Maternal smoking is a known teratogen (1) and is associated with complications of pregnancy (2). Furthermore there is robust evidence that maternal smoking in pregnancy is causally associated with low birth weight in offspring (3;4). Observational studies have also reported associations of maternal smoking in pregnancy with various child outcomes such as increased obesity (5;6), reduced stature (7), lower cognitive development and behavioural problems (8;9) and higher blood pressure (10). However, results for these outcomes have been inconsistent and there is evidence that some of these associations reflect confounding by socioeconomic factors (10-13) rather genuine biological effects of intrauterine exposure to smoke.

We have explored associations of maternal smoking on offspring outcomes observationally in ALSPAC and have previously reported no association with child obesity (11), no association with child blood pressure (14) and an inverse association with child stature (15). We recently gained approval to study the relationship between maternal smoking and offspring cognition.

We would like to build on these existing observational analyses and explore the role of confounding further by using the rs1051730 genetic variant as a means of testing the causality of putative associations between maternal smoking in pregnancy and offspring outcomes.

It has recently been observed that rs1051730 genotype is associated with variations in smoking behaviour in pregnancy. An analysis using pooled data from ALSPAC and The Exeter Family Study of Childhood Health has shown that each additional copy of the rs1051730 risk allele is associated with higher odds ratios of continuing to smoke during the first trimester (Freathy et al., in press). Thus this genetic variant can be used to explore causality in relation to maternal smoking in pregnancy and offspring outcomes.

In sum, we would like to explore the associations of maternal rs1051730 genotype (associated with continued smoking behaviour in pregnancy) with:

1) child adiposity

2) child stature

3) child blood pressure

4) child cognition

For table of requested variables, please see attached.

Reference List

1. Dwyer JB, Broide RS, Leslie FM. Nicotine and brain development. Birth Defects Res C Embryo Today 2008;84:30-44.

2. Andres RL, Day MC. Perinatal complications associated with maternal tobacco use. Semin Neonatol 2000;5:231-41.

3. Sexton M, Hebel JR. A clinical trial of change in maternal smoking and its effect on birth weight. JAMA 1984;251:911-5.

4. Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychosocial stress. BMJ 1989;298:795-801.

5. Chen A, Pennell ML, Klebanoff MA, Rogan WJ, Longnecker MP. Maternal smoking during pregnancy in relation to child overweight: follow-up to age 8 years. Int J Epidemiol 2006;35:121-30.

6. Al Mamun A, Lawlor DA, Alati R, O'Callaghan MJ, Williams GM, Najman JM. Does maternal smoking during pregnancy have a direct effect on future offspring obesity? Evidence from a prospective birth cohort study. Am J Epidemiol 2006;164:317-25.

7. Lampl M, Kuzawa CW, Jeanty P. Prenatal smoke exposure alters growth in limb proportions and head shape in the midgestation human fetus. Am J Hum Biol 2003;15:533-46.

8. Julvez J, Ribas-Fito N, Torrent M, Forns M, Garcia-Esteban R, Sunyer J. Maternal smoking habits and cognitive development of children at age 4 years in a population-based birth cohort. Int J Epidemiol 2007;36:825-32.

9. Wakschlag LS, Pickett KE, Cook E Jr, Benowitz NL, Leventhal BL. Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 2002;92:966-74.

10. Brion MJ, Leary SD, Lawlor DA, Smith GD, Ness AR. Modifiable Maternal Exposures and Offspring Blood Pressure: A Review of Epidemiological Studies of Maternal Age, Diet and Smoking. Pediatr Res 2008;63:593-8.

11. Leary S, Davey Smith G, Rogers I, Reilly J, Wells J, Ness A. Smoking during pregnancy and offspring fat and lean mass in childhood. Obesity 2006;14:2284-93.

12. Gilman SE, Gardener H, Buka SL. Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor? Am J Epidemiol 2008;168:522-31.

13. Batty GD, Der G, Deary IJ. Effect of maternal smoking during pregnancy on offspring's cognitive ability: empirical evidence for complete confounding in the US national longitudinal survey of youth. Pediatrics 2006;118:943-50.

14. Brion MJA, Leary SD, Davey Smith G, Ness AR. Similar associations of parental prenatal smoking suggest child blood pressure is not influenced by intrauterine effects. Hypertension 2007;49:1-7.

15. Leary S, Davey Smith G, Ness A. Smoking during pregnancy and components of stature in offspring. Am J Hum Biol 2006;18:502-12.