A transgenerational, epigenetic effect of anesthesia, particularly fluorinated agents, has been examined in rat models, but translation to humans is unclear. This study examined associations of maternal lifetime exposure to anesthesia and pregnancy exposure to fluorinated anesthetics with child cognitive and educational outcomes. Women in the US Collaborative Perinatal Project (1959–1963) reported lifetime history of surgeries, and the obstetric record captured pregnancy exposure to anesthetics. Children were followed to age 7 for global cognitive ability and educational outcomes (n=47,977). Logistic and linear regressions were adjusted for maternal and child birth years, race and ethnicity, smoking, education, parity, study site. Many outcomes were not associated with exposure to maternal surgery that occurred at various life stages. However, maternal surgery in early childhood was associated both with being in a special school or not in school (adj OR=1.42; 95% CI 1.02, 1.98) and with slightly better cognitive ability across childhood (e.g., WISC IQ (adj β=0.59; CI 0.13, 1.04) (especially among boys)). Maternal surgery in puberty was associated with slightly lower IQ (adj β = –0.42; CI –0.79, –0.05) and poorer spelling at age 7. Children’s prenatal exposure to fluorinated anesthetics was associated with slightly better spelling ability (adj β = 1.20; CI 0.02, 2.38) but lower performance IQ at age 7 (only among boys, adj β = –1.97; CI –3.88, –0.06). This study shows inconsistent evidence of effects of maternal exposure to surgery or prenatal exposure to fluorinated agents on child developmental and educational outcomes Residual confounding by indication and socioeconomic status may explain observed associations.

Adverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.

Markers of metabolic abnormalities are commonly found in rodents fed a fructose-rich diet. The purpose of this study was to determine whether the administration of a short-term standard diet to rats is able to improve the lipid profile altered by a fructose-rich diet. The male pups, immediately after birth, were divided in three groups according to the diet for 90 days. Standard diet: a standard diet for the whole experimental period; fructose (60% fructose-rich diet): fructose-rich diet during the entire experimental period; fructose/standard (FS): fructose-rich diet from the neonatal period up to 60 days of age and standard diet from 60 to 90 days of age. A fructose-rich diet from the neonatal period to 60 days reduced weight gain (P<0.05), as well as the weight of adipose tissues in all the regions analyzed (epididymal, mesenteric, retroperitoneal and posterior subcutaneous), and it altered the lipid profile (elevation of triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) cholesterol; P<0.05). When a standard diet was administered after the fructose-rich diet, it was able to partially reverse changes to the lipid profile, as total cholesterol levels were significantly different in all the groups (P<0.05), and triglyceride and VLDL cholesterol levels were similar between the control and FS group. In summary, a fructose-rich diet altered the lipid profile, and a standard diet can partially reverse the changed parameters in short term.

The Lifeways study is novel in having information on three generations of the same families. It is well established that infant birth weight (IBW) predicts individuals’ risk of adult chronic disease and more recently studies report cross-generation transmission of risk patterns. The aims of this analysis were to examine whether adults’ birth weights were associated with measures of own health status or social position and to relate adults’ birth weights to that of the index child’s IBW. Finally, we assessed whether birth weight of either adults or children was associated with adult body mass index (BMI) of parents and grandparents. We included 1075 children whose IBW was recorded at recruitment from hospital records and 2546 adult cohort members followed from 2001 until 2014. At baseline, a sub-group of 920 adults had reported own birth weight (RBW). Results showed male adults’ RBW were significantly higher than females’ (P=0.001). Mothers’ RBW was significantly correlated with IBW (r=0.178, P<0.001). In mixed effects linear models with BMI as the outcome variable, of all adults, and in sub-groups of adults with RBW and of mothers only, the IBW was associated with adult BMI adjusting for other predictors. Adults’ BMI was positively associated with age (P=0.013), index child’s IBW (P=0.001), gender (P<0.001) but not own RBW, adjusting for family identification number. When mothers were removed from the adult models however, IBW ceased to be associated with BMI, a final model showed RBW being associated with adult BMI (P=0.04). There are cross-generational associations in the Lifeways cohort, the maternal association being stronger.

