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While nicotine replacement therapy during pregnancy is potentially hazardous, it is likely that nicotine therapy is less hazardous than cigarette smoking, which exposes both the mother and foetus to both nicotine and a myriad of other toxicants.

Nicotine replacement therapy (NRT) may have two potential benefits during pregnancy. It could reduce or eliminate the exposure of the foetus to other toxicants in cigarette smoke (especially carbon monoxide), and reduce the overall dose and duration of exposure to nicotine (i.e. if used in a treatment course and the result is smoking cessation). One short-term study of nicotine gum use by pregnant smokers demonstrated that the nicotine concentrations and overall exposure (as measured by levels of cotinine) were markedly less than smoking 10 cigarettes per day or greater (Oncken et al., 1996). Furthermore, maternal and foetal haemodynamic effects were generally less with gum versus continued smoking. Studies of transdermal nicotine patch use during pregnancy show that the nicotine exposure is either comparable to, or less than, usual smoking in women who smoke 10 cigarettes per day or greater (Wright et al., 1997; Oncken et al., 1997; Ogburn et al., 1999). In a study of nicotine patch use for four days, morning heart rate decreased after smoking cessation with 22 mg patch use. It was postulated that this could represent a less adverse effect on uterine blood flow or decreased foetal sympathetic activation with nicotine patch compared with usual smoking (Ogburn et al., 1999). One randomized, placebo-controlled study of 250 pregnant smokers found that randomization to 11 weeks of nicotine patch (16 hours/day) did not increase quit rates over placebo (end of pregnancy quit rates were 28% and 25% in the patch versus placebo groups, respectively). Surprisingly, the mean birth weight was 186 grams higher in the nicotine patch group compared to placebo (Wisborg et al., 2000). Although the reason for this finding is unknown, it suggests that NRT does not adversely affect birth weight.

In an open label study, Pollak et al randomized 181 pregnant women to cognitive behavioral therapy with or without NRT (choice of patch, gum or lozenge) and found that women randomized to NRT were more likely to be abstinent at 7 weeks after the quit date and at 38 weeks gestation (Pollak et al., 2007). The study was terminated early by the data safety monitoring board due to a higher incidence of serious adverse events in the NRT treatment condition vs. the control condition (30% vs. 17%).  The most frequent cause of serious adverse events was preterm labor.  It is noteworthy that, women randomized to NRT were more likely to have had a previous preterm delivery than those in the control condition (32% versus 12%). After controlling for history of preterm delivery, the difference in the rate of serious adverse events between the two groups was no longer statistically significant. The authors concluded that this study could not support or negate concerns about adverse effects of NRT during pregnancy.

Morales-Suarez-Varela et al (2005) conducted a retrospective cohort study and suggested that the use of NRT by nonsmokers in the first 12 weeks of pregnancy was associated with a small but significant increase in congenital malformations. However this study suffers from multiple, substantial methodological problems, making its findings difficult to interpret (Le Houezec and Benowitz, 2005). The number of malformations in the NRT group was quite small, and the relative prevalence rate ratios in cases compared to controls were of borderline significance. Concerns exist about possible undetected spontaneous abortion among continuing smokers. Finally, most women who use NRT do so in the second or third trimester, and no adverse event data were reported in these women.

The most rigorous safety data of NRT use  during pregnancy on birth outcomes is from two large randomized placebo-controlled trials  (Wisborg et al., 2000; Oncken et al. 2008).  These studies supported safety (i.e., beneficial effects of nicotine patch or gum vs. placebo on birth weight), but did not support the efficacy  for smoking cessation.  Additionally, nicotine gum vs. placebo gum for smoking treatment reduced the incidence of preterm delivery in one study (Oncken et al. 2008). Although one prospective study did find an increased risk of adverse events with NRT during pregnancy, these findings were not statistically significant after controlling for potential confounders. The safety of NRT is difficult to interpret in this study because of the open label study design, confounding variables, and because approximately one quarter of subjects randomized to NRT reported not using it. Placebo-controlled studies are needed to better assess the safety of various formulations of NRT in pregnancy.  Until definitive safety and efficacy data are available, it is prudent to limit the duration of patch use (i.e. 16 hours versus 24 hours) or to use intermittent dosing forms of NRT (i.e. gum, lozenge, spray or inhaler). Although some authorities recommend that NRT should be reserved for those individuals who are unable to quit without pharmacotherapy, this recommendation should be weighed against the fact that the benefits of cessation are greatest if the cessation occurs early in pregnancy.

Although breast feeding is strictly speaking not part of pregnancy, the issue of nicotine replacement therapy beyond the end of pregnancy, and in particular to prevent relapse to smoking postpartum, is clearly relevant (Benowitz & Dempsey, 2004). The route of nicotine exposure differs between the mother and the baby. The mother's exposure is via the lungs (i.e. the full dose of nicotine is absorbed), whereas the baby absorbs the nicotine through the gastrointestinal tract, after considerable first-pass metabolism (metabolism by the liver before entry into the systemic circulation). In adults, the systemic bioavailability of nicotine after oral administration is 30%-40%. The oral bioavailability of nicotine in the infant is not known but is likely to be much less than 100%.

