The effects of tobacco usage and exposure on pregnancy outcomes remain a public health priority because 15% of mothers continue to smoke throughout pregnancy, and an estimated 43 million women in the United States are exposed to cigarette smoke from others [9, 10]. Several articles have linked smoking during pregnancy to increased risk of spontaneous abortions [11, 12]. Other research has shown that maternal smoking during pregnancy is linked to a higher rate of Sudden Infant Death Syndrome (SIDS) [11, 13] in addition to decreased fecundity [14, 15].

Although an abundance of studies links maternal smoking to various pregnancy difficulties (PD), fewer studies have examined SHS exposure and pregnancy difficulties. Two studies published in the early 1990s showed that exposure to SHS was associated with an increase in spontaneous abortions [16, 17]. More recent research found that SHS exposure during pregnancy was associated with an increased occurrence of spontaneous abortion [3, 18]. Other studies found that exposure to SHS early in life (in utero or in childhood) were linked with miscarriage [19, 20] and reduced fecundity in adulthood [21, 22].

Descriptive characteristics of those women who did and did not experience pregnancy difficulties are displayed in Table 1. Those who reported having experienced pregnancy difficulties were significantly (p<0.05) younger at admission and older at the time of their most recent pregnancy. Pregnancy difficulties did not differ by marital status, but those with a higher family income and those who attained a higher educational level were more likely to have experienced pregnancy difficulties. While caffeine consumption was not associated with pregnancy difficulties (p=0.78), women who consumed a greater amount of alcohol reported a higher proportion of pregnancy difficulties (p<0.01). Women who reported pregnancy difficulties had fewer children and a greater proportion of menstrual irregularity (p<0.01).

Table 2 displays the results examining the association between childhood SHS exposure and the various study outcomes based upon unadjusted and adjusted models. Women exposed as children to SHS from their parents reported trouble becoming pregnant (childhood SHS; OR = 1.27; 95%CI = 1.03–1.56) more often than those not exposed to SHS during childhood. Childhood SHS exposure was not associated with the other study outcomes.

Table 3 displays the results examining the association between SHS exposure as an adult and the various pregnancy difficulties. Women exposed to SHS as an adult reported trouble becoming pregnant (adult SHS; OR = 1.24; 95%CI = 1.03–1.51) more often than those not exposed to SHS. SHS exposure as an adult was associated with fetal loss (adult SHS; OR = 1.23; 95%CI = 1.08–1.40). Lastly, adult SHS exposure increased the odds of either pregnancy difficulties or fetal loss (adult SHS; OR = 1.30; 95%CI = 1.15–1.47).

Table 4 displays the association between combined childhood and adult SHS exposure with pregnancy difficulties. Combined adult and childhood SHS exposure was associated with difficulty becoming pregnant (OR = 1.68; 95%CI = 1.28–2.20). Women exposed to SHS both as an adult and during childhood had significantly increased odds of fetal loss (OR = 1.39; 95%CI = 1.17–1.66). Multiple fetal losses were examined in relation to adult and childhood SHS, where the odds ratios found were similar to that of fetal loss (OR = 1.62; 95%CI = 1.25–2.11).

The results presented in this study are consistent with a number of previous publications examining the association between secondhand smoke exposure and various pregnancy difficulties [3, 16–20]. The odds ratio estimates obtained in this study are similar in magnitude to the risk estimates in the studies that reported an association between SHS and PD [17, 28]. Although a small number of studies have found an association between SHS and PD, not all studies have reported a positive association [29].

Overall, the exact etiologies of prenatal pregnancy difficulties remain uncertain. Some mechanism which may explain these occurrences include chromosomal and uterine abnormalities, endocrine abnormalities, stress, exposure to environmental factors (e.g. tobacco smoke), and unidentified factors [30]. Compared to mainstream smoke (inhaled by the smoker), diluted side-stream smoke (the major component of SHS), especially after it has aged, can be more toxic [31]. DNA comet assays demonstrate more cells with DNA damage in never smokers exposed to secondhand smoke than in active smokers [32]. Likewise, toxins that create more reactive oxygen species (ROS) with resulting oxidative stress are also found in higher concentrations in side-stream smoke [33].

