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No associations of prenatal maternal psychosocial stress with fasting glucose metabolism in offspring at 5–6 years of age
Abstract
Highly prevalent maternal psychosocial complaints are accompanied by increases in glucocorticoid stress hormones, which may predispose the offspring for type 2 diabetes and cardiovascular disease later in adulthood. The aim of the current research is to study whether prenatal maternal psychosocial stress is associated with parameters of blood glucose metabolism in their children aged 5-6 years. The study design was a prospective birth cohort (the Amsterdam Born Children and their Development study, the Netherlands). Depressive symptoms, pregnancy-related anxiety, parenting daily hassles and job strain were recorded by questionnaire (gestational week 16). A cumulative score was also calculated. Possible sex differences in the associations were considered. The subjects were 1952 mother-child pairs. Outcome measures were fasting glucose (n=1952), C-peptide and insulin resistance (HOMA2-IR) (n=1478) in the children at the age of 5-6 years. The stress scales, single and cumulative, were not associated with glucose/C-peptide/insulin resistance (all P>0.05). We did not find evidence for sex differences. In conclusion, we did not find evidence for an association between psychosocial stress during early pregnancy and parameters of glucose metabolism in offspring at the age of 5-6 years. Differences emerging later in life or in response to a metabolic challenge should not be ruled out.
... One distinct psychological stressor is a severe life event (SLE) such as a bereavement, serious family illness, family conflict, and socio-economic problems [12]. Early SLEs have been linked to an increased risk of T1D and islet autoimmunity [10,[13][14][15], although data are conflicting [13][14][15], with very young individuals apparently more vulnerable to the immunomodulatory effects of SLEs than older children and adults [16]. A growing body of evidence proposes that the ability of the individual to cope with stress and adversity may also be affected by factors that can be estimated using quality of life or sense of coherence measures [17,18]. ...
... One distinct psychological stressor is a severe life event (SLE) such as a bereavement, serious family illness, family conflict, and socio-economic problems [12]. Early SLEs have been linked to an increased risk of T1D and islet autoimmunity [10,[13][14][15], although data are conflicting [13][14][15], with very young individuals apparently more vulnerable to the immunomodulatory effects of SLEs than older children and adults [16]. A growing body of evidence proposes that the ability of the individual to cope with stress and adversity may also be affected by factors that can be estimated using quality of life or sense of coherence measures [17,18]. ...
... Prenatal stress has been shown to increase T1D risk [32], but these results are disputed [14]. The impact of stress and SLEs on T1D risk has been more thoroughly studied [13,15,33]. ...
Aims Stress and severe life events (SLEs) modify autoimmune disease susceptibility. Here, we aimed to establish if SLEs reported by parents during the first 2 years of life influence the risk of developing type 1 diabetes (T1D) using data from the prospective Diabetes Prediction in Skåne (DiPiS) study.
Methods Prospective questionnaire data recorded at 2 months (n = 23,187) and 2 years of age (n = 3784) from the DiPiS cohort of children were included in the analysis. SLEs were analyzed both by groups and as a combined variable. A Cox proportional hazards model was used to calculate hazard ratios (HRs) for T1D diagnosis for the total cohort and for the HLA-DQ2/8 high-risk population. Affected first-degree relatives, HLA-DQ risk group, paternal education level, and parents’ country of birth were included as covariates.
Results There was a significantly increased risk of T1D in children with SLEs occurring during the child’s first 2 years of life for both the total cohort (HR 1.67; 95% CI 1.1, 2.7; p = 0.03) and the DQ2/8 cohort (HR 2.2; 95% CI 1.1, 4.2; p = 0.018). Subgroup analysis of events related to unemployment, divorce, or family conflict showed a significant hazard for these events occurring both during and after pregnancy in the DQ2/8 cohort (HR 2.17; 95% CI 1.1, 4.3; p = 0.03 and HR 4.98; 95% CI 2.3, 11; p < 0.001, respectively) and after pregnancy in the total cohort (multiple regression HR 2.07; 95% CI 1.01, 4.2; p = 0.047). Conclusions Children of parents experiencing an SLE during the child’s first 2 years of life were at increased risk of T1D. Further studies including those measuring immune and stress-related biomarkers are necessary to validate the findings.
... However, two human studies on measures of glucose metabolism and insulin sensitivity after ELA exposure showed no sex differences. In a large study with 1478 participants, prenatal psychosocial stress exposure did not correlate to fasting glucose and insulin resistance (HOMA-IR; measure for insulin resistance based on circulating glucose and insulin levels) in 5-6-year-old children (Van Dijk et al., 2014). A small study (32 participants) reported a positive association between prenatal stress due to an ice storm with insulin secretion at 13 years of age in both boys and girls (Dancause et al., 2013). ...
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.
... Table SI 11.3 shows data collected on the relationship between PS and offspring's glucose metabolism. Four studies on offspring's glucose and PS were identified in our review and all of them found no association between glucose and PS (negative life events, job strain and exposure to earthquake) [40,46,53,54]. We found only one study reporting on PS and insulin without significant assoaciations [40]. ...
Background:
Metabolic Syndrome (MetS) can be considered as a consequence of a complex interplay between genetic and environmental factors and can be influenced by changes in the environment early in life. Prenatal stress (PS) exposure likely represents an important adverse intrauterine environment that may impact the biology of the developing organism. The aim of this study was to quantitatively synthesize the available data on the effects of PS on offspring's obesity, estimated indirectly by body mass index (BMI) and body fat; blood pressure, plasma glucose and blood lipid concentrations (triglycerides and high-density lipoprotein cholesterol).
Methods:
Literature searches for eligible studies on PubMed were conducted until October 8, 2018. Full text review yielded 24 publications for inclusion into the systematic review. Meta-analyses were performed for the outcomes BMI and body fat. 62 effect sizes from 19 studies together with relevant moderators were collected. Summary estimates were calculated by using random-effects model.
Results:
The combined standardized mean difference (d) for the relation between BMI and PS indicated that despite significant heterogeneity, stress exposure of expectant mothers was associated with increased BMI of their offspring [d (95% CI) = 0.268 (0.191; 0.345)]. Both objective and subjective stress have been linked to increased overweight. Preliminary results of the relationship between PS and body fat suggested that the contribution of PS to body fat should be at least further considered [d (95% CI) = 0.167 (0.016; 0.317)]. Evidence from a limited number of published studies do not sustains an effect on blood pressure, glucose metabolism or circulating lipids, however these outcomes have only been scarcely investigated.
Conclusions:
A direct association between PS and BMI was found and further studies are needed to confirm the relationship between maternal stress during gestation and body fat. Overall, findings suggest that PS could contribute to alterations to the post-natal offspring phenotype.
... 67,68 On the contrary, in 5-6-year-old children, no association of prenatal stress and glucose, C-peptide or insulin resistance were found potentially because the relation was examined early in life. 69 Further, young adults exposed to maternal prenatal stress had higher very low-density lipoprotein and lower high-density lipoproteins, suggesting differences in fat storage processes. 67 To our knowledge, no studies on the asso- ciation between prenatal stress and lipid profile in childhood have been performed. ...
Maternal psychological distress is common in pregnancy and may influence the risk of adverse outcomes in children. Psychological distress may cause a suboptimal intrauterine environment leading to growth and developmental adaptations of the fetus and child. In this narrative review, we examined the influence of maternal psychological distress during pregnancy on fetal outcomes and child cardiometabolic, respiratory, atopic and neurodevelopment-related health outcomes. We discussed these findings from an epidemiological and life course perspective and provided recommendations for future studies. The literature in the field of maternal psychological distress and child health outcomes is extensive and shows that exposure to stress during pregnancy is associated with multiple adverse child health outcomes. Because maternal psychological distress is an important and potential modifiable factor during pregnancy, it should be a target for prevention strategies in order to optimize fetal and child health. Future studies should use innovative designs and strategies in order to address the issue of causality.
... PS, often defined as maternal prenatal psychological symptoms of depression or anxiety or perceived stress related to major life events or daily hassles, [7][8][9] can be considered as one of the first ELS phenomena directly affecting offspring development and also rendering the child more vulnerable to the effects of postnatal exposures. [10][11][12][13] However, existing data on the offspring effects of ELS, and especially PS, remain inconclusive, 8,10,12,14,15 partially owing to the large variation in both PS/ELS and offspring phenotype measures and subsequent differences in biological pathways underlying the associations. Additionally, timing and duration of the stress exposure matter, so attempts to disentangle these complex pathways in prospective studies are important. ...
