Experts' views on translating NHS support to stop smoking in pregnancy into a comprehensive digital intervention.

Many pregnant smokers need support to quit successfully. In the United Kingdom, trained smoking cessation advisors deliver structured behavioural counselling alongside access to free nicotine replacement therapy (NRT); known as the 'Standard Treatment Programme' (STP). Pregnant smokers who access STP support are more likely to quit, but uptake is low. A digital intervention could be offered as an adjunct or alternative to existing STP support to increase cessation rates. However, there are few pregnancy-specific digital options routinely available and, among those that are, there is limited evidence of their effectiveness. This study investigated experts' views on the feasibility of translating the STP into a comprehensive digital intervention. Virtual group and individual interviews were undertaken with 37 experts (11 focus groups, 3 interviews) with a real-time voting activity in the focus groups to prompt discussion. Framework Analysis was applied to the data to examine themes and patterns. Experts were supportive of a digital translation of the STP and considered most behavioural counselling content to be transferable. However, replicating human-to-human accountability, empathy and the ability to go 'off-script' was thought more challenging. Suggestions for how this might be achieved included tailoring and personalisation, use of artificial intelligence tools, peer support and the option to escalate contact to a human advisor. Experts had mixed views on the role that exhaled breath carbon monoxide monitoring might have in a digital cessation intervention for pregnancy. Electronic provision of free NRT, and potentially e-cigarettes, without interpersonal support was generally well received. However, experts had concerns about it exacerbating low NRT adherence, governance issues (e.g. being accountable for the suitability of recommended products), and people's ability to misrepresent their eligibility. The STP was considered largely transferable to a digital intervention and potentially helpful for cessation in pregnancy, so merits further development and evaluation.

The effectiveness of text support for stopping smoking in pregnancy (MiQuit): multi-trial pooled analysis investigating effect moderators and mechanisms of action.

INTRODUCTION: Digital cessation support appeals to pregnant smokers. In two pooled RCTs, MiQuit, a pregnancy-specific tailored text messaging intervention, did not show effectiveness for validated prolonged abstinence. However, secondary outcomes and potential moderators and mediators have not been investigated. We aimed to determine, using pooled RCT data: 1) MiQuit effectiveness for a range of smoking outcomes; 2) whether baseline tobacco dependence or quit motivation moderate effectiveness; 3) whether hypothesized mechanisms of action (quitting determination, self-efficacy, baby harm beliefs, lapse prevention strategies) mediate effectiveness. METHODS: Pooled data analysis from two procedurally identical RCTs comparing MiQuit (N=704) to usual care (N=705). Participants were smokers, <25 weeks pregnant, recruited from 40 English antenatal clinics. Outcomes included self-reported seven-day abstinence at four weeks post-baseline and late pregnancy, and prolonged abstinence. Late pregnancy outcomes were also biochemically validated. We used hierarchical regression and Structural Equation Modelling. RESULTS: MiQuit increased self-reported, seven-day abstinence at four weeks (OR=1.73 [95% CI 1.10-2.74]) and was borderline significant at late pregnancy (OR=1.34 [0.99-1.82]) but not for prolonged or validated outcomes. Effectiveness was not moderated by baseline dependence (Heaviness of Smoking "low" versus "moderate-high") or motivation (planning to quit ≤30 days [high] versus >30days [low]), but effects on self-reported outcomes were larger for the high motivation sub-group. MiQuit had a small effect on mean lapse prevention strategies (MiQuit 8.6 [SE 0.17], UC 8.1 [SE 0.17]; P=0.030) but not other mechanisms. CONCLUSIONS: MiQuit increased short-term but not prolonged or validated abstinence and may be most effective for those motivated to quit sooner. IMPLICATIONS: Digital cessation support appeals to pregnant smokers. MiQuit, a tailored, theory-guided text messaging program for quitting smoking in pregnancy, has not shown effectiveness for validated prolonged abstinence in two previous RCTs but its impact on other smoking outcomes and potential mechanisms of action are unknown. When pooling trial data, MiQuit increased self-reported short-term abstinence, including making a quit attempt and abstinence at four-week follow-up, but not late pregnancy, sustained or validated abstinence. MiQuit appeared effective at late pregnancy for participants with high quitting motivation, but its mechanisms of action remain uncertain. Additional support components are likely required to enhance effectiveness.

Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

Prognostic factors for mortality, intensive care unit and hospital admission due to SARS-CoV-2: a systematic review and meta-analysis of cohort studies in Europe.

