGF counts was determined by calculating the observed coefficient of error (OCE). Intra-observer variability and variation in NGF number between ovaries within a pair were also determined. RESULTS The mean OCE was 16.6% with larger variations observed at lower follicle counts. In recount experiments of the same ovary, NGF number estimates varied by 15-29%, except at very low follicle counts where variation was greater, but absolute differences were small. There was no significant difference in NGF number between ovaries within a pair (Wilcoxon signed rank test, P = 0.81). CONCLUSIONS Modern stereology methods provide an unbiased, efficient method for estimating NGF number in the human ovary. Both ovaries within a pair contain similar numbers of NGFs.

Objective: To examine parent protection and its correlates among 8-year-old ELBW children compared with normal birth weight (NBW) controls., Methods: The population included 217 eight-year-old ELBW children born 1992-1995 (92% of the surviving birth cohort; mean birth weight, 811 g; mean gestational age, 26.4 weeks) and 176 NBW controls. The primary outcome measure, the Parent Protection Scale (PPS), included a total score and four domains including Supervision, Separation, Dependence, and Control. Multivariate analyses were performed to examine the predictors of parental protection and overprotection., Results: After adjusting for socioeconomic status (SES), race, sex, and age of the child, parents of ELBW children reported significantly higher mean total Parent Protection Scale scores (31.1 vs 29.7, p = .03) than parents of NBW children and higher scores on the subscale of Parent Control (8.0 vs 7.5, p = .04). These differences were not significant when the 36 children with neurosensory impairments were excluded. Parents of ELBW children also reported higher rates of overprotection than controls (10% vs 2%, p = .001), findings that remained significant even after excluding children with neurosensory impairments (8% vs 2%, p = .011). Multivariate analyses revealed lower SES to be associated with higher total Parent Protection Scale scores in both the ELBW (p < .001) and NBW (p < .05) groups. Additional correlates included neurosensory impairment (p < .05) and functional limitations (p < .001) in the ELBW group and black race (p < .05) and maternal depression (p < .01) in the NBW group. Lower child IQ was significantly associated with higher PPS scores only in the neurosensory impaired subgroup of ELBW children., Conclusions: Longer term follow-up will be necessary to examine the effects of the increased parent protection on the development of autonomy and interpersonal relationships as the children enter adolescence.

A cohort of 219 children with extremely low birth weight (<1000 g, extremely low birth weight [ELBW]) born from 1992 to 1995 was followed to mean age 8 years to evaluate outcomes and identify risk factors. We compared 204 of these children with 176 term-born normal birth weight (NBW) controls on neuropsychological skills, academic achievement, and adaptive behavior. The ELBW group had worse outcomes than the NBW on all measures. Within the ELBW group, lower scores on NEPSY tests of executive function and memory were related to <750 g birth weight, B (SE) = -0.93 (0.36), p =.010; cranial ultrasound abnormality, B = -1.03 (0.22), p =.002; postnatal steroid therapy, B = -1.00 (0.33), p =.003; and necrotizing enterocolitis, B = -2.26 (0.75), p =.008. A lower score on the Test of Motor Proficiency was related to chronic lung disease, B = -7.33 (1.98), p <.001. Neuropsychological skills mediated the effects of neonatal risk on achievement and adaptive functioning. The findings document the neuropsychological consequences of ELBW at school age in a recently born cohort and identify risks for adverse outcomes.

Objectives: Although children with very low birth weight (VLBW, <1500 g) are at high risk for developmental impairments, we know little about the long-term effects of VLBW on families. This study examined long-term family outcomes and their stability over time., Methods: Participants were the families of 64 children with <750 g birth weight, 54 with 750-1499 g birth weight, and 66 term-born controls. Family burden and parental distress were assessed annually as part of longitudinal follow-up of the children from mean ages 11-14 years., Results: Family burden and parental distress were higher in the <750 g group than in the term-born group, but differences varied with the child's age and family environment., Conclusions: The findings document long-term effects of VLBW on families that are moderated by the degree of low birth weight, child's age, and family environment.

As part of a longitudinal study of the outcomes of very low birth weight children (<1.5 kg), we sought to examine the perinatal, childhood, and young adult predictors of internalizing symptoms among very low birth weight young women and their normal birth weight controls. The cohort included 125 very low birth weight and 124 normal birth weight 20-year-old subjects. Perinatal, childhood, and young adult predictors were examined via stepwise multivariate analyses. Results revealed very low birth weight to be a significant predictor of parent-reported internalizing symptoms of their daughters but only among white subjects who had mothers with high levels of psychological distress. Additional significant predictors of 20-year internalizing symptoms included child I.Q. and internalizing symptoms at age 8 years and family expressiveness. When the results were analyzed according to the young adult self-report, additional predictors of internalizing symptoms included a history of asthma and exposure to violence. Perinatal risk factors were not found to be predictive of internalizing symptoms at age 20 years. Future studies should prospectively examine social and environmental factors associated with the neonatal intensive care experience that might explain the effect of very low birth weight on later psychopathology.

