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Background: Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values during pregnancy is inconclusive. A possible explanation for this is that other maternal factors overshadow any potential effects of stress on cortisol levels. We studied a large cohort of pregnant women with extensive data on pregnancy characteristics to determine the respective contributions of biological, environmental and psychosocial stress factors to cortisol levels in pregnancy., Methods: We used data from 3039 women from the Amsterdam Born Children and their Development-study cohort. Serum cortisol was measured in blood, collected at the first prenatal visit, at different gestational ages (median=91days, range=40-256days), and at various time points during the day (median=11:45h, range=08:00-18:30h). We assessed associations between maternal serum cortisol in pregnancy and biological factors, lifestyle factors and stress factors, including depression, anxiety, pregnancy-related anxiety, work stress, parenting stress and fatigue., Results: In multivariable analysis, variables that were associated with higher cortisol levels in pregnancy were lower maternal age [1.5nmol/l, 95%CI (0.6-2.4)], being nulliparous [21.5 nmol/l (15.9-27.1)], lower pre-pregnancy body mass index (BMI) [1.3nmol/l (0.3-2.4)], higher C-reactive protein (CRP) [1.0nmol/l (0.4-1.5)], carrying a female fetus [9.2nmol/l (1.8-16.5)], non-smoking [14.2nmol/l (0.6-27.7)], sufficient sleep [8.5nmol/l (0.9-16.1)], and being unemployed [12.7nmol/l (2.2-23.2)]. None of the psychosocial stressors was significantly associated with serum cortisol levels in pregnancy. A total of 32% of all variance in cortisol was explained by gestational age, maternal age, time of day, parity, pre-pregnancy BMI, CRP, fetal sex, smoking behavior, self-reported sleep sufficiency, and employment., Conclusions: Our data suggest that maternal cortisol during pregnancy is mainly affected by biological and lifestyle factors, but not by psychosocial factors. We suggest that psychosocial stress in pregnancy might program the fetus through other mechanisms than through altering maternal cortisol levels., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Accumulating studies suggest that prenatal experiences can shape a child's neurodevelopment. Malnutrition and depression occur in pregnancy relatively often and may affect child neurodevelopment independently as well as synergistically. We aimed to provide an overview of recent studies that have examined malnutrition and (or) depression in pregnancy and associations with child behavioural problems and cognitive function. We conducted a literature search in PubMed, using the following main search terms: 'depression', 'nutrition', 'BMI', 'pregnancy', 'offspring', 'cognition', and 'behaviour'. We included studies in human populations published from 2013 onwards. The literature search yielded 1531 articles, of which 55 were included in the current review. We presented the evidence on the associations between prenatal markers of nutritional status and (or) depression and child behaviour and (or) cognitive function. We additionally discussed interventions and mechanisms. Both malnutrition and depression in pregnancy are associated with increased externalizing behavioural problems and attentional deficits, and to some extent with poorer cognitive function in the child, but the evidence is not conclusive. Studies on synergistic effects of both factors on child behaviour and cognitive function are still scarce, and more research is needed. Potential shared mechanisms include the hypothalamic-pituitary-adrenal axis, the immune system, epigenetics, and oxidative stress. Key words: prenatal programming, malnutrition, depression, pregnancy, cognition, behaviour, mechanisms. Un nombre croissant d'etudes laissent entrevoir que les experiences prenatales peuvent faconner le developpement neurologique chez l'enfant. La malnutrition et la depression surviennent relativement frequemment pendant la grossesse, et elles pourraient affecter le developpement neurologique de l'enfant de maniere independante ainsi que synergique. Nous visions a fournir un apercu des etudes recentes qui ont examine la malnutrition ou la depression pendant la grossesse, ainsi que les associations avec les problemes de comportement et les fonctions cognitives chez l'enfant. Nous avons mene une recherche de litterature dans PubMed avec les principaux termes de recherche suivants : << depression >>, << alimentation >>, << IMC >>, << grossesse >>, << progeniture >>, << fonctions cognitives >> et << comportement >>. Nous avons inclus des etudes publiees menees aupres de populations humaines a partir de 2013. La recherche de litterature a fourni 1531 articles, et nous en avons inclus 55 dans le present article de synthese. Nous avons presente les donnees portant sur les associations entre des marqueurs prenataux de l'etat nutritionnel ou de la depression et le comportement ou les fonctions cognitives chez l'enfant. Nous avons aussi discute des interventions et des modes d'action. Pendant la grossesse, la malnutrition et la depression sont toutes deux associees avec une augmentation de l'exteriorisation des problemes comportementaux et de deficit de l'attention, et jusqu'a un certain point avec de moins bonnes fonctions cognitives chez l'enfant, mais les donnees observees ne sont pas concluantes. Les etudes portant sur les effets synergiques des deux facteurs sur le comportement et les fonctions cognitives de l'enfant sont toujours peu nombreuses, et plus de recherches sont necessaires. Parmi les modes d'action pouvant etre communs, on compte l'axe hypothalamohypophyso-surrenalien, le systeme immunitaire et le stress oxydatif. [Traduit par la Redaction] Mots-cles : programmation prenatale, malnutrition, depression, grossesse, fonctions cognitives, comportement, modes d'action., Introduction The fetal brain is plastic--it is able to adapt to its environment. This neurodevelopmental plasticity allows for learning and shaping of the brain, and acts by adjusting physiological processes [...]

