Only a very small number (8) of smoking mothers stated they smoked other types of tobacco than cigarettes, and they were excluded from the analyses. The RPR was close to 1 in both smoking strata, specifically, 1.09 for 10 cigarettes per day or fewer and 1.02 for more than 10 cigarettes per day, with no indication of a dose–response association (Table 5). We had hospital reports of 19 malformations and an RPR of 1.61 (95% CI 1.01–2.58) for nonsmokers who used nicotine substitutes during the first 12 weeks of pregnancy (Table 5). Among these, 14 were musculoskeletal congenital malformations (7 were dislocation of the hip). The RPR for congenital malformations of the musculoskeletal type (excluding dislocation of the hip) in nicotine substitute users was 2.63, (95% CI 1.53–4.52), compared with nonsmokers who did not use nicotine substitutes.
By following the criteria from EUROCAT’s guide Part 7 (Criteria for Minor Anomalies for Exclusion), minor congenital malformation types were eliminated. Then, the analyses were repeated for all major congenital malformations and major musculoskeletal congenital malformations (Table 6). In both groups, the RPR was close to 1 among smokers, with no indication of a dose–response association. For nonsmokers using nicotine substitutes, an RPR of 1.13 (95% CI 0.62–2.07) was observed for all the major congenital malformation groups, and an RPR of 2.05 (95%CI 0.91–4.63) was seen for major musculoskeletal congenital malformations.
Our results showed no increased overall prevalence of congenital malformations among smokers. We found a slightly increased relative prevalence ratio for major malformations, but with no dose–response pattern.
The prevalence of certain specific malformations, such as cleft lip and palate malformations of the respiratory and circulatory systems, is probably increased by smoking habits, although this may be counterbalanced by a lower prevalence in other malformation types (urinary system, and eye, ear, face, and neck).11,12,21,22 A low prevalence of malformations does not necessarily indicate a preventive effect of smoking, but it may reflect an increased abortion rate in affected offspring among the smokers.
The increased prevalence of congenital malformation in smokers for cleft lip and others is in accordance with previous studies in both humans11,12,21–23 and animals,24,25 and in vitro studies have shown that nicotine inhibits palate fusion. Other animal experiments24,25 indicate that tobacco smoke leads to a reduction in the numbers of skeletal ossifications.
Our findings indicate that nicotine may be teratogenic when used in nicotine substitutes, although they are based upon small numbers. If nicotine is teratogenic, why is this not seen for smokers? The reasons could be that inhaled heated nicotine in tobacco smoke is absorbed by a different route (ingested or transdermal).26–29 Nicotine used to substitute tobacco smoking may furthermore reach higher peak doses than we find for smokers, and nicotine in substitutes is not heated as in tobacco. Furthermore, chewing nicotine gum may also increase exposure to mercury, for example, from amalgam dental fillings.30
A slight change in the RPR was observed after eliminating minor congenital malformations. The overall RPR dropped from 2.63 to 2.05, indicating that nicotine may be more strongly associated with minor congenital malformations that are difficult to diagnose.
Experiments with rodents show that nicotine has a higher dose–response effect in adolescents than in adults; nicotine activity increases,31 there is more oxidative damage,30 there is cardiac turnover of catecholamines,32 and nicotine reacts with the hypothalamus and pituitary gland.32 Nicotine has an effect on the fetus in animal studies, but whether it includes a teratogenic effect remains uncertain.31,32
Tobacco contains several hundred chemical substances. Some of these cross the placental barrier, whereas others do not. Because the possible teratogenic effect of smoking is very slight and is only present for a few specific malformations, it is likely that most potential teratogenic substances do not pass the placental barrier.33,34 It is also possible that a teratogenic effect of tobacco smoking may be masked by a fetotoxic effect, leading to early spontaneous abortions. It is known that smoking leads to subfecundity,25 and subfecundity may reflect early (preclinical) abortions.
Prenatal screening may also reduce the association between an exposure and the prevalence of malformations, although screening at the time of data collection only included screening for Down’s syndrome as a routine for women aged older than 35 years and for women who had previously had a child with a congenital malformation. We have no reason to believe that screening was performed more often in smokers. Because women with a history of congenital malformation may reduce smoking in a subsequent pregnancy, we restricted some of the analyses to first-born children alone, and the results found were similar to those presented.
Smoking is an accepted habit in Denmark, even during pregnancy, and we believe the self-reporting to be quite accurate. Furthermore, the proportion of smokers we found is in line with other reports from the same period. We have not included data on passive smoking because this exposure is low compared with active smoking.
Data on congenital malformations stem from the hospital registry and include not only malformations diagnosed at birth (less than 60% of all malformations), but also malformations diagnosed during the first year of life. Validation studies show16,35 that these diagnoses are not without error, but the misclassification is likely to be nondifferential.
The association found for specific malformations is low and may be caused by uncontrolled confounding, although results were adjusted for a number of life-style factors and social indicators. There is, however, sufficient evidence for a harmful, overall fetotoxic effect of smoking to warn pregnant women not to smoke at all during pregnancy.36–39 The potential role of nicotine substitutes in causing musculoskeletal congenital malformations must be more carefully studied, especially for smokers who are considering pregnancy.
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