BACKGROUND: As mortality from coronavirus disease 2019 (COVID-19) is strongly age-dependent, we aimed to identify population subgroups at an elevated risk for adverse outcomes from COVID-19 using age-/gender-adjusted data from European cohort studies with the aim to identify populations that could potentially benefit from booster vaccinations. METHODS: We performed a systematic literature review and meta-analysis to investigate the role of underlying medical conditions as prognostic factors for adverse outcomes due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including death, hospitalisation, intensive care unit (ICU) admission and mechanical ventilation within three separate settings (community, hospital and ICU). Cohort studies that reported at least age and gender-adjusted data from Europe were identified through a search of peer-reviewed articles published until 11 June 2021 in Ovid Medline and Embase. Results are presented as odds ratios with 95% confidence intervals and absolute risk differences in deaths per 1000 COVID-19 patients. FINDINGS: We included 88 cohort studies with age-/gender-adjusted data from 6 653 207 SARS-CoV-2 patients from Europe. Hospital-based mortality was associated with high and moderate certainty evidence for solid organ tumours, diabetes mellitus, renal disease, arrhythmia, ischemic heart disease, liver disease and obesity, while a higher risk, albeit with low certainty, was noted for chronic obstructive pulmonary disease and heart failure. Community-based mortality was associated with a history of heart failure, stroke, diabetes and end-stage renal disease. Evidence of high/moderate certainty revealed a strong association between hospitalisation for COVID-19 and solid organ transplant recipients, sleep apnoea, diabetes, stroke and liver disease. INTERPRETATION: The results confirmed the strong association between specific prognostic factors and mortality and hospital admission. Prioritisation of booster vaccinations and the implementation of nonpharmaceutical protective measures for these populations may contribute to a reduction in COVID-19 mortality, ICU and hospital admissions.

Experiences and views of parents on the prevention of second-hand smoke exposure in Middle Eastern countries: a qualitative systematic review.

OBJECTIVE: The objective of this review was to identify, appraise, and synthesize the evidence related to experiences and views of parents, children, and professionals on the prevention of second-hand smoke exposure to women and children in Middle Eastern countries. INTRODUCTION: Second-hand smoke exposure is a major health concern. It is problematic during pregnancy because of potential adverse reproductive effects and poor fetal outcomes. Childhood second-hand smoke exposure is linked to increased morbidity and mortality. Smoking prevalence is high among men in Middle Eastern countries and, as a result, large numbers of non-smoking men, women, and children are exposed to second-hand smoke daily. INCLUSION CRITERIA: Studies were considered for inclusion if they explored experiences and views on the prevention of second-hand smoke exposure among women and children in homes, workplaces, schools, personal vehicles, and public places in 17 Middle Eastern countries. This review included studies that focused on qualitative data, including, but not limited to, designs such as phenomenology, grounded theory, ethnography, qualitative descriptive, and feminist research. METHODS: MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and Scopus databases were searched to identify published studies from inception to January 2021. The search for unpublished studies included EThOS, OpenGrey, and ProQuest Dissertations and Theses. No language restrictions were applied. The JBI guidelines for qualitative systematic reviews were followed in conducting the review. The JBI process of meta-aggregation was used to identify categories and synthesize findings. RESULTS: Of 5229 records identified, two qualitative studies (in three publications) met the eligibility criteria and were included in the review. One study was conducted in Turkey and the other study (reported in two papers) was conducted in Israel. The methodological quality of the studies was high. The participants in the included studies were parents (n = 118 participants) aged between 18 and 42 years. The methods used for data collection were interviews analyzed using thematic content analysis. A total of 50 findings were extracted and aggregated into eight categories, based on the similarity of meaning. Three synthesized finding were generated (all with moderate confidence): i) Parents were aware of second-hand smoke and that exposure to second-hand smoke is harmful, although the health dangers of second-hand smoke exposure were not commonly discussed with parents during pregnancy;ii) Smoking is a socially and culturally accepted norm, with parents reporting cultural beliefs about traditional values as a barrier to reducing second-hand smoke exposure in the home and personal psychological factors to quitting smoking; iii) Parents implemented different physical restrictions on smoking, such as having rules about where smoking can take place, with psychological motivators reported as drivers to decrease second-hand smoke exposure among children in the home, but tended to lack certainty or confidence regarding whether such protective measures were needed or would be effective. CONCLUSIONS: The findings of this study offer an insight into parents' views on second-hand smoke exposure and its prevention in Middle Eastern countries. Parents have conflicting views on second-hand smoke exposure and techniques to minimize it. Interventions are needed to increase parents' knowledge about the harms of second-hand smoke to reduce women's and children's exposure to second-hand smoke. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42019137006.

Impact of Smoking and Vaping in Films on Smoking and Vaping Uptake in Adolescents: Systematic Review and Meta-Analysis.

