Sex-dependence and comorbidities of the early-life adversity induced mental and metabolic disease risks: Where are we at?

Early-life adversity (ELA) is a major risk factor for developing later-life mental and metabolic disorders. However, if and to what extent ELA contributes to the comorbidity and sex-dependent prevalence/presentation of these disorders remains unclear. We here comprehensively review and integrate human and rodent ELA (pre- and postnatal) studies examining mental or metabolic health in both sexes and discuss the role of the placenta and maternal milk, key in transferring maternal effects to the offspring. We conclude that ELA impacts mental and metabolic health with sex-specific presentations that depend on timing of exposure, and that human and rodent studies largely converge in their findings. ELA is more often reported to impact cognitive and externalizing domains in males, internalizing behaviors in both sexes and concerning the metabolic dimension, adiposity in females and insulin sensitivity in males. Thus, ELA seems to be involved in the origin of the comorbidity and sex-specific prevalence/presentation of some of the most common disorders in our society. Therefore, ELA-induced disease states deserve specific preventive and intervention strategies.

Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944-45: The Dutch famine Birth Cohort.

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944-45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.

Cohort profile: the Dutch famine birth cohort (DFBC)- a prospective birth cohort study in the Netherlands.

PURPOSE: The Dutch famine birth cohort study was set up to investigate the effects of acute maternal undernutrition of the 1944-1945 Dutch famine during the specific stages of gestation on later health, with a particular focus on chronic cardiovascular and metabolic diseases, ageing and mental health. PARTICIPANTS: The Dutch famine birth cohort consists of 2414 singletons born alive and at term in the Wilhelmina Gasthuis in Amsterdam around the time of the Dutch famine (1943-1947) whose birth records have been kept. The cohort has been traced and studied since 1994, when the first data collection started. The cohort has been interviewed and physically examined in several waves of data collection since that time, allowing repeated measures of a wide range of phenotypic information as well as the collection of biological samples (blood, urine, buccal swabs), functional testing (of heart, lungs, kidney, HPA axis) and imaging of the brain (MRI) and vasculature (ultrasound). Additionally, genetic and epigenetic information was collected. Through linkage with registries, mortality and morbidity information of the entire cohort has been obtained. FINDINGS TO DATE: Prenatal famine exposure had lasting consequences for health in later life. The effects of famine depended on its timing during the gestation and the organs and tissues developing at that time, with most effects after exposure to famine in early gestation. The effects of famine were widespread and affected the structure and function of many organs and tissues, resulted in altered behaviour and increased risks of chronic degenerative diseases and increased mortality. The effects of famine were independent of size at birth, which suggests that programming may occur without altering size at birth. FUTURE PLANS: As the cohort ages, we will be assessing the effects of prenatal undernutrition on (brain) ageing, cognitive decline and dementia, as well as overall morbidity and mortality. REGISTRATION: The Dutch famine birth cohort is not linked to a clinical trial.

Cognitive Behavioral Therapy for Antenatal Depression in a Pilot Randomized Controlled Trial and Effects on Neurobiological, Behavioral and Cognitive Outcomes in Offspring 3-7 Years Postpartum: A Perspective Article on Study Findings, Limitations and Future Aims.

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).

Hypothalamic-pituitary-adrenal axis and autonomic nervous system reactivity in children prenatally exposed to maternal depression: A systematic review of prospective studies.

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.

Prenatal Psychological Stress Exposure and Neurodevelopment and Health of Children.

Depression and anxiety are highly prevalent in pregnancy, with an estimated prevalence of 12% for depression [...].

Programming Effects of Prenatal Stress on Neurodevelopment-The Pitfall of Introducing a Self-Fulfilling Prophecy.

