Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression.

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

Prenatal maternal and cord blood vitamin D concentrations and negative affectivity in infancy.

Higher maternal vitamin D concentration during pregnancy is associated with better child mental health. Negative affectivity, an early-emerging temperamental trait, indicates an increased risk of psychopathology. We investigated if maternal early/mid-pregnancy 25-hydroxyvitamin D (25(OH)D) and neonatal cord blood 25(OH)D concentrations are associated with Negative affectivity in infancy. We studied term-born infants from the vitamin D Intervention in Infants study (VIDI, n = 777, follow-up rate 80%, Finland), and the Generation R Study (n = 1505, follow-up rate 40%, Netherlands). We measured maternal serum 25(OH)D at 6-27 weeks (VIDI) or 18-25 weeks (Generation R) of pregnancy, and cord blood 25(OH)D at birth (both cohorts). Caregivers rated infant Negative affectivity at 11.7 months (VIDI) or 6.5 months (Generation R) using the Revised Infant Behavior Questionnaire. Using linear regression, we tested associations between 25(OH)D and Negative affectivity adjusted for infant age, sex, season of 25(OH)D measurement, maternal age, education, smoking, and body-mass-index. Per 10 nmol/l increase in maternal early/mid-pregnancy 25(OH)D, infant Negative affectivity decreased by 0.02 standard deviations (95% confidence interval [CI] - 0.06, - 0.004) in VIDI, and 0.03 standard deviations (95% CI - 0.03, - 0.01) in Generation R. Cord blood 25(OH)D was associated with Negative affectivity in Generation R (- 0.03, 95% CI - 0.05, - 0.01), but not VIDI (0.00, 95% CI - 0.02, 0.02). Lower maternal 25(OH)D concentrations were consistently associated with higher infant Negative affectivity, while associations between cord blood 25(OH)D concentrations and Negative affectivity were less clear. Maternal vitamin D status during early- and mid-pregnancy may be linked with early-emerging differences in offspring behavior.

Association of Very Preterm Birth or Very Low Birth Weight With Intelligence in Adulthood: An Individual Participant Data Meta-analysis.

Importance: Birth before 32 weeks' gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW). Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants. Data Sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]). Study Selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults. Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects. Main Outcomes and Measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group. Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood. Conclusions and Relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Lifestyle and glycemic health 5 years postpartum in obese and non-obese high diabetes risk women.

AIM: Women with prior gestational diabetes (GDM) are at increased diabetes risk. This study aimed to assess whether lifestyle is associated with glycemic health of high-risk women 5 years postpartum, taking into account the pre-pregnancy BMI. METHODS: The RADIEL study enrolled before or in early pregnancy 720 women with pre-pregnancy BMI ≥ 30 kg/m2 and/or prior GDM. The follow-up visit 5 years postpartum included questionnaires and measurements of anthropometrics, blood pressure, and physical activity (PA) as well as analyses of glucose metabolism, lipids, and inflammatory markers. We measured body composition (Inbody) and calculated a Healthy Food Intake Index (HFII) from Food Frequency Questionnaires (FFQ). ArmBand measured PA, sedentary time, and sleep. To take into account the diverse risk groups of GDM, we divided the women based on pre-pregnancy BMI over/under 30 kg/m2. RESULTS: Altogether 348 women attended the follow-up. The obese and non-obese women showed similar prevalence of glycemic abnormalities, 13% and 19% (p = 0.139). PA levels were higher among the non-obese women (p < 0.05), except for step count, and their HFII was higher compared to the obese women (p = 0.033). After adjusting for age, education, and GDM history, PA and HFII were associated with glycemic health only among obese women. When both lifestyle factors were in the same model, only PA remained significant. PA associated with other markers of metabolic health also among the non-obese women, excluding HbA1c. CONCLUSION: Lifestyle 5 years postpartum was associated with better glycemic health only among the obese high-risk women. PA, however, is essential for the metabolic health of all high-risk women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.com , NCT01698385.

Early life stress and physical and psychosocial functioning in late adulthood.