Prevention of smoking uptake in young people is an essential public health target. We have previously reported a systematic review and meta-analysis of the effect of exposure to smoking imagery in films on the risk of smoking uptake in young people. This study updates that review, and includes studies of the effects of exposure to media vaping imagery on vaping uptake. Four electronic databases (MEDLINE, EMBASE, PsycINFO, and IBSS) were searched to August 2020 for studies reporting the association between exposure to smoking/vaping in films and smoking/vaping uptake in adolescents. Two authors independently screened papers, extracted data, and assessed quality. This review included 26 studies. Exposure to high levels of smoking imagery in films was associated with an increased likelihood of having ever smoked in nine cross-sectional studies and of smoking uptake in 11 longitudinal studies. Vaping imagery in films was associated with increased likelihood of ever vaping in two cross-sectional studies and vaping uptake in five longitudinal studies. This review concluded that exposure to smoking imagery in films increases the risk of smoking among young people. It is likely that a similar association exists between exposure to vaping imagery and vaping uptake. Therefore, this review recommends introduction of new policies to minimize the impact of this in films which contain smoking or vaping and are likely to be viewed by children and adolescents.

Effectiveness of offering tailored text message, self-help smoking cessation support to pregnant women who want information on stopping smoking: MiQuit3 randomised controlled trial and meta-analysis.

AIMS: To test the efficacy of 'MiQuit', a tailored, self-help, text message stop smoking programme for pregnancy, as an adjunct to usual care (UC) for smoking cessation in pregnancy. DESIGN: Multicentre, open, two-arm, parallel-group, superiority randomised controlled trial (RCT) and a trial sequential analysis (TSA) meta-analysis combining trial findings with two previous ones. SETTING: Twenty-four English hospital antenatal clinics. PARTICIPANTS: A total of 1002 pregnant women who were ≥16 years old, were ≤25 weeks gestation and smoked ≥1 daily cigarette and accepted information on cessation with no requirement to set quit dates. INTERVENTIONS: UC or UC plus 'MiQuit': 12 weeks of tailored, smoking cessation text messages focussed on inducing and aiding cessation. MEASUREMENTS: Primary outcome: biochemically validated cessation between 4 weeks after randomisation and late pregnancy. SECONDARY OUTCOMES: shorter and non-validated abstinence periods, pregnancy outcomes and incremental cost-effectiveness ratios. FINDINGS: RCT: cessation was 5.19% (26/501) and 4.59% (23/501) in MiQuit and UC groups (adjusted odds ratio [adj OR] for quitting with MiQuit versus UC, 95% CI = 1.15 [0.65-2.04]); other abstinence findings were similar, with higher point estimates. Primary outcome ascertainment was 61.7% (309) and 67.3% (337) in MiQuit and UC groups with 71.1% (54/76) and 69.5% (41/59) abstinence validation rates, respectively. Pregnancy outcomes were similar and the incremental cost per quality-adjusted life year was -£1118 (95% CI = -£4806-£1911). More MiQuit group women reported making at least one quit attempt (adj OR [95% CI]) for making an attempt, 1.50 (1.07-2.09). TSA meta-analysis: this found no significant difference in prolonged abstinence between MiQuit and UC (pooled OR = 1.49, adjusted 95% CI = 0.62-3.60). CONCLUSIONS: Irrespective of whether they want to try quitting, when offered a tailored, self-help, text message stop smoking programme for pregnancy (MiQuit) as an adjunct to usual care, pregnant women are not more likely to stop smoking until childbirth but they report more attempts at stopping smoking.

Effectiveness of cascade testing strategies in relatives for familial hypercholesterolemia: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Cascade testing in relatives of index cases is the most cost-effective approach to identifying people with familial hypercholesterolemia (FH); however, it is currently unclear which strategy to contact relatives would be the most effective. A systematic review was performed to quantify the effectiveness of different strategies in cascade testing of FH. METHODS: Comprehensive searches of three electronic databases and grey literature sources were done (from inception to May 2020). Screening, data extraction and assessments of methodological quality were made independently by two reviewers. Meta-analyses of proportions were performed using random effects models. Effect measures are reported as percentages with 95% confidence intervals. RESULTS: 24 non-comparative studies were included, of which 11 used a direct, 8 used an indirect, and 5 used a combination of both direct and indirect cascade strategies. The median number of new relatives with FH per known index case was approximately 1. The combination strategy resulted in the largest yields of relatives tested for FH out of those contacted (40%, 95% CI 37%-42%, 1 study) and relatives responding to testing out of those contacted (54%, 1 study); however, the direct strategy had the largest yield of index cases participating in cascade testing out of those with FH confirmed (94%, 8 studies) compared to other strategies (p ≤ 0.01 for all comparisons). CONCLUSIONS: Evidence is limited; however, a combination strategy, which allows the index case to decide on method of contacting relatives, appears to lead to better yields compared to using the direct or indirect strategy.

Comparing the performance of the novel FAMCAT algorithms and established case-finding criteria for familial hypercholesterolaemia in primary care.

