Childhood Obesity and Severe Antenatal Maternal Stress

Obesity is a complex public health problem that is a growing threat to children's health, as well as a current and future drain on National Health Service (NHS) resources. Obesity already costs the NHS directly around £1 billion a year and the UK economy a further £2.3 to £2.6 billion in indirect costs. If this present trend continues, by 2010 the annual cost to the economy could be £3.6 billion a year.

By the IOTF's international standards nearly 27.5% of girls and 22% of boys in UK aged 2-15 were found to be overweight, including 5.5% of boys and 7.2% of girls who were obese in 2002. The IOTF analysis indicates a marked acceleration in the trend from the mid-1980s onwards. Using the national Body Mass Index percentiles approach (adopted by the Department of Health assuming 15% overweight including 5% obesity in 1990) 30.7% of girls and 30.3 % of boys were overweight, including 16% who were obese, by 2002.(See DH weblink)Furthermore, childhood obesity is one of the key predictors of adult obesity. Evidence of the long term effectiveness of obesity interventions is mixed (see Mend website; ) once obesity is established (see Oude Luttikhuis et al 2009). Identifying early risk factors for child obesity may have important preventive implications for future public health strategy.

In humans, adverse early life experiences such as childhood trauma, neglect and abuse are associated with the development of psychosocial disorders (Heim & Nemeroff, 1999; Kaufman et al., 2000; Heim et al., 2002; MacDonald et al., 2008). In animal models, an adverse early life experience causes abnormalities in neurodevelopment (Pickering et al., 2006), increased stress response as measured by plasma corticosterone (Meaney et al., 1993; Pihoker et al., 1993), and behavioural deficits (Pryce and Feldon, 2003; Pryce et al., 2005; Slotten et al., 2006) in adulthood.

Numerous studies report relationships between palatable food (rich in sugar and saturated fat), and emotional states and stress. In humans and in animal models, emotions influence food intake and choice of food and palatable foods high in fat and carbohydrate improve mood and modify stress responsivity. For example, subjects report a preference for palatable food rich in saturated fat and sugar during negative emotions (Macht, 2008) and adult individuals subjected to psychological stress in a laboratory setting are reported to eat greater amounts of palatable food compared to control groups (Oliver et al., 2000). In adults, depression and anxiety can also be linked to compulsive behaviours and craving for palatable food which induce feelings of pleasure (Kelley et al., 2005; Paterson and Markou, 2007). A study in UK school children reported that higher self-reported stress scores were associated with increased intake of fatty food compared to fruits and vegetables (Cartwright et al., 2003). These data suggest that the direction of the association is that humans subjected to stressful circumstances (chronically and acutely) are more likely to crave palatable, high saturated fat and high sugar containing foods or 'comfort foods'.

Dallman (2005) described the phenomenon of 'comfort food' or 'comfort eating' as self-medication with food.Adam and Epel, 2007 propose that stress-stimulated consumption of palatable food is a form of reward-based eating because palatable high-fat diet or 'comfort food' modulates hypothalamic-pituitary-adrenal (HPA) axis activity and indirectly blunts the stress response. In other words, the craving for such foods derives from their effect on the HPA axis which the presence of the stress has activated acutely or chronically. Animal data support the notion that consuming such a diet can have a beneficial effect by modulating the stress response: rats consuming molar sucrose solution and sweetened vegetable shortening (lard), in addition to regular chow, showed attenuated ACTH responses to restraint stress and lower plasma corticosteronecompared to those consuming chow alone (Pecoraro et al., 2004;la Fleur 2005). Similarly, rats exposed to lard for 2 h per day for 7 weeks also showed a decreased stress response compared to rats consuming chow only (Kinzig et al., 2008). Alterations in hippocampal GR mRNA and hypothalamic CRH mRNA, key mediators of HPA axis activity, are thought to be the mechanisms by which these diets alter the stress response (e.g. Morris 2010). Thus, data suggest that palatable high fat diets or comfort food have a role in ameliorating stress and possibly stress-related behaviour whether given chronically or as an option.

These studies focus on postnatal events in humans and animal models. It is well recognised that prenatal maternal stress alters HPA axis sensitivity in rodent models (e.g. Kapoor et al 2008; Liu et al 1997). Our work and others has provided evidence that in utero exposure to severe maternal stress can increase the risk of neuropsychiatric disorder i.e. schizophrenia and affective disorder (Khashan et al 2008; Khashan et al submitted) both of which are considered in part to result from altered HPA axis sensitivity.

Research Question

Does pregnancy-related and early postnatal exposure to domestic violence predict increased BMI in offspring of exposed mothers in the ALSPAC cohort?

Hypotheses

Primary hypothesis: a child exposed to severe early life stressors is more likely to become overweight or obese than children not exposed in this way manifest as a rightwards shift in the BMI (and or DXA derived fat mass) distribution by age 15 of exposed versus unexposed children.

Secondary hypotheses: i) as a result of exposure to maternal stress in utero, HPA axis sensitivity in exposed children is greater than in unexposed children (tested using salivary cortisol measures) ii) overweight or obesity occurs through increased intake of palatable or comfort foods in exposed versus unexposed children iii) intake of a high saturated fat and high carbohydrate diet reduces or modulate HPA axis sensitivity iv) overweight or childhood obesity is associated with reduced HPA axis sensitivity (mean salivary cortisol levels) in exposed children compared to exposed non-obese or normal weight children

Future hypotheses i) We will examine whether we may use birth weight (BW) of children exposed and unexposed as a proxy for early life stress. We would then examine BW and its association with later life BMI through the use of genotypes associated with it via the presence of key genetic loci associated with birth weight(Freathy et al 2010).

