BACKGROUND Smoking in pregnancy is a substantial public health problem. When used by non-pregnant smokers, pharmacotherapies [nicotine replacement therapy (NRT), bupropion and varenicline] are effective treatments for smoking cessation, however, their efficacy and safety in pregnancy remains unknown. OBJECTIVE To determine the efficacy and safety of smoking cessation pharmacotherapies, including NRT, varenicline and bupropion (or any other medications) when used to support smoking cessation in pregnancy. METHODS We searched the Pregnancy and Childbirth Group's Trials Register (5 March 2012), checked references of retrieved studies and contacted authors in the field. METHODS Randomised controlled trials (RCTs) with designs that permit the independent effects of any type of NRT (e.g. patch, gum etc.) or any other pharmacotherapy on smoking cessation to be ascertained were eligible for inclusion. Trials must provide very similar (ideally identical) levels of behavioural support or cognitive behaviour therapy (CBT) to participants in active drug and comparator trial arms.The following RCT designs are considered acceptable.Placebo RCTs: any form of NRT or other pharmacotherapy, with or without behavioural support/CBT, or brief advice compared with placebo NRT and additional support of similar intensity.RCTs providing a comparison between i) behavioural support/CBT or brief advice and ii) any form of NRT or other pharmacotherapy added to behavioural support of similar (ideally identical) intensity.Parallel- or cluster-randomised design trials are eligible for inclusion. However, quasi-randomised, cross-over and within-participant designs are not eligible for inclusion due to the potential biases associated with these designs. METHODS Two review authors independently assessed trials for inclusion and risk of bias and extracted data. Two assessors independently extracted data and cross checked individual outcomes of this process to ensure accuracy. The primary efficacy outcome was smoking cessation in later pregnancy (in all but one trial, at or around delivery); safety was assessed by seven birth outcomes that indicated neonatal well being and we also collated data on adherence. RESULTS Six trials of NRT enrolling 1745 pregnant smokers were included; we found no trials of varenicline or bupropion. No statistically significant difference was seen for smoking cessation in later pregnancy after using NRT as compared to control (risk ratio (RR) 1.33, 95% confidence interval (CI) 0.93 to 1.91, six studies, 1745 women). Subgroup analysis comparing placebo-RCTs with those which did not use placebos found that efficacy estimates for cessation varied with trial design (placebo RCTs, RR 1.20, 95% CI 0.93 to 1.56, four studies, 1524 women; non-placebo RCTs, RR 7.81, 95% CI 1.51 to 40.35, two studies, 221 women; P value for random-effects subgroup interaction test = 0.03). There were no statistically significant differences in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care or neonatal death between NRT or control groups. CONCLUSIONS Nicotine replacement therapy is the only pharmacotherapy for smoking cessation that has been tested in RCTs conducted in pregnancy. There is insufficient evidence to determine whether or not NRT is effective or safe when used to promote smoking cessation in pregnancy or to determine whether or not using NRT has positive or negative impacts on birth outcomes. Further research evidence of efficacy and safety is needed, ideally from placebo-controlled RCTs that investigate higher doses of NRT than were tested in the included studies.