OBJECTIVE: Familial hypercholesterolaemia (FH) is a common inherited disorder causing premature coronary heart disease (CHD) and death. We have developed the novel Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT 1) case-finding algorithm for application in primary care, to improve detection of FH. The performance of this algorithm was further improved by including personal history of premature CHD (FAMCAT 2 algorithm). This study has evaluated their performance, at 95% specificity, to detect genetically confirmed FH in the general population. We also compared these algorithms to established clinical case-finding criteria. METHODS: Prospective validation study, in 14 general practices, recruiting participants from the general adult population with cholesterol documented. For 260 participants with available health records, we determined possible FH cases based on FAMCAT thresholds, Dutch Lipid Clinic Network (DLCN) score, Simon-Broome criteria and recommended cholesterol thresholds (total cholesterol >9.0 mmol/L if ≥30 years or >7.5 mmol/L if <30 years), using clinical data from electronic and manual extraction of patient records and family history questionnaires. The reference standard was genetic testing. We examined detection rate (DR), sensitivity and specificity for each case-finding criteria. RESULTS: At 95% specificity, FAMCAT 1 had a DR of 27.8% (95% CI 12.5% to 50.9%) with sensitivity of 31.2% (95% CI 11.0% to 58.7%); while FAMCAT 2 had a DR of 45.8% (95% CI 27.9% to 64.9%) with sensitivity of 68.8% (95% CI 41.3% to 89.0%). DLCN score ≥6 points yielded a DR of 35.3% (95% CI 17.3% to 58.7%) and sensitivity of 37.5% (95% CI 15.2% to 64.6%). Using recommended cholesterol thresholds resulted in DR of 28.0% (95% CI 14.3% to 47.6%) with sensitivity of 43.8% (95% CI 19.8% to 70.1%). Simon-Broome criteria had lower DR 11.3% (95% CI 6.0% to 20.0%) and specificity 70.9% (95% CI 64.8% to 76.5%) but higher sensitivity of 56.3% (95% CI 29.9% to 80.2%). CONCLUSIONS: In primary care, in patients with cholesterol documented, FAMCAT 2 performs better than other case-finding criteria for detecting genetically confirmed FH, with no prior clinical review required for case finding. TRIAL REGISTRATION NUMBER: NCT03934320.

Strategies for screening for familial hypercholesterolaemia in primary care and other community settings.

BACKGROUND: Familial hypercholesterolaemia is a common inherited condition that is associated with premature cardiovascular disease. The increased cardiovascular morbidity and mortality, resulting from high levels of cholesterol since birth, can be prevented by starting lipid-lowering therapy. However, the majority of patients in the UK and worldwide remain undiagnosed. Established diagnostic criteria in current clinical practice are the Simon-Broome and Dutch Lipid Clinical network criteria and patients are classified as having probable, possible or definite familial hypercholesterolaemia. OBJECTIVES: To assess the effectiveness of healthcare interventions strategies to systematically improve identification of familial hypercholesterolaemia in primary care and other community settings compared to usual care (incidental approaches to identify familial hypercholesterolaemia in primary care and other community settings). SEARCH METHODS: We searched the Cochrane Inborn Errors of Metabolism Trials Register. Date of last search: 13 September 2021. We also searched databases (Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, PubMed, Embase, CINAHL, Web of Science, and SCOPUS) as well as handsearching relevant conference proceedings, reference lists of included articles, and the grey literature. Date of last searches: 05 March 2020.  SELECTION CRITERIA: As per the Effective Practice and Organisation of Care (EPOC) Group guidelines, we planned to include randomised controlled trials (RCTs), cluster-RCTs and non-randomised studies of interventions (NRSI). Eligible NRSI were non-randomised controlled trials, prospective cohort studies, controlled before-and-after studies, and interrupted-time-series studies. We planned to selected studies with healthcare interventions strategies that aimed to systematically identify people with possible or definite clinical familial hypercholesterolaemia, in primary care and other community settings. These strategies would be compared with usual care or no intervention. We considered participants of any age from the general population who access primary care and other community settings. DATA COLLECTION AND ANALYSIS: Two authors planned to independently select studies according to the inclusion criteria, to extract data and assess for risk of bias and the certainty of the evidence (according to the GRADE criteria). We contacted corresponding study authors in order to obtain further information for all the studies considered in the review. MAIN RESULTS: No eligible RCTs or NRSIs were identified for inclusion, however, we excluded 28 studies. AUTHORS' CONCLUSIONS: Currently, there are no RCTs or controlled NRSI evidence to determine the most appropriate healthcare strategy to systematically identify possible or definite clinical familial hypercholesterolaemia in primary care or other community settings. Uncontrolled before-and-after studies were identified, but were not eligible for inclusion. Further studies assessing healthcare strategies of systematic identification of familial hypercholesterolaemia need to be conducted with diagnosis confirmed by genetic testing or validated through clinical phenotype (or both).

Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery.