... However, evidence demonstrating metabolic pathway responses to early-life exposures is quite limited. Early-life social adversity has been inconsistently associated with metabolic markers of lipid and glucose metabolism (Entringer et al., 2008;Slopen et al., 2013;van Dijk et al., 2014). Stress and the social environment trigger epigenetic changes (Gudsnuk et al., 2012), while changes in DNA methylation associated with unfavorable environmental exposures may alter metabolic pathways involved in the etiology of chronic diseases, such as obesity (Dick et al., 2014). ...
Introduction:
An unfavorable psychosocial environment has been associated with an increased prevalence of obesity among children. However, the available evidence on the association of low socioeconomic status and parent-child relationships with childhood obesity is scarce. The aim of our study was to conduct a simultaneous evaluation of the risks associated with pathological mother-child relationships, education level, and overweight/obesity among 4-6 year-old children.
Methods:
This cross-sectional study included 1489 mother-child pairs living in Kaunas city, Lithuania. The Parenting Stress Index was measured using the Parent-Child Dysfunctional Interaction subscale. Children's overweight/obesity was defined as the body mass index ≥18kg/m(2). Logistic regression models as well as crude and adjusted odds ratios (OR) and their 95% confidence intervals (CI) were used to indicate the strength of the associations between childhood overweight/obesity, maternal education level, and psychosocial stress.
Results:
The percentage of children with overweight/obesity rose with an increasing Parenting Stress Index score. The percentage of children with overweight/obesity in the group of parents with better education and normal mother-child relations was 6.0%, while in the group of less educated parents and pathological mother-child relations, this percentage reached 13.9%. The stratified multivariable model showed that, with reference to the group of better educated parents and normal mother-child relations, lower education level and pathological mother-child relations were statistically significant risk factors for overweight/obesity in 4-6 year-old children, increasing the OR of overweight/obesity (aOR: 2.43; 95% CI: 1.31-4.51). Pathological mother-child relations and maternal smoking mediated the effect of low maternal education level on children's BMI z-scores.
Conclusion:
Pathological mother-child relations, lower parental education levels, and smoking may be predictors of children's overweight/obesity. Measures oriented towards health behavior and psychosocial stress management should be encouraged among parents in order to decrease the risk of overweight/obesity in their children.
... In contrast, there have been studies demonstrating that stress during pregnancy has no effect on offspring disease outcomes. Specifically, a human study involving 1952 mother-child pairs found no associations between prenatal maternal psychosocial stress and glucose metabolism in children between 5 and 6 years of age (31). Similarly, in the rat, prenatal stress had no effect on basal plasma glucose or insulin concentrations in either sex at 3 months, although female offspring were hyperinsulinaemic following glucose administration (32). ...
Low birth weight increases adult metabolic disease risk in both the first (F1) and second (F2) generation. Physiological stress during pregnancy in F1 females that were born small induces F2 fetal growth restriction, but the long-term metabolic health of these F2 offspring is unknown. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed in F0 rats. F1 females (Control, Restricted) were allocated to Unstressed or Stressed pregnancies. F2 offspring exposed to maternal stress in utero had reduced birth weight. At 6 months, F2 Stressed males had elevated fasting glucose. In contrast, F2 Restricted males had reduced pancreatic β-cell mass. Interestingly, these metabolic deficits were not present at 12 month. F2 males had increased adrenal mRNA expression of Star (Steroidogenic acute regulatory protein) and Igf1r (Insulin-like growth factor 1 receptor) when their mothers were born small or exposed to stress during pregnancy. Stressed Control F2 males had increased expression of adrenal genes that regulate androgen signalling at 6 months, whilst expression increased in Restricted male and female offspring at 12 months. F2 females from Stressed mothers had lower area under the glucose curve during glucose tolerance testing at 12 months compared to Unstressed females but were otherwise unaffected. If F1 mothers were either born small or exposed to stress during her pregnancy, F2 offspring had impaired physiological outcomes in a sex- and age-specific manner. Importantly, stress during pregnancy did not exacerbate disease risk in F2 offspring of mothers born small, suggesting that they independently program disease in offspring through different mechanisms.
... Because C-peptide was below the detection limit of 0.34 nmol/L in 62% of the subjects, survival analysis was used to impute these values. This was completed in previous research on the ABCD cohort, where a more extensive description of the procedure can be found: in short, imputed C-peptide values were determined on the basis of child age, gender and BMI using a survival analysis method in the statistical package R [25,26] (R Foundation for Statistical Computing, Vienna, Austria). Insulin resistance (IR) was estimated with a homeostatic model assessment (HOMA2-IR) score calculated from the C-peptide and glucose concentrations [27]. ...
Both maternal 25-hydroxyvitamin D(25OHD) status and pre-pregnancy BMI(pBMI) may influence offspring cardio-metabolic outcomes. Lower 25OHD concentrations have been observed in women with both low and high pBMIs, but the combined influence of pBMI and 25OHD on offspring cardio-metabolic outcomes is unknown. Therefore, this study investigated the role of pBMI in the association between maternal 25OHD concentration and cardio-metabolic outcomes in 5-6 year old children. Data were obtained from the ABCD cohort study and 1882 mother-child pairs were included. The offspring outcomes investigated were systolic and diastolic blood pressure, heart rate, BMI, body fat percentage(%BF), waist-to-height ratio, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose, C-peptide, and insulin resistance(HOMA2-IR). 62% of the C-peptide samples were below the detection limit and were thus imputed using survival analysis. Models were corrected for maternal and offspring covariates and tested for interaction with pBMI. Interaction with pBMI was observed in the associations with insulin resistance markers: in offspring of overweight mothers(≥25.0kg/m2), a 10 nmol/L increase in maternal 25OHD was associated with a 0.007(99%CI:-0.01,-0.001) nmol/L decrease in C-peptide and a 0.02(99%CI:-0.03,-0.004) decrease in HOMA2-IR. When only non-imputed data were analyzed, there was a trend for interaction in the relationship but the results lost significance. Interaction with pBMI was not observed for the other outcomes. A 10 nmol/L increase in maternal 25OHD was significantly associated with a 0.13%(99%CI:-0.3,-0.003) decrease in %BF after correction for maternal and child covariates. Thus, intrauterine exposure to both low 25OHD and maternal overweight may be associated with increased insulin resistance in offspring, while exposure to low 25OHD in utero may be associated with increased offspring %BF with no interactive effects from pBMI. Due to the limitations of this study, these results are not conclusive, however the observations of this study pose important research questions for future studies to investigate.
Prenatal stress programs offspring cognitive and mental health outcome. We reviewed whether prenatal stress also programs cardiovascular dysfunction which potentially modulates cerebrovascular, cognitive and mental health disorders. We focused on maternal stress and prenatal glucocorticoid (GC) exposure which have different programming effects. While maternal stress induced cortisol is mostly inactivated by the placenta, synthetic GCs freely cross the placenta and have different receptor-binding characteristics. Maternal stress, particularly anxiety, but not GC exposure, has adverse effects on maternal-fetal circulation throughout pregnancy, probably by co-activation of the maternal sympathetic nervous system, and by raising fetal catecholamines. Both effects may impair neurodevelopment. Experimental data also suggest that severe maternal stress and GC exposure during early and mid-gestation may increase the risk for cardiovascular disorders. Human data are scarce and especially lacking for older age. Programming mechanisms include aberrations in cardiac and kidney development, and functional changes in the renin-angiotensin-aldosterone-system, stress axis and peripheral and coronary vasculature. Adequate experimental or human studies examining the consequences for cerebrovascular, cognitive and mental disorders are unavailable.
Background and aims:
Previous studies suggest that psychological distress during pregnancy may lead to fetal developmental adaptations, which programme cardio-metabolic disease of the offspring. We examined the associations of maternal overall psychological distress, depression and anxiety during pregnancy with cardio-metabolic risk factors in 10-year-old children and explore potential sex-specific differences.
