Obstetrics & Gynecology:
Smoking Habits, Nicotine Use, and Congenital Malformations
Morales-Suárez-Varela, María M. MD, PhD1,2; Bille, Camilla3; Christensen, Kaare3; Olsen, Jorn MD, PhD4,5
From the 1Unit of Public Health and Environmental Care, Department of Preventive Medicine, University of Valencia, Valencia, Spain; 2Unit of Clinical Epidemiology, Dr. Peset University Hospital, Valencia, Spain; 3Institute of Public Health, Epidemiology, University of Southern Denmark, Odense, Denmark; 4Danish Epidemiology Science Centre, University of Aarhus, Aarhus, Denmark; and 5Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California.
Supported by a grant from the Danish Research Agency (No. 1105-93 and 11099-96). Financing from the Danish National Research Foundation resulted in the Danish National Birth Cohort. Additional support was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Augustinus Foundation.
Corresponding author: María Morales-Suárez-Varela, Unit of Public Health and Environmental Care, Department of Preventive Medicine, University of Valencia, Avda, Vicente Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain; e-mail: firstname.lastname@example.org.
OBJECTIVE: We examined whether maternal smoking and use of nicotine substitutes during the first 12 weeks of pregnancy increased the prevalence of congenital malformations in general and of certain congenital malformations in particular.
METHODS: In the Danish National Birth Cohort (1997–2003) we identified 76,768 pregnancies (and their subsequent singleton births); 20,603 were exposed to tobacco smoking during the first 12 weeks of pregnancy. Birth outcomes were collected by linkage to the Central Population Register, the National Patients Register, and the National Birth Register. We identified congenital malformations from the Hospital Medical Birth Registry as they were recorded at birth or in the first year of follow-up.
RESULTS: Smoking mothers were younger, weighed less, consumed more alcohol, and had received less education. Children exposed to prenatal tobacco smoking had no increase in congenital malformations prevalence compared with the nonexposed children in both crude and adjusted analyses. Children born to nonsmokers, but who used nicotine substitutes, had a slightly increased relative congenital malformations prevalence ratio; relative prevalence rate ratio was 1.61 (95% confidence interval 1.01–2.58), which represents a 60% increased risk. When the analysis was restricted to musculoskeletal malformations, the relative prevalence rate ratio was 2.63 (95% confidence interval 1.53–4.52).
CONCLUSION: Our results showed no increase in congenital malformations related to prenatal tobacco smoking. However, we identified an increase of malformations risk in nonsmokers using nicotine substitutes. This finding needs to be replicated in other data sources.
LEVEL OF EVIDENCE: II-2
Tobacco smoking is the most prevalent fetotoxic exposure during pregnancy in many countries.1–3 Tobacco smoking reduces fetal growth, increases the risk of certain placenta complications and fetal death. Some studies show a long-lasting effect on childhood health, especially asthma, perhaps also reduced semen quality,4 and attention deficit and hyperactivity disorder.5–7 Whether smoking during pregnancy increases the prevalence of congenital malformations at birth is still unsettled, but the existing literature shows no strong teratogenic effects, if any at all,8–15 except for oral clefts. However, many of the studies have been based on small sample sizes or based on a retrospective recall of smoking that may mask an effect, because women who had a child with a congenital malformation may underestimate their smoking habits. Large cohort studies with prospective data on smoking and confounders are therefore needed.
Smoking cessation programs should always be offered to smokers who plan a pregnancy, but whether these smoking cessation programs should include nicotine substitutes is unknown. Nicotine is fetotoxic, but one could argue that if nicotine replacement (patches, gum, or inhalers) is the only effective smoking cessation tool for some pregnant women, it is a better alternative than smoking, because hundreds of potentially harmful substances are replaced by a single 1. On the other hand, nicotine substitutes have a different absorption route and may reach higher peak values. The objective of this study is to estimate the relative prevalence ratio of congenital malformations in smokers as well as in women who used nicotine substitutes in the Danish National Birth Cohort during the first 12 weeks of pregnancy.