BACKGROUND: Postoperative pain is a common consequence of surgery and can have many negative perioperative effects. It has been suggested that the administration of analgesia before a painful stimulus may improve pain control. We defined pre-emptive nonsteroidal anti-inflammatories (NSAIDs) as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. OBJECTIVES: To assess the efficacy of preventive and pre-emptive NSAIDs for reducing postoperative pain in adults undergoing all types of surgery. SEARCH METHODS: We searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED and CINAHL (up to June 2020). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication. SELECTION CRITERIA: We included parallel-group randomized controlled trials (RCTs) only. We included adult participants undergoing any type of surgery. We defined pre-emptive NSAIDs as those given before surgery but not continued afterwards and preventive NSAIDs as those given before surgery and continued afterwards. These were compared to a control group given the NSAIDs after surgery instead of before surgery. We included studies that gave the medication by any route but not given on the skin. DATA COLLECTION AND ANALYSIS: We used the standard methods expected by Cochrane, as well as a novel publication bias test developed by our research group. We used GRADE to assess the certainty of the evidence for each outcome. Outcomes included acute postoperative pain (minimal clinically important difference (MCID): 1.5 on a 0-10 scale), adverse events of NSAIDs, nausea and vomiting, 24-hour morphine consumption (MCID: 10 mg reduction), time to analgesic request (MCID: one hour), pruritus, sedation, patient satisfaction, chronic pain and time to first bowel movement (MCID: 12 hours). MAIN RESULTS: We included 71 RCTs. Seven studies are awaiting classification. We included 45 studies that evaluated pre-emptive NSAIDs and 26 studies that evaluated preventive NSAIDs. We considered only four studies to be at low risk of bias for most domains. The operations and NSAIDs used varied, although most studies were conducted in abdominal, orthopaedic and dental surgery. Most studies were conducted in secondary care and in low-risk participants. Common exclusions were participants on analgesic medications prior to surgery and those with chronic pain. Pre-emptive NSAIDs compared to post-incision NSAIDs For pre-emptive NSAIDs, there is probably a decrease in early acute postoperative pain (MD -0.69, 95% CI -0.97 to -0.41; studies = 36; participants = 2032; I2 = 96%; moderate-certainty evidence). None of the included studies that reported on acute postoperative pain reported adverse events as an outcome. There may be little or no difference between the groups in short-term (RR 1.00, 95% CI 0.34 to 2.94; studies = 2; participants = 100; I2 = 0%; low-certainty evidence) or long-term nausea and vomiting (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 228; I2 = 29%; low-certainty evidence). There may be a reduction in late acute postoperative pain (MD -0.22, 95% CI -0.44 to 0.00; studies = 28; participants = 1645; I2 = 97%; low-certainty evidence). There may be a reduction in 24-hour morphine consumption with pre-emptive NSAIDs (MD -5.62 mg, 95% CI -9.00 mg to -2.24 mg; studies = 16; participants = 854; I2 = 99%; low-certainty evidence) and an increase in the time to analgesic request (MD 17.04 minutes, 95% CI 3.77 minutes to 30.31 minutes; studies = 18; participants = 975; I2 = 95%; low-certainty evidence). There may be little or no difference in opioid adverse events such as pruritus (RR 0.40, 95% CI 0.09 to 1.76; studies = 4; participants = 254; I2 = 0%; low-certainty evidence) or sedation (RR 0.51, 95% CI 0.16 to 1.68; studies = 4; participants = 281; I2 = 0%; low-certainty evidence), although the number of included studies for these outcomes was small. No study reported patient satisfaction, chronic pain or time to first bowel movement for pre-emptive NSAIDs. Preventive NSAIDs compared to post-incision NSAIDs For preventive NSAIDs, there may be little or no difference in early acute postoperative pain (MD -0.14, 95% CI -0.39 to 0.12; studies = 18; participants = 1140; I2 = 75%; low-certainty evidence). One study reported adverse events from NSAIDs (reoperation for bleeding) although the events were low which did not allow any meaningful conclusions to be drawn (RR 1.95; 95% CI 0.18 to 20.68). There may be little or no difference in rates of short-term (RR 1.26, 95% CI 0.49 to 3.30; studies = 1; participants = 76; low-certainty evidence) or long-term (RR 0.85, 95% CI 0.52 to 1.38; studies = 5; participants = 456; I2 = 29%; low-certainty evidence) nausea and vomiting. There may be a reduction in late acute postoperative pain (MD -0.33, 95% CI -0.59 to -0.07; studies = 21; participants = 1441; I2 = 81%; low-certainty evidence). There is probably a reduction in 24-hour morphine consumption (MD -1.93 mg, 95% CI -3.55 mg to -0.32 mg; studies = 16; participants = 1323; I2 = 49%; moderate-certainty evidence). It is uncertain if there is any difference in time to analgesic request (MD 8.51 minutes, 95% CI -31.24 minutes to 48.27 minutes; studies = 8; participants = 410; I2 = 98%; very low-certainty evidence). As with pre-emptive NSAIDs, there may be little or no difference in other opioid adverse events such as pruritus (RR 0.56, 95% CI 0.09 to 3.35; studies = 3; participants = 211; I2 = 0%; low-certainty evidence) and sedation (RR 0.84, 95% CI 0.44 to 1.63; studies = 5; participants = 497; I2 = 0%; low-certainty evidence). There is probably little or no difference in patient satisfaction (MD -0.42; 95% CI -1.09 to 0.25; studies = 1; participants = 72; moderate-certainty evidence). No study reported on chronic pain. There is probably little or no difference in time to first bowel movement (MD 0.00; 95% CI -15.99 to 15.99; studies = 1; participants = 76; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There was some evidence that pre-emptive and preventive NSAIDs reduce both pain and morphine consumption, although this was not universal for all pain and morphine consumption outcomes. Any differences found were not clinically significant, although we cannot exclude this in more painful operations. Moreover, without any evidence of reductions in opioid adverse effects, the clinical significance of these results is questionable although few studies reported these outcomes. Only one study reported clinically significant adverse events from NSAIDs administered before surgery and, therefore, we have very few data to assess the safety of either pre-emptive or preventive NSAIDs. Therefore, future research should aim to adhere to the highest methodology and be adequately powered to assess serious adverse events of NSAIDs and reductions in opioid adverse events.

