Factors Associated with Early Versus Late Uptake of the COVID-19 Vaccine during Pregnancy over Time in Australia: A Population-Based Cohort Study.

BACKGROUND: Pregnant women are at an increased risk of hospitalisation, admission to the intensive care unit, mechanical ventilation, and death from SARS-CoV-2 infection. The aim of this study is to determine the predictive factors associated with COVID-19 vaccine uptake during pregnancy over time in a population with a high background uptake of maternal influenza and pertussis vaccination. METHODS: This is a population-based, cohort study of all pregnant women who gave birth in Victoria, Australia between 1 July 2021 and 30 June 2022. Data from the Victorian Perinatal Data Collection were analysed using univariable and multivariable logistic regression. RESULTS: This study reports on 77,719 women who gave birth over a 12 month period, of whom 49,281 (63.4%) received a COVID-19 vaccine, 54,887 (70.6%) received an influenza vaccination and 63,594 (81.8%) received a pertussis vaccine by the time of delivery. Pregnant women aged >30 years (aOR 1.31 CI 1.27, 1.36), who had >=8 antenatal visits (aOR 1.08 CI 1.04, 1.12), and those who received influenza vaccine (aOR 1.23 CI 1.19, 1.28) were more likely to have received a COVID-19 vaccine. Those who smoked (aOR 0.7 CI 0.66, 0.74), were First Nations (aOR 0.83 CI 0.74, 0.93) and those who gave birth in public hospitals (aOR 0.65 CI 0.63, 0.68) were less likely to receive COVID-19 vaccine in the first 12 months of the rollout. CONCLUSION: Maternal age, smoking, parity and Indigenous status were factors associated with delayed and sustained lower coverage, even in a population with background maternal influenza and pertussis coverage of 70.6% and 81.8%, respectively.

Primary postpartum haemorrhage adversely impacts breastfeeding initiation in Victoria, Australia.

PROBLEM: Breastfeeding has many important benefits for both mother and baby but sustained breastfeeding is sub-optimal. BACKGROUND: Identifying women who need increased support to establish breastfeeding has the potential to improve this. Analysis of the relationship between primary postpartum haemorrhage (PPH) and primary severe PPH and breastfeeding may prove informative as PPH has potentially negative impacts on breastfeeding. AIM: To determine the relationship between PPH and severe PPH and breastfeeding at postnatal discharge and formula use for breastfed babies in hospital. METHODS: Population-based retrospective cohort study using the Victorian Perinatal Data Collection for all liveborn singleton births at ≥ 37 weeks' gestation (n = 339,854) for 2009-13 in Victoria. Estimated blood loss was categorised as PPH ≥ 500 mL and severe PPH ≥ 1500 mL. Descriptive analysis was conducted and multivariable logistic regression was used to determine the adjusted odds ratio for the relationship between PPH/severe PPH and breastfeeding outcomes after adjustment for relevant confounders. FINDINGS: Overall, 94.9% of women initiated breastfeeding. Babies whose mother had a PPH or severe PPH were less likely than others to be exclusively breastfeeding at discharge (aOR 0.88; (95% CI 0.86, 0.90) and aOR 0.57; (95% CI 0.53, 0.61) respectively). Formula - given to 25.9% of all breastfed babies - was more likely for those whose mothers had a PPH or severe PPH (aOR 1.15; (95% CI 1.12, 1.17) and aOR 2.15; (95% CI 2.01, 2.29) respectively. CONCLUSIONS: Women have greater challenges establishing exclusive breastfeeding following PPH and severe PPH. Improving support in hospital for women following PPH may increase breastfeeding success.

The effect of comorbidities on the sFLT-1:PlGF ratio in preeclampsia.

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications.

Associations Between Maternal Immunisation and Reduced Rates of Preterm Birth and Stillbirth: A Population Based Retrospective Cohort Study.