BACKGROUND: Severe stress experienced in early life may have long-term effects on adult physiological and psychological health and well-being. We studied physical and psychosocial functioning in late adulthood in subjects separated temporarily from their parents in childhood during World War II. METHODS: The 1803 participants belong to the Helsinki Birth Cohort Study, born 1934-44. Of them, 267 (14.8%) had been evacuated abroad in childhood during WWII and the remaining subjects served as controls. Physical and psychosocial functioning was assessed with the Short Form 36 scale (SF-36) between 2001 and 2004. A test for trends was based on linear regression. All analyses were adjusted for age at clinical examination, social class in childhood and adulthood, smoking, alcohol intake, physical activity, body mass index, cardiovascular disease and diabetes. RESULTS: Physical functioning in late adulthood was lower among the separated men compared to non-separated men (b = -0.40, 95% confidence interval [95% CI]: -0.71 to -0.08). Those men separated in school age (>7 years) and who were separated for a duration over 2 years had the highest risk for lower physical functioning (b = -0.89, 95% CI: -1.58 to -0.20) and (b = -0.65, 95% CI: -1.25 to -0.05), respectively). Men separated for a duration over 2 years also had lower psychosocial functioning (b = -0.70, 95% CI: -1.35 to -0.06). These differences in physical and psychosocial functioning were not observed among women. CONCLUSION: Early life stress may increase the risk for impaired physical functioning in late adulthood among men. Timing and duration of the separation influenced the physical and psychosocial functioning in late adulthood.

Lower conditioning leisure-time physical activity in young adults born preterm at very low birth weight.

BACKGROUND: Adults born preterm at very low birth weight (VLBW, <1500 g) have elevated levels of risk factors for cardiovascular diseases and type 2 diabetes. Preliminary observations suggest that this could partly be explained by lower rates of physical activity. The aim of this study was to assess physical activity in healthy young adults born preterm at very low birth weight compared with term-born controls. METHODOLOGY/PRINCIPAL FINDINGS: We studied 94 unimpaired young adults, aged 21-29 years, born at VLBW and 101 age-, sex-, and birth hospital-matched term-born controls from one regional center in Southern Finland. The participants completed a validated 30-item 12-month physical activity questionnaire and the NEO-Personality Inventory based on the Big Five taxonomy, the most commonly used classification of personality traits. Yearly frequency, total time, total volume and energy expenditure of conditioning and non-conditioning leisure-time physical activity (LTPA) and commuting physical activity were compared between VLBW and term-born subjects. A subset of participants underwent dual-energy x-ray absorptiometry for body composition measurement. Data were analyzed by multiple linear regression. Compared with controls, VLBW participants had lower frequency [-38.5% (95% CI; -58.9, -7.7)], total time [-47.4% (95% CI; -71.2, -4.1)], total volume [-44.3% (95% CI; -65.8, -9.2)] and energy expenditure [-55.9% (95% CI; -78.6, -9.4)] of conditioning LTPA when adjusted for age, sex, body mass index, smoking, parental education and personality traits. Adjusting for lean body mass instead of body mass index attenuated the difference. There were no differences in non-conditioning LTPA or commuting physical activity. CONCLUSIONS/SIGNIFICANCE: Compared with term-born controls, unimpaired VLBW adults undertake less frequent LTPA with lower total time and volume of exercise resulting in lower energy expenditure. Differences in personality that exist between the VLBW and term-born groups do not seem to explain this association.

Longitudinal study of smoking cessation before pregnancy and children's cognitive abilities at 56 months of age.