Understanding willingness to access and experiences of NHS Stop Smoking Services: a qualitative systematic review with meta-aggregation synthesis.

OBJECTIVES: NHS Stop Smoking Services (NHS-SSS) have been available in the United Kingdom (UK) since 2000. The service has proven to be effective, however uptake remains below aspirations. Understanding people's willingness and reasons for accessing and engaging with NHS-SSS is, therefore, important. The aim of this systematic review is to summarise the findings from qualitative research to understand people's views, perceptions and willingness to access NHS-SSS. STUDY DESIGN: Qualitative systematic review with meta-aggregation synthesis. METHODS: Four electronic databases were searched for published qualitative studies, from Jan 2000 to Jan 2020. Following the screening, data extraction and quality assessment, data synthesis was conducted using meta-aggregation based on a patient-centred theoretical framework. We explored five 'demand-side' dimensions of service accessibility: the ability to perceive, seek, reach, pay and engage. Confidence in the synthesised findings relating to dependability and credibility was established using CONQual. RESULTS: Seventeen studies were included in the review. Twelve categories emerged, contributing to five synthesised statements, all with a CONQual rating of moderate confidence. Access and willingness to use NHS-SSS were found to be related to an individual's readiness to perceive that smoking is a problem for which a solution should be sought, their ability to seek a perceived effective treatment, to conveniently reach NHS-SSS, their perceptions around associated costs and tailoring care to improve engagement with individuals. CONCLUSIONS: By using a theoretical framework incorporating healthcare access, this study provides policymakers valuable insights into people's willingness to access these services. Willingness to access NHS-SSS is multifaceted, nuanced and complex. Strategies to promote NHS-SSS uptake should include making services more attractive, relevant and responsive to individual perceptions around smoking and health. Given the higher prevalence of smoking in less affluent socioeconomic groups and in some ethnic minority groups, the importance of having a comprehensive and inclusive tobacco control policy, one that is linguistically and culturally sensitive, cannot be overstated.

Experiences and views of women, children, and professionals regarding second-hand smoke exposure prevention in Middle Eastern countries: a qualitative systematic review protocol.

OBJECTIVE: This systematic review aims to identify and explore the experiences and views of women, children, and professionals regarding second-hand smoke exposure prevention in the home, workplace, school, personal vehicles, and public places in Middle Eastern countries. INTRODUCTION: Exposure to second-hand smoke is a significant public health problem globally, but particularly in Middle Eastern countries. Whilst many Middle Eastern countries have implemented tobacco-control programs and have legislation that bans smoking in public places, the legislation is not always comprehensively implemented or enforced. Therefore, women and children continue to be exposed to second-hand smoke in public and private settings. INCLUSION CRITERIA: This review will consider studies that include the views and experiences of any of the following three groups: (i) women (including pregnant women and mothers), (ii) children (primary and secondary school age), and (iii) professionals (including health professionals and policy makers), regarding the prevention of second-hand smoke exposure in women and children in Middle Eastern countries. METHODS: MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and Scopus, and sources of gray literature will be searched for eligible studies. Databases will be searched from their inception dates and no language restrictions will be applied. Two reviewers will independently screen studies and assess methodological quality and extract data from the included studies following JBI systematic review guidelines. The JBI process of meta-aggregation will be used to identify categories and synthesize findings. The ConQual approach will be used to assess confidence in the findings. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO (CRD42019137006).

Fetal safety of nicotine replacement therapy in pregnancy: systematic review and meta-analysis.

