Periconceptional Maternal Psychological Stress - Research Proposal Example

Periconceptional maternal psychological stress as a risk factor for fetal ventricular septal defect – a retrospective case-control study of urban Texas population Aim(s) of the study To explore the probability of a relationship between the maternal psychological stress events during the periconceptional period and the incidence of fetal ventricular septal defects, in urban Texas population. To quantitate the risk, of an infant being born with ventricular septal defect, associated with the exposure to the number of stress-events during the first trimester of pregnancy. Hypothesis - The risk of fetal ventricular septal defect increases in proportion to the number of the stressful events during early pregnancy. Background Heart develops during early fetal life - it starts with a hollow tube in the embryo that gets partitioned into four chamber mature heart during the first eight weeks of pregnancy. The morphogenesis of a four chamber heart from a single chamber involves partitioning with the help of atrio-ventricular and the interventricular septa. Growth deficiency, misalignment or failure of fusion of the components of the interventricular septum, viz., endocardial cushions, aorticopulmonary septum and the muscular part of the septum, is the primary cause of the ventricular septal defects (Shinebourne et al, 2006). A hole or complete absence of the septum allows the blood to mix in the ventricles, which is supplied to the lungs as well as the rest of the body giving rise to symptoms like ‘blue babies’. Soto et al (1980) gave an objective classification of the ventricular septal defects (VSD). On the basis of angiograms of 220 children with VSD, they observed that the defects in the septum could present with the following morphologies - perimembranous defects; muscular defects and subarterial infundibular defects. Perimembranous defects as well as the muscular defects were further divided into three sub-groups each. A stressful life of the mother has been studied as a risk factor for a number of congenital malformation in the offspring, e.g. orofacial cleft (Montenegro et al, 1995), neural tube defects (Carmichael and Shaw, 2000) and conotruncal heart defects (Suarez, 2003). Carmichael et al (2007) have conducted a comprehensive population based case-control study involving 1355 mothers and calculated a ‘stressful life event score’ based on exposure to 18 possible stress-events and its association with congenital birth defects. Their results showed that a 3-point increase in the stress score increases the odds-ratio of a birth defect to 1.45 ( C.I. 1.03-2.06) and the risk is further aggravated to O.R. of 2.35 (CI = 1.47 – 3.77), if the mother is not taking vitamin (folic acid) supplement during early pregnancy. Hansen et al (2000), in a rare 12 year prospective study with a 16 months retrospective component, reported an increased incidence of cranial-neural-crest malformations as well as other congenital malformations in children born to mothers exposed to severe life events like death, hospitalization for cancer and acute myocardial infarction. They observed that death of an older child during pregnancy has more profound effect on the outcome of pregnancy as a birth defect. Ventricular septal defects, just like most of the infantile malformations, have a very strong genetic or hereditary component. Although a direct gene defect has not been yet linked to VSD, the defect appears to run in the family, with second sibling being at a higher risk to inherit the malformation. The developmental disturbances caused by monosomy 22q11 have been documented (Hofbeck et al, 1980) to be the cause of a number of malformations including VSD, pulmonary atresia, and major aorto-pulmonary collateral arteries. The personal habits and the environmental factors also appear to contribute to the causation of the cardiac malformations, in general, and VSD, in particular. Alcohol consumption, smoking and drug abuse have been studied by a number of research workers and most of them have observed a positive correlation of VSD with these factors. The National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention produced data that show maternal marijuana use during the preconception period is associated with an increased risk of simple VSD. Infections, e.g. syphilis and tuberculaosis and exposure to ionizing radiation (Doyle et al, 2000) have also been implicated in the causation of VSD. In view of the above, the present study has been designed to ascertain and quantitate the risk of VSD in the offspring in mothers exposed to peri-conceptional stress. Study design The proposed work is planned as a five year (1999-2003) retrospective age-matched case-control study in the targeted population (urban population of Texas state of USA). The mothers of all the infants born with ventricular septal defects shall be included in the study and 500 age-matched control subjects (healthy deliveries) will be selected from the birth registry data. A prospective longitudinal study on the topic is not feasible, but the data from a case-control study can, nevertheless, be used to quantitate the odds-ratio and the risk-ratio of the severity of exposure (stress events) with the outcome (incidence of live births with VSD). The age-matched controls from the same population will eliminate a number of confounding factors related with physiological as well psychological disparity. Materials and Methods Study Subjects: The Texas Birth Defects Registry data will be accessed to select all the children born with ventricular septal defect(s) between 1st January 1999 and 31st December 2003. More than 80% of approximately 21 million Texas population is urban and about 300,000 children are born in the hospitals in the metropolis across the state of Texas every year. Considering an incidence of fetal ventricular septal defects of 22-24 per 10,000 live births, there would have been approximately 3250 births with this defect. After taking an informed consent (the consent form attached), the mothers of these children, who are willing to participate in the project, would be recruited for the present study. Control Subjects: The state birth registry data would also be accessed to select 500 mothers who have given birth to healthy children during the study period. The selection would also include an age filter so that the proportion of mothers in different age-groups matches with that in the study population. The data on the age groups would be randomized and a set proportion of mothers would be selected for recruitment for the study. Exclusion Criteria: The mothers of more than one SVD children would be excluded as genetics plays a major role in the congenital abnormalities. A number of chronic illnesses have been implicated as risk factors for congenital defects, therefore, mothers with chronic illness like Diabetes Mellitus, Renal failure, Arthritis or any cardiac disorder would be excluded from the study. Mothers with hypertension, preeclampsia or a history of spontaneous abortions would also be excluded. Methods Exposure: The periconceptional stress events would recorded from the telephonic interview of the willing mothers. The stress parameters specified by Kaiser Permanente/California Department of Health Study of Pregnancy and Stress would be objectively documented. These parameters have been adapted from the more comprehensive stress scale given by Halmes and Rahe (1967). The major stress events would include – Death of spouse, Divorce, Separation from spouse, Loss of job, Diagnosis of a severe sickness, Surgery / Hospitalization, Accident, Financial loss, Legal complications, Loan repayment problem, Altercations within family or neighborhood. The selection of the events also takes care of the ability of the mothers to recall the events objectively. The number as well as severity (duration) of exposure to the stress events would be recorded in the objective questionnaire. Confounding factors that could influence the analysis include maternal race, ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. These factors will be taken care of during the analysis. Association of VSD with chromosomal disorders like Down syndrome and Digeorge syndrome would also be studied. Data Analysis The data generated from the questionnaires would be analyzed using SPSS Ver 16 and/or Epi Info (2009), latter is an excellent statistical software for analysis of epidemiological data. The total stress score (based on the sum of the weights of stressful events) would be evaluated using logistic regression and odds ratio would be calculated. The categorical evaluation of each stress-event would also be done using 2x2 tables and the weightage of each stress event in the over-all causation of the disease would be assessed by chi-square of linear trend. An attempt would be made to develop a mathematical multivariate model to know whether the association of different risk factors has a threshold effect or is nonlinear. Table 1: Example of a 2x2 table Expected findings: To prove our hypothesis that the increased incidence of stressful life events during the periconceptional period is causally related to the occurrence of ventricular septal defect, the mean stress score would be calculated in the two groups i.e. VSD and control groups as shown in Table 2. We expect the difference in the mean ± SEM between the two groups would be statistically significant (p-value Read More