BACKGROUND: An inverse relationship exists between the rates of maternal smoking during pregnancy and children's cognitive abilities. The effect of maternal cessation of smoking before pregnancy on child's cognitive development is less clear. AIMS: To study whether maternal cessation of smoking before pregnancy is associated with children's cognitive abilities. STUDY DESIGN AND SUBJECTS: The original cohort included all 1535 live-born infants admitted to the neonatal wards during 1 year and 658 randomly recruited non-admitted infants. The present study sample comprised 1019 (68.2%) children of the original sample born at term and free of any major impairment followed up to 56 months. OUTCOME MEASURES: Child's general reasoning, visual-motor integration, verbal competence, and language comprehension at 56 months of age. RESULTS: The results showed that children whose mothers smoked >10 cigarettes per day before pregnancy but none during pregnancy, fared 12.07 (95% confidence interval [CI]: 4.07 to 20.08) and 11.23 (95% CI: 2.81 to 19.66) age-standardized points poorer in general reasoning and in language comprehension tests, respectively, than children of never-smokers. All results were adjusted for the sex, gestational age-adjusted birth weight, multiple/singleton pregnancy, birth order, preeclampsia, maternal diabetes, admission to neonatal ward, 5-minute Apgar score (<7), breastfeeding, parental level of education, maternal age, BMI at the end of pregnancy and single parenting. CONCLUSIONS: Heavy smoking before pregnancy is associated with children's lower cognitive abilities even if the mother has quit smoking before pregnancy. Identification and intervention of heavy smoking women of fertile age would potentially improve not only their odds to become pregnant but also benefit the offspring's cognitive functioning.

Adults born at very low birth weight exercise less than their peers born at term.

OBJECTIVE: To study the effects of very low birth weight (VLBW, <1500 g) birth on physical activity, an important protective and modifiable factor. STUDY DESIGN: VLBW participants (n=163) with no major disability and 188 individuals born at term (mean age, 22.3 years; range, 18.5-27.1) completed a standardized questionnaire of physical activity. RESULTS: VLBW participants reported less leisure-time conditioning physical activity. They were 1.61-fold more likely to "not exercise much," 1.61-fold more likely to exercise infrequently (once a week or less), 2.75-fold more likely to exercise with low intensity (walking), and 3.11-fold more likely to have short exercise sessions (<30 minutes). The differences were present even in subjects with no history of bronchopulmonary dysplasia or asthma and were only slightly attenuated when adjusted for height, parental education, lean body mass, and percent body fat. CONCLUSIONS: Unimpaired adults who were VLBW exercise less during their leisure time than adults born at term. Promoting physical activity may be particularly important in the VLBW population to counteract the risks of chronic disease in adult life.

Prenatal origins of poor sleep in children.

STUDY OBJECTIVES: We examined whether small body size at birth and prenatal tobacco or alcohol exposure predict poor sleep and more sleep disturbances in children. DESIGN: An epidemiologic cohort study of 289 eight-year-old children born at term. MEASUREMENTS AND RESULTS: Sleep duration and efficiency were measured by actigraphy for 7 consecutive nights (mean = 7.1, SD = 1.2). We used both continuous measures of poor sleep and binary variables of short sleep and low sleep efficiency ( < or = 10th percentiles). Parents completed the Sleep Disturbance Scale for Children. Lower birth weight and shorter length at birth were associated with lower sleep efficiency. For every 1-SD decrease in weight and length at birth, the odds for low sleep efficiency increased by 1.7 fold (95% confidence interval [CI]: 1.1 to 2.7) and 2.2 fold (95% CI: 1.3 to 3.7), respectively. For every 1-SD decrease in ponderal index at birth, the risk of parent-reported sleep disorders increased by 1.4 fold (95% CI: 1.0 to 2.0). Moreover, children exposed prenatally to alcohol had a 2.9-fold (95% CI: 1.1 to 7.6) and 3.6-fold (95% CI: 1.3 to 10.0) increased risk for having short sleep and low sleep efficiency, respectively. The associations were not confounded by sex, gestational length, prenatal and perinatal complications, body mass index at 8 years, asthma, allergies, or parental socioeconomic status. CONCLUSIONS: Poor sleep in children may have prenatal origins. Possible mechanisms include alcohol consumption during pregnancy and other conditions associated with small body size at birth.

Young adults with very low birth weight: leaving the parental home and sexual relationships--Helsinki Study of Very Low Birth Weight Adults.