Methods and results:
In a population-based prospective cohort study among 4,088 mothers and their children, information about overall psychological distress, including depression and anxiety was obtained through the Brief Symptom Inventory during pregnancy. We measured child blood pressure and heart rate and insulin, glucose, serum lipids and C-reactive protein blood concentrations at 10 years. Analyses were performed in the total group and in boys and girls separately. Psychological distress during pregnancy was associated with higher childhood heart rate among boys only (differences 0.34 (95% Confidence Interval (CI) 0.18, 0.50) standard deviation scores (SDS), 0.22 (95% CI 0.06, 0.38) SDS, 0.33 (95% CI 0.19, 0.48) SDS, for overall psychological distress, depression and anxiety, respectively). Maternal anxiety during pregnancy was associated with higher childhood triglycerides among girls (difference 0.35 (95% CI 0.17, 0.53) SDS). Maternal psychological distress was not associated with childhood blood pressure, cholesterol, insulin, glucose and C-reactive protein concentrations.
Conclusions:
Maternal psychological distress may influence their offspring heart rate and triglycerides concentrations. Further studies are needed to replicate these findings and assess the long-term cardio-metabolic consequences of maternal psychological distress.
Problem:
Incorporating biomarkers of chronic stress into pediatric research studies may help to explicate the links between exposure to adversity and lifelong health, but there are currently very few parameters to guide nurse researchers in choosing appropriate biomarkers of chronic stress for use in research with children and adolescents.
Methods:
Biomarkers of chronic stress are described, including primary mediators (glucocorticoids, catecholamines, and cytokines) and secondary outcomes (neurologic, immune, metabolic, cardiovascular, respiratory, and anthropometric) of the chronic stress response.
Results:
Evidence of the use of each biomarker in pediatric research studies is reviewed. Recommendations for pediatric researchers, including selection of appropriate biomarkers, measurement considerations, potential moderators, and future directions for research, are presented.
Discussion:
A wide range of biomarkers is available for use in research studies with children. While primary mediators of chronic stress have been frequently measured in studies of children, measurement of secondary outcomes, particularly immune and metabolic biomarkers, has been limited. With thoughtful and theoretically based approaches to selection and measurement, these biomarkers present an important opportunity to further explore the physiologic pathways linking exposure to chronic stress with later health and disease.
Conclusion:
The incorporation of chronic stress biomarkers into pediatric research studies may provide valuable insight into the mechanisms through which stressful environments "get under the skin" and ultimately inform efforts to promote health and reduce inequities among children exposed to adversity.
Prenatal maternal stress could have permanent effects on the offspring's tissue structure and function, which may predispose to cardiovascular diseases. We investigated whether maternal psychosocial stress is a prenatal factor affecting the blood pressure (BP) of offspring.
In the Amsterdam Born Children and their Development (ABCD) study, around gestational week 16, depressive symptoms, state-anxiety, pregnancy-related anxiety, parenting daily hassles and job strain were recorded by questionnaire. A cumulative stress score was also calculated (based on 80(th) percentiles). Systolic and diastolic BP and mean arterial pressure (MAP) were measured in the offspring at age 5-7 years. Inclusion criteria were: no use of antihypertensive medication during pregnancy; singleton birth; no reported cardiovascular problems in the child (N = 2968 included).
After adjustment for confounders, the single stress scales were not associated with systolic and diastolic BP, MAP and hypertension (p>0.05). The presence of 3-4 psychosocial stressors prenatally (4%) was associated with 1.5 mmHg higher systolic and diastolic BP (p = 0.046; p = 0.04) and 1.5 mmHg higher MAP in the offspring (p = 0.02) compared to no stressors (46%). The presence of 3-4 stressors did not significantly increase the risk for hypertension (OR 1.8; 95% CI 0.93.4). Associations did not differ between sexes. Bonferroni correction for multiple testing rendered all associations non-significant.
The presence of multiple psychosocial stressors during pregnancy was associated with higher systolic and diastolic BP and MAP in the child at age 5-7. Further investigation of maternal prenatal stress may be valuable for later life cardiovascular health.
Background
Socioeconomic inequalities in cardiovascular disease are pervasive, yet much remains to be understood about how they originate. The objective of this study was to explore the relations of socioeconomic status to lipid and glucose metabolism as indicators of cardiovascular health in 5–6 year olds. Additionally to explore the explanatory role of maternal factors, birth outcome, and child factors.
Methods
In 1308 5–6 year old ethnic Dutch children from the ABCD cohort study, lipids (cholesterol, LDL, HDL, triglycerides), glucose and C-peptide were measured after an overnight-fast.
Results
There were no differences in cholesterol, HDL, LDL, and triglycerides between socioeconomic groups, as indicated by maternal education and income adequacy. However, children of low educated mothers had on average a higher glucose (β = 0.15; 95% confidence interval (CI) 0.03 – 0.27), logC-peptide (β = 0.07; 95% CI 0.04 – 0.09), and calculated insulin resistance (HOMA-IR) (β = 0.15; 95% CI 0.08 – 0.22) compared to children of high educated mothers. Only childhood BMI partly explained these differences (models controlled for age, height, and sex).
Conclusions
The socioeconomic gradient in cardiovascular risk factors seems to emerge in early childhood. In absence of underlying mechanisms these empirical findings are relevant for public health care and further explanatory research.
Autonomic nervous system (ANS) misbalance is a potential causal factor in the development of cardiovascular disease. The ANS may be programmed during pregnancy due to various maternal factors. Our aim is to study maternal prenatal psychosocial stress as a potential disruptor of cardiac ANS balance in the child.
Mothers from a prospective birth cohort (ABCD study) filled out a questionnaire at gestational week 16 [IQR 12-20], that included validated instruments for state anxiety, depressive symptoms, pregnancy-related anxiety, parenting daily hassles and job strain. A cumulative stress score was also calculated (based on 80(th) percentiles). Indicators of cardiac ANS in the offspring at age 5-6 years are: pre-ejection period (PEP), heart rate (HR), respiratory sinus arrhythmia (RSA) and cardiac autonomic balance (CAB), measured with electrocardiography and impedance cardiography in resting supine and sitting positions.
2,624 mother-child pairs, only single births, were available for analysis. The stress scales were not significantly associated with HR, PEP, RSA and CAB (p≥0.17). Accumulation of maternal stress was also not associated with HR, PEP, RSA and CAB (p≥0.07).
Results did not support the hypothesis that prenatal maternal psychosocial stress deregulates cardiac ANS balance in the offspring, at least in rest, and at the age of five-six years.
Rapid early growth in infants may influence overweight and CVD in later life. Both rapid growth and these disease outcomes disproportionately affect some ethnic minorities. We determined ethnic differences in growth rate (Δ standard deviation scores, ΔSDS) during the first 6 months of life and assessed the explanatory role of infant feeding. Data were derived from a multiethnic cohort for the Amsterdam Born Children and their Development study (The Netherlands). Growth data (weight and length) of 2998 term-born singleton infants with no fetal growth restriction were available for five ethnic populations: Dutch (n 1619), African descent (n 174), Turkish (n 167), Moroccan (n 232) and other non-Dutch (n 806). ΔSDS for weight, length and weight-for-length between 4 weeks and 6 months were defined using internal references. Infant feeding pattern (breast-feeding duration, introduction of formula feeding and complementary feeding) in relation to ethnic differences in growth rate was examined by multivariate linear regression. Results showed that the growth rate was higher in almost all ethnic minorities, with β between 0·07 and 0·41 for ΔSDS weight and between 0·12 and 0·42 for ΔSDS length, compared with ethnic Dutch infants. ΔSDS weight-for-length was similar across groups, except for Moroccan infants (β 0·25, P < 0·05) after correction for confounders. In general, exclusive breast-feeding for 4 months was associated with slower growth for all three growth measures. Feeding factors explained, to a small degree, the higher weight and length gain in African descent infants, but not the higher ΔSDS weight-for-length in the Moroccan population. More research is needed to elucidate the underlying mechanisms of the high infant growth rate in Turkish and Moroccan infants.
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population-based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
We followed 65,212 children born in Denmark from 1970-1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08-2.61) at 12 years of age and 1.63 (95% CI 1.00-2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71-6.42 at age 12, and OR 2.31, 95% CI 1.08-4.97 at age 13).
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
The secondary sex ratio (i.e., the odds of a male birth) reportedly declines following natural disasters, pollution events, and economic collapse. It remains unclear whether this decline results from an excess of male fetal loss or reduced male conceptions. The literature also does not converge as to whether the terrorist attacks of September 11, 2001 induced "communal bereavement", or the widespread feeling of distress among persons who never met those directly involved in the attacks. We test the communal bereavement hypothesis among gravid women by examining whether male fetal deaths rose above expected levels in the US following September 11, 2001.
