Is the apparently protective effect of maternal nicotine replacement therapy (NRT) used in pregnancy on infant development explained by smoking cessation?: secondary analyses of a randomised controlled trial.

OBJECTIVE: To investigate relationships between maternal smoking status in pregnancy and infant development. The largest randomised controlled trial of nicotine replacement therapy (NRT) for smoking cessation in pregnancy, the smoking, nicotine and pregnancy (SNAP) trial, found that at 1 month after randomisation, smoking cessation rates were doubled in the NRT group compared with the placebo group. At delivery, there was no significant difference in cessation rates between groups. Surprisingly, infants born to women randomised to NRT were more likely to have unimpaired development at 2 years. We hypothesised that this apparently protective effect was due to smoking cessation caused by NRT and so, investigate this relationship using the same cohort. DESIGN: Secondary analysis of a randomised controlled trial. SETTING: Seven antenatal hospitals in the Midlands and North-West England. PARTICIPANTS: Eight hundred and eighty-four pregnant smokers randomised to receive either NRT patches or visually-identical placebo in the SNAP trial. Participants' smoking behaviour were recorded at randomisation, 1 month after their target quit date and at delivery. METHODS: Using logistic regression models, we investigated associations between participants' smoking measures and infant development (assessed using the Ages and Stages questionnaire) at 2 years. MAIN OUTCOME MEASURES: 2 year infant development. RESULTS: Developmental impairment was reported for 12.7% of study 2 year olds. Maternal heaviness of smoking at randomisation (OR: 1.26, 95% CI: 0.82 to 1.96, p=0.091), validated smoking abstinence recorded at 1 month after a quit date (OR: 1.02, 95% CI: 0.60 to 1.74, p=0.914) and validated smoking abstinence recorded at both 1 month after a quit date and at the end of pregnancy (OR: 1.52, 95% CI: 0.81 to 2.85, p=0.795) were not independently associated with infant developmental impairment at 2 years. CONCLUSION: We found no evidence that NRT treatment improved infants' developmental outcomes through smoking cessation. TRIAL REGISTRATION NUMBER: CTA03057/0002/001-0001; Post-results.

Systematic Review and Meta-Analysis to Assess the Safety of Bupropion and Varenicline in Pregnancy.

INTRODUCTION: Smoking in pregnancy is a substantial public health issue, but, apart from nicotine replacement therapy (NRT), pharmacological therapies are not generally used to promote cessation. Bupropion and varenicline are effective cessation methods in nonpregnant smokers and this systematic review investigates their safety in pregnancy. METHODS: We searched MEDLINE, EMBASE, CINAHL, and PsychINFO databases for studies of any design reporting pregnancy outcomes after bupropion or varenicline exposure. We included studies of bupropion used for smoking cessation, depression, or where the indication was unspecified. Depending on study design, quality was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias Tool. Most findings are reported narratively but meta-analyses were used to produce pooled estimates for the proportion of live births with congenital malformations and of the mean birthweight and gestational age at delivery following bupropion exposure. RESULTS: In total, 18 studies were included: 2 randomized controlled trials, 11 cohorts, 2 case- control studies, and 3 case reports. Study quality was variable. Gestational safety outcomes were reported in 14 bupropion and 4 varenicline studies. Meaningful meta-analysis was only possible for bupropion exposure, for which the pooled estimated proportion of congenital malformations amongst live-born infants was 1.0% (95% CI = 0.0%-3.0%, I2 = 80.9%, 4 studies) and the mean birthweight and mean gestational age at delivery was 3305.9 g (95% CI = 3173.2-3438.7 g, I2 = 77.6%, 5 studies) and 39.2 weeks (95% CI = 38.8-39.6 weeks, I2 = 69.9%, 5 studies), respectively. CONCLUSIONS: There was no strong evidence that either major positive or negative outcomes were associated with gestational use of bupropion or varenicline. PROSPERO registration number CRD42017067064. IMPLICATIONS: We believe this to be the first systematic review investigating the safety of bupropion and varenicline in pregnancy. Meta-analysis of outcomes following bupropion exposure in pregnancy suggests that there are no major positive or negative impacts on the rate of congenital abnormalities, birthweight, or premature birth. Overall, we found no evidence that either of these treatments might be harmful in pregnancy, and no strong evidence to suggest safety, but available evidence is of poor quality.

Estimating the health-care costs of children born to pregnant smokers in England: cohort study using primary and secondary health-care data.