Early development, throughout gestation and lactation, represents a period of extreme vulnerability during which susceptibility to later metabolic and cardiovascular injuries increases. Maternal diet is a major determinant of the foetal and newborn developmental environment; maternal undernutrition may result in adaptive responses leading to structural and molecular alterations in various organs and tissues, such as the brain and kidney. New nephron anlages appear in the renal cortex up to postnatal day 4 and the last anlages to be formed develop into functional nephrons by postnatal day 10 in rodents. We used a model of undernutrition in rat dams that were food-restricted during the first half of the lactation period in order to study the long-term effects of maternal diet on renal development, behaviour and neural hydromineral control mechanisms. The study showed that after 40% food restriction in maternal dietary intake, the dipsogenic responses for both water and salt intake were not altered; Fos expression in brain areas investigated involved in hydromineral homeostasis control was always higher in the offspring in response to isoproterenol. This was accompanied by normal plasma osmolality changes and typical renal histology. These results suggest that the mechanisms for the control of hydromineral balance were unaffected in the offspring of these 40% food-restricted mothers. Undernutrition of the pups may not be as drastic as suggested by dams’ restriction.

Prenatal sex steroid exposure plays an important role in determining child development. Yet, measurement of prenatal hormonal exposure has been limited by the paucity of newborn/infant data and the invasiveness of fetal hormonal sampling. Here we provide descriptive data from the MIREC-ID study (n=173 girls; 162 boys) on a range of minimally invasive physical indices thought to reflect prenatal exposure to androgens [anogenital distances (AGDs); penile length/width, scrotal/vulvar pigmentation], to estrogens [vaginal maturation index (VMI) – the degree of maturation of vaginal wall cells] or to both androgens/estrogens [2nd-to-4th digit ratio (2D:4D); areolar pigmentation, triceps/sub-scapular skinfold thickness, arm circumference]. VMI was found to be associated with triceps skinfold thickness (β=0.265, P=0.005), suggesting that this marker may be sensitive to estrogen levels produced by adipose tissue in girls. Both estrogenic and androgenic markers (VMI: β=0.338, P=0.031; 2D:4D – right: β=−0.207, P=0.040; left: β=−0.276, P=0.006; AGD-fourchette − β=0.253, P=0.036) were associated with areolar pigmentation in girls, supporting a role for the latter as an index of both androgen and estrogen exposure. We also found AGD-penis (distance from the anus to the penis) to be associated with scrotal pigmentation (β=0.290, P=0.048), as well as right arm circumference (β=0.462, P<0.0001), supporting the notion that these indices may be used together as markers of androgen exposure in boys. In sum, these findings support the use of several physical indices at birth to convey a more comprehensive picture of prenatal exposure to sex hormones.

Diabetic pregnancies are cleary associated with maternal type 2 diabetes and metabolic syndrome as well as atherosclerotic diseases in the offspring. The global prevalence of hyperglycemia in pregnancy was estimated as 15.8% of live births to women in 2019, with an upward trend. Numerous parental risk factors as well as trans-generational mechanisms targeting the utero-placental system, leading to diabetes, dysmetabolic and atherosclerotic conditions in the next generation, seem to be involved within this pathophysiological context. To focus on the predictable impact of trans-generational diabetic programming, we studied age- and gender-matched offspring of diabetic and nondiabetic mothers. The offspring generation consists of three groups: C57BL/6-J-Ins2Akita (positive control group), wild-type C57BL/6-J-Ins2Akita (experimental group), and C57BL/6-J mice (negative control group). We undertook intraperitoneal glucose tolerance tests at 3 and 11 weeks of age. Moreover, this in vivo model was complemented by a corresponding in silico model. Although at 3 weeks of age, no significant effects could be observed, we could demonstrate at 11 weeks of age characteristic and significant differences in relation to maternal diabetic imprinting based on the in silico model-based predictors. These predictors allow the generation of a concise classification tree assigning maternal diabetic imprinting correctly in 91% of study cases. Our data show that hyperglycemic in utero milieu contributes to trans-generational diabetic programming leading to impaired glucose tolerance in the offspring of diabetic mothers early on. These observations can be clearly and early distinguished from genetically determined diabetes, for example, type 1 diabetes, in which basal glucose values are significantly raised.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22–3.06; aOR2 = 2.05, 95% CI: 1.33–3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30–3.11; aOR2 = 2.51, 95% CI: 1.69–3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03–2.45; aOR2 = 1.99, 95% CI: 1.05–3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

