Introduction

The aetiology of gastroschisis, a congenital anomaly of the abdominal wall with herniation of the intestines and serious morbidity [1,2], is unknown [3]. Birth prevalence is reported to have increased in many countries over the last 15 years [4,5]. Evidence of a degree of clustering of cases [6] which can lead to public alarm [7] raised the question of possible point sources of pollution as a causative factor, but to date no definitive environmental exposures have been identified. Case control studies of gastroschisis have consistently found associations with the behaviour-related risk factors of low maternal BMI, younger age of mother, smoking [8], and more recently risks associated with recreational drug use [9], genitourinary infection [10] and diet poor in fruit and vegetables, and reduced folic acid intake [11] have been reported. In addition to exploring these risk factors we have drawn on growing scientific interest in the potential role of maternal stress in causing adverse birth outcomes [12,13] including congenital anomalies [14-16]. In this analysis we tested the hypothesis that major stressful life events in the first trimester were associated with increased risk of gastroschisis, and that social support was protective (Figure 1), using data from an incident case control study [11].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 1. Hypothesised pathway diagram for Stress, Social support, Lifestyle and Nutrition in the aetiology of Gastroschisis.

https://doi.org/10.1371/journal.pone.0080103.g001

Method

The case control study was carried out in five regions of the United Kingdom [11]. A full description of the methods has been reported previously [11]. Briefly, women were recruited between July 2007 and February 2010. Cases were identified following the ultrasound scan offered routinely to all pregnant women in England and Wales at 18-20 weeks gestation and intended to identify fetal anomalies. We included singleton pregnancies in which uncomplicated gastroschisis (ICD-10 Q79.3) was diagnosed. For women in Scotland routine ultrasound scan at 18-20 weeks was not offered routinely in all areas so instead we followed up mothers whose routine serum alpha fetoprotein level was high and who then went on to have ultrasound investigations. We excluded babies with multiple anomalies. We recruited three controls for each case using routine National Health Service records of the antenatal clinics where the case mothers attended. We matched for maternal age within 1 year (or within 3 years where this was not obtainable). Ethical approval was given by the Research Ethics Committee for Wales (05/MRE09/97) and required informed written consent was obtained from all the women.

Women were interviewed by a trained interviewer using a standard structured questionnaire. We sought to minimise recall bias by asking mothers to use diaries and calendars to think about the period in question. Questions on stressful maternal events were taken from The U.S. National Birth Defects Prevention Study [16] which were based on several validated assessment tools for stressful life events [14,16-18] and social support [19,20]. Questions covered five stressful life events during the first trimester: serious relationship difficulties with husband or partner (including separation or divorce), the woman or partner having serious financial or legal problems, the woman or someone close was a victim of violence or violent crime, the woman or someone close having a serious illness or injury, and someone close died. The definition of “someone close” was decided by the participant. We also included as a stressful event change of address in the first trimester [21]. Questions about social support covered availability of emotional support with problems and decisions, financial help (with bills, food and clothes), help with daily tasks (such as grocery shopping, child care and cooking). Other questions included socio-demographic characteristics, change of partner between pregnancies, planned pregnancy, housing, nutrition (including use of folic acid supplements), infections, medication and recreational drug use, social events such as parties, hobbies, patterns of caffeine intake (cups of tea, coffee, caffeinated drinks a day), alcohol intake and cigarette smoking, during the first twelve weeks of pregnancy. To assess socio-economic status we used the National Statistics Socio-Economic grouping (NS-SEC) [22].

Statistical Analysis

In other studies of birth defects the cumulative number of stressful life events has been found to be associated with increased risk; therefore following examination of the distribution, we categorised the number of stressful events into 0, 1, 2+ events. We fitted univariate and multivariable conditional logistic regression models using STATA version 10 [23] (Statacorp, College Station, Texas). Most cases and controls reported having all three types of social support and therefore we categorised social support into a binary Yes (if they had all three types of social support) / No (if they did not have at least one type of social support) as the variable of interest in the logistic regression modelling. We found that units of alcohol consumed per week and reported binge drinking (greater or equal to 6 units in one sitting/day) were highly correlated, so we ran models using each alcohol variable in turn. Odds ratios were very similar and we report the data for the model using binge drinking.

We included two-way interaction terms between the number of stressful life events and the behavioural risks of smoking, binge drinking and caffeine intake, fruit and vegetable intake and duration of folic acid supplementation in the first trimester, and tested if these terms improved the fit of the model to the data using the log likelihood ratio test [24].

Results

Of the 124 eligible cases identified 91(73%) agreed to participate in the study as did 217 (70%) of 310 potential controls. The mean age was 23 years (SD 4.6 years) for cases and 23 years (SD 5.0 years) for controls. In univariate analysis, cases were almost twice as likely to report individually three of the five major stressful life events in the first trimester: serious relationship difficulties, legal or financial problems, or victim of violence or crime (Table 1).

There were no significant differences between cases and controls in the frequency of injury, illness or death in someone close. Forty one percent of cases reported a change of address in the first trimester compared to 18% of controls (OR 3.3; 95%CI 1.8-5.8). Cases were also more likely than controls to have changed partners for the current pregnancy (OR 3.0; 95% CI 1.4-6.4). Controls were more likely than cases to report having someone to provide emotional support (OR 0.3; 95% CI 0.1-0.8) but both had similar levels of financial support and help with daily tasks. Stressful life events were not consistently related to other risk factors (Table 2, Table S1).

