Summary

Maternal smoking during pregnancy is a well-established and preventable risk factor for low birthweight and its sequelae of poor physical, cognitive and behavioural development, excess morbidity, and increased rates of both perinatal and adult mortality. Preliminary findings from genetic epidemiology studies suggest that the degree to which prenatal tobacco exposure depresses birthweight may be moderated by foetal and maternal genotype for NQO1 Pro187Ser (rs1800566). We propose to genotype this variant in mothers and children participating in ALSPAC to test hypotheses about the moderating effects of maternal and foetal rs1800566 genotype on the effects of prenatal tobacco exposure to reduce birthweight, shorten gestation, and alter postnatal physical, cognitive, and behavioural development.

Background

Maternal smoking during pregnancy is a well-established and preventable risk factor for low birthweight (less than 2,500g) and its sequelae of poor physical, cognitive and behavioral development, excess morbidity, and increased rates of both perinatal and adult mortality (Kramer, 2003). The primary causes of low birthweight are preterm birth and intrauterine growth restriction (IUGR). The consequences of IUGR include both short-term and long-term morbidity and permanent deficits in growth and neurocognitive development (Kramer, 2003). Epidemiological studies have shown that maternal smoking is associated with both short gestation and IUGR (Kramer, 2003). Mothers who quit smoking while pregnant have longer gestations and heavier newborns than those who continue to smoke (Lumley, Oliver, Chamberlain, & Oakley, 1998). This fact is recognized in public policy: in the UK, formal smoking cessation programs are recommended as part of antenatal care to prevent low birthweight (Health Development Agency, 2004).

Preliminary findings from studies in genetic epidemiology (Sasaki et al., 2008; Price, Grosser, Plomin & Jaffee, in press) suggest that the degree to which prenatal tobacco exposure depresses birthweight may be moderated by foetal and maternal genotype for NQO1 Pro187Ser (rs1800566). To date, no study has replicated these initial findings, nor tested the effects of both maternal and foetal rs1800566 genotype, nor investigated the possibility that rs1800566 genotype interacts with prenatal tobacco exposure to influence postnatal physical, behavioural, and cognitive development.

Methods

Data collection. We propose to genotype approximately 10,000 mothers and 10,000 children participating in the ALSPAC study for the NQO1 Pro187Ser variant (rs1800566).

Existing data required

Concept

Specific Measure

Person

Source

Time Point(s)

Demographic variables (age, sex, ethnicity, marital status, family structure, SES, education, employment, income etc.)

Family

Questionnaire

Antenatal

Pregnancy health variables (nulliparity, pre-eclampsia, IUGR, gestational diabetes etc.)

Mother

Questionnaire, medical records

Antenatal

Parental anthropometrics (height weight)

Mother, Father

Questionnaire

Antenatal

Pregnancy exposure variables (tobacco, alcohol and drug use; chemical exposure; diet; nutrient supplementation; stress; life events; partner cruelty; lack of social support)

Mother

Questionnaire

Antenatal

Birth/delivery variables (weight/length, placental weight, gestational age, Caesarian), perinatal health

Child

Questionnaire, medical records

Birth/perinatal period

Childhood head injury

Child

Questionnaire

Birth - 4 years

Childhood temperament

Carey

Child

Questionnaire

24 months

Childhood behaviour

SDQ

Child

Questionnaire

42 - 157 months

ADHD

Child

Questionnaire

166 months

Antisocial behaviour

Child

Questionnaire

169 months - 198 months

Psychotic symptoms

Child

Questionnaire

140 months - 198 months

Adolescent substance use (tobacco, alcohol, drugs)

Child

Questionnaire

157 months - 198 months

Language development

McCarthy

Child

Questionnaire

24 months

Cognitive ability

WISC

Child

Clinic test

8 years

Scholastic achievement

Child

Questionnaire

166 months

Anthropometrics (Height, weight)

Child

Questionnaire

Birth - 157 months

Parental antisocial behaviour (antisocial behaviour as children or adults; contact with police; criminal convictions)

Mother, father

Questionnaire

Antenatal - 145 months

Childhood postnatal experiences (maternal depression and anxiety, parental discipline)

Mother

Questionnaire

Birth - 145 months

Parental postnatal substance use (tobacco, alcohol, drugs)

Mother, father

Questionnaire

Birth - 145 months

Data Analysis. Hypotheses about effects on birthweight and gestational age will be tested using linear models incorporating terms for prenatal tobacco exposure, maternal genotype, foetal genotype, interaction between maternal genotype and prenatal tobacco exposure, interaction between foetal genotype and prenatal tobacco exposure, plus relevant covariates (including demographics, pregnancy and antenatal health variables, and parental physical and behavioural characteristics). Analyses will be stratified by ethnicity to guard against spurious associations due to population admixture. Hypotheses concerning low birthweight and premature gestation will be tested similarly, but using a logistic regression model. Hypotheses about trajectories of postnatal physical, behavioural, and cognitive development will be tested using growth curve models and growth mixture models; in addition, mediation analyses will be conducted to test whether postnatal development is conditionally independent of genotype and prenatal tobacco exposure after controlling for any effects on birthweight and gestational age. Hypotheses about the effects of prenatal tobacco exposure will test for heterogeneity of the effects with respect to mode of exposure (maternal smoking/maternal exposure to second hand smoke), dose, and timing of smoking cessation. A parallel set of analyses will be conducted using paternal tobacco exposure as the environment of interest in order to validate the inference of intrauterine effects. Analyses will be conducted to assess the possible influence of attrition in the sample on the outcomes of interest. If necessary, informative missingness will be explicitly modelled.

References

Health Development Agency. (2004). The evidence of effectiveness of public health interventions - and the implications.

Kramer, M. S. (2003). The epidemiology of adverse pregnancy outcomes: An overview. Journal of Nutrition, 133, 1592S-1596S.

Lumley, J., Oliver, S., Chamberlain, C., & Oakley, L. (1998). Interventions for promoting smoking cessation during pregnancy. Cochrane Database of SystematicReviews, Art. No.: CD001055. DOI: 001010.001002/14651858.CD14001055.pub14651852.

Price, T. S., Grosser, T., Plomin, R., and Jaffee, S. R. (in press). Fetal genotype for the xenobiotic metabolizing enzyme NQO1 influences intrauterine growth among infants whose mothers smoked during pregnancy. Child Development.

Sasaki, S., Sata, F., Katoh, S., Saijo, Y., Nakajima, S., Washino, N., et al. (2008). Adverse birth outcomes associated with maternal smoking and polymorphisms in the N-nitrosamine-metabolizing enzyme genes NQO1 and CYP2E1. American Journal of Epidemiology, 167, 6.