Background: Undernutrition during critical periods of neurodevelopment can hinder the developing brain with lasting negative consequences for brain size, structure and function. In this study, we describe self-perceived cognitive problems of men and women who were born around the time of the Dutch famine of 1944–45. Methods: We compared self-perceived cognitive problems between men and women who had been exposed to the 1944–45 Dutch famine in late, mid or early gestation and those who were born before or conceived after the famine (and had thus not been exposed prenatally). We included 595 participants aged 71–74 years. Results: Women who had been exposed to famine in late gestation more often reported cognitive problems compared to those who had not been exposed (OR 2.2 [95% CI 1.1–4.4]), whereas for men, this was the case for those exposed in early gestation (OR 2.3 [0.9–5.5]). Furthermore, men and women exposed in early gestation more often reported consulting a healthcare practitioner for cognitive problems in the past 12 months (OR 3.2 [1.3–8.1]). Especially men exposed in early gestation reported having consulted a healthcare practitioner more often than unexposed men (OR 4.4 [1.2–16.0]). Conclusions: These findings suggest that prenatal undernutrition does not only have lasting effects on brain size, but also on its function, with more self-perceived cognitive problems at older age, which also require more medical attention. Also, the effects of undernutrition depend on sex and its timing during gestation. [ABSTRACT FROM AUTHOR]

Purpose of Article: In a previous pilot randomized controlled trial including 54 pregnant women with depression, maternal mood improved after Cognitive Behavioural Therapy (CBT) compared to treatment as usual (TAU), showing medium to large effect sizes. The effect persisted up to 9 months postpartum, with infant outcomes also showing medium to large effects favoring CBT in various child domains. This perspective article summarizes the results of a follow-up that was performed approximately 5 years later in the same cohort, assessing the effects of antenatal Cognitive Behavioural Therapy for depression and anxiety on child buccal cell DNA-methylation, brain morphology, behavior and cognition. Findings: Children from the CBT group had overall lower DNA-methylation compared to children from the TAU group. Mean DNA-methylation of all NR3C1 promoter-associated probes did not differ significantly between the CBT and TAU groups. Children from the CBT group had a thicker right lateral occipital cortex and lingual gyrus. In the CBT group, Voxel-Based-Morphometry analysis identified one cluster showing increased gray matter concentration in the right medial temporal lobe, and fixel-based analysis revealed reduced fiber-bundle-cross-section in the Fornix, the Optical Tract, and the Stria Terminalis. No differences were observed in full-scale IQ or Total Problems Score. When the total of hypotheses tests in this study was considered, differences in DNA-methylation and brain measurements were no longer significant. Summary: Our explorative findings suggest that antenatal depression treatment decreases overall child DNA-methylation, increases cortical thickness, and decreases white matter fiber-bundle cross-section in regions involved in cognitive function and the stress response. Nevertheless, larger studies are warranted to confirm our preliminary conclusion that CBT in pregnancy alters neurobiological outcomes in children. Clinical relevance remains unclear as we found no effects of antenatal CBT on child behavior or cognition (yet). [ABSTRACT FROM AUTHOR]