There is increasing interest for the potential harmful effects of prenatal stress on the developing fetal brain, both in scientific literature and in public press. Results from animal studies suggest that gestational stress leads to an altered offspring neurodevelopment with adverse behavioral and cognitive consequences. Furthermore, there are indications in human studies that severe prenatal stress has negative consequences for the child's neurodevelopment. However, stress is an umbrella term and studies of maternal stress have focused on a wide range of stress inducing situations, ranging from daily hassles to traumatic stress after bereavement or a natural disaster. Mild to moderate stress, experienced by many women during their pregnancy, has not consistently been shown to exert substantial negative effects on the child's neurodevelopment. Additionally, the vast majority of human studies are observational cohort studies that are hampered by their fundamental inability to show a causal relationship. Furthermore, our limited knowledge on the possible underlying mechanisms and the effects of interventions for prenatal stress on child neurodevelopmental outcomes emphasize our incomplete understanding of the actual effects of prenatal stress on child neurodevelopment. Until we have a better understanding, it seems counterproductive to alarm all pregnant women for possible harmful effects of all sorts of prenatal stress, if only to avoid the induction of stress itself.

Brain Magnetic Resonance Imaging Findings in Children after Antenatal Maternal Depression Treatment, a Longitudinal Study Built on a Pilot Randomized Controlled Trial.

Antenatal depression is associated with an increased risk of offspring neuro-developmental disorders, potentially as a consequence of an altered brain development in utero. We hypothesized that reducing maternal depression by Cognitive Behavioral Therapy (CBT) during pregnancy may ameliorate the offspring's brain (micro)structural outcomes. 54 pregnant women with a diagnosed clinical depression were randomly allocated to CBT or Treatment as Usual (TAU), showing moderate to large depression symptom improvements after CBT. In 16 of their children (69% boys, N(TAU) = 8, N(CBT) = 8, mean age = 5.9 years, range = 3.9-7.1 years) brain Magnetic Resonance Imaging (MRI) scans were conducted. Children from the CBT group had a thicker right lateral occipital cortex (difference: 0.13 mm, 95% CI = 0.005-0.26) and lingual gyrus (difference: 0.18 mm, 95% CI = 0.01-0.34). In the CBT group, Voxel-Based Morphometry analysis identified one cluster showing increased gray matter concentration in the right medial temporal lobe at p < 0.05 uncorrected, and fixel-based analysis revealed reduced fiber-bundle cross-section in the Fornix, the Optical Tract, and the Stria Terminalis at p < 0.01 uncorrected. However, none of the results survived correction for multiple testing. Our explorative analyses provided some indication that antenatal CBT for depression may ameliorate offspring's brain (micro)structural outcomes, but the sample size was extremely small, and our results should be cautiously interpreted. Larger studies are warranted to confirm our preliminary conclusions that CBT for antenatal depression affects brain development in children.

A 7-year follow-up of antenatal depression treatment with cognitive behavioral therapy: A case report of maternal and child outcomes.

There are few studies of cognitive behavioral therapy for women with antenatal depression including qualitative and quantitative data, and yet, individual cases can provide valuable information on personal experiences of treatment effectiveness and acceptability. The purpose of this case report is to explore the long-term qualitative outcomes following cognitive behavioral therapy for antenatal depression. A pregnant woman with a Diagnostic and Statistical Manual of Mental Disorders diagnosis of depression was allocated to receive seven sessions of cognitive behavioral therapy in a randomized controlled trial. We describe her experiences and mood during treatment, at 12 weeks, 9 months, 2 years, and 7 years postpartum, as well as markers of her child's development. The woman's mood symptoms were dramatically improved after treatment and remained in the mild to moderate range until 7 years postpartum. Her child showed overall age-appropriate development, with strengths highlighted in his nonverbal and problem-solving ability. Relative weaknesses were in the communication domain and his processing speed. This case report suggests that psychological treatment for depression during pregnancy can be both acceptable to women and potentially protective in the long term.

Exploring the effect of antenatal depression treatment on children's epigenetic profiles: findings from a pilot randomized controlled trial.

