Long-term stability of maternal prenatal steroid hormones from the National Collaborative Perinatal Project: still valid after all these years.

Large epidemiological samples, including the National Collaborative Perinatal Project (NCPP), in which blood/serum was collected during pregnancy and offspring followed longitudinally, offer the unique opportunity to examine neuroendocrine mechanisms underlying prenatal "programming" of adult health and disease. However, in order to conduct longitudinal analyses, it is critical to determine the validity of maternal prenatal samples stored over long periods. We investigated the validity of cortisol, testosterone, and their binding globulins (corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG)) in maternal prenatal serum from the NCPP after over 40 years of storage. Study 1 included 64 maternal serum samples collected on the day of delivery; study 2 involved 1099 third trimester serum samples collected between gestational weeks 31 and 36. Across both studies, cortisol and testosterone concentrations were consistent with values from published studies of fresh samples collected at similar points in gestation. CBG and SHBG were present, but showed some differences from published studies. Results support the validity of cortisol and testosterone values following 40+ years of storage. Results also provide validation for future longitudinal tests of prenatal "programming" hypotheses within the NCPP. Stability of steroid hormones over decades suggests that stored samples from other longitudinal studies may also allow opportunities to investigate links between prenatal steroids and long-term offspring outcomes.

Childhood cognitive performance and risk of generalized anxiety disorder.

BACKGROUND: Perception of control over one's environment, particularly when faced with an ambiguous situation, has been identified as a critical cognitive process involved in worry and generalized anxiety disorder (GAD). Similarly, it is thought that individuals with lower cognitive skills feel less in control, and do not cope as well as individuals with higher cognitive skills. This study tests the hypothesis that individuals with higher cognitive skills are less likely to develop a lifetime diagnosis of GAD, and considers onset in three developmental periods: childhood, adolescence and adulthood. METHODS: Survival analysis and multivariate regression models were used to evaluate the relationship between cognitive performance at age seven, and DSM-IV diagnosis of GAD. Study participants were 689 individuals in their mid-30s, who had been followed since birth as part of the National Collaborative Perinatal Project in Providence, RI, USA. RESULTS: A 15-point (1 SD) advantage in childhood cognitive performance was significantly associated with a 50% reduced risk of lifetime GAD and an 89 and 57% reduction in risk of GAD in childhood and adolescence, respectively, after adjusting for relevant covariates including socio-economic status and parent history of mental health problems. These results were not affected by behavioural inhibition or learning disabilities in childhood. CONCLUSIONS: Childhood cognitive performance is associated with a diagnosis of GAD in childhood and adolescence. Further research on the association between childhood cognitive performance and GAD is warranted.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

Prenatal glucocorticoids and maternal smoking during pregnancy independently program adult nicotine dependence in daughters: a 40-year prospective study.

BACKGROUND: Maternal smoking during pregnancy (MSDP) is an independent risk factor for offspring nicotine dependence (ND), but mechanisms remain unknown. We investigated prenatal glucocorticoid (cortisol) and androgen (testosterone) associations with offspring ND over 40 years and the possibility that prenatal glucocorticoids and androgens would mediate links between MSDP and offspring ND. METHODS: Participants were 1086 mother-adult offspring pairs (59% female) from the New England Family Study, a 40-year longitudinal follow-up of the Collaborative Perinatal Project. MSDP was assessed prospectively at each prenatal visit. Maternal cortisol, testosterone, and cotinine (nicotine metabolite) were assayed from third trimester maternal sera. Offspring lifetime ND was assessed via structured interview. RESULTS: Significant bivariate associations emerged for: 1) MSDP/cotinine and lifetime ND; and 2) maternal cortisol and lifetime ND, for daughters only. In multivariate models, maternal cortisol and MSDP/cotinine remained significantly and independently associated with increased odds of lifetime ND of daughters. However, cortisol did not mediate the MSDP-lifetime ND relation. No associations emerged between maternal testosterone and offspring ND. CONCLUSIONS: Results provide the first evidence in support of prenatal glucocorticoid programming of adult ND over 40 years in daughters only. Our study highlights two independent prenatal pathways leading to increased risk for ND in daughters: elevated prenatal glucocorticoids and MSDP/nicotine exposure. Daughter-specific effects of glucocorticoid and MSDP programming over 40 years highlight the breadth and persistence of sexually dimorphic programming effects in humans. Results do not support androgen programming of offspring ND.

Maternal smoking during pregnancy and neonatal behavior: a large-scale community study.