BACKGROUND AND AIMS: Little is known about the long-term economic consequences of smoking during pregnancy. We estimated the association between smoking in pregnancy and the costs of delivering health-care to infants and children in England, and investigated which aspects of care are the key drivers of these costs. METHODS: We used Hospital Episode Statistics (HES) linked with Clinical Practice Research Datalink (CPRD) data in England from January 2003 to January 2015 in children with longitudinal data for at least 1, 5 and 10 years after birth. Poisson regression provided rate ratios (RR) and 95% confidence intervals (CIs) comparing health-care episode rates between those exposed and not exposed to smoking during pregnancy. Linear regression was used to compare estimated costs between groups (£ sterling, 2015 prices) and generalized linear multivariable (GLM) models adjusted for potentially moderating factors. RESULTS: A total of 93 152 singleton pregnancies with the required data were identified. Maternal smoking in pregnancy was associated with higher primary care, prescription and hospital in-patient episode rates, but lower out-patient visit and diagnostic test rates. Adjusting for year of birth, socio-economic deprivation, parity, sex of child and delivery method showed that maternal smoking in pregnancy was associated with increased child health-care costs at 1 year [average cost difference for children of smokers, ß = £91.18, 95% confidence interval (CI) = £47.52-134.83 and 5 years of age (ß = £221.80, 95% CI = £17.78-425.83], but not at 10 years of age (ß = £365.94, 95% CI = -£192.72 to £924.60). CONCLUSION: In England, maternal smoking in pregnancy is associated with increased child health-care costs over the first 5 years of life; these costs are driven primarily by greater hospital in-patient care.

The Association Between Treatment Adherence to Nicotine Patches and Smoking Cessation in Pregnancy: A Secondary Analysis of a Randomized Controlled Trial.

INTRODUCTION: In nonpregnant "quitters," adherence to nicotine replacement therapy (NRT) increases smoking cessation. We investigated relationships between adherence to placebo or NRT patches and cessation in pregnancy, including an assessment of reverse causation and whether any adherence: cessation relationship is moderated when using nicotine or placebo patches. METHODS: Using data from 1050 pregnant trial participants, regression models investigated associations between maternal characteristics, adherence and smoking cessation. RESULTS: Adherence during the first month was associated with lower baseline cotinine concentrations (ß -0.08, 95% confidence interval [CI] -0.15 to -0.01) and randomization to NRT (ß 2.59, 95% CI 1.50 to 3.68). Adherence during both treatment months was associated with being randomized to NRT (ß 0.51, 95% CI 0.29 to 0.72) and inversely associated with higher nicotine dependence. Adherence with either NRT or placebo was associated with cessation at 1 month (odds ratio [OR] 1.11, 95% CI 1.08 to 1.13) and delivery (OR 1.06, 95% CI 1.03 to 1.09), but no such association was observed in the subgroup where reverse causation was not possible. Amongst all women, greater adherence to nicotine patches was associated with increased cessation (OR 2.47, 95% CI 1.32 to 4.63) but greater adherence to placebo was not (OR 0.98, 95% CI: 0.44 to 2.18). CONCLUSION: Women who were more adherent to NRT were more likely to achieve abstinence; more nicotine dependent women probably showed lower adherence to NRT because they relapsed to smoking more quickly. The interaction between nicotine-containing patches and adherence for cessation suggests that the association between adherence with nicotine patches and cessation may be partly causal. IMPLICATIONS: This study used placebo randomized controlled trial data to investigate both associations between women's characteristics and adherence to NRT patch treatment, and the relationship between adherence to NRT patch treatment and odds of cessation in pregnant quitters. Greater adherence was seen with NRT patches, and greater adherence with NRT patches increased the odds of smoking cessation. A likely explanation for findings is that NRT patches, if used sufficiently, may be effective for at least some pregnant women who try to stop smoking. Trials testing interventions which encourage women's adherence to higher dose NRT are indicated.

The Nicotine Metabolite Ratio in Pregnancy Measured by trans-3'-Hydroxycotinine to Cotinine Ratio: Characteristics and Relationship With Smoking Cessation.

