Associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth: Findings from Mendelian randomization and parental negative control studies

Abstract

Background: Maternal smoking during pregnancy is an established risk factor for low infant birth weight, but evidence on critical exposure windows and timing of fetal growth restriction is limited. Here we investigate the associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth by triangulating evidence from 3 analytical approaches to strengthen causal inference.

Methods and findings: We analysed data from 8,621 European liveborn singletons in 2 population-based pregnancy cohorts (the Generation R Study, the Netherlands 2002-2006 [n = 4,682]) and the Born in Bradford study, United Kingdom 2007-2010 [n = 3,939]) with fetal ultrasound and birth anthropometric measures, parental smoking during pregnancy, and maternal genetic data. Associations with trajectories of estimated fetal weight (EFW) and individual fetal parameters (head circumference, femur length [FL], and abdominal circumference [AC]) from 12-16 to 40 weeks' gestation were analysed using multilevel fractional polynomial models. We compared results from (1) confounder-adjusted multivariable analyses, (2) a Mendelian randomization (MR) analysis using maternal rs1051730 genotype as an instrument for smoking quantity and ease of quitting, and (3) a negative control analysis comparing maternal and mother's partner's smoking associations. In multivariable analyses, women who continued smoking during pregnancy had a smaller fetal size than non-smokers from early gestation (16-20 weeks) through to birth (p-value for each parameter < 0.001). Fetal size reductions in continuing smokers followed a dose-dependent pattern (compared to non-smokers, difference in mean EFW [95% CI] at 40 weeks' gestation was -144 g [-182 to -106], -215 g [-248 to -182], and -290 g [-334 to -247] for light, moderate, and heavy smoking, respectively). Overall, fetal size reductions were most pronounced for FL. The fetal growth trajectory in women who quit smoking in early pregnancy was similar to that of non-smokers, except for a shorter FL and greater AC around 36-40 weeks' gestation. In MR analyses, each genetically determined 1-cigarette-per-day increase was associated with a smaller EFW from 20 weeks' gestation to birth in smokers (p = 0.01, difference in mean EFW at 40 weeks = -45 g [95% CI -81 to -10]) and a greater EFW from 32 weeks' gestation onwards in non-smokers (p = 0.03, difference in mean EFW at 40 weeks = 26 g [95% CI 5 to 47]). There was no evidence that partner smoking was associated with fetal growth. Study limitations include measurement error due to maternal self-report of smoking and the modest sample size for MR analyses resulting in unconfounded estimates being less precise. The apparent positive association of the genetic instrument with fetal growth in non-smokers suggests that genetic pleiotropy may have masked a stronger association in smokers.

Conclusions: A consistent linear dose-dependent association of maternal smoking with fetal growth was observed from the early second trimester onwards, while no major growth deficit was found in women who quit smoking early in pregnancy except for a shorter FL during late gestation. These findings reinforce the importance of smoking cessation advice in preconception and antenatal care and show that smoking reduction can lower the risk of impaired fetal growth in women who struggle to quit.

Fig 1. Predicted differences in mean fetal size (with 95% CIs) across gestation comparing pre-pregnancy smokers who quit early in pregnancy and pre-pregnancy smokers who continued smoking through pregnancy with non-smokers (reference category).

Predicted differences in mean head circumference (mm), femur length (mm), abdominal circumference (mm), and estimated fetal weight (g) across gestation comparing pre-pregnancy smokers who quit in early pregnancy and those who continued smoking during pregnancy with non-smokers (reference category). Predicted mean differences (with 95% confidence intervals) in the pooled Generation R Study and Born in Bradford study cohort by analysis model: model 1 adjusting for cohort only (in white) and model 2 adjusting for cohort, infant sex, and maternal age, parity, height, body mass index, education level, and alcohol use during pregnancy (in black).

Fig 2. Predicted differences in mean fetal size (with 95% CIs) across gestation comparing different categories of smoking quantity in pre-pregnancy smokers who continued smoking through pregnancy with non-smokers (reference category).

Predicted differences in mean head circumference (mm), femur length (mm), abdominal circumference (mm), and estimated fetal weight (g) across gestation comparing pre-pregnancy smokers who continued smoking through pregnancy by smoking intensity with non-smokers (reference category). Predicted mean differences (with 95% confidence intervals) in the pooled Generation R Study and Born in Bradford study cohort by analysis model: model 1 adjusting for cohort only (in white) and model 2 adjusting for cohort, infant sex, and maternal age, parity, height, body mass index, education level, and alcohol use during pregnancy (in black).

Fig 3. Predicted differences in mean fetal size (with 95% CIs) across gestation per risk allele increase at rs1051730 in non-smokers, pre-pregnancy smokers who quit early in pregnancy, and pre-pregnancy smokers who continued smoking through pregnancy.

Predicted differences in mean head circumference (mm), femur length (mm), abdominal circumference (mm), and estimated fetal weight (g) per maternal rs1051730 T allele increase in non-smokers, pre-pregnancy smokers who quit smoking in early pregnancy, and pre-pregnancy smokers who continued smoking during pregnancy. Predicted mean differences (with 95% confidence intervals) by analysis model: model 1 adjusting for cohort (in white) and model 2 adjusting for cohort and fetal rs1051730 genotype (in black).

Fig 4. Predicted differences in mean fetal size (with 95% CIs) across gestation comparing mothers and mother’s partners who smoked to non-smokers (reference category).

Predicted differences in mean head circumference (mm), femur length (mm), abdominal circumference (mm), and estimated fetal weight (g) across gestation associated with maternal smoking (i.e., comparing maternal continued smoking through pregnancy with no maternal smoking during pregnancy [reference category]) and mother’s partner’s smoking (comparing partner smoking during pregnancy with no partner smoking during pregnancy [reference category]). Predicted mean differences associated with maternal smoking (in white) and partner smoking (in black) are adjusted for cohort, infant sex, parity (for maternal smoking only), and respective parental age, height, BMI, education level, and alcohol use during pregnancy, and mutually adjusted for the smoking behaviour of the other parent.