Health in pregnancy and infancy can affect the risk of chronic non-communicable diseases. We aimed to describe leptin and adiponectin concentrations in low birth weight (LBW) infants and identify possible associations with maternal nutritional status, adequacy for gestational age, nutritional recovery, and current dietary intake. A cross-sectional study with LBW infants (9–12 months) including maternal background and pre-pregnancy nutritional condition was performed. From the Infants: anthropometry at birth and current was expressed as z-score (weight: WAZ, length, head circumference), nutritional recovery, dietary intake, leptin, and adiponectin blood concentrations. The mean age of the 54 infants was 10.0 ± 1.5 months, 32 (59.3%) were female, 36 (66.7%) preterm, 23 (42.6%) small for gestational age (SGA), and 25 pregnancies (46.3%) were twin. Almost all (98%) of the infants intake energy and protein above the recommendation, and 47 (87.6%) consumed ultra-processed foods. At the time of the assessment, 8 (14.8%) were overweight and 4 (7.4%) had short stature. SGA infants showed faster weight recovery (WAZ 1.54; 95% CI 1.17, 1.91; p = 0.001), higher leptin’s concentration (3.0 ng/ml (1.7, 3.0) versus 1.6 ng/ml (0.9, 2.6); p = 0.032)), and leptin/adiponectin ratio (0.13 ± 0.08 versus 0.07 ± 0.07; p = 0.018). The pre-gestational BMI was a modifier of the effect of WAZ on leptin levels (p = 0.027) in LBW infants. Higher pre-gestational BMI increased the effect of WAZ variation (birth and current) on leptin levels. Concluding, LBW infants showed early changes in leptin and adiponectin concentrations, influenced by maternal (pre-gestational BMI), intrauterine (gestational age adequacy – SGA), and postnatal weight gain. This combination of factors may increase the risk of NCD for this group of children.

Previous studies have suggested an association between maternal smoking during pregnancy and asthma symptoms such as wheezing during childhood. However, few have evaluated this association in adolescence, especially in populations with high prevalence of wheezing as in Brazil. Using the 1993 Pelotas birth cohort, a longitudinal study set in southern Brazil of 5249 urban live births, we aimed to evaluate the association between maternal and the partner’s smoking during pregnancy and wheezing at 11 and 15 years of age. We evaluated smoking during pregnancy using number of cigarettes/day, and our main outcomes were as follows: wheezing in the last year and number of wheezing crises, at both 11 and 15 years of age, as well as persistent wheezing (having crises at 11 and 15 years of age) and medical asthma diagnosis at age 15. In addition, other socio-demographic variables were included as possible confounders and mediators of this association. We used Poisson regression models to evaluate crude and adjusted associations. Of the 5249 live births in 1993, 87.5% and 85.7% were followed-up to 11 and 15 years of age, respectively. Maternal smoking during pregnancy showed a dose-response association with number of wheezing crises at age 15 (P=0.023), presence of persistent wheezing (P=0.034) and asthma diagnosis (P=0.023). Partner’s smoking was not associated with any wheezing variables. Maternal smoking during pregnancy appears to exert an effect on respiratory morbidity of adolescents, evaluated by wheezing symptoms.