We apply interrupted time-series methods to all fetal deaths at or greater than the 20th week of gestation in the US from 1996 to 2002. Time-series methods control for trends, seasonality, and other forms of autocorrelation that could induce spurious associations.
Results support the hypothesis in that the fetal death sex ratio (i.e., the odds of a male fetal death) increased above its expected value in September 2001. Additional analysis of the secondary sex ratio indirectly supports that the terrorist attacks may have threatened the gestation of male more than female fetuses.
Societal responses to events such as September 11, 2001 do not appear confined only to persons who have ever met the deceased. The fetal death sex ratio in the US population may serve as a sentinel indicator of the degree to which pregnant women react to population stressors.
Recent evidence, both animal and human, suggests that modifiable factors during fetal and infant development predispose for cardiovascular disease in adult life and that they may become possible future targets for prevention. One of these factors is maternal psychosocial stress, but so far, few prospective studies have been able to investigate the longer-term effects of stress in detail, i.e. effects in childhood. Therefore, our general aim is to study whether prenatal maternal psychosocial stress is associated with an adverse cardio-metabolic risk profile in the child at age five.
Data are available from the Amsterdam Born Children and their Development (ABCD) study, a prospective birth cohort in the Netherlands. Between 2003-2004, 8,266 pregnant women filled out a questionnaire including instruments to determine anxiety (STAI), pregnancy related anxiety (PRAQ), depressive symptoms (CES-D), parenting stress (PDH scale) and work stress (Job Content Questionnaire). Outcome measures in the offspring (age 5-7) are currently collected. These include lipid profile, blood glucose, insulin sensitivity, body composition (body mass index, waist circumference and bioelectrical impedance analysis), autonomic nervous system activity (parasympathetic and sympathetic measures) and blood pressure. Potential mediators are maternal serum cortisol, gestational age and birth weight for gestational age (intrauterine growth restriction). Possible gender differences in programming are also studied.
Main strengths of the proposed study are the longitudinal measurements during three important periods (pregnancy, infancy and childhood), the extensive measurement of maternal psychosocial stress with validated questionnaires and the thorough measurement of the children's cardio-metabolic profile. The availability of several confounding factors will give us the opportunity to quantify the independent contribution of maternal stress during pregnancy to the cardio-metabolic risk profile of her offspring. Moreover, the mediating role of maternal cortisol, intrauterine growth, gestational age and potential gender differences can be explored extensively. If prenatal psychosocial stress is indeed found to be associated with the offspring's cardio-metabolic risk, these results support the statement that primary prevention of cardiovascular disease may start even before birth by reducing maternal stress during pregnancy.
Recent human studies have shown that a wide variety of prenatal stressors, from anxiety and partner relationship problems, to natural disasters, increase the risk for a diverse range of adverse neurodevelopmental outcomes in the child. These include impaired cognitive development and behavioral problems, autism and schizophrenia. However, many questions remain about the underlying processes. Much of the research, based on animal studies, has focussed on the maternal HPA axis, with mixed results. Maternal stress or anxiety during pregnancy has been found to be weakly associated with raised maternal cortisol, if at all. The placenta may be a more promising programming vector, because it controls fetal exposure to the maternal environment. Animal studies indicate that prenatal stress can affect the activity of the placental barrier enzyme 11-betaHSD2, which metabolises cortisol. We review the evidence for a similar mechanism in humans and how maternal stress may cause other changes in the placenta which affect fetal neurodevelopment.
Fetal glucocorticoid exposure is associated with later development of features of the metabolic syndrome such as central obesity and insulin resistance. Fat tissue, especially visceral fat, produces adiponectin, which is inversely associated with insulin resistance in older children and adults. Adipocytes also produce leptin, directly related to measures of adiposity. It is unknown how the secretion of these hormones in early childhood is related to pregnancy levels of CRH, a proxy of fetal glucocorticoid exposure.
Our aim was to study the relationship of maternal midpregnancy CRH levels with offspring levels of adiponectin and leptin in early childhood.
The study population consisted of 349 mother-children pairs from Project Viva, a prospective prebirth cohort study from eastern Massachusetts. We created a general linear model with log CRH levels in midpregnancy maternal blood as the predictor and adiponectin and leptin measured in the 3-yr-old offspring as outcomes, adjusting for covariates.
The means (sd) of log CRH, adiponectin, and leptin were 4.97 (0.65) log pg/ml, 22.4 (5.8) microg/ml, and 1.9 (1.8) ng/ml. For each unit increment in log CRH, mean value of offspring adiponectin was 1.10 microg/ml (95% confidence interval = 0.06-2.14) higher. We found no association with leptin (-0.08 ng/ml; 95% confidence interval = -0.40-0.24).
Higher maternal blood levels of CRH were associated with higher levels of adiponectin but unchanged levels of leptin at age 3 yr. The increased adiponectin levels might represent secretion from organs other than fat or reflect a compensatory mechanism to increase insulin sensitivity.
Perturbations to the prenatal environment have been associated with the development of adult chronic disease, findings that gave rise to the "Barker Hypothesis" or the "developmental origins of adult disease" concept. In this study, we used an animal model to determine the metabolic consequences of maternal prenatal stress and high-fat feeding on the developing offspring.
Pregnant female Sprague-Dawley rats were maintained on standard chow or 60% high-fat diet throughout gestation and lactation. Half of each group were exposed to a novel variable stress paradigm during the 3rd week of gestation, whereas control dams were left undisturbed. Body weight, body composition, glucose tolerance, and endocrine parameters were measured in offspring through early adulthood.
Male and female pups from dams that experienced prenatal stress and/or were on a high-fat diet weighed more beginning on postnatal day 7 compared with standard chow-control pups. Access to high-fat diet at weaning increased the body weight effect through early adulthood and was attributable to greater adiposity. Pups weaned onto standard chow diet showed no significant difference in glucose clearance or insulin secretion. However, pups weaned onto high-fat diet had impaired glucose tolerance if their dams were on a high-fat diet, experienced prenatal stress, or both.
Our data demonstrate that prenatal stress and/or high-fat diet during the intrauterine or postnatal environment affects offspring in a manner that increases their susceptibility to diet-induced obesity and leads to secondary adverse metabolic consequences.
The importance of major life stress and minor daily hassles associated with parenting was studied in 74 mothers and their 5-year-old children. Of interest were the relative and absolute contributions of the stress factors to indices of parental, child, and family functioning. Mothers completed questionnaires regarding stressors, aspects of parenting and individual psychological status, social support, family functioning, and child behavioral status. Mother-child pairs were also observed in interactions in a laboratory setting. Analyses indicated that life stress and parenting daily hassles significantly predicted aspects of child, parent, and family status. Hassles, however, proved to be a more powerful stress construct. Further analyses indicated that mothers' social support moderated the influence of hassles on indices of maternal behavior. The results are discussed in relation to the potential for minor parenting stresses to influence microsocial processes within parent-child relationships and contribute to dysfunction in children and families.
In this article, we attempt to distinguish between the properties of moderator and mediator variables at a number of levels. First, we seek to make theorists and researchers aware of the importance of not using the terms moderator and mediator interchangeably by carefully elaborating, both conceptually and strategically, the many ways in which moderators and mediators differ. We then go beyond this largely pedagogical function and delineate the conceptual and strategic implications of making use of such distinctions with regard to a wide range of phenomena, including control and stress, attitudes, and personality traits. We also provide a specific compendium of analytic procedures appropriate for making the most effective use of the moderator and mediator distinction, both separately and in terms of a broader causal system that includes both moderators and mediators.
Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11β-hydroxysteroid dehydrogenase type-2 (11β-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11β-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11β-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3±0.3; control 4.3±0.2 mmol/liter, P = 0.04), reactive hyperglycemia (treated 8.7±0.4; control 7.5±0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1±0.4; control 3.8±0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6- phosphatase, glucokinase, and 11β-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.
Due to recent changes in legislation on occupational health and safety, a national monitor on stress and physical load was developed in The Netherlands to monitor (a) risks and consequences of stress and physical load at work, (b) preventive actions in companies to reduce these risks, and (c) organisational and environmental variables that facilitate preventive actions.
Information was gathered from employers, employees, and employees' representatives. The monitor was used with a nationally representative sample of companies in industry, wholesale trade, and banking and finance, 782 companies in total.