In multivariable analysis having two or more major stressful life events as well as changing address in the first trimester were both strongly associated with increased odds of gastroschisis, independent of each other and of behavioural risk factors (Table 3). Odds ratios were similar in magnitude to the independent association with cigarette smoking. Social support was not independently associated with reduced risk of gastroschisis after adjustment for stressful life events. The risks associated with BMI, binge drinking, consumption of fruit or vegetables and folic acid supplements were unchanged from the estimates modelled without the stress variables. Socio-economic group, caffeine intake and change of partner were not associated with increased risk in the multivariate models.

There was no evidence of significant two-way interactions between the stress variables and the behavioural risk factors of cigarette smoking, binge drinking, caffeine intake, fruit or vegetable intake or folic acid use. In order to account for potential residual confounding with maternal age we repeated the analysis including maternal age as a continuous variable but this did not substantially alter the results.

Discussion

The embryological pathogenesis of gastroschisis is uncertain [1,25-28]. Hypotheses have mainly focussed on vascular abnormality and consequent infarction and necrosis of the body wall at about 6-10 weeks of gestation, but Feldkamp et al [26] have argued that animal model data suggest that the causes may operate even earlier in embryogenesis than previously thought and propose that gastroschisis is caused by abnormal folding of the body wall resulting in a ventral body wall defect and gut herniation at 3-5 weeks post conception. Our study was aimed at pin pointing time specific aetiological exposures although the closest we could come realistically in interview was to specify the first trimester period.

Epidemiological studies have identified several potential risk factors but only a few have been found consistently and these are low maternal age, low BMI and smoking [8]. Associations with alcohol intake is less consistent [8,11]. The association with low BMI may suggest nutritional deficiency, and recently we have reported an association with low intake of fruit and vegetables and reduced duration of folic acid supplementation in the first trimester which were as strongly linked to gastroschisis as smoking and low maternal age [11]. However, the association with nutritional factors was independent of maternal BMI. Indeed our data suggested that rather than low BMI being a risk factor, obesity was protective. The consistent and strong independent association with younger maternal age as well as the increasing incidence in gastroschisis in recent years in many countries suggests a role for other modern life style related risk factors. We considered the potential role of recreational and across the counter drugs, as have others [9,29,30] and also the relatively new phenomenon of binge drinking in women, but these were not independently associated with gastroschisis [11].

We hypothesised that stressful maternal life events increase the risk of gastroschisis, possibly through biochemical and immunological stress pathways. Similar hypotheses have been proposed for adverse perinatal events such as low birthweight and prematurity [12,13,31,32] and some other congenital anomalies [14], particularly cleft palate and cleft lip [15,16]. There are a number of ways in which maternal stress during pregnancy may lead to gastroschisis. Stress may lead to increase in behaviours already implicated as risk factors such as cigarette smoking or poor nutrition [16]. We were able to take account of these factors in our analysis and maternal stress had a strong association with gastroschisis, independent of the risks associated with cigarette smoking or poor nutrition. Increased levels of cortisol due to stress may have a direct effect on the fetus, but to our knowledge there is no evidence for this from animal models. Cortisol plays a role in vascular and thrombotic pathways, both of which have been hypothesised as key factors in the development of gastroschisis [25,27]. More recently, high levels of oestrogen have been proposed to play a role [33]. High levels of oestrogen are associated with increased risk of thrombosis, and oestrogen is also associated with negative reactions to stress [34], such that women who were already at increased risk of gastroschisis due to high level of oestrogen may have perceived more stress. Finally, cortisol is known to be associated with dysregulation of the immune and inflammatory pathway but its effect in pregnancy is less well known [35]. It is possible that these immune and inflammatory pathways play a role in the development of gastroschisis [8].

As far as we are aware this is the first study to test this hypothesis in gastroschisis. We found univariate associations between gastroschisis and the individual life events of serious relationship difficulties, legal or financial problems for the women or their partners, and with the women or someone close being a victim of violence or crime. Access to emotional support was associated with a reduced risk. However, in multivariate analysis we found that two or more major life events compared to one or less, and moving home in the first trimester, each were independent of each other and of maternal age, BMI, smoking and nutritional factors. The strength of the associations we found for gastroschisis was similar to the independent effects of smoking or poor diet and suggests a major role for direct stress pathways independent of other lifestyle factors. Using the estimates from the multivariate model, though with very wide confidence intervals, the risk to a woman who smokes and who has two or more stressful life events in the first trimester was 21.0 (95% CI 2.2-203.5). If in addition she moved address the risk estimate increases to 81.3 (95% CI 3.2-2083.2). Although social support has been proposed as a moderating factor for stress we did not find that it was independently associated in any protective way. There was no evidence of interactions between these stress variables and other variables included in the model.

Supporting Information

Acknowledgments

We wish to thank all the women who took the time to take part in this study, the research nurses who undertook interviews and data collection: Sandra Edwards-Fenton, Anne Chamberlain, Marit Bodley, Sharon Brown, Isobel Clegg, Catherine Collins and the British Isles Network of Congenital Anomaly Registers (BINOCAR) for their support in facilitating this study.