The concentrations of nicotine in breast milk and mother's serum are highly correlated. However, nicotine is present in higher concentrations in milk than in serum (ratio~2.5-2.9), because the pH of breast milk is relatively acidic (pH~6.8-7.0) compared with serum (7.4). The dose of nicotine taken by the infant from breast milk can be estimated to be around 113 µg nicotine per day by the baby of a smoker or 45 µg per day by the baby of the patch user. For a 4.5-kg baby, this would amount to 25 µg/kg/day and 10 µg/kg/day, respectively. Using the more direct approach of measuring nicotine concentrations in the milk of individual mothers who smoked cigarettes and estimating milk consumption by weighing their infants before and after a feeding, an average daily nicotine dose of 6 µg/kg/day has been calculated. Because the infant is taking nicotine orally with some degree of first-pass metabolism, the systemic dose is probably even less than is estimated by these methods. In contrast, nicotine intake in a 70-kg adult smoking 20 cigarettes per day or using a 21-mg nicotine patch is about 300 µg/kg/day. An adult heavily exposed to secondhand smoke would have a daily intake of 1-2 ug/kg/day. Serum concentrations of nicotine have been measured in infants of breast-feeding mothers and were found to be quite low (range~0-1.6 ng/ml) with an infant-to-maternal serum ratio of 0.06, supporting the idea that infant exposure is quite low.

Thus, the exposure of the infant to nicotine from a mother using nicotine replacement therapy is quite small compared with that of an adult smoker or compared with an adult using nicotine replacement therapy (Illett et al., 2003). It is unlikely that the low level of exposure is hazardous to the infant. In contrast, good evidence indicates that exposure to environmental tobacco smoke by the respiratory route is hazardous to the infant (Oberg et al., 2011). Provision of nicotine replacement therapy to the mother, resulting in her not smoking, would be of great potential benefit to the infant because of reduced exposure to harmful second-hand smoke. On balance, the benefits of breast feeding and smoking abstinence during the postpartum period greatly outweigh the risks of nicotine replacement therapy in the postpartum period.

Oncken CA, Hatsukami DK, Lupo VR, Lando HA, Gibeau LM, Hansen RJ. Effects of short-term use of nicotine gum in pregnant smokers. Clin Pharmacol Ther. 1996; 59: 654-661.

Wright LN, Thorp JM JR, Kuller JA, Shrewsbury RP, Ananth C, Hartmann K. Transdermal nicotine replacement in pregnancy: maternal pharmacokinetics and fetal effects. Am J Obstet Gynecol. 1997; 176: 1090-1094.

Ogburn PL, Hurt RD, Croghan IT, Schroeder DR, Ramin KD, Offord KP, Moyer TP. Nicotine patch use in pregnant smokers: nicotine and cotinine levels and fetal effects. Am J Obstet Gynecol. 1999; 181: 736-743.

Oncken CA, Hardardottir, H, Hatsukami DK, Lupo VR, Rodis JF, Smeltzer JS. Effects of transdermal nicotine or smoking on nicotine concentrations and maternal-fetal hemodynamic effects. Obstet Gynecol. 1997; 90: 569-574.

Wisborg K , Henriksen TB, Jespersen LB, Secher NJ. Nicotine patches for pregnant smokers: a randomized controlled study. Obstet Gynecol. 2000; 96: 967-971.

Pollak KI, Oncken CA, Lipkus IM, Lyna P, Swamy GK, Pletsch PK, Peterson BL, Heine RP, Brouwer RJ, Fish L, Myers ER. Nicotine replacement and behavioral therapy for smoking cessation in pregnancy. Am J Prev Med. 2007; 33: 297-305.

Morales-Suarez-Varela MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol. 2006; 107: 51-57.

Le Houezec J, Benowitz NL. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol, 2006; 107: 1166; author reply 1168. Erratum in: Obstet Gynecol. 2006; 108: 215.

Benowitz N, Dempsey D. Pharmacotherapy for smoking cessation during pregnancy. Nicotine Tob Res. 2004; 6 Suppl 2: S189-S202.

Ilett KF, Hale TW, Page-Sharp M, Kristensen JH, Kohan R, Hackett LP. Use of nicotine patches in breast-feeding mothers: transfer of nicotine and cotinine into human milk. Clin Pharmacol Ther. 2003; 74: 516-524.

Oberg M, Jaakkola MS, Woodward A, Peruga A, Prüss-Ustün A. Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from 192 countries. Lancet. 2011; 377(9760): 139-146. logo
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