Background: Serum FSH elevations and decreases in inhibin B have been consistently demonstrated in the early follicular phase of cycles in women of advanced reproductive age. However, secretory products of the dominant follicle (estradiol and inhibin A) in the serum of older ovulatory women are maintained at levels similar to those of their younger counterparts. The goal of this investigation was to determine if ovarian secretory capacity is dependent on relative FSH levels and if basal measures of ovarian reserve reflect ovarian secretory capacity., Methods: We administered equivalent low, but effective doses of recombinant FSH for 5 days to a group of older subjects (40-45 years, n=9) and younger controls (20-25 years, n=10) after pituitary suppression with a GnRH agonist. Outcome measures included follicular development as determined by serial transvaginal ultrasound examinations and serum levels of estradiol, inhibin A and inhibin B., Results: Serum levels of estradiol and inhibin A were not statistically different between the two groups, while the number of large follicles formed was greater in the younger subjects. Basal parameters of ovarian reserve were not significantly correlated with ovarian secretory capacity, but did correlate with the number of follicles recruited in response to low-dose FSH., Conclusions: By providing equivalent serum levels of FSH in older and younger reproductive aged women, this study demonstrates that the secretory capacity of recruited follicles is maintained in older reproductive aged women.

Previous studies have reported that the monotropic rise in FSH in older women is associated with decreased inhibin B and/or A levels and increased levels of activin A. Whereas most investigators have found decreased follicular-phase inhibin B, the roles of inhibin A and activin A as modulators of the FSH rise are unclear. The objectives of this study were to determine whether deficiencies in circulating levels of inhibin A, inhibin B, and/or activin A exist during the intercycle interval in ovulatory older (age, 40-45 yr; n = 16), compared with younger women (age, 20-25 yr; n = 13). Blood samples were obtained daily throughout one menstrual cycle and the follicular phase of the subsequent cycle and were analyzed for LH, FSH, estradiol, inhibin A and B, and activin A. Despite significant FSH elevation, no deficiencies in inhibin A, activin A, or estradiol were detected in older subjects. In fact, inhibin A was significantly higher in older participants during the intercycle phase (P = 0.01), whereas inhibin B was significantly lower. Thus, the monotropic rise in FSH does not appear to result from changes in inhibin A or activin A, supporting the concept that inhibin B plays a critical role in mediating the FSH rise in older women.

Data are equivocal regarding the long-term consequences of prenatal exposure to cocaine on school-aged children. We compared 101 children exposed prenatally to cocaine with 130 unexposed children on measures of intelligence, visual motor, and motor abilities at age 7 years. Bivariate analyses revealed that cocaine-exposed children scored significantly lower than comparison children on the abbreviated Wechsler Intelligence Scale for Children-Third Edition Verbal and Full Scale IQ scores, the Visual Motor Integration and Motor Coordination standardized scores, and the Bruininks-Oseretsky Fine Motor Composite score. Regression analyses indicated that the biological mother's vocabulary and home environment assessed at the same 7-year visit were stronger predictors of developmental outcome than prenatal drug exposure. Level of cocaine exposure, however, predicted visual motor and motor skills. The results indicate that although prenatal cocaine exposure may confer some degree of developmental disadvantage in the visual motor domain, it frequently occurs in the context of an inadequate rearing environment, which may be a stronger determinant than prenatal cocaine exposure of children's outcome.

Objective: The aim of this study was to better characterize the ranges and intercycle variability for day 3 follicle-stimulating hormone, estradiol, and inhibin B levels in normal eumenorrheic women., Study Design: Healthy eumenorrheic volunteers were recruited, of whom 27 women were 20 to 25 years old (peak reproductive age) and 36 women were 40 to 45 years old (study population). Blood samples were obtained on day 3 of two consecutive menstrual cycles. In some women, an additional blood sample on day 3 was obtained within 1 year., Results: In normal women aged 20 to 25 years versus women aged 40 to 45 years, the day 3 follicle-stimulating hormone geometric mean is 5.6 IU/L (95% CI, 3.3-9.5 IU/L) versus 9.6 IU/L (95% CI, 3.8-23.8 IU/L), the day 3 estradiol geometric mean is 44.0 pg/mL (95% CI, 20.4-95.0 pg/mL) versus 52.4 pg/mL (95% CI, 22.4-122.8 pg/mL), and the day 3 inhibin B geometric mean is 100.4 pg/mL (95% CI, 51.7-195.0 pg/mL) versus 52.4 pg/mL (95% CI, 9.5-289.3 pg/mL). Furthermore, 22% of women in the older age group have a normal day 3 follicle-stimulating hormone and estradiol level in one cycle but an elevated value in a consecutive cycle (P=.008)., Conclusion: In women of peak reproductive age, the upper limit of day 3 follicle-stimulating hormone and estradiol levels are 9.5 IU/L and 95.0 pg/mL, respectively, and the lower limit of day 3 inhibin B level is 51.7 pg/mL. If the initial day 3 follicle-stimulating hormone and estradiol levels in an older woman are normal, then a second measurement in a subsequent cycle should be obtained before counseling this woman regarding her reproductive potential.

