This commentary is an author response to Yu and colleagues regarding the manuscript entitled ‘Cardiovascular risk factors in offspring exposed to gestational diabetes mellitus in utero: Systematic review and meta-analysis’. We address their concern regarding minor errors in our manuscript, our search strategy and assessment of heterogeneity.

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non ‘growth’ (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension.

Stunting (<−2 SD of length- or height-for-age on WHO growth curves) is the most used predictor of child neurodevelopmental (ND) risk. Occipitofrontal head circumference (OFC) may be an equally feasible, but more direct and robust predictor. We explored association of the two measurements with ND outcome, separately and combined, and examined if cutoffs are more efficacious than continuous measures in predicting ND risk. Infants and young children in rural Guatemala (n = 642; age range = 0.1–35.9 months) were enrolled in a prospective natural history study, and their ND was tested using the Mullen Scales of Early Learning (MSEL) longitudinally. Length- or height-for-age and OFC-for-age were calculated. We performed age-adjusted multivariable regression analyses to explore the association between 1) length or height and ND, 2) OFC and ND, and 3) both length or height and OFC combined, with ND; concurrently, predictively, and longitudinally, as continuous variables and using WHO z-score cutoffs. Continuous length- or height-for-age and OFC z-scores were more strongly associated with MSEL than the traditional -2 SD WHO cutoff. The combination of height-for-age z-score and OFC z-score was consistently, strongly associated with the MSEL Early Learning Composite concurrently (p-values 0.0004–0.11), predictively (p-value 0.001–0.07), with the exception of the 18–24 months age group which had very few records, and in the longitudinal model (p-value <0.0001–0.004). The combination of continuous length- or height-for-age and OFC shows additional utility in estimating ND risk in infants and young children. Measurement of OFC may improve precision of prediction of ND risk in infants and young children.

Changes in anthropometrics often reflect changes in living conditions, and one’s characteristics at birth may be associated with future health. The aim of this study was to investigate the secular trends in maternal and neonatal anthropometrics in the Helsinki Birth Cohort Study. The study participants, thus, comprised all 13,345 live births recorded in Helsinki, Finland, between 1934 and 1944. Adult characteristics of the clinical subsample comprised of 2003 individuals, alive during 2003, were also analyzed. Linear Regression analysis with seasonal terms was applied to see whether clinically and statistically significant trends can be found in maternal age, height and body mass index (BMI) at pregnancy; gestational age, birth weight, ponderal index and sex ratio; and adult height, BMI and fat percentage. Statistically significant trends were found in maternal age and maternal BMI with abrupt changes between 1941 and 1944. Gestational age increased by an average of 0.11% per year (P<0.0001), and the proportion of premature births dropped from 7.9% in 1934 to 4.5% in 1944 (P<0.0001). In the clinical sample, a statistically significant, although small, average annual increase of 0.1% in adult heights was detected (P=0.0012 for men and P=0.0035 for women). In conclusion, although no significant changes were found in either neonatal or adult anthropometrics of babies born in Helsinki between 1934 and 1944, there were abrupt changes in the characteristics of their mothers.

Rates of weight gain in infancy and early childhood can influence later neurocognitive, metabolic and cardiovascular health. We studied the relationship of weight gain during infancy and early childhood to intelligence quotient (IQ), blood pressure (BP) and body mass index (BMI) at age 9 in children born with very low birth weight (VLBW). Sixty-five children born prematurely with VLBW were followed longitudinally and at 9 years IQ, BP and BMI were measured. The mean weight z-scores at birth, neonatal intensive care discharge, 1 year corrected for prematurity, 5 and 9 years were −0.17, −2.09, −1.3, −0.68 and 0.06, respectively. Weight gain during infancy (discharge to 1 year corrected for prematurity) and early childhood (1 year corrected age to 5 years) was expressed as rate of change in weight, rate of change in weight z-score and interval change in weight z-score. In multiple regression analyses that adjusted for race, gender, maternal education, antenatal steroids, birth weight z-score, major intracranial lesions on ultrasound and chronic lung disease, rates of weight gain in infancy and early childhood were predictive of BMI z-score at 9 years, regression coefficients (95% confidence intervals); 0.19 (0.02, 0.36) and 0.37 (0.11, 0.63), respectively, expressed as change in BMI z-score per 10 g/week weight increase. Rates of weight gain were not predictive of systolic BP z-score, Verbal IQ or Performance IQ. In VLBW infants, more rapid weight gain during infancy, and especially early childhood, is associated with higher BMI at school age.