The information from the employees, aggregated at the company level, was not found to be correlated with that from the employer from the same companies. Although many employers do recognise risk factors for both physical load and stress as a problem they often seem to underestimate the problem when compared with employees or their representatives. This is particularly the case for psychosocial risk factors. Also, the perception of outcome measures, especially employers who consider emotional exhaustion to be work related, were fewer than the employees' representatives of the same organisation. Preventive measures on physical load are much more popular than measures against stress. It is the responsibility of the employer to take more preventive action of all kinds. They need to recognise risk factors as problems and health outcomes to be related to work. Employees of larger companies should participate with employers to consider effective measures, and more use should be made of support at branch level. For specific preventive measures, specific predictors emerged. Except for measures to prevent work stress, information from employees did not sufficiently contribute to the initiation of preventive measures in the workplace.
Part I discusses the Job Content Questionnaire (JCQ), designed to measure scales assessing psychological demands, decision latitude, social support, physical demands, and job insecurity. Part II describes the reliability of the JCQ scales in a cross-national context using 10,288 men and 6,313 women from 6 studies conducted in 4 countries. Substantial similarity in means, standard deviations, and correlations among the scales, and in correlations between scales and demographic variables, is found for both men and women in all studies. Reliability is good for most scales. Results suggest that psychological job characteristics are more similar across national boundaries than across occupations.
Numerous epidemiological studies have related an increased risk of adult-onset cardiovascular and metabolic disease to an adverse intra-uterine environment at critical periods. We have shown that fetal sheep exposed to dexamethasone for only 2 days at 27 days of gestation (term approximately 150 days) became hypertensive adults, whereas those exposed at 64 days of gestation remained normotensive, as did controls. In the same sheep, now nearly 5 years old, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to study the insulin sensitivity of glucose, amino acid and non-esterified fatty acid metabolism. Glucose tolerance, calculated as the area under the curve, after intravenous administration of bolus glucose and insulin secretion in response to a glucose challenge were not altered in any group. There were no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin, measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69+/-1.2% at steady-state plasma insulin levels ( approximately 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8+/-6.5% in the controls (P<0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4+/-5.1%, which did not reach significance compared with the controls (P=0.10). Thus brief dexamethasone exposure during early gestation programmed hypertension independently of insulin resistance of glucose or amino acid metabolism; however, it did lead to increased insulin sensitivity of the inhibition of lipolysis, which may increase susceptibility to the development of obesity postnatally.
Our aim was to determine the postnatal effects of single and repeated glucocorticoid injections during late gestation. Repeated (104, 111, 118, 125 days) or single (104 days) injections of betamethasone or saline were given to the ewe or by ultrasound guided injection to the fetus (term 150 days). Lambs were born spontaneously and studied at 3 and 6 mo and 1 yr of age. Arterial pressure was measured at each age, and we performed intravenous glucose tolerance tests at 6 mo and 1 yr. Repeated maternal, but not single maternal or fetal, betamethasone injections prolonged gestation, reduced weight at birth and 3 mo, and was associated with low arterial pressure at 3 mo but not at 6 mo and 1 yr. Glucose metabolism was altered in all betamethasone treatment groups, regardless of the number or route of injections. Our data demonstrate that glucocorticoid-induced fetal growth restriction is associated with a transient reduction in postnatal arterial pressure, but glucocorticoid exposure with or without growth restriction alters glucose metabolism.
Disruptions in homeostasis (ie, stress) place demands on the body that are met by the activation of 2 systems, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Stressor-induced activation of the HPA axis and the SNS results in a series of neural and endocrine adaptations known as the "stress response" or "stress cascade." The stress cascade is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge. Here we discuss the key elements of the HPA axis and the neuroendocrine response to stress. A challenge to homeostasis (a stressor) initiates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which in turn results in release of adrenocortiotropin hormone (ACTH) into general circulation. ACTH then acts on the adrenal cortex resulting in release of a species-specific glucocorticoid into blood. Glucocorticoids act in a negative feedback fashion to terminate the release of CRH. The body strives to maintain glucocorticoid levels within certain boundaries and interference at any level of the axis will influence the other components via feedback loops. Over- or underproduction of cortisol can result in the devastating diseases of Cushing's and Addison's, respectively, but less severe dysregulation of the HPA axis can still have adverse health consequences. These include the deposition of visceral fat as well as cardiovascular disease (eg, atherosclerosis). Thus, chronic stress with its physical and psychological ramifications remains a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. To date, treatments have been based on the existing knowledge concerning the brain areas and neurobiological substrates that subserve the stress response. Thus, the CRH blocker, antalarmin, is being investigated as a treatment for chronic stress because it prevents CRH from having its ultimate effect-a protracted release of glucocorticoids. New therapeutic strategies will depend on the discovery of novel therapeutic targets at the cellular and intracellular level. Advances in molecular biology provide the tools and new opportunities for identifying these therapeutic targets.
Understanding gene expression profiles during early human pancreas development is limited by comparison to studies in rodents. In this study, from the inception of pancreatic formation, embryonic pancreatic epithelial cells, approximately half of which were proliferative, expressed nuclear PDX1 and cytoplasmic CK19. Later, in the fetal pancreas, insulin was the most abundant hormone detected during the first trimester in largely non-proliferative cells. At sequential stages of early fetal development, as the number of insulin-positive cell clusters increased, the detection of CK19 in these cells diminished. PDX1 remained expressed in fetal beta cells. Vascular structures were present within the loose stroma surrounding pancreatic epithelial cells during embryogenesis. At 10 weeks post-conception (w.p.c.), all clusters containing more than ten insulin-positive cells had developed an intimate relationship with these vessels, compared with the remainder of the developing pancreas. At 12-13 w.p.c., human fetal islets, penetrated by vasculature, contained cells independently immunoreactive for insulin, glucagon, somatostatin and pancreatic polypeptide (PP), coincident with the expression of maturity markers prohormone convertase 1/3 (PC1/3), islet amyloid polypeptide, Chromogranin A and, more weakly, GLUT2. These data support the function of fetal beta cells as true endocrine cells by the end of the first trimester of human pregnancy.
The CES-D scale is a short self-report scale designed to measure depressive symptomatology in the general population. The items of the scale are symptoms associated with depression which have been used in previously validated longer scales. The new scale was tested in household interview surveys and in psychiatric settings. It was found to have very high internal consistency and adequate test- retest repeatability. Validity was established by pat terns of correlations with other self-report measures, by correlations with clinical ratings of depression, and by relationships with other variables which support its construct validity. Reliability, validity, and factor structure were similar across a wide variety of demographic characteristics in the general population samples tested. The scale should be a useful tool for epidemiologic studies of de pression.
Studied the effect of maternal emotions during the pregnancy in 30 of 70 nulliparous women (age 18–30 yrs) with varying levels of anxiety. Emotions were studied during each pregnancy trimester and in the 1st, 10th, and 28th wk after birth, using the State-Trait Anxiety Inventory. During pregnancy Ss were tested for a number of variables, including social support, coping abilities, personality, and pregnancy anxiety, in addition to the administration of the Maternal–Fetal Attachment Scale. After birth, Ss answered questionnaires on the birth experience and the behavior of the neonates. Maternal emotions had a small but significant effect on occurrence and duration of fetal motor activity. Fetuses of women with high anxiety tended to be more active than fetuses of women with low anxiety. The prenatal influence was reflected in neonatal behavior. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Background:
Prevalence rates of psychosocial stress during pregnancy are substantial. Evidence for associations between psychosocial stress and birth outcomes is inconsistent. This study aims to identify and characterize different clusters of pregnant women, each with a distinct pattern of psychosocial stress, and investigate whether birth outcomes differ between these clusters.
Methods:
Latent class analysis was performed on data of 7740 pregnant women (Amsterdam Born Children and their Development study). Included constructs were depressive symptoms, state anxiety, job strain, pregnancy-related anxiety and parenting stress.
Results:
Five clusters of women with distinct patterns of psychosocial stress were objectively identified. Babies born from women in the cluster characterized as 'high depression and high anxiety, moderate job strain' (12%) had a lower birth weight, and those in the 'high depression and high anxiety, not employed' cluster (15%) had an increased risk of pre-term birth.
Conclusions:
Babies from pregnant women reporting both high levels of anxiety and depressive symptoms are at highest risk for adverse birth outcomes.