OBJECTIVE: To investigate the influence of prospectively measured smoking during pregnancy on aspects of neonatal behavior in a large community sample. METHODS: Participants were mothers and infants from the Providence, Rhode Island, cohort of the National Collaborative Perinatal Project enrolled between 1960 and 1966. Mothers with pregnancy/medical complications and infants with medical complications and/or born premature or of low birth weight were excluded. The final sample included 962 mother-infant pairs, 23% of whom were black. Maternal smoking was measured prospectively at each prenatal visit. Neonatal behavior was assessed by using the Graham-Rosenblith Behavioral Examination of the Neonate. Items from the examination were reduced to 3 subscales: irritability, muscle tone, and response to respiratory challenge. RESULTS: Sixty-two percent of the sample reported smoking during pregnancy, with 24% of smokers reporting smoking 1 pack per day or more. We found a significant influence of maternal smoking exposure (none, moderate/less than 1 pack per day, heavy/1 pack per day or more) on irritability and muscle tone in the neonate, with exposed infants showing greater irritability and hypertonicity. Effects remained significant after controlling for significant covariates: maternal socioeconomic status, age, and race and infant birth weight and age. Posthoc tests suggested particular effects of heavy smoking on increased infant irritability and both moderate and heavy smoking exposure on increased muscle tone. CONCLUSIONS: In a large community sample, exposure to maternal smoking was associated with increased irritability and hypertonicity in neonates. Exposure to maternal smoking did not influence neonatal response to respiratory challenge. This study is the largest-scale investigation to date of the effects of maternal smoking (heavy and moderate) on examiner-assessed neonatal behavior. Given the associations between both maternal smoking and infant irritability and later behavioral dysregulation, results have important implications for early identification and intervention with at-risk offspring.

Parental smoking and adolescent smoking initiation: an intergenerational perspective on tobacco control.

OBJECTIVE: Adolescence is an important period of risk for the development of lifelong smoking behaviors. Compelling, although inconsistent, evidence suggests a relationship between parental smoking and the risk of smoking initiation during adolescence. This study investigates unresolved issues concerning the strength and nature of the association between parent smoking and offspring smoking initiation. METHODS: We enrolled 564 adolescents aged 12 to 17, along with 1 of their parents, into the New England Family Study between 2001 and 2004. Lifetime smoking histories were obtained from parents and their adolescent offspring. Discrete-time survival analysis was used to investigate the influence of parental smoking histories on the risk of adolescent smoking initiation. RESULTS: Parental smoking was associated with a significantly higher risk of smoking initiation in adolescent offspring. In addition, the likelihood of offspring smoking initiation increased with the number of smoking parents and the duration of exposure to parental smoking, suggesting a dose-response relationship between parental smoking and offspring smoking. Offspring of parents who had quit smoking were no more likely to smoke than offspring of parents who had never smoked. The effects of parental smoking on offspring initiation differed by sex (with a stronger effect of fathers' smoking on boys than girls), developmental period (with a stronger effect of parental smoking before the adolescent was age 13 than afterward), and residence of parents (with effects of fathers' smoking being dependent on living in the same household as the adolescent). Parental smoking was also associated with stronger negative reactions to adolescents' first cigarette, a potential marker of the risk of progression to higher levels of use. CONCLUSIONS: Parental smoking is an important source of vulnerability to smoking initiation among adolescents, and parental smoking cessation might attenuate this vulnerability.

Neonatal blood pressure and salt taste responsiveness.

To test the association between neonatal blood pressure (BP) and salt taste response, 283 healthy hospitalized neonates were administered small drops (0.06 mL) of water and 0.1 molar (mol/L) and 0.3 mol/L NaCl solutions by means of cannulas through a nipple with a pressure transducer to record sucking responses. Neonatal and 1-month BPs were recorded by ultrasound. Mean number of sucks per burst was scored as "aversive" if the 0.3 mol/L salt minus water difference score was < or =-10 mean sucks per burst, "preferential" if this difference was >0, and "neutral" otherwise. Babies with "preferential" responses had higher diastolic BPs than those with neutral (1.9 mm Hg) or aversive responses (3.1 mm Hg) (P trend=0.05). After adjustment for age, gender, birth weight, and activity for babies with at least one grandparent receiving antihypertensive medication, mean adjusted systolic pressure was 6.7 mm Hg higher (P=0.003) (P trend=0.003) and mean adjusted diastolic pressure was 5.0 mm Hg higher (P=0.010) (P trend=0.011) in neonates with preferential versus aversive salt taste responses. There was no relation of BP to sucking responses to sweet (sucrose) stimuli. Neonates can distinguish between dilute salt solutions and water. This response is related to BP and might be a potential risk factor for high BP later in life.