BACKGROUND AND AIMS: Smoking in pregnancy causes substantial avoidable harm to mothers and offspring; nicotine replacement therapy (NRT) may prevent this, and is used to help women to quit. A recently updated Cochrane Review of randomized controlled trials (RCTs) investigating impacts of NRT in pregnancy focuses primarily on efficacy data, but also reports adverse impacts from NRT. Here we identify and summarize NRT impacts on adverse pregnancy outcomes reported in non-randomized controlled trials (non-RCTs). METHODS: Systematic reviews and meta-analyses of RCTs and non-RCT studies of NRT in pregnancy, with design-specific risk of bias assessment and grading of recommendations, assessment, development and evaluations (GRADE) criteria applied to selected outcomes. FINDINGS: Relevant Cochrane Review findings are reported alongside those from this new review. Seven RCTs were included; n = 2340. Nine meta-analyses were performed; non-statistically significant estimates indicated potentially reduced risk from NRT compared with smoking for mean birth weight, low birth weight, preterm birth, intensive care admissions, neonatal death, congenital anomalies and caesarean section and potentially increased risks for miscarriage and stillbirth. GRADE assessment for mean birth weight and miscarriage outcomes indicated 'low' confidence in findings. Twenty-three non-RCTs were included; n = 931 163. Eleven large studies from five routine health-care cohorts reported clinical outcomes; 12 small studies investigated mainly physiological outcomes within in-patient women given NRT. Findings from meta-analyses for congenital anomalies, stillbirth and preterm birth were underpowered and not in a consistent direction; GRADE assessment of confidence in findings was 'very low'. Routine health-care studies were of higher quality, but implications of reported findings were unclear as there was inadequate measurement and reporting of women's smoking. CONCLUSIONS: Available evidence from randomized controlled trials and non-randomized comparative studies does not currently provide clear evidence as to whether maternal use of nicotine replacement therapy during pregnancy is harmful to the fetus.

Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention.

BACKGROUND: Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms. METHODS: We describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention's effects. RESULTS: We provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. CONCLUSIONS: Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

Interventions for basal cell carcinoma of the skin.

BACKGROUND: Basal cell carcinoma (BCC) is the commonest cancer affecting white-skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First-line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non-surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely. OBJECTIVES: To assess the effects of interventions for BCC in immunocompetent adults. SEARCH METHODS: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically-proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant- and observer-rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low-risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty-two studies were industry-funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies. Overall, surgical interventions have the lowest recurrence rates. For high-risk facial BCC (high-risk histological subtype or located in the facial 'H-zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low-certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low-certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post-operatively (one study; low-certainty evidence); however, no raw data were available for this outcome. When comparing imiquimod and SE for nBCC or sBCC at low-risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate-certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate-certainty evidence). There may be little to no difference in the number of participant-rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low-certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer-rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low-certainty evidence). Both cosmetic outcomes were measured at three years. Based on one study of 347 participants with high- and low-risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low-certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low-certainty evidence). Radiotherapy probably results in a smaller number of good participant- (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer-rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate-certainty evidence). Methyl-aminolevulinate (MAL)-PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low-risk nBCC in the head and neck area; low-certainty evidence). There were no useable data for measurement at five years. MAL-PDT probably results in greater numbers of participant- (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer-rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low-risk nBCC and sBCC; moderate-certainty evidence). Based on moderate-certainty evidence (single low-risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL-PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer-rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant-rated cosmetic outcomes were not measured for this comparison. AEs with surgical interventions include wound infections, graft necrosis and post-operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non-surgical interventions. Treatment-related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL-PDT. AUTHORS' CONCLUSIONS: Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high-risk facial primary BCC (low-certainty evidence). Non-surgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non-surgical treatments, imiquimod has the best evidence to support its efficacy. Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer-term follow-up.

Quality of smoking cessation advice in guidelines of tobacco-related diseases: An updated systematic review.

Tobacco smoking is a major risk factor for a wide range of diseases, and smoking cessation significantly reduces these risks. Clinical guidelines for diseases associated with smoking should therefore include guidance on smoking cessation. This review updated evidence on the proportion of clinical guidelines that do so. We conducted a systematic review investigating clinical guidelines and recommendations developed by UK national or European transnational medical specialty associations and societies between January 2014 and October 2019 on 16 diseases to be at least twice as common among smokers than non-smokers. Outcomes of interest were the reporting of smoking as a risk factor, and the inclusion either of smoking cessation advice or referral to other cessation guidance. We compared our findings with an earlier review of guidelines published between 2000 and 2013. We identified 159 clinical guidelines/recommendations. Over half (51%) made no mention of smoking, while 43% reported smoking as a risk factor for the development of the disease, 31% recommended smoking cessation and 19% provided detailed information on how to deliver smoking cessation support. These proportions were similar to those in our earlier review. Smoking cessation continues to be neglected in clinical management guidance for diseases caused by smoking.