Background: Monitoring of reproductive steroid hormones at the population level requires frequent measurements, hormones or metabolites that remain stable under less than ideal collection and storage conditions, a long-term supply of antibodies, and assays useful for a range of populations. We developed enzyme immunoassays for urinary pregnanediol 3-glucuronide (PDG) and estrone conjugates (E1Cs) that meet these criteria., Methods: Enzyme immunoassays based on monoclonal antibodies were evaluated for specificity, detection limit, parallelism, recovery, and imprecision. Paired urine and serum specimens were analyzed throughout menstrual cycles of 30 US women. Assay application in different populations was examined with 23 US and 42 Bangladeshi specimens. Metabolite stability in urine was evaluated for 0-8 days at room temperature and for 0-10 freeze-thaw cycles., Results: Recoveries were 108% for the PDG assay and 105% for the E1C assay. Serially diluted specimens exhibited parallelism with calibration curves in both assays. Inter- and intraassay CVs were <11%. Urinary and serum concentrations were highly correlated: r = 0.93 for E1C-estradiol; r = 0.98 for PDG-progesterone. All Bangladeshi and US specimens were above detection limits (PDG, 21 nmol/L; E1C, 0.27 nmol/L). Bangladeshi women had lower follicular phase PDG and lower luteal phase PDG and E1Cs than US women. Stability experiments showed a maximum decrease in concentration for each metabolite of <4% per day at room temperature and no significant decrease associated with number of freeze-thaw cycles., Conclusions: These enzyme immunoassays can be used for the field conditions and population variation in hormone metabolite concentrations encountered in cross-cultural research.

This study sought to determine whether the shortened follicular phase in ovulatory older women is secondary to advanced (i.e. earlier) or accelerated (i.e. more rapid) folliculogenesis. Normal ovulatory women, aged 40-45 yr (n = 15) and 20-25 yr (n = 13), underwent daily venipuncture and transvaginal ultrasonography throughout the follicular phase of a spontaneous menstrual cycle (control cycle) and after pituitary down-regulation with a GnRH agonist (study cycle). As expected, the older subjects in the control cycles demonstrated an elevated d 3 FSH and a shortened follicular phase compared with the younger subjects. After release from hypothalamic-pituitary-ovarian axis suppression, the early follicular phase FSH peak occurred earlier (6.8 vs. 9.8 d; P < 0.01) and was of a greater magnitude (12.1 vs. 6.5 mIU/ml; P < 0.01) in the older subjects. The time from release of suppression until the subsequent LH surge was also shorter (17.5 vs. 20.8 d; P < 0.01) in the older group. However, the time from FSH peak to LH surge was similar in the older and younger groups (10.7 vs. 11.0 d; P = 0.74). Compared with younger women, older subjects had normal follicular phase levels of estradiol and inhibin A and lower levels of inhibin B in both control and study cycles. We conclude that the shortened follicular phase observed in older ovulatory women is due to earlier dominant follicle selection, independent of hormonal influences from the preceding luteal phase.

Background: Very-low-birth-weight infants (those weighing less than 1500 g) born during the initial years of neonatal intensive care have now reached young adulthood., Methods: We compared a cohort of 242 survivors among very-low-birth-weight infants born between 1977 and 1979 (mean birth weight, 1179 g; mean gestational age at birth, 29.7 weeks) with 233 controls from the same population in Cleveland who had normal birth weights. We assessed the level of education, cognitive and academic achievement, and rates of chronic illness and risk-taking behavior at 20 years of age. Outcomes were adjusted for sex and sociodemographic status., Results: Fewer very-low-birth-weight young adults than normal-birth-weight young adults had graduated from high school (74 percent vs. 83 percent, P=0.04). Very-low-birth-weight men, but not women, were significantly less likely than normal-birth-weight controls to be enrolled in postsecondary study (30 percent vs. 53 percent, P=0.002). Very-low-birth-weight participants had a lower mean IQ (87 vs. 92) and lower academic achievement scores (P<0.001 for both comparisons). They had higher rates of neurosensory impairments (10 percent vs. <1 percent, P<0.001) and subnormal height (10 percent vs. 5 percent, P=0.04). The very-low-birth-weight group reported less alcohol and drug use and had lower rates of pregnancy than normal-birth-weight controls; these differences persisted when comparisons were restricted to the participants without neurosensory impairment., Conclusions: Educational disadvantage associated with very low birth weight persists into early adulthood.