Method

We wish to use a model of early life stress indexed by the maternal experience of adverse life events and of domestic violence before conception, during pregnancy or in the first year of life, in order to assess effects on childhood growth and rates of overweight and obesity. We shall examine the distribution of the BMI and body composition (DXA) of children exposed in utero and postnatally to maternal domestic abuse and compare it to that of unexposed children and assess HPA axis sensitivity using salivary cortisol levels in obese/overweight and normal weight exposed children. Variables assigning abuse status to individual participants have already been derived (see below) and we seek permission to examine these in light of anthropometric, serological and genetic data.

All analysis will be undertaken collaboratively by Nic Timpson at the MRC CAiTE centre and as such we have not requested data transfer.

Exposure variables: Antenatal domestic violence has been assessed in the ALSPAC cohort at 18 weeks gestation. Participants were asked two questions on whether their partner had been emotionally cruel, and whether their partner had physically hurt them since the start of the pregnancy and to state how much it affected them on a scale from 'no effect' to 'affected a lot'. A woman will be considered to have experienced antenatal domestic violence if she responded positively (any level of effect) to either physical or emotional cruelty since the start of the pregnancy. Questions asking if their partner had been emotional or physically cruel have also been used to define postnatal domestic violence and this was reported at 2, 8, 21 and 33 months after the child was born, in each case referring to the period since the last questionnaire. Violence from the partner to the mother, partner to the child and mother to the child was reported by the mother in the same way at these times. The repeated responses will be summarised into a variable indicating the number of time points that violence was experienced since the birth, a separate variable for each of: violence occurring to the mother, to the child from partner or child from the mother. Other stressful life events will be assessed using the life events scale covering 13 life events including serious illness/death in the family, marital difficulties, financial problems etc. These were recorded by the mother at 8, 21 and 33 months after the birth.

Outcome variables:

Child Biometric Data: Information collected on birthweight and gestational age will be used along with the height, weight, ethnicity of the mother and parity of the child, to determine the birthweight centile of the child using the Gestation Network calculator; children in the lowest 10% will be counted as small for gestational age (SGA).BMI recorded atages21 months, 4, 7, 9, 11 and13 years of age usingheight and weight measurements in GP reports; as well asDXA fat mass at the same ages.

HPA axis sensitivity: we shall use salivary cortisol measures collected at ages xxx and compare mean and SD between exposed and unexposed children. (need to check availability).

Dietary records at age 10 yrs will be used to account for dietary/calorie intake.

Potential confounders: The following maternal characteristics will be measured as potential confounders of any association between stressors and child biometric measures: maternal age at the birth of the child, maternal socioeconomic status as assessed by the following variables: maternal education, (recorded at 32 weeks gestation simplified from a 5 item response into 3 categories: low (CSE, vocational), medium (O-level), high (A-level, degree)) and homeownership status, grouped as: own/mortgage versus rented (Cleland et al 2010; Crawford et al 2010). Smoking and alcohol use during pregnancy were determined at 18 weeks gestation. Women are considered to have smoked during pregnancy if they had smoked any form of tobacco in the 2 weeks prior to completion of the 18 week questionnaire. Women were also questioned on their alcohol use during pregnancy at 18 weeks gestation, responses were categorised into less than 1 glass (unit) per day and 1 or more glasses (units) per day.

Analysis

Simple analyses will be used to assess the association between severe early life stress exposure, measured at 18 weeks gestation and up to 33 weeks postnatally, and the biometric outcome variables.Multivariable analysis will be conducted using logistic regression to adjust for the following possible confounding factors: SES (maternal education, homeownership status), maternal marital status, maternal age, parity, ethnicity and paternal depression. Biometric variables will be handled as continuous variables initially to look for shifts in the distribution of weight in the exposed and unexposed groups by age. Bivariable associations between overweight, antenatal domestic violence and baseline characteristics of the mother and child will be assessed using chi-squared or t-tests. The association between antenatal domestic violence and child overweight will be further investigated using logistic regression. Generally, the data will be analysed in three stages: (i) calculation of unadjusted odds ratio of severe early life stressor (domestic violence and life events score) in relation to overweight; (ii) adjustment for possible confounding factors; (iii) addition of potential mediators to the model. To investigate the possible mediating effect of maternal depression on the association, mother with recorded depression (EPDS score greater than 13) will be excluded in a sensitivity analysis. A variable for domestic violence exposure i.e. no violence, antenatal violence only, antenatal and postnatal violence, postnatal violence only, will also be used to give a direct comparison of the different levels of exposure. If numbers are sufficient, gender interactions will also be explored.

A second set of analyses using a Chi square tests will assess the secondary hypotheses: the relationship between exposure and mean salivary cortisol levels. The divide the cases into exposed overweight/obese and exposed normal weight and

Multivariable analysis will be conducted using logistic regression to adjust for the following possible confounding factors: SES (maternal education, homeownership status), maternal marital status, maternal age, parity, smoking, ethnicity and paternal depression. Bivariable associations between salivary cortisol levels, antenatal domestic violence and baseline characteristics of the mother and child will be assessed using chi-squared or t-tests. The association between antenatal domestic violence and childhood salivary cortisol levels will be further investigated using logistic regression. Finally, dietary intake will be assessed as high or low in palatable food and/or calorie and a chi square test used to examine the association between maternal stress/domestic violence and dietary intake. Multivariable analysis will be conducted using logistic regression to adjust for the following possible confounding factors: SES (maternal education, homeownership status), maternal marital status, maternal age, smoking, parity, ethnicity and paternal depression.

Missing Data: We shall use the (MICE) with the ice command in Stata to impute missing values using chained equations. This will be carried out on the full dataset including all variables used in this analysis as well as additional variables known to be related to non-response.