Abstract: We included 11 trials that enrolled a total of 2412 pregnant women who smoked at enrolment, nine trials of NRT and two trials of bupropion as adjuncts to behavioural support, with comparable behavioural support provided in the control arms. No trials investigated varenicline or ECs. We assessed four trials as at low risk of bias overall. The overall certainty of the evidence was low across outcomes and comparisons as assessed using GRADE, with reductions in confidence due to risk of bias, imprecision, and inconsistency. Compared to placebo and non-placebo (behavioural support only) controls, there was low-certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). However, in subgroup analysis by comparator type, there was a subgroup difference between placebo-controlled and non-placebo controlled RCTs (test for subgroup differences P = 0.008). There was unclear evidence of an effect in placebo-controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non-placebo-controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women). An additional subgroup analysis in which studies were grouped by the type of NRT used found no difference in the effectiveness of NRT in those using patches or fast-acting NRT (test for subgroup differences P = 0.08). There was no evidence of a difference between NRT and control groups in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, caesarean section, congenital abnormalities, or neonatal death. In one study infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' at two years of age compared to the placebo group. Non-serious adverse effects observed with NRT included headache, nausea, and local reactions (e.g. skin irritation from patches or foul taste from gum), but data could not be pooled. Adherence to NRT treatment regimens was generally low. We identified low-certainty evidence that there was no difference in smoking abstinence rates observed in later pregnancy in women using bupropion when compared to placebo control (RR 0.74, 95% CI 0.21 to 2.64; I² = 0%, 2 studies, 76 women). Evidence investigating the safety outcomes of bupropion use was sparse, but the existing evidence showed no difference between the bupropion and control group. NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non-placebo-controlled RCTs were excluded from the analysis. Future studies may therefore change this conclusion. We found no evidence that NRT has either positive or negative impacts on birth outcomes; however, the evidence for some of these outcomes was also judged to be of low certainty due to imprecision and inconsistency. We found no evidence that bupropion may be an effective aid for smoking cessation during pregnancy, and there was little evidence evaluating its safety in this population. Further research evidence on the efficacy and safety of pharmacotherapy and EC use for smoking cessation in pregnancy is needed, ideally from placebo-controlled RCTs that achieve higher adherence rates and that monitor infants' outcomes into childhood. Future RCTs of NRT should investigate higher doses than those tested in the studies included in this review.

Plain-language summary: We searched for evidence on 20 May 2019 and identified 11 randomised studies (studies in which participants are assigned to one of two or more treatment groups using a random method) that enrolled a total of 2412 women. Nine studies tested NRT used alongside counselling to stop smoking, whilst the other two studies tested bupropion. Low-quality evidence suggests that NRT combined with behavioural support might help women to stop smoking in later pregnancy more than behavioural support alone. Medication trials often use placebos, that is tablets or patches that look like the drug but do not actually include it, so that each comparison group has equal expectation of success and there is a fairer test of the benefits of the medicine itself. When just the higher-quality, placebo-controlled trials were analysed, the evidence suggested that NRT was more effective than placebo NRT. There was no evidence that either nicotine patches or fast-acting NRT (such as gum or lozenge) was more effective than the other. Low-quality evidence suggests that bupropion may be no more effective than placebo in helping women quit smoking later in pregnancy. We found no trials investigating other smoking cessation pharmacotherapies or electronic cigarettes. There was insufficient evidence to conclude whether NRT had either positive or negative impacts on rates of miscarriage, stillbirth, preterm birth (less than 37 weeks), mean birthweight, low birthweight (less than 2500 g), admissions of babies to neonatal intensive care, or newborn deaths. However, in one trial where infants were followed until two years of age, those infants born to women who had been randomised to NRT were more likely to have healthy development. Similarly, it is unclear whether bupropion had a positive or negative impact on birth outcomes. Studies that looked at whether women used their stop smoking medications as instructed found that use was generally low, and the majority of women used little of the NRT they were given. More research evidence is needed, in particular placebo-controlled trials that test higher doses of NRT, encourage women to use sufficient medication, and follow infants into childhood. Furthermore, more studies are required investigating the effect and safety of bupropion, electronic cigarettes, and varenicline for giving up smoking during pregnancy.