Objective: Early life stress has been shown to influence the developing autonomic nervous system. Stressors in infancy may program the autonomic nervous system resting state set point, affecting cardiovascular function in later life. Excessive crying may be an indicator of increased stress arousal in infancy. We hypothesized that excessive infant crying is related to altered cardiac autonomic nervous system activity and increased blood pressure at age 5–6 years. Methods: In the Amsterdam Born Children and their Development study, excessive crying, maternal burden of infant care and maternal aggressive behavior in the 13th week after birth (range 11–16 weeks) were reported using questionnaires. Blood pressure, heart rate, heart rate variability and indicators of cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia) were measured at age 5–6 years during rest. Inclusion criteria were singleton birth, term-born, and no reported congenital or cardiovascular problems (N = 2153 included). Results: Excessive crying (2.8%) was not associated with resting heart rate, heart rate variability, pre-ejection period, respiratory sinus arrhythmia nor with blood pressure at age 5–6 years. Conclusions: Excessive infant crying as an indicator of increased stress arousal does not seem to be related to resting activity of the autonomic nervous system or blood pressure at age 5–6. Potential associations may become visible under stressed conditions. [ABSTRACT FROM AUTHOR]

Background: Energy restriction in prenatal life has detrimental effects on later life health and longevity. Studies in rats have shown that the shortening of telomeres in key tissues plays an important role in this association. Objective: The aim of the current study was to investigate leukocyte telomere length in relation to prenatal famine exposure. Design: The Dutch famine birth cohort consists of 2414 term singleton men and women who were born between 1943 and 1947 in Amsterdam around the time of the famine. At a mean age of 68 y, telomere length and the percentage of short telomeres was assessed in a subsample of 131 cohort members, of whom 45 were born before the famine (control), 41 were exposed to famine during early gestation, and 45 were conceived after the famine (control). Median telomere length was determined in peripheral blood leukocytes by a high-throughput quantitative fluorescent in situ hybridization-based technology. Results: Leukocyte telomere length and the percentage of short telomeres did not differ between those exposed to famine during early gestation and those unexposed during gestation. A lower socioeconomic status at birth, frequent consumption of alcohol (specifically consumption of spirits), a history of cancer, and a lower self-reported health status were significantly associated with shorter leukocyte telomere length (all P ≤ 0.03). Currently having a job was significantly associated with a smaller percentage of short telomeres (P = 0.04). Conclusion: The results of the current study suggest that prenatal exposure to famine is not associated with the shortening of telomeres in peripheral blood leukocytes at age 68 y. [ABSTRACT FROM AUTHOR]