Predicting major adverse cardiovascular events for secondary prevention: protocol for a systematic review and meta-analysis of risk prediction models.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. With advances in early diagnosis and treatment of CVD and increasing life expectancy, more people are surviving initial CVD events. However, models for stratifying disease severity risk in patients with established CVD for effective secondary prevention strategies are inadequate. Multivariable prognostic models to stratify CVD risk may allow personalised treatment interventions. This review aims to systematically review the existing multivariable prognostic models for the recurrence of CVD or major adverse cardiovascular events in adults with established CVD diagnosis. METHODS AND ANALYSIS: Bibliographic databases (Ovid MEDLINE, EMBASE, PsycINFO and Web of Science) will be searched, from database inception to April 2020, using terms relating to the clinical area and prognosis. A hand search of the reference lists of included studies will also be done to identify additional published studies. No restrictions on language of publications will be applied. Eligible studies present multivariable models (derived or validated) of adults (aged 16 years and over) with an established diagnosis of CVD, reporting at least one of the components of the primary outcome of major adverse cardiovascular events (defined as either coronary heart disease, stroke, peripheral artery disease, heart failure or CVD-related mortality). Reviewing will be done by two reviewers independently using the pre-defined criteria. Data will be extracted for included full-text articles. Risk of bias will be assessed using the Prediction model study Risk Of Bias ASsessment Tool (PROBAST). Prognostic models will be summarised narratively. If a model is tested in multiple validation studies, the predictive performance will be summarised using a random-effects meta-analysis model to account for any between-study heterogeneity. ETHICS AND DISSEMINATION: Ethics approval is not required. The results of this study will be submitted to relevant conferences for presentation and a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42019149111.

Pharmacological interventions for promoting smoking cessation during pregnancy.

BACKGROUND: Tobacco smoking in pregnancy causes serious health problems for the developing fetus and mother. When used by non-pregnant smokers, pharmacotherapies (nicotine replacement therapy (NRT), bupropion, and varenicline) are effective for increasing smoking cessation, however their efficacy and safety in pregnancy remains unknown. Electronic cigarettes (ECs) are becoming widely used, but their efficacy and safety when used for smoking cessation in pregnancy are also unknown. OBJECTIVES: To determine the efficacy and safety of smoking cessation pharmacotherapies and ECs used during pregnancy for smoking cessation in later pregnancy and after childbirth, and to determine adherence to smoking cessation pharmacotherapies and ECs for smoking cessation during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 May 2019), trial registers, and grey literature, and checked references of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) conducted in pregnant women, comparing smoking cessation pharmacotherapy or EC use with either placebo or no pharmacotherapy/EC control. We excluded quasi-randomised, cross-over, and within-participant designs, and RCTs with additional intervention components not matched between trial arms. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. The primary efficacy outcome was smoking cessation in later pregnancy; safety was assessed by 11 outcomes (principally birth outcomes) that indicated neonatal and infant well-being. We also collated data on adherence to trial treatments. We calculated the risk ratio (RR) or mean difference (MD) and the 95% confidence intervals (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

The Effects of Tobacco Smoking, and Prenatal Tobacco Smoke Exposure, on Risk of Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between cigarette smoking and schizophrenia is well established. However, up to 90% of people with schizophrenia begin smoking before the onset of their illness; thus, smoking could be an independent risk factor for schizophrenia. Prenatal exposure to maternal cigarette smoke is also associated with psychiatric problems in adolescence. Therefore, our aim was to undertake a systematic review and meta-analysis to explore the effect of smoking, and prenatal smoke exposure, on risk of schizophrenia. METHOD: We systematically searched Medline, EMBASE, PsychInfo, Maternity and Infant Care, and Web of Science (from inception to February 2018) to identify comparative observational studies of the risk of schizophrenia in relation to smoking status. Measures of relative risk (RR) were pooled in a meta-analysis with 95% confidence intervals (CI), using random effects model. RESULTS: Twelve studies (9 cohort, 3 case-control) were included. Odds ratios (OR) and hazard ratios (HR) were pooled together to estimate pooled relative risks and estimates combined in a meta-analysis on an assumption of constant risk over time. Smokers had a significantly increased risk of schizophrenia compared with nonsmokers (RR = 1.99, 95% CI = 1.10% to 3.61%, I2 = 97%, 5 studies). Exposure to prenatal smoke increased the risk of schizophrenia by 29% (95% CI = 1.10% to 1.51%, I2 = 71%, 7 studies). Sensitivity analyses identified no significant differences between the results from studies reporting OR and hazard ratio. CONCLUSIONS: Our findings suggest smoking, and prenatal smoke exposure, may be an independent risk factor for schizophrenia. Care should be taken when inferring causation, given the observational nature of the studies. IMPLICATIONS: In this meta-analysis of 12 studies, smokers had a significantly increased risk of schizophrenia compared with nonsmokers. Exposure to prenatal tobacco smoke also increased the risk of schizophrenia by 29% compared with those with no exposure to prenatal tobacco smoke. Our findings suggest that smoking, and prenatal tobacco smoke exposure, may be independent risk factors for schizophrenia. These results may have important public health implications for decreasing the incidence of schizophrenia. The possibility of a causal link between smoking and schizophrenia warrants further investigation.