Consistent with cumulative risk hypotheses of psychopathology, studies examining prenatal adversity and later mental health largely suggest that pre and postnatal stress exposures have summative effects. Fewer data support that a mismatch in stress levels between pre- and postnatal life increases risk (the mismatch hypothesis). In this retrospective cohort study using data from the 1983 Ontario Child Health Study (OCHS), we examined interactions between birth weight status and childhood/adolescent stress to predict major depression in adulthood. Ninety-five participants born at low birth weight (LBW; <2500 g) and 972 normal birth weight (NBW) control participants completed the Composite International Diagnostic Interview Short-Form Major Depression module at 21–34 years of age. A youth risk scale consisting of five stressful exposures (family dysfunction, socioeconomic disadvantage, parental criminality, maternal mental illness, exposure to other life stresses) indexed child/adolescent adversity. Birth weight groups did not differ by childhood risk score nor depression levels. A significant interaction was observed between birth weight and the youth risk scale whereby exposure to increasing levels of exposure to childhood/adolescent adversity predicted increased levels of depression in the NBW group, but lower rates in those born at LBW. Consistent with the mismatch hypothesis, data from a large, longitudinally followed cohort suggest that the mental health of adults born LBW may be more resilient to the adverse effects of childhood/adolescent stress. Taken in the context of previous studies of low birth weight infants, these findings suggest that the nature of associations between gestational stress and later mental health may depend on the magnitude of prenatal stress exposure, as well as the degree of resilience and/or plasticity conferred by their early-life environment.

Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.

This study was designed to explore the association between undernutrition in the growth period and cardiovascular risk factors in a middle-aged Chinese population. A total of 1756 subjects, aged 45–60 years, were invited to participate in the Hefei Nutrition and Health Study and divided into three groups according to their self-reported animal food intake in the growth period. Group 1, Group 2 and Group 3 were defined as undernutrition, nutritional improvement and the good nutrition group, respectively. In the three groups, the subjects in Groups 1 and 2 had more oil and salt intake (P<0.001), and less eggs and milk intake (P<0.001), when compared with the subjects in Group 3. After adjusting for age, education, smoking status and other confounding factors, it was found that male participants who experienced nutritional improvement before age 18 had higher risk of hypertension [odds ratio (OR)=1.68; 95% confidence intervals (CI): 1.05, 2.69] than those with good nutrition, and female participants with undernutrition (OR=1.52; 95% CI: 1.01, 2.29) and nutritional improvement (OR=1.68; 95% CI: 1.04, 2.69) before age 18 had a higher risk of hypertension than those with good nutrition. For diabetes, obesity, hypercholesterolemia and hypertriglyceridemia, our results did not found difference among the three groups both in male and female. Our findings indicated that nutritional deficiency in childhood was associated with bad dietary behaviors and a significantly increased risk of hypertension in middle age. Therefore, early adequate nutrition is very important for the prevention of non-communicable diseases later.

Two pregnancy cohorts were used to investigate the association between single-nucleotide polymorphisms (SNPs) in genes within the insulin-like growth factor (IGF)-axis and antenatal and postnatal growth from birth to adolescence. Longitudinal analyses were conducted in the Raine pregnancy cohort (n = 1162) using repeated measures of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) from 18 to 38 weeks gestation and eight measures of postnatal height and weight (1–17 years). Replications of significant associations up to birth were undertaken in the Generation R Study (n = 2642). Of the SNPs within the IGF-axis genes, 40% (n = 58) were associated with measures of antenatal growth (P ⩽ 0.05). The majority of these SNPs were in receptors; IGF-1R (23%; n = 34) and IGF-2R (13%; n = 9). Fifteen SNPs were associated with antenatal growth (either AC or HC or FL) in Raine (P ⩽ 0.005): five of which remained significant after adjusting for multiple testing. Four of these replicated in Generation R. Associations were identified between 38% (n = 55) of the IGF-axis SNPs and postnatal height and weight; 21% in IGF-1R (n = 31) and 9% in IGF-2R (n = 13). Twenty-six SNPs were significantly associated with both antenatal and postnatal growth; 17 with discordant effects and nine with concordant effects. Genetic variants in the IGF-axis appear to play a significant role in antenatal and postnatal growth. Further replication and new analytic methods are required in order to better understand this key metabolic pathway integrating biologic knowledge about the interaction between IGF-axis components.