INTRODUCTION: Nicotine replacement therapy (NRT) helps nonpregnant smokers quit, but there is no evidence that standard dose NRT is effective in pregnancy. As nicotine metabolism increases in pregnancy, this could reduce NRT efficacy. Using the ratio of trans-3'-hydroxycotinine to cotinine, the nicotine metabolite ratio (NMR), we investigated relationships between the rate of nicotine metabolism, maternal characteristics and smoking cessation in pregnant women recruited to a randomized controlled trial of NRT. METHODS: Data from 1,050 pregnant smokers in the Smoking, Nicotine and Pregnancy trial who were of 12-24 weeks gestation had exhaled carbon monoxide readings of ≥8 ppm at recruitment and who were randomized to NRT or placebo patches were used. Linear and logistic regression investigated associations between maternal characteristics and NMR and also between NMR and subsequent validated cessation from smoking. RESULTS: Six hundred and sixty-two women (63%) provided blood samples for NMR estimation. Higher NMR was associated with increased cigarette consumption prior to pregnancy. At 1 month (odds ratio [OR] = 0.87; 95% CI = 0.76-0.99; p = .043) and delivery (OR = 0.79; 95% CI = 0.66-0.95; p = .010), there was a significant negative association between a 0.1 unit increase in NMR and odds of achieving cessation after adjusting for possible confounders. There was no evidence for an interaction between a 0.1 unit increase in NMR and treatment assignment on the odds of cessation at 1 month post-quit date (p = .556). CONCLUSION: Pregnant women who metabolize nicotine more rapidly are less likely to achieve cessation when they try to quit smoking. There is no evidence that NRT is more effective in women who metabolize nicotine more slowly.

Comparison of cotinine levels in pregnant women while smoking and when using nicotine replacement therapy.

BACKGROUND: Nicotine replacement therapy (NRT) helps smokers quit smoking, but trials indicate that there is no evidence that it is effective during pregnancy. As metabolism increases during pregnancy, NRT may deliver insufficient nicotine to alleviate withdrawal symptoms. There is mixed evidence as to what levels of cotinine are reached from nicotine exposure during pregnancy while using NRT compared with smoking. METHODS: We analyzed data on 33 pregnant participants from the NRT arm of a randomized control trial who had stopped smoking and were still using 15 mg/16 hr nicotine patches 1 month after quitting. Salivary cotinine levels when smoking at baseline were compared with levels on NRT at 1 month using the Wilcoxon test. RESULTS: Cotinine levels were a median of 98.5 ng/ml while smoking and 62.8 ng/ml while using NRT and remaining abstinent (p = .045). Participants with the highest cotinine measurements when smoking also tended to have the steepest reduction in cotinine levels while using NRT. This was most noticeable among participants with baseline cotinine levels more than 150 ng/ml (n = 9) who had a greater reduction in median cotinine levels (median difference -134.8 ng /ml [95% CI = -144.5 to -125.9]) than those with a baseline cotinine level under 150 ng/ml (n = 24; median difference -27.9 ng/ml [95% CI = -49.35 to -1.75]). CONCLUSIONS: In a pragmatic trial that replicated clinical practice, cotinine levels generated using NRT during pregnancy were lower than levels achieved from smoking. Although the sample size of this study was small, our findings are significant and are consistent with the hypothesis that NRT patches deliver an inadequate dose of nicotine to aid smoking cessation during pregnancy.

Factors associated with smoking cessation in early and late pregnancy in the smoking, nicotine, and pregnancy trial: a trial of nicotine replacement therapy.

INTRODUCTION: Previous studies have found partners' smoking status, multiparity, and nicotine dependence to be associated with smoking cessation in pregnancy. However, no studies have investigated influences on cessation among women using nicotine replacement therapy (NRT). We analyzed data from a trial of NRT in pregnancy to determine factors associated with shorter- and longer-term cessation. METHODS: Data were collected at baseline, 1 month, and delivery from 1,050 pregnant women. Two multivariable logistic models for validated cessation at 1 month and delivery were created with a systematic strategy for selection of included factors. RESULTS: All findings are from multivariable analyses. At 1 month, odds of cessation were greater among those who completed full time education at >16 years of age (odds ratio [OR] = 1.82, 95% confidence interval CI = 1.24-2.67, p = .002) but they were lower in women with higher baseline cotinine levels (OR = 0.93, 95% CI = 0.90-0.95, p < .001). At delivery, the odds of cessation were greater among those who completed full time education at >16 years of age (OR = 1.89, 95% CI = 1.16-3.07, p = 0.010) but were inversely associated with higher baseline cotinine levels (OR = 0.96, 95% CI = 0.92-0.99, p = .010). CONCLUSIONS: Women who are better educated and have lower pretreatment cotinine concentrations had higher odds of stopping smoking and factors associated with shorter and longer term cessation were similar.