Central Nervous System Agent (Smoking Deterrent)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo/Fetal Risk Contraindicated (with any use of tobacco)
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Nicotine is a toxic, highly addictive compound. Although additional studies are needed to determine the magnitude of the embryo/fetal risk from using nicotine replacement therapy (NRT), the risk from cigarette smoking is well known. Cigarette smoke contains more than 3000 different compounds, including nicotine, carbon monoxide, ammonia, polycyclic aromatic hydrocarbons, hydrogen cyanide, and vinyl chloride (see Cigarette Smoking).
Nonpharmacologic approaches to smoking cessation are the safest for the mother and her embryo/fetus, but if these methods have failed, the use of nicotine replacement therapy (NRT) during pregnancy might be reasonable. Women must be counseled that if they continue to smoke while using NRT, such as the dermal patch, the risk to their embryo and/or fetus might be greater than when either is used alone. Reducing smoking before or early in gestation and before starting the dermal patch should be attempted. Other strategies that might lessen the fetal risk include starting the patches after organogenesis, wearing the patches for 16 hours a day, and adherence to the tapering schedule so that the patches can be discontinued after 8–10 weeks. These strategies apply to all NRTs. Nevertheless, a pregnant woman should be informed that exposure to any nicotine, whatever the source, carries a risk of embryo and/or fetal harm.
FETAL RISK SUMMARY
Nicotine is a stimulant that is a major component of tobacco smoke. NRT is used to reduce withdrawal symptoms, including nicotine craving, associated with quitting smoking. The products include skin patches (nicotine transdermal patches), chewing gum (nicotine polacrilex [nicotine resin complex]), nicotine inhaler, and nicotine nasal sprays. Only the inhaler and nasal sprays require a prescription in the United States.
Shepard (1) briefly reviewed a number of animal studies that found widespread nicotine-induced toxicity during pregnancy. The animal species included mice, rats, and rabbits, and accidentally exposed swine. Toxicity included stillbirths, reduced fetal body weight, skeletal defects, cleft palate, limb deformities, hydrocephalus, changes in the brain, toxicity to germ cells and oocytes, and retarded placental development. Schardein also discusses the teratogenicity of tobacco in livestock and experimental animals (2).
The pharmacokinetics of nicotine, its effects on uterine blood flow, and its presence in the fetal compartment are described in the review of cigarette smoking (see Cigarette Smoking). NRT avoids the high nicotine levels associated with cigarette smoking (1). However, it may actually deliver more nicotine to the embryo and fetus (see reference 12 below).
In 2006, a study using data from the Danish National Birth Cohort (1997–2003) evaluated the outcomes of 20,603 women who smoked during the first 12 weeks of pregnancy compared with 56,165 nonexposed controls (3). In the smoking group, there were 1034 (5.0%) liveborn infants with congenital malformations compared with 2733 (4.9%) liveborn infants in the control group (not significant). Malformations of cleft lip, the digestive tract, and the cardiovascular system had significantly high odds ratios. There were 19 (7.6%) liveborn infants with congenital malformations among 250 women who used NRT during the first 12 weeks of pregnancy. Six of the defects were major musculoskeletal congenital malformations. After exclusion of seven cases of dislocation of the hip and one minor defect, the relative prevalence rate ratio (RPR) for major malformations was 1.13 (95% confidence interval [CI] 0.62–2.07) and for musculoskeletal defects was 2.05 (95% CI 0.91–4.63). For smokers, the RPR ranged from 1.01 to 1.09 with no indication of a dose–response association. However, early spontaneous abortions in smokers may have altered the findings. The authors concluded that the data suggested an increased risk of congenital defects in nonsmokers using NRT (3).
Four groups of authors criticized the above study for various reasons, but all were most concerned over the study’s conclusion that smoking may be safer for the fetus than NRT (4–7). Other concerns included the small size of the NRT group, the absence of maternal history, when the NRT was started, the levels of nicotine obtained with smoking compared with NRT, lack of a statistical power estimation, lack of statistical significance, differences between subjects and controls, and the potential for misclassification. In a reply, the authors responded to the concerns and stated that while they did not claim the association to be causal, causality could not be excluded (8).
Women who are attempting to conceive and those who are pregnant should be encouraged to stop smoking (9–13). In addition to the obvious health benefits for the woman, smoking cessation can significantly decrease the known risks to the embryo, fetus, newborn, infant, and adolescent. For example, women who quit smoking in the first 3 or 4 months of pregnancy can lower the risk of a low-birth-weight infant to that of nonsmoking women (9). Smoking cessation also reduces the risk of prematurity and perinatal deaths, and results in fewer infant/adolescent complications (9). Many different strategies have been developed to promote smoking cessation (9–13). A nonpharmacologic approach is preferred, but many women may be heavily addicted to smoking and require NRT and other agents. However, NRT has not been adequately studied in pregnancy. One concern is the potential for nicotine-induced decreased uterine blood flow and increased uterine vascular resistance that could result in impaired fetal growth and other complications.
Transdermal systems appear to be more effective than chewing gum because of improper use and taste of the latter (10). On the other hand, transdermal patches may actually deliver more nicotine to the embryo/fetus because continuous blood levels of nicotine, in contrast to periodic levels from episodic smoking, are available to cross the placenta (12). One strategy to reduce the amount of embryo–fetal nicotine exposure is to apply the patches for only 16 hours a day (4).
Based on four published studies of NRT in pregnancy, two involving patches, gum in one, and any type of NRT in one, a 2010 review concluded that the therapy decreased the risk for low birth weight and preterm delivery compared with continued smoking (14).
BREASTFEEDING SUMMARY
No reports describing the use of NRT during lactation have been located. Nicotine is excreted into breast milk (see Cigarette Smoking). Although there are significant risks from cigarette smoking for the mother and her nursing infant, the risks of exposure to NRT have not been defined. The American Academy of Pediatrics encourages smoking cessation during lactation, but makes no recommendation for or against NRT because of insufficient data (15).
References
1.Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:361–2.
2.Schardein JL. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:981–2.
3.Morales-Suarez-Varela MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:51–7.
4.Le Houezec J, Benowitz NL. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:1166.
5.Davidson P. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:1166–7.
6.Einarson A, Sarkar M, Djulus J, Koren G. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:1167.
7.Dempsey DA, Stewart SI. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:1167–8.
8.Morales-Suarez-Varela MM, Olsen J, Bille C, Christensen K. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:1168.
9.Adams J. Statement of the Public Affairs Committee of the Teratology Society on the importance of smoking cessation during pregnancy. Birth Defects Res A Clin Mol Teratol 2003;67:895–9.
10.Kendrick JS, Merritt RK. Women and smoking: an update for the 1990s. Am J Obstet Gynecol 1996;175:528–35.
11.Floyd RL, Rimer BK, Giovino GA, Mullen PD, Sullivan SE. A review of smoking in pregnancy: effects on pregnancy outcomes and cessation efforts. Annu Rev Publ Health 1993;14:379–411.
12.Slotkin TA. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther 1998;285:931–45.
13.American College of Obstetricians and Gynecologists. Smoking cessation during pregnancy. Committee Opinion. No. 471, November 2010. Obstet Gynecol 2010;116:1241–4.
14.Forinash AB, Pitlick JM, Clark K, Alsat V. Nicotine replacement therapy’s effect on pregnancy outcome. Ann Pharmacother 2010;44: published online, 26 Oct 2010, theannals.com. doi:10.1345/aph.1P279.
15.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.