Numerous studies have shown associations between maternal stress and poor birth outcomes, but evidence is unclear for causal inference. Natural disasters provide an opportunity to study effects of quasi-randomized hardship with an accurate measure of onset and duration. In a population-based quasi-experimental study, we examined the effect of maternal exposure to the January 1998 Québec ice storm on birth outcomes by comparing pregnant mothers who lived in an area hard hit by the ice storm with those in two unaffected regions. In a total of 147,349 singleton births between 1995 and 2001, we used a difference-in-differences method to estimate the effects of the ice storm on gestational age at delivery (GA), preterm birth (PTB), weight-for-gestational-age z-scores (BWZ), large for gestational age (LGA), and small for gestational age (SGA). After adjusting for maternal and sociodemographic characteristics, there were no differences between the exposed and the unexposed mothers for birth outcomes. The estimated differences (exposed vs. unexposed) were 0.01 SDs (95% CI: −0.02, 0.05) for BWZ; 0.10% point (95% CI: −0.95%, 1.16%) for SGA; 0.25% point (95% CI: −0.78%, 1.28%) for LGA; −0.01 week (95% CI: −0.07, 0.05) for GA; and 0.16% point (95% CI: −0.66%, 0.97%) for PTB. Neither trimester-specific nor dose–response associations were observed. Overall, exposure to the 1998 Québec ice storm as a proxy for acute maternal stress in pregnancy was not associated with poor birth outcomes. Our results suggest that acute maternal hardship may not have a substantial effect on adverse birth outcomes.

Intrauterine growth-restricted (IUGR) offspring are at increased risk of adult obesity, as a result of changes in energy balance mechanisms. We hypothesized that impairment of hypothalamic insulin signaling contributes to hyperphagia in IUGR offspring. Study pregnant dams were 50% food restricted from days 10 to 21 to create IUGR newborns. At 5 weeks of age, food intake was measured following intracerebroventricular (icv) injection of vehicle or insulin (10 mU) in control and IUGR pups. At 6 weeks of age, with pups in fed or fasted (48 h) states, pups received icv vehicle or insulin after which they were decapitated, and hypothalamic arcuate (ARC) nucleus dissected for RNA and protein expression. IUGR rats consumed more food than controls under basal conditions, consistent with upregulated ARC phospho AMP-activated protein kinase (pAMPK) and neuropeptide Y (NPY). Insulin acutely reduced food intake in both control and IUGR rats. Consistent with anorexigenic stimulation, central insulin decreased AMP-activated protein kinase and NPY mRNA expression and increased proopiomelanocortin mRNA expression and pAkt, with significantly reduced responses in IUGR as compared with controls. Despite feeding, IUGR offspring exhibit a persistent state of orexigenic stimulation in the ARC nucleus and relative resistance to the anorexigenic effects of icv insulin. These results suggest that impaired insulin signaling contributes to hyperphagia and obesity in IUGR offspring.

We aimed to evaluate the impact of maternal exercise training on the offspring metabolism and body size caused by father obesity. C57BL/6 male 4-week-old mice were fed a high-fat diet (HF father) or control diet (C father), while equal age female mice were fed only a C diet and were separated into two groups: trained (T mother) and non-trained (NT mother), and at 12 weeks of age mice were mated. A continuous swimming protocol was applied for 10 weeks (before and during gestation), and offspring were followed since weaning until sacrifice (at 12 weeks of age). HF father, compared to C father, showed obesity, elevated total cholesterol (TC) and triglycerides (TG), and glucose intolerance. Both sexes HF/NT offspring showed hyperglycemia, glucose intolerance and high levels of TC and TG, without obesity. However, HF/T offspring showed data close to C/NT, demonstrating the beneficial effect of maternal exercise in the offspring of obese fathers.