To date, there have been conflicting reports of the association of psychosocial stressors with prenatal corticotropin-releasing hormone (CRH) levels.
We examined whether racial discrimination, community violence, interpersonal violence (IPV), negative life events, considered independently, and as a composite measure of cumulative stress, were associated with prenatal CRH levels in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a multiethnic pre-birth cohort in urban Boston. Blood was collected between 20 and 37 weeks gestation (Mean=28.1, SD=4.6 weeks gestation). During pregnancy, women were administered the Conflict Tactics Scale survey to assess IPV, the Crisis in Family Systems-Revised survey to assess negative life events, the My Exposure to Violence survey to assess community violence, and the Experiences of Discrimination survey. A cumulative stress measure was derived from these instruments to characterize exposure to high levels of multiple stressors.
None of the individual stressors or cumulative stress was associated with CRH in combined analyses including Whites (n=20), Blacks (n=46), and Hispanics (n=110). In separate analyses of Blacks and Hispanics, racial discrimination, community violence, and cumulative stress were associated with CRH in Blacks, but were not associated with CRH in Hispanics.
Though these results require replication, they suggest that the effects of stress on prenatal CRH levels may be mediated by factors that differ between racial/ethnic groups. Further studies in larger samples are warranted to clarify whether associations of chronic stressors and prenatal CRH levels differ by race/ethnicity and to better understand underlying mechanisms.
Prenatal exposure to maternal stress may program the fetal HPA axis, potentially leading to altered metabolism in later life, associated with adiposity and diabetes.
This association is little studied in humans, and thus we explore whether high maternal job strain during early pregnancy, as well as maternal cortisol levels are associated with increased body mass index (BMI), central adiposity or body fat mass in the offspring at age five. Additionally, we explore whether these associations are modified by gender or mediated by gestational age and fetal growth restriction.
2939 pregnant women (ABCD cohort study) completed a questionnaire around gestational week 16 including the Job Content Questionnaire, assessing job strain. Serum total cortisol was assessed in a subsample (n=1320). Gestational age (≥37 weeks), standardized birth weight and information on many covariates were available. At the age five health check, height, weight (BMI, kg/m(2)), waist circumference (waist-to-height ratio, WHtR) and Fat Mass Index (FMI, kg/m(2)) were assessed.
Job strain was not associated with higher BMI, WHtR or FMI. Higher maternal cortisol was independently associated with marginally higher FMI in girls, but marginally lower FMI in boys (β 0.09 and β -0.10 per 100 unit increase in serum cortisol, respectively. p<0.01). This association was not mediated by gestational age or fetal growth restriction.
Results show that prenatal maternal job strain and cortisol may not program obesity and adiposity in the next generation in humans, but gender differences should always be considered.
The "fetal origin of adult disease Hypothesis" originally described by Barker et al. identified the relationship between impaired in utero growth and adult cardiovascular disease risk and death. Since then, numerous clinical and experimental studies have confirmed that early developmental influences can lead to cardiovascular, pulmonary, metabolic, and psychological diseases during adulthood with and without alterations in birth weight. This so called "fetal programming" includes developmental disruption, immediate adaptation, or predictive adaptation and can lead to epigenetic changes affecting a specific organ or overall health. The intrauterine environment is dramatically impacted by the overall maternal health. Both premature birth or low birth weight can result from a variety of maternal conditions including undernutrition or dysnutrition, metabolic diseases, chronic maternal stresses induced by infections and inflammation, as well as hypercholesterolemia and smoking. Numerous animal studies have supported the importance of both maternal health and maternal environment on the long term outcomes of the offspring. With increasing rates of obesity and diabetes and survival of preterm infants born at early gestational ages, the need to elucidate mechanisms responsible for programming of adult cardiovascular disease is essential for the treatment of upcoming generations.
The objective of this study was to evaluate the relationship between psychosocial stress in pregnancy and negative perinatal outcomes and to identify key moderators of this relationship. To evaluate this relationship, a meta-analytic review was conducted of studies that prospectively assessed the relationship between psychosocial stress in pregnancy and perinatal outcomes. A total of 35 studies, written or published between 1991 and 2009, involving 31,323 women were located. The overall association between psychosocial stress and negative perinatal outcomes was significant, but negligibly small in size (r (35) = -0.04, CI = -0.08, -0.01). Examining specific perinatal outcomes, only the associations with neonatal weight (r (14) = -0.07, CI = -0.03, -0.01) and risk for low birth weight (r (5) = 0.07, CI = 0.03, 0.10) were statistically significant, but again, very small. Results support that psychosocial stress explains a negligible to very small amount of the variability in perinatal outcomes. Future research should focus on identifying other psychosocial and lifestyle variables that alone or in interaction with other factors explain larger amounts of the variability in perinatal outcomes. Future research should also examine whether psychosocial stress increases risk for negative outcomes in combination with other biomedical and psychosocial risk factors.
Ertel KA, Koenen KC, Rich-Edwards JW, Gillman MW. Antenatal and postpartum depressive symptoms are differentially associated with early childhood weight and adiposity. Paediatric and Perinatal Epidemiology 2010; 24: 179–189.
Antenatal depression is associated with small-for-gestational age, but few studies have examined associations with weight during childhood. Similarly, few studies address whether antenatal and postpartum depression differentially affect child weight. Among 838 mother–child dyads in Project Viva, a prospective cohort study, we examined relationships of antenatal and postpartum depression with child weight and adiposity. We assessed maternal depression at mid-pregnancy and 6 months postpartum with the Edinburgh Postnatal Depression Scale (score ≥13 indicating probable depression). We assessed child outcomes at age 3 years: body mass index (BMI) z-score, weight-for-height z-score, sum of subscapular (SS) and triceps (TR) skinfold thickness (SS + TR) for overall adiposity, and SS : TR ratio for central adiposity.
Sixty-nine (8.2%) women experienced antenatal depression and 59 (7.0%) postpartum depression. Mean (SD) outcomes at age 3 were: BMI z-score, 0.45 (1.01); SS + TR, 16.72 (4.03) mm; SS : TR, 0.64 (0.15). In multivariable models, antenatal depression was associated with lower child BMI z-score (−0.24 [95% confidence interval: −0.49, 0.00]), but higher SS : TR (0.05 [0.01, 0.09]). There was no evidence of a dose–response relationship between antenatal depression and these outcomes. Postpartum depression was associated with higher SS + TR (1.14 [0.11, 2.18]). In conclusion, whereas antenatal depression was associated with smaller size and central adiposity at age 3 years, postpartum depression was associated with higher overall adiposity.
There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice.
There are several independent prospective studies showing that a wide variety of forms of prenatal stress can have long-term effects on the behavioural and cognitive outcome for the child. Animal studies have shown that prenatal stress, as well as affecting behaviour, can also reprogram the function of the HPA axis in the offspring. However, the effects on the HPA axis are very variable depending on the nature of the stress, its timing in gestation, the genetic strain of the animal, the sex and age of the offspring and whether basal or stimulated HPA axis responses are studied. There are also several recent studies showing long-term effects of prenatal stress on basal cortisol levels, or cortisol responses to stress, in humans. The designs of these studies differ considerably, many are small, and the effects on outcome are also varied. There is little evidence, so far, that altered function of the HPA axis in the child mediates the behavioural or cognitive alterations observed to be associated with prenatal stress.
Selective non-response is an important threat to study validity as it can lead to selection bias. The Amsterdam Born Children and their Development study (ABCD-study) is a large cohort study addressing the relationship between life style, psychological conditions, nutrition and sociodemographic background of pregnant women and their children's health. Possible selective non-response and selection bias in the ABCD-study were analysed using national perinatal registry data. ABCD-study data were linked with national perinatal registry data by probabilistic medical record linkage techniques. Differences in the prevalence of relevant risk factors (sociodemographic and care-related factors) and birth outcomes between respondents and non-respondents were tested using Pearson chi-squared tests. Selection bias (i.e. bias in the association between risk factors and specific outcomes) was analysed by regression analysis with and without adjustment for participation status.
The ABCD non-respondents were significantly younger, more often non-western, and more often multiparae. Non-respondents entered antenatal care later, were more often under supervision of an obstetrician and had a spontaneous delivery more often. Non-response however, was not significantly associated with preterm birth (odds ratio 1.10; 95% CI 0.93, 1.29) or low birthweight (odds ratio 1.16; 95% CI 0.98, 1.37) after adjustment for sociodemographic risk factors. The associations found between risk factors and adverse pregnancy outcomes were similar for respondents and non-respondents. Anonymised record linkage of cohort study data with national registry data indicated that selective non-response was present in the ABCD-study, but selection bias was acceptably low and did not influence the main study questions.