Summary: Experimental studies in animals show that prenatal undernutrition leads to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Some studies have shown associations between low birth weight and an increased HPA response to psychological stress. We tested the hypothesis that prenatal exposure to the Dutch 1944–1945 famine leads to an elevated HPA response to psychological stress in adult life. We measured salivary cortisol responses to a psychological stress protocol among 694 adults who were born as term singletons in Amsterdam, the Netherlands, around the time of the 1944–1945 Dutch famine. We compared cortisol profiles of participants exposed to famine during late , mid , or early gestation to profiles of participants unexposed to famine during gestation . The mean increase in cortisol concentrations from baseline was 30% (95% CI 23–37). There were no statistically significant differences in the mean profile of cortisol response to the psychological stress protocol between participants exposed and unexposed to famine in utero. The mean sex and BMI adjusted difference in cortisol response for those exposed compared to those unexposed was −6% (95% CI: −15 to 2). The cortisol profiles of those exposed in late (−4% [95% CI: −16 to 7]), mid (−9% [95% CI: −22 to 3]) or early gestation (−4% [95% CI: −20 to 10]) did not differ from the profile of those unexposed to famine. We conclude that prenatal exposure to famine does not seem to be associated with the response of the HPA axis to psychological stress. However, the stress protocol we have used may have been unsuccessful in inducing a strong enough HPA axis activation to be able to detect famine related differences. [Copyright &y& Elsevier]

Background: Limited evidence suggests that maternal undernutrition at the time of conception is associated with increased cardiovascular disease risk in adult offspring. Objective: We investigated whether persons conceived during the Dutch famine of World War II had an early onset of coronary artery disease (CAD). Design: We compared the age at onset and cumulative incidence of CAD between persons born as term singletons who were exposed to the 1944-1945 Dutch famine during late (n=160), mid- (n=138), or early (n = 87) gestation and 590 unexposed subjects at age 50 or 58 y. Age at CAD onset was defined as the age at which angina pectoris was identified (according to the Rose questionnaire), Q waves were observed on an electrocardiogram (Minnesota codes 1-1 or 1-2), or coronary revascularization was performed (by angioplasty or bypass surgery). Results: Of the 83 CAD cases identified, persons conceived during the famine were 3 y younger than the unexposed persons at the time of CAD diagnosis (47 y compared with 50 y) and had a higher cumulative incidence of CAD [13%; hazard ratio (HR) adjusted for sex: 1.9; 95% CI: 1.0, 3.8] than did the unexposed persons. The HR changed little after adjustment for smoking (HR: 1.8), social class (HR: 2.0), or size at birth (HR: 2.0). Conclusions: We found an earlier onset of CAD among persons conceived during the famine, which suggests that maternal nutrition in early gestation may play a role in the onset of CAD. This finding agrees with evidence from animal experiments that identify periconceptional maternal diet as important in the offspring's adult health. [ABSTRACT FROM AUTHOR]

Worldwide, childhood obesity is rapidly increasing, making it a pressing public health issue. Obesity is strongly linked to eating behaviour and energy intake but little is known about their prenatal determinants. In an exploratory study of data collected within the Amsterdam Born Children and their Development (ABCD) study, we hypothesized that intra-uterine exposure to increased lipids is associated with adverse eating behaviour and increased energy intake in the offspring at age 5. During early gestation, a non-fasting blood sample was taken from 1463 non-diabetic Dutch women, including: total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), Apolipoprotein A1 (ApoA1) and Apolipoprotein B (ApoB). Eating behaviour, measured using the Children’s Eating Behaviour Questionnaire, included food approaching (enjoyment of food, food responsiveness) and food avoidant behaviour (satiety responsiveness, slowness of eating). Energy intake (total energy, fat and carbohydrate intake) was measured using a validated food frequency questionnaire. Associations were analysed using multivariable linear regression. Increased maternal TC concentrations were associated with lower enjoyment of food, higher satiety responsiveness and increased slowness of eating, as well as decreased kcal and fat intake in the offspring. Elevated ApoA1 was associated with increased slowness of eating, lower enjoyment of food and lower kcal, fat and carbohydrate intake. ApoB was positively associated with satiety responsiveness and slowness of eating. Higher TG concentrations were associated with higher food responsiveness. Maternal FFA did not show significant associations. Findings demonstrated that the maternal prenatal lipid profile was associated with offspring’s eating behaviour and energy intake, although not always in the hypothesized direction. [ABSTRACT FROM AUTHOR]

