Overall, an association between in utero exposure to maternal tobacco smoke and the daughter's risk of fetal loss later in life was not supported in these data. A slightly increased risk of late miscarriages in women who reported being exposed to tobacco smoke in utero was observed but the estimate was imprecise. The findings for miscarriage and stillbirth were the same when the analysis was restricted to women who were non-smokers as adults (the majority).
We also observed that women who stopped smoking while pregnant had a statistically significant higher risk of stillbirths or any fetal deaths if they were exposed to tobacco smoke in utero
. Compared with women who continued to smoke, women who stopped smoking during pregnancy were less likely to have second hand tobacco exposure, and more likely to binge drink during pregnancy, to be nulliparous, and to have higher education and income. In addition, these women smoked less before pregnancy (data not shown). Previous studies have also shown that women who quit smoking during pregnancy tend to have smoked less before pregnancy (<20 cigarettes/day), and are more likely have higher education and income (Hakansson et al., 1999
; Solomon and Quinn, 2004
). For each of the attributes associated with smoking cessation during pregnancy, we evaluated whether they modified the association of in utero
smoking with fetal loss. None accounted for the effect modification. However, after excluding women who smoked 10+ cigarettes/day before pregnancy, the effect of modification observed by a woman's own smoking status during pregnancy was no longer there (data not shown). Perhaps the finding was due to an abrupt, large change in exposure to nicotine, or to an unmeasured factor correlated with smoking cessation in pregnancy.
To date, no previous results on in utero
tobacco smoke and women's risk of fetal loss later in life have been reported. Women who smoke during pregnancy tend to continue smoking after the child is born (Weinberg et al., 1989
; Tong et al., 2009
), thus studies of childhood exposure to tobacco smoke might be expected to give results somewhat comparable to ours. Two studies, however, evaluated the association between childhood exposure to parental tobacco smoke and the risk of fetal loss. Childhood exposure to tobacco smoke from both parents was associated with an increased risk of spontaneous miscarriage [adjusted odds ratio (OR) = 1.75; 95% CI, 1.01–3.04] among women who conceived after the use of ART. This association, however, was not observed when only the mother was a smoker (adjusted OR = 0.98) (Meeker et al., 2007
). Childhood exposure to tobacco smoke was not associated with increased risk of fetal deaths (miscarriages and stillbirths) in a retrospective study among women who visited a cancer hospital (adjusted OR = 1.07; 95% CI, 0.87–1.32) (Peppone et al., 2009
). The results were similar to those we observed.
Most miscarriages occur early in pregnancy, by week 12 of GA (Wilcox et al., 1988
; Goldhaber and Fireman, 1991
) and a limitation of the present study is that we could include only late miscarriages. Subsequently, the power to evaluate the association of in utero
smoking exposure with this outcome was limited. Additionally, as recently noted, women with previous stillbirths were underrepresented in the MoBa cohort (Nilsen et al., 2009
), which may have lead us to an underestimation of the HRs for this outcome.
Smoking while pregnant increases fetal loss (CDC, 2002
), thus subjects who were susceptible to smoking's adverse effects may not have survived to participate in the present study. The study population may have been resilient and thus shows no effect of in utero
exposure. A possible exception may have been the subset exposed in utero
who stopped smoking when pregnant. Some aspects of susceptibility such as threatened abortion may have triggered the cessation of smoking.
The intensity of in utero exposure to tobacco smoking was not ascertained in MoBa; therefore we could not evaluate a dose–response relationship. If women who experienced very intense exposure to maternal tobacco smoking in utero were underrepresented in our study population, we may have underestimated the HRs for late miscarriages and stillbirths. Another limitation was our inability to discriminate between in utero tobacco smoke and childhood exposure; as noted above it is likely that women whose mothers smoked while pregnant with them (i.e. exposed in utero) also experienced continuous exposure during childhood. Information on childhood exposure to tobacco smoke from both parents as well as in utero exposure to SHTS (e.g. from father) was not asked in MoBa. Thus, residual confounding by childhood exposure to tobacco smoke from parents cannot be ruled out. In addition, a considerable number of women who did not know their exposure status were excluded from the present analysis; the effect of this exclusion in our estimated HRs could be either an under- or overestimation. However, the percentage of women who did not know their exposure to tobacco smoking in utero did not vary among cases and non-cases; it was also comparable between those with a previous spontaneous miscarriage or stillbirth and those without a previous adverse outcome.
Random errors in the classification of the exposure might have occurred, causing an underestimation of the HRs. Previous studies have shown however that the reported exposure to maternal tobacco smoke in utero
by the adult offspring is a valid and reliable measure (Simard et al., 2008
; Cupul-Uicab et al., 2010
). In addition, we were able to show evidence supporting the validity of the reported in utero
exposure to tobacco smoke based on the birthweight of a subset of the MoBa participants. Maternal smoking during pregnancy has been associated with an average reduction of 149 g in birthweight (Kramer, 1987
), and in the present study we observed a 202 g average reduction.
The validity of in utero
exposure to tobacco smoke is also supported by data on the prevalence of smoking in Norway during the calendar years when the MoBa participants were born (Table ). Reproductive aged women had a higher prevalence of smoking compared with the mothers of the women in MoBa, which has two explanations. First, women enrolled in MoBa smoked less than the general population (Nilsen et al., 2009
) and the same pattern may have held for their mothers. Second, pregnant women tend to quit smoking (in 1987, 16% of women in Norway who smoked daily stopped smoking before their first prenatal check-up (Haug et al., 1992
)). After pregnancy the prevalence of smoking increases but not to pre-pregnancy levels (see last column in Table ) (Haug et al., 1998
; Solomon and Quinn, 2004
Information on important covariates was recorded early in pregnancy; usually women reported their in utero
exposure to tobacco smoke before knowing their pregnancy outcome, therefore a serious recall bias is unlikely in the present study. The outcomes of interest were obtained from the MBR, which contains well-documented information on all deliveries in Norway since 1967 (Irgens, 2000
). Therefore, the studied outcomes were not subject to recall bias.
Although women who participated in MoBa are not a representative sample of all pregnant women from Norway during the period of interest, previous analyses suggest that bias in the estimated parameters due to self-selection is negligible when evaluating exposure-outcome associations in the cohort (Nilsen et al., 2009
In this large study of pregnant women from Norway, exposure to maternal tobacco smoke in utero was not associated with an increased risk of fetal losses in the daughters later in life. Our results, however, were suggestive of a slight increased risk of miscarriage in women who experience in utero tobacco smoke from their mothers, but our statistical power was limited for this outcome.