We sought to identify factors associated with high antenatal psychosocial stress and describe the course of psychosocial stress during pregnancy.
We performed a cross-sectional analysis of data from an ongoing registry. Study participants were 1522 women receiving prenatal care at a university obstetric clinic from January 2004 through March 2008. Multiple logistic regression identified factors associated with high stress as measured by the Prenatal Psychosocial Profile stress scale.
The majority of participants reported antenatal psychosocial stress (78% low-moderate, 6% high). Depression (odds ratios [OR], 9.6; 95% confidence interval [CI], 5.5-17.0), panic disorder (OR, 6.8; 95% CI, 2.9-16.2), drug use (OR, 3.8; 95% CI, 1.2-12.5), domestic violence (OR, 3.3; 95% CI, 1.4-8.3), and having > or =2 medical comorbidities (OR, 3.1; 95% CI, 1.8-5.5) were significantly associated with high psychosocial stress. For women who screened twice during pregnancy, mean stress scores declined during pregnancy (14.8 +/- 3.9 vs 14.2 +/- 3.8; P < .001).
Antenatal psychosocial stress is common, and high levels are associated with maternal factors known to contribute to poor pregnancy outcomes.
The Demecal set enables medically unskilled persons to produce diluted plasma from a single drop of capillary blood at any time and place. The sample is mailed to a certified laboratory for analysis. A marker compound in the dilution buffer enables to correct for individual blood sampling variation. A test dependent factor corrects for recovery of analytes.
Glucose, cholesterol, triglycerides, HDL and LDL cholesterol, creatinine, BUN, uric acid and HbA1c were evaluated. We studied the correction procedure for sampling variation by the marker compound, the precision of the analyzer in the low range, the influence of characteristics of the set on analyte recovery, and the stability of the samples at different temperatures.
Using the marker compound in the buffer, variation in sampling could be corrected accurately. For dilutions up to 15 times, the precision of the analyzer was sufficient. Application of test specific recovery factors gave a good correlation with results of venous blood samples. Samples were stable for 4 days at 4 degrees C, 2-3 days at room temperature and 1 day at 37 degrees C.
The Demecal set can be considered an alternative for venous blood sampling for the tested parameters, enabling patient friendly management of chronic disease.
Epidemiological studies have reported associations between measures of size and weight at birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying mechanism. The present study investigated in humans the association of prenatal psychosocial stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of response to challenge and feedback sensitivity. Healthy young adults whose mothers experienced severe stress during their pregnancy in form of major negative life events (e.g. death of someone close; prenatal stress (PS) group, n=31) and an age-matched comparison group (CG, n=30) underwent the Trier Social Stress Test (TSST) and a 1 microg ACTH(1-24) stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations following a standardized behavioural challenge paradigm (TSST) were marginally significantly higher in PS subjects than in CG subjects (p=.06). Pre-TSST adrenocortical (cortisol) levels were lower (p=.007), whereas the increase in cortisol in response to the TSST was higher (p=.03) in PS subjects compared to CG subjects. Cortisol concentrations following a pharmacological stimulation test simulating pituitary activity (ACTH(1-24) test) were significantly lower in PS than in CG subjects (p=.006). No differences emerged between the two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an association between prenatal psychosocial stress exposure and subsequent alterations in the regulation of the HPA axis.
Maternal stress or anxiety during pregnancy can lead to neurodevelopmental and other problems in the child, and cortisol is one possible mediator. Animal models show that maternal prenatal stress can affect placental function, including regulation of placental 11beta-HSD2, the main barrier to the placental passage of cortisol. It is not known whether a parallel process exists in humans. The aim of the current study was to determine whether maternal anxiety increases the association between maternal plasma cortisol and amniotic fluid cortisol. The sample consisted of 262 women having amniocentesis, with normal pregnancies, who completed Spielberger State and Trait anxiety scales, from whom a plasma sample and an aliquot of amniotic fluid was obtained. The correlation between maternal and amniotic fluid cortisol was strongly dependent on both State and Trait maternal anxiety; in the most anxious State quartile r(62)=.59, p<.001 and in the least r(60)=.05, ns, a significant difference (p<.0015). The moderating effect of maternal anxiety on the association between maternal plasma and amniotic fluid cortisol remained when gestational age, maternal age, fetal sex, medication and time of collection were controlled for. There was no difference in amniotic fluid cortisol levels between the most and least anxious groups of mothers. However, the finding that there is a stronger correlation between maternal and fetal cortisol among more anxious pregnant women does suggests that the maternal emotional state can affect the function of the placenta.
In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin-dependent) diabetes mellitus. The concept underlying our hypothesis is that poor fetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.
This review focuses on the research concerning the relation between psychosocial factors and pregnancy outcome. The following four outcome measures are dealt with: (1) birth weight, (2) preeclampsia, (3) preterm labour, and (4) intrapartum complications. The most consistent finding concerns the association between maternal exposure to taxing situations and preterm delivery. Three possible pathways are hypothesized: (1) an indirect influence via unhealthy coping and life style behaviour, (2) a direct influence via stress-dependent hormones, and (3) an additional direct influence via psycho-immunological factors. Intervention studies aimed at improving pregnancy outcome show fairly mixed results. It is recommended that studies on the relationship between psychosocial factors and pregnancy outcome should employ a prospective design with due attention to chronic stressors, should include appropriate biochemical assessments, and multivariate techniques are applied.
This article analyzes the conceptual and methodological approaches which have been used to investigate effects of prenatal maternal stress on birth outcomes and highlights the major findings of this research. By viewing the most widely used operational definitions of prenatal stress in a broader theoretical framework, it can be seen that most studies have failed to conceptualize stress reliably. This, in addition to common methodological and design flaws which are described in the article, has produced equivocal findings about the role of stress in adverse birth outcomes such as preterm delivery and low birth weight. Recent studies using more powerful, multidimensional approaches to stress definition and measurement provide more definitive evidence and suggest some precise effects. Implications and strategies for future research are presented.
To investigate if psychological distress during pregnancy is associated with increased risk of preterm delivery.
Prospective, population based, follow up study with repeated measures of psychological distress (general health questionnaire), based on the use of questionnaires.
Antenatal care clinic and delivery ward, Aarhus University Hospital, Denmark.
8719 women with singleton pregnancies attending antenatal care for the initial visit between 1 August 1989 and 30 September 1991; 5872 women (67%) completed all questionnaires.
Preterm delivery. Estimation of gestational age at delivery was mainly based on early ultrasound measurements.
In 197 cases (3.6%) the woman delivered prematurely (less than 259 days). A dose-response relation between psychological distress in the 30th week of pregnancy and risk of preterm delivery was found, but distress measured in the 16th week was not related to preterm delivery. Control of confounding was secured by the use of multivariate logistic regression models. Relative risk for preterm delivery was 1.22 (95% confidence interval 0.84 to 1.79) for moderate distress and 1.75 (1.20 to 2.54) for high distress in comparison to low distress.
Psychological distress later in pregnancy is associated with an increased risk of preterm delivery. Future interventional studies should focus on ways of lowering psychological distress in late pregnancy.
Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".
The present study was designed to test the relation between stressful life events experienced during pregnancy and the risk of preterm delivery and shortened duration of pregnancy. We collected data prospectively in a general population sample, including repeated questionnaire measures of exposure to stressful life events during pregnancy. Between August 1989 and September 1991, 8,719 Danish-speaking women with singleton pregnancies attended antenatal care. Of these women, 5,873 (67%) completed all questionnaires. When indicating an event, the woman was asked to rate the amount of stress induced by this event. Measurement of gestational duration was primarily based on early ultrasound scan. When we evaluated life events independently of the individual's appraisal, we found no association with duration of gestation or risk of preterm delivery. In contrast, life events assessed by the subject as highly stressful were associated with shorter mean duration of gestation and increased risk of preterm delivery. This association was observed primarily with events experienced between the 16th and 30th week of gestation. Women who had one or more highly stressful life events had a risk of preterm delivery 1.76 times greater than those without stressful events (95% confidence interval = 1.15-2.71). We found no evidence for a buffering effect of social support.