Topiramate (TOP) is a psychotropic drug prescribed for the treatment of epilepsy in children older than 2 years of age and for migraine prophylaxis in adolescents. There is evidence that TOP promotes negative effects on the reproductive system of male rats. This study aimed to evaluate the immediate and late treatment effects of TOP during childhood and adolescence on the male rat reproductive system. Two experimental groups received 41 mg/kg of TOP daily, by gavage, from postnatal day (PND) 16 to 28 (TOPc group) or from PND 28 to 50 (TOPa group). Control groups (CTRc group or CTRa group) received water daily. Half of the anim–als were evaluated 24 h after the end of treatment (PND 29 and PND 51, respectively) and the remainder were evaluated in adulthood (PND120). The following parameters were determined: anogenital distance, sperm evaluation, testis’ histomorphometry and plasma testosterone concentration. At PND 120, the volume (CTRc:62.58 ± 2.13; TOPc: 54.54 ± 2.10*%, p = 0.018) and total length (CTRc: 25.48 ± 1.61; TOPc: 18.94 ± 2.41*, p = 0.035) of seminiferous tubules were decreased and the volume of interstitial tissue (CTRc:37.41 ± 2.13; TOPc: 45.45 ± 2.09*%, p = 0.018) and number of Leydig cells/testis (CTRc: 277.00 ± 36.70; TOPc: 400.20 ± 13.23*, p = 0.013) were increased in the TOPc group. The other parameters remained similar between the groups. Therefore, the present study contributes to our understanding that childhood treatment with TOP has an impact on the rat reproductive system in adulthood, suggesting that this period is more sensitive to TOP exposure than adolescence.

Earlier research suggests that maternal pelvic size is associated with offspring’s stroke risk in later life. We followed 6362 men and women from Uppsala, Sweden, born between 1915 and 1929 from 1964 to 2008 to assess whether maternal pelvic size was associated with incidence of thrombotic stroke (TS), haemorrhagic stroke (HS) and other stroke (OS). Offspring whose mothers had a flat pelvis had lower birth weight and birth-weight-for-gestational-age compared with those who did not. Inverse linear associations of birth-weight-for-gestational-age were observed with TS and OS. Female offspring whose mothers had a flat pelvis had increased risk of TS, but flat pelvis was not associated with other types of stroke. A smaller difference between intercristal and interspinous diameters and a smaller external conjugate diameter were independently associated with HS, whereas no pelvic measurements were associated with OS. We conclude that a smaller pelvis in women may impact the health of their offspring in adulthood.

Consumption of sugar-sweetened beverages (SSBs) during pregnancy has been associated with childhood obesity. Research in which rodent dams have been given high-fat/high-sugar diets has consistently found metabolic alterations in their offspring. However, what remains unclear is the potential impact on the developing fetus of giving sugar in isolation at concentrations similar to SSBs to the mothers. Therefore, we conducted a systematic review and meta-analysis (Protocol No: 127115 on Prospero) to identify potential relationships between maternal sucrose consumption and metabolic outcomes in offspring of rodent (rat or mouse) models. We analysed studies that provided rodent mothers dams with access to sucrose solutions (8–20% w/v) prior to conception, during pregnancy and/or lactation and that reported offspring outcomes of body weight (BW), body composition and glycaemic control. Following a systematic search of four databases (PubMed, EMBASE, Web of Science and Scopus) performed on 15 January 2019, maternal and offspring data from 15 papers were identified for inclusion. Only rat studies were identified. Meta-analyses were performed on standardised mean differences for maternal and offspring BW and fasting glucose levels, with subgroup analyses of strain, sucrose concentration, exposure period and sex of offspring. A bias towards the inclusion of only data from male offspring was identified and this limited interpretation of potential sexually dimorphic outcomes. Maternal sucrose exposure was associated with an increased risk of obesity and poor glucose disposal in adult and aged offspring.

Adults who were born preterm are at increased risk of hypertension and cardiovascular disease in later life. Infants born late preterm are the majority of preterm births; however, the effect of late preterm on risk of cardiovascular disease is unclear. The objective of this study was to assess whether vascular health and cardiac autonomic control differ in a group of late preterm newborn infants compared to a group of term-born infants.

A total of 35 healthy late preterm newborn infants, with normal growth (34–36 completed weeks’ gestation) and 139 term-born infants (37–42 weeks’ gestation) were compared in this study. Aortic wall thickening, assessed as aortic intima–media thickness (IMT) by high-resolution ultrasound, and cardiac autonomic control, assessed by heart rate variability, were measured during the first week of life. Postnatal age of full-term and late preterm infants at the time of the study was 5 days (standard deviation [SD] 5) and 4 days (SD 3), respectively.