OBJECTIVE: Although most children and adults who are born very preterm live healthy lives, they have, on average, lower cognitive scores, more internalizing behaviors, and deficits in social skills. This could well affect their transition to adulthood. We studied the tempo of first leaving the parental home and starting cohabitation with an intimate partner and sexual experience of young adults with very low birth weight (<1500 g). METHODS: In conjunction with the Helsinki Study of Very Low Birth Weight Adults, 162 very low birth weight individuals and 188 individuals who were born at term (mean age: 22.3 years [range: 18.5-27.1]) and did not have any major disability filled out a questionnaire. For analysis of their ages at events which had not occurred in all subjects, we used survival analysis (Cox regression), adjusted for gender, current height, parents' ages at the birth, maternal smoking during pregnancy, parental educational attainment, number of siblings, and parental divorce/death. RESULTS: During their late teens and early adulthood, these very low birth weight adults were less likely to leave the parental home and to start cohabiting with an intimate partner. In gender-stratified analyses, these hazard ratios were similar between genders, but the latter was statistically significant for women only. These very low birth weight adults were also less likely to experience sexual intercourse. This relationship was statistically significant for women but not for men; however, very low birth weight women and men both reported a smaller lifetime number of sex partners than did control subjects. CONCLUSIONS: Healthy young adults with very low birth weight show a delay in leaving the parental home and starting sexual activity and partnerships.

Very low birth weight and behavioral symptoms of attention deficit hyperactivity disorder in young adulthood: the Helsinki study of very-low-birth-weight adults.

OBJECTIVE: Children with very low birth weight (<1500 g) are at increased risk for attention deficit hyperactivity disorder (ADHD). Whether this increased risk continues into adulthood is unknown. The authors assessed behavioral symptoms of ADHD in a well-characterized cohort of very-low-birth-weight young adults who were either small for gestational age (less than two standard deviations below the Finnish mean) or appropriate for gestational age (within two standard deviations of the mean). METHOD: A total of 162 very-low-birth-weight subjects (small for gestational age: N=52; appropriate for gestational age: N=110) and 172 term comparison subjects 18 to 27 years of age completed the Adult Problem Questionnaire, which yielded six exploratory factor analysis-derived subscales. Participants were also asked about substance use. RESULTS: Very-low-birth-weight adults in the small for gestational age subgroup scored higher on the executive dysfunctioning and emotional instability subscales of the Adult Problem Questionnaire than did those in the appropriate for gestational age subgroup and the comparison group. The appropriate for gestational age and comparison groups had similar scores on these subscales. On the alcohol use subscale of the Adult Problem Questionnaire, both the appropriate and small for gestational age subgroups scored lower than comparison subjects and also reported fewer risk-taking behaviors (alcohol, smoking, and use of recreational drugs) than did comparison subjects. CONCLUSIONS: Rather than very low birth weight per se, intrauterine growth retardation, as reflected by small for gestational age status in the very-low-birth-weight subjects, confers a risk for behavioral and emotional adversity related to ADHD in young adulthood.

Personality of young adults born prematurely: the Helsinki study of very low birth weight adults.

BACKGROUND: Today, the first generations of very low birth weight (VLBW

Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults.

OBJECTIVE: We investigated whether very low birth weight (<1500 g) is associated with the risk of sleep-disordered breathing in young adulthood. METHODS: The study was a retrospective longitudinal study of 158 young adults born with very low birth weight and 169 term-born control subjects (aged 18.5-27.1 years). The principal outcome variable was sleep-disordered breathing defined as chronic snoring. RESULTS: The crude prevalence of chronic snoring was similar in both groups: 15.8% for the very low birth weight group versus 13.6% for the control group. However, after controlling for the confounding variables in multivariate logistic regression models (age, gender, current smoking, parental education, height, BMI, and depression), chronic snoring was 2.2 times more likely in the very low birth weight group compared with the control group. In addition, maternal smoking during pregnancy was significantly and independently of very low birth weight related to risk of sleep-disordered breathing. Maternal preeclampsia, standardized birth weight, and, for very low birth weight infants, small-for-gestational-age status were not related to sleep-disordered breathing. CONCLUSIONS: Premature infants with very low birth weight have a twofold risk of sleep-disordered breathing as young adults. In addition, maternal smoking during pregnancy increases the risk of sleep-disordered breathing by more than twofold.