Early life experiences could determine brain and behavioral development. Neurotrophic factors are likely to mediate the effects of the experience on brain structures and function. Brain-derived neurotrophic factor (BDNF) plays a central role in psychiatric disorders. To investigate the effects of early rearing condition on the amygdala – and serum – BDNF levels, we reared male Wistar rats from weaning (postnatal days 21) to adulthood (postnatal days 119) in three different rearing conditions: (1) enriched, (2) standard and (3) isolated. We found that long-term post-weaning environmental enrichment leads to lower amygdala – and serum – BDNF levels as well as lower brain weights. Grouped rearing in standard laboratory cages enhanced body weight. Thus, early rearing condition might play a crucial role in adult healthiness by predetermining individual BDNF profiles.

Testosterone (T) and cortisol (C) are steroid hormones that have been argued to play opposing roles in shaping physical and behavioral development in humans. While there is evidence linking T and C to different memory processes during adulthood, it remains unclear how the relative levels of T and C (TC ratio) may influence brain and behavioral development, whether they are influenced by sex of the child, and whether or not they occur as a result of stable changes in brain structure (organizational changes), as opposed to transient changes in brain function (activational changes). As such, we tested for associations among TC ratio, cortico-hippocampal structure, and standardized tests of executive, verbal, and visuo-spatial function in a longitudinal sample of typically developing 4–22-year-old children and adolescents. We found greater TC ratios to be associated with greater coordinated growth (i.e. covariance) between the hippocampus and cortical thickness in several areas primarily devoted to visual function. In addition, there was an age-related association between TC ratio and parieto-hippocampal covariance, as well as a sex-specific association between TC ratio and prefrontal-hippocampal covariance. Differences in brain structure related to TC ratio were in turn associated with lower verbal/executive function, as well as greater attention in tests of visuo-spatial abilities. These results support the notion that TC ratio may shift the balance between top-down (cortex to hippocampus) and bottom-up (hippocampus to cortex) processes, impairing more complex, cortical-based tasks and optimizing visuospatial tasks relying primarily on the hippocampus.

Malathion is an insecticide that is used to control arboviruses and agricultural pests. Adolescents that are exposed to this insecticide are the most vulnerable as they are in the critical period of postnatal sexual development. This study aimed to evaluate whether malathion damage can affect sperm function and its respective mechanisms when adolescents are exposed during postnatal sexual development. Twenty-four male Wistar rats (PND 25) were divided into three experimental groups and treated daily for 40 d: control group (saline 0.9%), 10 mg/kg (M10 group), or 50 mg/kg (M50 group) of malathion. At PND 65, the rats were anesthetized and euthanized. Testicles were collected for the evaluation of gene expression. Sperm cells from the epididymis were used for evaluation of the oxidative profile or spermatic function. Data showed that a lower dose of malathion downregulated the gene expression of androgen receptors and testosterone converter enzyme 17-β-HSD in the testis. The acrosomal integrity of sperm cells was compromised in the M50 group, but not the M10 group. The mitochondrial activity was not impaired by exposure. Finally, although no alterations in malondialdehyde and glutathione levels were observed, malathion, at both doses, increased antioxidant enzyme catalase activity and, at a higher dose, superoxide dismutase activity. The present study showed that low doses of malathion considered to be inoffensive are capable of impairing sperm quality and function through the downregulation of testicular genic expression of AR enzyme 17-β-HSD and can damage the spermatic antioxidant profile during critical periods of development.

In recent years, the rapidly increasing incidence of obesity is becoming a worldwide public health problem. Obesity is a chronic disease which may have a major negative effect on the people’s quality of life. Previous studies on the comprehensive effects of multivitamins on central obesity and general obesity are relatively few. The aim of this study was to evaluate association of vitamins exposure with obesity risk and obesity-related indicators. We fitted three statistical models (linear regression model, logistic regression model, and Bayesian kernel machine regression model) to evaluate the correlation between vitamin levels and obesity in the study population. The vitamin score represents the overall level of vitamin in serum, which was mutually verified with the results obtained from statistical model. The vitamin (A, C, and D) levels were significantly higher among non-obesity group compared to the obesity group. Using the lowest quartile of vitamin level as a referent, vitamin A, C, and D levels showed significantly negative correlation with the obesity risk in both adjusted and unadjusted models. When considering all vitamin as a mixed exposure, we found a generally negative relationship between vitamin mixtures with binary outcome (obesity) and continuous outcome (BMI, waist circumference, and hsCRP). Reduced levels of vitamins (A, C and D) increased the risk of obesity. Increased levels of vitamin mixtures can significantly reduce obesity risk and obesity-related indicators. Vitamins may reduce the risk of obesity by suppressing inflammatory responses.