Infants born late preterm show reduced aortic IMT (574 μm [SD 51] vs. 612 μm [SD 73]) and reduced heart rate variability [log total power 622.3 (606.5) ms2 vs. 1180. 6 (1114.3) ms2], compared to term infants. These associations remained even after adjustment for sex and birth weight.

Infants born late preterm show selective differences in markers of cardiovascular risk, with potentially beneficial differences in aortic wall thickness in contrast to potentially detrimental differences in autonomic control, when compared with term-born control infants. These findings provide pathophysiologic evidence to support an increased risk of hypertension and sudden cardiac death in individuals born late preterm.

Fructose (C6H12O6) is acutely obesogenic and is a risk factor for hypertension, cardiovascular disease, and nonalcoholic fatty liver disease. However, the possible long-lasting effects of early-life fructose consumption have not been studied. We tested for effects of early-life fructose and/or wheel access (voluntary exercise) in a line of selectively bred High Runner (HR) mice and a non-selected Control (C) line. Exposures began at weaning and continued for 3 weeks to sexual maturity, followed by a 23-week "washout" period (equivalent to ∼17 human years). Fructose increased total caloric intake, body mass, and body fat during juvenile exposure, but had no effect on juvenile wheel running and no important lasting effects on adult physical activity or body weight/composition. Interestingly, adult maximal aerobic capacity (VO2max) was reduced in mice that had early-life fructose and wheel access. Consistent with previous studies, early-life exercise promoted adult wheel running. In a 3-way interaction, C mice that had early-life fructose and no wheel access gained body mass in response to 2 weeks of adult wheel access, while all other groups lost mass. Overall, we found some long-lasting positive effects of early-life exercise, but minimal effects of early-life fructose, regardless of the mouse line.

The brain is highly susceptible to adverse effects of drugs of abuse during early phases of life. Prenatal nicotine exposure (PNE), a preventable cause of gestational and infant mortality, can alter neuron wiring and induce sustained deficits in attention and learning. Here, a rat model of PNE (embryonic days 7–21) was used to examine the maturing hippocampus, which encodes new memories and processes emotional memory. Components of synaptic signaling were evaluated at postnatal day 14 (P14), a period of prolific synaptogenesis in rats, to determine if glutamatergic transmission-associated molecules are regulated in subregions of hippocampus as early as P14. PNE resulted in reduced expression of GluN2B, GluA2 and CaMKIIα, but elevated SNAP25 proteins specifically in the CA3 but not CA1. Only CaMKIIα was regulated in dentate gyrus at this age. These results suggest that glutamatergic and synaptic dysregulation of learning and memory may occur in hippocampus in a temporally and subregionally specific manner.

Perimenopausal disorders (PDs) are prevalent and importantly affect quality of life among middle-aged women. Yet, very little is known about the developmental origins of these disorders. The objective of this study was to investigate the associations of birth characteristics with PDs. This cohort study is based on archived birth records for birth weight and gestational age, and followed prospectively in Swedish inpatient and outpatient registers for 8 years (n=3212). The main outcomes were menopausal and climacteric states (e.g. flushing, sleeplessness), perimenopausal bleeding and other PDs (e.g. atrophic vaginitis). Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for three subtypes of PDs separately. During the follow-up, 218 women had PDs, among whom 125 had menopausal and climacteric states, 61 had perimenopausal bleeding and 58 had other PDs as first recorded disorder. Birth weight was linearly associated with incidence rate of menopausal and climacteric states [HR=1.66 per 1 kg increase, 95% confidence interval (95% CI)=1.14–2.41]. Gestational age (rather than birth weight) was associated with incidence rate of other PDs (HR=0.87 per 1 week increase, 95% CI=0.79–0.95). Neither birth weight nor gestational age was associated with perimenopausal bleeding. Similar results were found after adjustment for other early-life and adult socio-demographic characteristics. This observational study provides, for the first time, evidence regarding the developmental origins of PDs. Future research is required to investigate the underlying causal mechanisms, which may shed further light on the etiology of this class of disorders.