• Maternal stress, anxiety and depression change offspring structural brain development. • Maternal nutrient restriction and micronutrient deficiencies affect offspring brain structure. • Prenatal stress affects mainly the amygdala, malnutrition affects total brain volume. • Structural changes associate with cognitive, behavioral and mental health problems. • Routine MRI-based markers may have the potential to predict cognitive and behavioral problems. Cognitive and mental health are major determinants of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to genetic factors and lifestyle, prenatal environmental influences may program neuropsychiatric disorders in later life. While several human studies have examined the effects of prenatal stress and nutrient restriction on brain function and mental health in later life, potentially mediating effects of prenatal stress and nutrient restriction on offspring neuroanatomy in humans have been studied only in recent years. Based on neuroimaging and anatomical data, we comprehensively review the studies in this emerging field. We relate prenatal environmental influences to neuroanatomical abnormalities in the offspring, measured in utero and throughout life. We also assess the relationship between neuroanatomical abnormalities and cognitive and mental disorders. Timing- and gender-specific effects are considered, if reported. Our review provides evidence for adverse effects of an unfavorable prenatal environment on structural brain development that may contribute to the risk for cognitive, behavioral and mental health problems throughout life. [ABSTRACT FROM AUTHOR]

The prevalence of obesity among women of childbearing age has been rising dramatically over the last decades. Pre-pregnancy obesity may have negative neurodevelopmental consequences for the offspring. The present study examined the association of maternal pre-pregnancy overweight and obesity with child behavior problems and executive functioning at age 5 years. Data of 4094 mother-child pairs of the Amsterdam Born Children and their Development birth cohort study was used. Child behavioral problems were assessed with the maternal and teacher version of the Strengths and Difficulties Questionnaire. Two executive functioning constructs, inhibitory control and cognitive flexibility, were measured with the Response Organization Objects task of the Amsterdam Neuropsychological Tasks test battery. Increased maternal pre-pregnancy BMI was associated with an increase in children's behavioral problems (OR total behavioral problems reported by mothers pre-pregnancy obesity versus normal weight: 1.78 [95% CI 1.17 to 2.69] and reported by teachers for pre-pregnancy overweight versus normal weight: 1.32 [1.00 to 1.74]). Maternal pre-pregnancy obesity was associated with an increase in peer relationship problems reported by teachers (OR: 1.77 [1.18 to 2.64]). It was also associated with a small decrease in cognitive flexibility (increased Reaction Time in ms: B  = 67.59 [5.88 to 129.30] and Within Subject Standard Deviation in ms: B  = 76.46 [32.00 to 120.92]), but not with inhibitory control. Cognitive flexibility did not mediate the association between maternal pre-pregnancy BMI and children's behavioral problems. [ABSTRACT FROM AUTHOR]

• Prenatal depression negatively affects offspring behavior. • Altered development of fetal stress systems has been proposed as underlying mechanism. • Stress reactivity reflects adaptive responding above resting function of stress systems. • Evidence of an association between prenatal depression and stress reactivity is limited. • Postnatal depression, caregiving behavior and partner support act as moderators. Depression is a common condition affecting up to 20% of all pregnant women, and is associated with subsequent developmental and behavioral problems in children, such as conduct disorder and ADHD. One proposed mechanism underlying these associations is modification of the fetal hypothalamic pituitary adrenal (HPA)-axis and the autonomic nervous system (ANS), resulting in altered responses to stress. This review examined the evidence regarding altered HPA-axis and ANS reactivity in children prenatally exposed to high maternal depressive symptoms. A systematic search was conducted in the electronic databases MEDLINE, EMBASE and PsycINFO, for studies published till 25 July 2017. A total of 13 studies comprising 2271 mother-infant dyads were included. None of the studies were suitable for meta-analysis. Risk of bias assessment showed low risk for four studies. Only three studies described an independent association between exposure to high maternal prenatal depressive symptoms and altered stress reactivity in children. There is limited evidence of an independent association between prenatal exposure to maternal depression and altered HPA or ANS reactivity in children. [ABSTRACT FROM AUTHOR]