MATERIALS AND METHODS
The Danish National Research Foundation established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. Altogether, 78,500 pregnant women were enrolled in the Danish National Birth Cohort at the time of study and gave birth between January 1997 and December 2003.16 If a woman provided more than 1 pregnancy to the cohort, we excluded all subsequent pregnancies (n = 1,708). The remaining women (76,792) all had their first pregnancies in the cohort during the study period. By linking the enrolled mothers to both the Central Population Register, the National Patients Register, and the Medical Birth Registry by means of the unique personal identification numbers, we identified 76,768 pregnancies that resulted in live births and where the mothers had answered the smoking questions. Data from the medical birth register identified the congenital malformations diagnosed by hospital doctors at birth or during the first year of life. We excluded pregnancies in women who had ovarian cancer or cervical cancer or who gave birth to twins or triplets, because malformations are more common in multiple pregnancies than in singleton pregnancies.17,18 There were 20,603 pregnancies resulting in live births of mothers who reported that they had smoked during the first 12 weeks of pregnancy and 56,165 live births of mothers who did not smoke during this pregnancy period (Fig. 1).
During the first interview (11–25 completed weeks of gestation) the women were asked in detail about their smoking habits. The interview assessed smoking at the time of the interview, which weeks of gestation they smoked, how much they smoked on average, and the type of tobacco they smoked. They were also asked about their use of nicotine gum, nicotine patches, or nicotine inhalers during the first 12 weeks of the pregnancy.
All live births were reported to the National Birth Register by the hospitals where the birth took place, and the reports included detailed information on the newborn and the delivery. Data on congenital malformations were obtained from the Medical Birth Registry, which includes all congenital malformations (International Classification of Disease, 10th Revision, codes Q00-Q99) diagnosed at birth or during the first year of life. Data on hereditary diseases and chromosome abnormalities diagnosed during the first year of life were obtained from the National Hospital Discharge Registry. We based our results upon the clinical diagnoses reported in the first year of life because we have complete follow-up for these diagnoses.
As potential confounders, we included data that were found to be risk factors for congenital malformations11–14 and were available in the database (Table 1).
We examined tobacco smoking and nicotine use as determinants of congenital malformations by taking the variables in Table 1 as potential confounders into consideration. All these variables were included in logistic regression models and were dropped one by one unless they changed the effect size by more than 5%.
Frequency and volume of alcohol intake were converted into number of drinks. In Denmark, 1 drink on average contains 12 g of alcohol (1 glass of wine, 1 beer, or 40 mL of spirits). The total grams of ethanol per day were categorized into quartiles.
We classified all malformations before performing data analyses, using the groups presented in Table 1. Subsequently, we classified all the congenital malformations (as major or minor congenital malformations) following the EUROCAT criteria (part 7 of the former EUROCAT Guide 1.219). We furthermore excluded hip dislocation from the major congenital malformations because they are known to be frequently overdiagnosed. The major congenital malformations were then divided into musculoskeletal malformations and others. The relative prevalence rate ratios (RPRs) were calculated for specific congenital malformations given the fact that the study was based on a cohort.20 All confidence intervals (CIs) were 95%. Analyses were performed with SPSS 11.5 software (SPSS Inc., Chicago, IL). All the personal identification numbers were deleted after register linkage. The cohort was approved by all the ethic committees in the country and by the Danish Data Protection Board.
The baseline characteristics of smokers and nonsmokers during the first 12 weeks of pregnancy are shown in Table 1. In the entire study, 26.8% stated they had smoked during that period. During the pregnancy, the smoking members of the cohort were younger, had a lower body weight, a higher alcohol intake, and were less educated than nonsmokers.
No significant difference was observed between the overall congenital malformation prevalence in the 2 cohorts (5.0% among smokers and 4.9% among nonsmokers) (Table 2). The distribution of congenital malformation types also showed a rather similar pattern in the 2 cohorts, albeit with a slight excess of circulatory malformations among smokers (Table 3).
In Table 4, we observed an RPR of 1.1. for all congenital malformations among smokers. We calculated the RPR for specific congenital malformations after adjusting for potential confounders (age and alcohol intake) (Table 4). Malformations of cleft lip or the digestive or cardiovascular system had significantly high odds ratios. Malformations of eye, ear, neck, and face, urinary, or musculoskeletal system were slightly less frequent among smoking-exposed children than they were for children who were not exposed to smoking during their first trimester of fetal life.
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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