Summary Recent human epidemiological studies have linked low birth weight with a substantially increased risk of non-insulin-dependent
diabetes mellitus in later life. These data suggest that the intrauterine environment plays a crucial role in determining
later glucose homeostasis, but the mechanism is unknown. We have proposed that exposure of the fetus to excess maternal glucocorticoids
may underpin the epidemiological findings. Normally placental 11 β -hydroxysteroid dehydrogenase type 2 (11 β -HSD-2) protects the fetus from the normally higher maternal levels of glucocorticoids by inactivating corticosterone and
cortisol to inert 11-keto products. Here we show that administration of carbenoxolone, an inhibitor of placental 11 β -HSD 2, to pregnant rats, leads to a significant reduction in average birth weight (20 % fall). At 6 months of age, the male
offspring of carbenoxolone-treated pregnancies had similar weights to controls, but showed significantly higher fasting plasma
glucose (6.0 ± 0.3 vs 4.8 ± 0.2 mmol/l; p < 0.01) and exhibited significantly greater plasma glucose (10 % higher) and insulin (38 % higher) responses to an oral glucose
load. These effects of carbenoxolone require intact maternal adrenal glands suggesting that inhibition of feto-placental 11 β -HSD 2 is key. These data support the notion that defiency of placental 11 β -HSD, by exposing the fetus to excess maternal glucocorticoids, reduces growth and predisposes to hyperglycaemia in later
life. [Diabetologia (1996) 39: 1299–1305]
To examine the role of psychosocial risk factors for low birthweight.
A prospective study.
Obstetric outpatient clinics of the University Hospital Vrije Universiteit, Amsterdam.
Three hundred and ninety-six nulliparous women.
Questionnaires on background variables, daily stressors, psychological and mental wellbeing, social support and work factors were completed by the women in the first, second and third trimester of pregnancy. Low birthweight for gestational age was defined at different cut off points: 1. < or = 10th customised birthweight centile (n = 69); 2. < or = 5th customised birthweight centile (n = 54); 3. < 3rd customised birthweight centile (n = 35); and 4. < or = the 10th Dutch birthweight centile (n = 40). Multivariate logistic regression was applied and the results were expressed in odds ratios and their 95% confidence intervals.
When the cut off level was defined < or = 5th and < 3rd customised centile, the number of daily stressors in the first trimester was a statistically significant risk factor (OR 1.04, 95% CI 1.01-1.07 and OR 1.04, 95% CI 1.01-1.08). No significant psychosocial risk factors could be identified when low birthweight for gestational age was defined < or = the 10th customised birthweight centile. When low birthweight for gestational age was defined < or = the 10th Dutch birthweight centile, number of hours housekeeping per week in the first trimester (OR 1.59, 95% CI 1.03-2.46), low subjective severity rating of daily stressors in the first trimester (OR 0.41, 95% CI 0.17-0.97) and depressive mood in the first trimester (OR 1.12, 95% CI 1.01-1.24) were statistically significant psychosocial risk factors after controlling for maternal weight and height, number of cigarettes smoked per day and educational level.
In the first trimester of pregnancy maternal psychosocial factors are associated with an increased risk of low birthweight. The specific psychosocial risk factors found were different when the definition of low birthweight was changed. Therefore, in this field of research, we suggest use of the most valid outcome measure for low birthweight, being the customised birthweight centiles.
Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.
The purpose of this study was to assess the association between fetal sex and the occurrence of fetal distress during labor.
This was a prospective cohort study that incorporated data about 423,033 singleton pregnancies from the national perinatal database for secondary obstetric care in The Netherlands. All singleton pregnancies on record that were delivered under the responsibility of obstetricians in The Netherlands between January 1, 1990, and December 31, 1994, were analyzed. Data about fetal sex, gestational age at delivery, birth weight, fetal distress during labor, mode of delivery, signs of asphyxia at birth, and perinatal death were collected. The associations between sex and the occurrence of operative delivery for fetal distress, low 5-minute Apgar score (score, 0-3), and perinatal death were evaluated by logistic regression analysis.
Male fetuses are at increased risk for fetal distress during labor, for low Apgar scores, and for perinatal death. After adjustment for fetal birth weight and gestational age at delivery, the odds ratios were 1.48, 1.27, and 1.27, respectively. All three associations were highly statistically significant (P <.0001).
Male fetuses are at increased risk during labor and delivery.
To determine the relationship of birth weight to later glucose and insulin metabolism.
Systematic review of the published literature. Data sources were Medline and Embase. Included studies were papers reporting the relationship of birth weight with a measure of glucose or insulin metabolism after 1 year of age, including the prevalence of Type 2 diabetes mellitus (DM). Three reviewers abstracted information from each paper according to specified criteria.
Forty-eight papers fulfilled the criteria for inclusion, mostly of adults in developed countries. Most studies reported an inverse relationship between birth weight and fasting plasma glucose concentrations (15 of 25 papers), fasting plasma insulin concentrations (20 of 26), plasma glucose concentrations 2 h after a glucose load (20 of 25), the prevalence of Type 2 DM (13 of 16), measures of insulin resistance (17 of 22), and measures of insulin secretion (16 of 24). The predominance of these inverse relationships and the demonstration in a minority of studies of other directions of the relationships could not generally be explained by differences between studies in the sex, age, or current size of the subjects. However, the relationship of birth weight with insulin secretion was inconsistent in studies of adults.
The published literature shows that, generally, people who were light at birth have an adverse profile of later glucose and insulin metabolism. This is related to higher insulin resistance, but the relationship to insulin secretion in adults is less clear.
Suboptimal maternal nutrition and catch-up growth in early childhood predispose to insulin resistance and other components of metabolic syndrome in later life. A central metabolic syndrome (CMS) has been identified comprising obesity, dyslipidaemia and insulin resistance. This study was designed to investigate determinants of risk for CMS.
Persons born in Newcastle in May and June 1947 (n = 358) were followed to 1996-1998. A lifecourse approach was used to estimate the proportion of variance in a summary measure of CMS at age 49-51 years accounted for by factors operating at different stages of life.
After adjustment for other early life variables, childhood catch-up growth in men accounted for significant variation in the CMS score independent of adult lifestyle. In adulthood, exercise level in men and smoking in both genders were independently associated with CMS. Over two-thirds of explained variation in the CMS score in women, and almost half in men, was accounted for exclusively by factors measured in adulthood.
While risk for CMS in men is compounded by early life disadvantage, promotion of a healthier adult lifestyle and a reduction in the number of people taking up smoking would appear to be the public health interventions most likely to reduce the prevalence of CMS in middle age.
We have previously shown that repeated antenatal synthetic glucocorticoid exposure has sex-specific effects on hypothalamic-pituitary-adrenal development in the fetal and adult guinea pig. However, little is known about the mechanisms that underlie these sex-specific outcomes. In the current study we demonstrated that glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) exhibit sex differences in their temporal and spatial expression during fetal and early postnatal life. During development, we observed decreased GR mRNA in the paraventricular nucleus, decreased MR mRNA and MR protein in the hippocampus, and increased GR mRNA and GR protein in the hippocampus. We have also shown that on gestational d 50, maternally administered betamethasone (BETA) reduces fetal plasma ACTH and cortisol concentrations. BETA significantly affected hippocampal MR protein expression, and this effect was greatest in males. BETA was unable to autoregulate GR protein during fetal life, indicating that regulation of brain corticosteroid receptors is fundamentally different in fetal compared with adult life. The sex differences in the pattern of GR and MR expression during development may indicate different windows of vulnerability to prenatal glucocorticoid exposure in fetal life.
Studying the effect of maternal asthma during pregnancy on placental function and fetal development has highlighted that there is a strong interaction between mother, placenta and fetus and these interactions appear to be sex-specific. This work has found that the female fetus alters maternal asthma during pregnancy by upregulating maternal inflammatory pathways. When asthma-associated inflammatory pathways are not treated with inhaled steroids during pregnancy, the female fetus has reduced growth and adrenal function due to alterations in placental glucocorticoid metabolism. When the mother uses inhaled steroid for the treatment of her asthma during pregnancy, female fetal growth and placental function are comparable to the control population. The growth of the male fetus appears to be unaffected by asthma or inhaled steroid use. These findings indicate there may be different mechanisms regulating placental glucocorticoid and immune mechanisms depending on fetal sex in both asthmatic and non-asthmatic pregnancies.