Few population studies have sufficient follow-up period to examine early-life exposures with later life diseases. A critical question is whether involuntary exposure to tobacco smoke from conception to adulthood increases the risk of cardiometabolic diseases (CMD) in midlife. In the Collaborative Perinatal Project, serum-validated maternal smoking during pregnancy (MSP) was assessed in the 1960s. At a mean age of 39 years, 1623 offspring were followed-up for the age at first physician-diagnoses of any CMDs, including diabetes, heart disease, hypertension, or hyperlipidemia. Detailed information on their exposure to environmental tobacco smoke (ETS) in childhood and adolescence was collected with a validated questionnaire. Cox regression was used to examine associations of in utero exposure to MSP and exposure to ETS from birth to 18 years with lifetime incidence of CMD, adjusting for potential confounders. We calculated midlife cumulative incidences of hyperlipidemia (25.2%), hypertension (14.9%), diabetes (3.9%), and heart disease (1.5%). Lifetime risk of hypertension increased by the 2nd -trimester exposure to MSP (adjusted hazard ratio: 1.29, 95% confidence interval: 1.01–1.65), ETS in childhood (1.11, 0.99–1.23) and adolescence (1.22, 1.04–1.44). Lifetime risk of diabetes increased by joint exposures to MSP and ETS in childhood (1.23, 1.01–1.50) or adolescence (1.47, 1.02–2.10). These associations were stronger in males than females, in never-daily smokers than lifetime ever smokers. In conclusion, early-life involuntary exposure to tobacco smoke increases midlife risk of hypertension and diabetes in midlife.

Major obstetrics and gynecology societies offer inconsistent recommendation regarding optimal delivery timing in uncomplicated dizygotic twins. We sought to investigate the impact of delivery timing within term gestation, in dizygotic twins, on the short- and long-term offspring morbidity. A prospectively analyzed cohort of dizygotic twin deliveries was conducted. All women delivered at a regional tertiary medical center, at term (≥37 0/7), between the years 1991 and 2014, were included. The primary exposure was delivery at 37 0/7–37 + 6/7 weeks, while delivery at ≥38 0/7 weeks’ gestation was considered the reference. Neonatal short- and long-term outcomes according to hospitalizations of offspring up to 18 years of age due to cardiac, respiratory, hematological, neurological, and infectious morbidity were compared. Kaplan–Meier survival curves were used to compare cumulative incidences per each major-system hospitalization. Cox regression models were used to estimate the adjusted hazard ratios, while adjusting for variables with clinical importance. During the study period, 612 dizygotic twin deliveries met the inclusion criteria. Of them, 200 (31.3%) occurred at 37–37 6/7 weeks, and 412 (68.7%) occurred at ≥38 0/7 weeks’ gestation. In the long-term analysis, rates of hospitalizations involving several major morbidity categories exhibited comparable rates in both groups. The Cox regression models did not demonstrate an independent association between gestational age within term and later major pediatric morbidity in offspring (total long-term morbidity: adjusted hazard ratio 1.33, 95% confidence interval 0.77–2.29). Dizygotic twin deliveries occurring at different gestational ages within term do not appear to significantly impact on major short- and long-term outcomes.

Mitochondrial dysfunction and resulting changes in adiposity have been observed in the offspring of animals fed a high fat (HF) diet. As iron is an important component of the mitochondria, we have studied the offspring of female rats fed complete (Con) or iron-deficient (FeD) rations for the duration of gestation to test for similar effects. The FeD offspring were ~12% smaller at weaning and remained so because of a persistent reduction in lean tissue mass. The offspring were fed a complete (stock) diet until 52 weeks of age after which some animals from each litter were fed a HF diet for a further 12 weeks. The HF diet increased body fat when compared with animals fed the stock diet, however, prenatal iron deficiency did not change the ratio of fat:lean in either the stock or HF diet groups. The HF diet caused triglyceride to accumulate in the liver, however, there was no effect of prenatal iron deficiency. The activity of the mitochondrial electron transport complexes was similar in all groups including those challenged with a HF diet. HF feeding increased the number of copies of mitochondrial DNA and the prevalence of the D-loop mutation, however, neither parameter was affected by prenatal iron deficiency. This study shows that the effects of prenatal iron deficiency differ from other models in that there is no persistent effect on hepatic mitochondria in aged animals exposed to an increased metabolic load.