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Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy

BMJ 2014; 348 doi: (Published 11 March 2014) Cite this as: BMJ 2014;348:g1622

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Re: Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy

The study of the nicotine patch in pregnancy by Berlin (1) was well conducted and powered but did not find increased smoking cessation rates compared to placebo control, in spite of attempting to correct for the inadequate nicotine dosing and poor compliance seen in previous studies.

Apart from the issues raised by the authors and the accompanying editorial, (2) one possible explanation for the disappointing result is the failure to allow for the increased rate of nicotine and cotinine metabolism in pregnancy in calculating the replacement nicotine dose.

The dose of nicotine replacement was based on a conversion ratio derived from a previous study of 10 men and 10 non-pregnant women. (3) In this study, 1 mg of nicotine per day was found to equate to each 12.5 ug/L of salivary cotinine. However, this formula needs to be modified for pregnancy as cotinine levels in pregnancy are significantly lower for a given dose of nicotine compared to non-pregnant populations. The clearance of nicotine and cotinine is much faster (60 and 140% respectively) and the half-life of cotinine is much shorter (8.8 versus 16.6 h) during pregnancy. (4)

A study of cotinine levels in 40 pregnant women found that the median cotinine per cigarette in pregnancy is about one third of the cotinine level found postnatally (3.5ng/ml vs 9.8ng/ml). (5) The authors conclude that ‘the available equivalencies between cotinine level and nicotine intake obtained from adult non-pregnant populations cannot be directly applied during pregnancy’.

A similar study of 21 pregnant women (third trimester), concluded ‘At steady state, while receiving nicotine patch therapy and not smoking … morning serum cotinine levels were significantly lower in pregnant subjects compared with non-pregnant women’. (6)

Therefore, the dose of nicotine prescribed for the pregnant women based on serum cotinine using the unadjusted conversion formula may have been less than optimal. This would explain why the mean daily dose of nicotine prescribed was low (18mg in the nicotine patch group) compared to a median daily dose of 35.5mg prescribed for men and non-pregnant women in a previous trial using the same formula. (7)

The absence of a significant difference in nicotine withdrawal and craving relief between the active and placebo groups is also consistent with nicotine underdosing.

Further studies in pregnancy which use this method for calculating the dose of nicotine for individual patients should consider using a modified conversion ratio based on values from pregnant women, so that adequate nicotine replacement can be assured.


1. Berlin I, Grangé G, Jacob N, Tanguy M. Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy. BMJ 2014;348:g1622 doi: 10.1136/bmj.g1622
2. Brose LS. Helping pregnant smokers to quit. BMJ 2014;348:g1808 doi: 10.1136/bmj.g1808
3. Benowitz NL, Jacob P 3rd. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994;56:483-93
4. Dempsey D, Jacob P 3rd, Benbowitz NL. Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharm Exp Ther 2002;3012):594-598
5. Rebagliato M, Bolúmar F, du V Florey C, Jarvis MJ, Perez-Hoyos SP, Hernandez-Aguado I et al. Variations in cotinine levels in smokers during and after pregnancy. Am J Obstet Gynecol 1998;178:568-71
6. Ogburn PL N Jr, Hurt RD, Croghan IT, Schroeder DR, Ramin KD, Offord KP et al. Nicotine patch use in pregnant smokers: Nicotine and cotinine levels and fetal effects. Am J Obstet Gynecol 1999;181:736-43
7. Berlin I, Jacob N, Coudert M, Perriot J, Schultz L, Rodon N. Adjustment of nicotine replacement therapies according to saliva cotinine concentration: the ADONIS* trial—a randomized study in smokers with medical comorbidities. Addiction 2010;106:833–843

Competing interests: Dr Colin Mendelsohn has received payments for teaching, consulting and conference expenses from Pfizer Australia, GlaxoSmithKline and Johnson & Johnson Pacific. Dr Gillian Gould receives an NHMRC and National Heart Foundation postgraduate research scholarship.

07 May 2014
Colin P Mendelsohn
Tobacco Treatment Specialist
Gillian S Gould
The Sydney Clinic
26 Murray St, Bronte 2024 Australia