It is possible that secondhand smoke exposure involves the inhibition of reproductive hormone synthesis (estrogens and progesterones) at various sites including the ovary, the fat stores and the placenta if the woman is pregnant. Aromatase converts androgens to estradiol in the granulosa cells of ovarian follicles and in placental trophoblasts. Nicotine, cotinine and anabasine from tobacco smoke are endocrine disruptors that inhibit aromatase activity in granulosa cells and in trophoblasts, which reduce fertility [34]. In addition, secondhand smoke constituents produce changes in cervical mucus, which can impair fertility [15, 35].

Although estrogens are associated with fertility and fecundity, progesterone is strongly linked to ovarian cyclicity and maintenance of pregnancy [36]. Cadmium, at levels found in secondhand smoke, inhibits the synthesis of progesterone in trophoblasts and interferes with multiple intrafollicular processes including meiotic maturation and oocyte cumulus expansion [36]. Nicotine, cotinine, and anabasine also inhibit progesterone synthesis in granulosa cells [37]. Oxidative stress, generated by hypoxia and detoxification of xenobiotics via phase I enzymes and more so, phase II enzymes (the glutathione S transferase family), is implicated in pregnancy difficulties, especially spontaneous abortion, mainly as a result of endothelial cell damage to placental vessels [26]. All of the mechanisms are induced via exposure to second-hand smoke and may account for the findings of this study.

The present study had a number of advantages and disadvantages. The data used in this study is prevalence data. Because the participants were reporting on past behaviors, it is unknown whether their reported exposure levels were those that prevailed at the time of the prenatal pregnancy difficulty. Research shows that SHS exposure steadily decreases over a woman’s lifetime [38]. If misclassification was present, it was most likely in the conservative direction, underestimating SHS exposure, which would bias the odds estimates towards the null [39]. While recall bias may be a limitation of this study, it is unclear if this would be differential between cases and controls, especially for an exposure that was generally considered commonplace and socially acceptable. Because of the prevalent nature of the data, it is impossible to establish temporality. Another limitation of this study is the potential of misclassification of the exposure and the various outcomes, since the data used in this study were self-reported. For example, the questionnaire only asked about parental smoking in the home during childhood, but there could have been other relatives living in the house who smoked. Much of this misclassification was an underestimation of their true SHS exposure and there is no evidence to suggest the bias was differential in any direction [40]. Data presented in table 5 shows a U-shaped relationship between hours of daily exposure and study outcomes. While the point estimate for those in 2–5 hours/day category is slightly less than those in the 0.5–1.5 hours/day category, their confidence intervals overlap considerably. Due to this, we have relied on the overall test for trend across the categories as noted on the table. Lastly, only 50% of eligible women who came to RPCI completed the PEDS questionnaire. There is no way to determine whether those individuals who did not complete the questionnaire differed from participants in this study with respect to SHS exposure and the occurrence of PD, which could affect the generalizability of the results. Other authors have used the PEDS database for case-control studies examining cancer odds and successfully replicated those associations [23, 41]. Furthermore, both the descriptive characteristics and odds found in this study are consistent with previous literature examining the association between SHS and PD [10, 17, 28].

Strengths of this study include the diversity of information collected on a number of variables. The exposure variables used in this study included both past exposure to SHS from parents and adult exposure at home, at work, and in other locations. This study is also one of the few with the ability to examine the association between SHS exposure and a number of prenatal pregnancy difficulties (PD). A large number of potential confounders that were used in previous publications were used in this study, which reduced the likelihood that the results seen in this study were due to confounding [10, 20]. Other strengths of this study include the number of women included in the statistical analyses. This study used approximately 4,800 lifelong never-smoking women to examine the association between SHS exposure and PD. The large sample permitted this study to stratify exposures by multiple levels, which allowed for the observation of dose-response relationships while maintaining adequate statistical power. Lastly, another strength of this study is the consistency of the association observed across the various SHS exposure measures for each of the various PD.

The results from this study are consistent with results from a number of other studies that linked SHS exposure to various adverse pregnancy outcomes [3, 16–22]. Although one cannot infer from this study that exposure to SHS causes various adverse pregnancy outcomes, this study adds valuable evidence to the current scientific knowledge and demonstrates the imperative need for further research into this area. The significance of the associations between SHS exposure and adverse pregnancy outcomes underscores the public health doctrine that all persons, especially women in their reproductive years, should be fully protected from tobacco smoke. Based on the current state of knowledge, clinicians are encouraged to strongly recommend smoking cessation and the reduction SHS exposure to women of child bearing age, and to their household contacts, in an attempt to minimize prenatal pregnancy difficulties.