Nicotine replacement therapy in pregnancy

Smoking harms unborn children. It increases the risk of growth restriction, preterm birth, miscarriage, and perinatal death,¹,² but despite this over a quarter of pregnant women in the United Kingdom smoke.³ Pregnancy motivates a minority to stop for at least part of the pregnancy, but most start again after giving birth.³ Compared with women who manage to stop, those who continue are younger and less educated; more likely to be single and in manual occupations;⁴ and much less likely to perceive smoking as a risk to their baby.³ Reducing smoking in pregnancy is an obvious health priority, but progress has been slow.³

Non-pregnant smokers are most likely to quit if offered a combination of behavioural support and pharmacotherapy with either nicotine replacement therapy⁵ or bupropion.⁶ The addition of pharmacotherapy increases quit rates obtained with behavioural support by 1.5-fold to 2-fold. Behavioural support is also effective in pregnancy,⁷ but is usually provided alone because of concerns that drugs may harm the fetus.⁸ This is understandable for bupropion, which is an avoidable drug, but nicotine is different. Nicotine is part of the exposure of smoking, and if nicotine replacement is used instead of cigarettes, exposure to the many other toxins in tobacco smoke is avoided. If nicotine replacement were as effective in pregnant smokers as in non-pregnant smokers, withholding it would be harmful.

To date, however, the efficacy of nicotine replacement therapy in pregnancy is not known. The only completed and published randomised controlled trial of nicotine replacement (delivered by transdermal patches) showed no difference from placebo, but the numbers studied were small, and the trial was underpowered to determine whether nicotine replacement was effective.⁹ Nevertheless, babies born to women in the nicotine treatment group had significantly higher birth weights than those in the placebo group (mean difference 186 g (95% confidence interval 35 g to 336 g)), indicating that the intrauterine growth restriction caused by smoking is probably not attributable to nicotine. Little other evidence supports the recommendation of the UK National Institute for Clinical Excellence (NICE), that pregnant women can use nicotine replacement “after discussion with a health professional.”¹⁰ This lack of evidence also explains the caution evident in UK and US guidelines for managing smoking cessation, which state, respectively, that “the use of [nicotine replacement therapy] by pregnant smokers may benefit mother and foetus if it leads to smoking cessation”⁸ and “special consideration” is needed before using nicotine replacement in pregnancy.¹¹

Nicotine is metabolised more quickly in pregnancy.¹² Plasma clearances of nicotine and cotinine (its principal metabolite) are increased by 60% and 140%, respectively, and the half life of cotinine is reduced in pregnant women (9 h v 17 h in non-pregnant women). Among continuing smokers this could, in theory, lead to compensatory smoking to maintain desired nicotine concentrations, and hence increase fetal harm. It may also reduce the efficacy of nicotine replacement since conventional doses will provide less nicotine substitution. Higher doses of nicotine replacement might, therefore, be needed in pregnancy, but could these increase the risk of fetal damage?

Nicotine gum and patches cause dose related increases in maternal blood pressure and heart rate and lesser effects on the fetal heart rate, but these changes are less pronounced than those caused by smoking.¹³ In rodents chronic nicotine exposure, albeit at much higher plasma concentrations than occur in pregnant smokers or nicotine replacement users, is associated with dose dependent changes in behavioural and cognitive responses, a diminished adrenal response to hypoxia that may predispose to sudden infant death syndrome, and central nervous system toxicity.¹³

The route of nicotine administration may also be important by altering the time profile of exposure. Nasal sprays and chewing gum tend to produce high plasma nicotine concentrations for short periods, and when these are used regularly throughout the day nicotine exposure is similar to that from smoking. Patches produce lower, longer lasting, steadier concentrations, and when these are worn for 24 hours they cause continual exposure of the fetus to nicotine, even throughout the night. It is not clear whether this additional nocturnal exposure matters.

Determining policy about nicotine replacement in pregnancy is difficult. Logically nicotine replacement should be safer than smoking, but there is no direct evidence that this is so. Conventional doses may be less effective in pregnancy, but too much nicotine could damage the fetus, and the time profile of nicotine exposure from longer acting nicotine replacement products may also contribute to fetal harm. The overall ratio of benefits and harms of using nicotine replacement in pregnancy depends on any extra effectiveness of nicotine replacement when used in addition to behavioural support⁷ and any additional risk incurred from effective doses of nicotine delivered via different delivery modes. Any harm caused by nicotine replacement must be compared with that caused by continued smoking—which is extremely harmful to both the woman and her child. Clear evidence of effectiveness and safety is required. We need definitive randomised, placebo controlled, clinical trials of a range of doses and administration routes for nicotine replacement in pregnancy.