BACKGROUND: Children prenatally exposed to maternal depression more often show behavioral and emotional problems compared to unexposed children, possibly through epigenetic alterations. Current evidence is largely based on animal and observational human studies. Therefore, evidence from experimental human studies is needed. In this follow-up of a small randomized controlled trial (RCT), DNA-methylation was compared between children of women who had received cognitive behavioral therapy (CBT) for antenatal depression and children of women who had received treatment as usual (TAU). Originally, 54 women were allocated to CBT or TAU. A beneficial treatment effect was found on women's mood symptoms. FINDINGS: We describe DNA methylation findings in buccal swab DNA of the 3-7-year-old children (CBT(N) = 12, TAU(N) = 11), at a genome-wide level at 770,668 CpG sites and at 729 CpG sites spanning 16 a priori selected candidate genes, including the glucocorticoid receptor (NR3C1). We additionally explored associations with women's baseline depression and anxiety symptoms and offspring DNA methylation, regardless of treatment. Children from the CBT group had overall lower DNA methylation compared to children from the TAU group (mean Ƨ = - 0.028, 95% CI - 0.035 to - 0.022). Although 68% of the promoter-associated NR3C1 probes were less methylated in the CBT group, with cg26464411 as top most differentially methylated CpG site (p = 0.038), mean DNA methylation of all NR3C1 promoter-associated probes did not differ significantly between the CBT and TAU groups (mean Ƨ = 0.002, 95%CI - 0.010 to 0.011). None of the effects survived correction for multiple testing. There were no differences in mean DNA methylation between the children born to women with more severe depression or anxiety compared to children born to women with mild symptoms of depression or anxiety at baseline (mean Ƨ (depression) = 0.0008, 95% CI - 0.007 to 0.008; mean Ƨ (anxiety) = 0.0002, 95% CI - 0.004 to 0.005). CONCLUSION: We found preliminary evidence of a possible effect of CBT during pregnancy on widespread methylation in children's genomes and a trend toward lower methylation of a CpG site previously shown by others to be linked to depression and child maltreatment. However, none of the effects survived correction for multiple testing and larger studies are warranted. TRIAL REGISTRATION: Trial registration of the original RCT: ACTRN12607000397415 . Registered on 2 August 2007.

Malnutrition and depression in pregnancy and associations with child behaviour and cognitive function: a review of recent evidence on unique and joint effects 1.

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.

Determinants of cortisol during pregnancy - The ABCD cohort.

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.

Prenatal Undernutrition and Physical Function and Frailty at the Age of 68 Years: The Dutch Famine Birth Cohort Study.

BACKGROUND: There is evidence suggesting that the aging process has its origins in utero. We have previously shown that prenatal exposure to the Dutch famine is associated with chronic noncommunicable diseases and poorer cognitive function in men and women and increased mortality in women. We investigated whether prenatal undernutrition during early gestation is associated with decreased physical function in later life. METHODS: Between November 2012 and September 2013, we have studied a random subsample of 150 members of the Dutch famine birth cohort at the age of 68 years, of which 49 were exposed to prenatal undernutrition. In this observational study, we measured indicators of physical function including grip strength and the short physical performance battery. We composed categories of frailty, according to the Fried frailty scale. We also assessed self-reported activity and self-perceived health. RESULTS: Men, but not women, exposed to prenatal undernutrition had significantly lower grip strength (B = -4.2kg; 95% confidence interval: -8.2 to -0.3) and a lower physical performance score (B = -0.8 points; 95% confidence interval: -1.5 to 0.0) than unexposed men, independent of relevant confounders. There were no differences in frailty, self-reported activity, or self-perceived health between exposed and unexposed groups. CONCLUSIONS: Our study results suggest that prenatal undernutrition is associated with decreased physical function in later life in men, but not in women. Our findings provide further evidence for the hypothesis that prenatal undernutrition may lead to an accelerated aging process in humans. We currently do not have sufficient power to detect effects on frailty.