Stillbirth and preterm birth (PTB) remain two of the most important, unresolved challenges in modern pregnancy care. Approximately 10% of all births are preterm with nearly one million children dying each year due to PTB. It remains the most common cause of death among children under five years of age. The numbers for stillbirth are no less shocking with 2.6 million babies stillborn each year. With minimal impact on the rate of these adverse birth outcomes over the past decade there is an urgent need to identify more effective interventions to tackle these problems. In this retrospective cohort study, we used whole-of-population data, to determine if maternal immunization during pregnancy against influenza and/or pertussis, is associated with a lower risk of PTB, delivering a small-for-gestational age (SGA) infant, developing preeclampsia or stillbirth. Women with a singleton pregnancy at 28 or more weeks' gestation delivering in Victoria, Australia from July 2015 to December 2018 were included in the analysis. Log-binomial regression was used to measure the relationship between vaccination during pregnancy against influenza and against pertussis, with preterm birth, SGA, preeclampsia and stillbirth. Variables included in the adjusted model were maternal age, body mass index, first or subsequent birth, maternal Indigenous status, socio-economic quintile, smoking, public or private maternity care and metropolitan or rural location of the hospital. Women who received influenza vaccine were 75% less likely to have a stillbirth (aRR 025; 95% CI 0.20, 0.31), and 31% less likely to birth <37 weeks (aRR 0.69; 95% CI 0.66, 0.72). Women who received pertussis vaccine were 77% less likely to have a stillbirth (aOR 0.23; 95% CI 0.18, 0.28) and 32% less likely to birth <37 weeks gestation (aRR 0.68; 95% CI 0.66, 0.71). Vaccination also reduced the odds of small for gestational age by 13% and reduced the odds of pre-eclampsia when restricted to primiparous women. This association was seen over four different influenza seasons and independent of the time of year suggesting that any protective effect on obstetric outcomes afforded by maternal vaccination may not be due to a pathogen-specific response but rather due to pathogen-agnostic immune-modulatory effects.

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.

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.

Risk factors for severe postpartum haemorrhage: A population-based retrospective cohort study.

BACKGROUND: Severe postpartum haemorrhage (PPH) is a serious clinical problem that is increasing in incidence. AIM: To identify risk factors for severe PPH. MATERIALS AND METHODS: Population-based retrospective cohort study of all women who gave birth in Victoria in 2009-2013 using the validated Victorian Perinatal Data Collection. Three multivariable logistic regression models estimated the adjusted risk of severe PPH. Adjusted odds ratios (aOR) and their 95% confidence intervals are reported. The primary outcome was severe PPH (estimated blood loss of ≥1500 mL). RESULTS: Severe PPH occurred in 1.4% of all births (n = 5122). Maternal characteristics significantly associated with severe PPH included: multiple pregnancy; older maternal age; overweight/obesity; first births. Other risk factors included placental complications, macrosomia, instrumental vaginal birth, third and fourth degree perineal lacerations, in-labour caesarean section, birth at a gestation other than 37-41 weeks, duration of labour 12 to <24 h, and use of oxytocin infusions in labour. Planned pre-labour caesarean section was associated with reduced odds of severe PPH. Severe PPH also occurred in 0.7% (n = 104) of women with none of the identified risk factors. CONCLUSIONS: Numerous risk factors for severe PPH are identified but some cases are not modifiable or predictable. Limiting use of oxytocin infusions in labour to cases with clear indications, and strategies to prevent severe perineal lacerations would prevent some severe PPHs. Close surveillance of all women in the hours immediately following birth is crucial to detect and manage excessive blood loss and reduce severe PPH and associated morbidity.

Incidence, trends and severity of primary postpartum haemorrhage in Australia: A population-based study using Victorian Perinatal Data Collection data for 764 244 births.

BACKGROUND: Increasing incidence and severity of postpartum haemorrhage, together with postpartum haemorrhage-associated morbidities, have been reported in many high-resource countries. In-depth analysis of such factors in Victorian births since 2002 was lacking. AIMS: Our aim was to determine the incidence and trends for primary postpartum haemorrhage (World Health Organization and International Classification of Diseases 10th revision, Australian Modification definitions) for all confinements in Victoria, Australia, for the years 2003-2013 and the incidence and trends for severe postpartum haemorrhage (≥1500 mL) for 2009-2013. MATERIALS AND METHODS: In this population-based cross-sectional study de-identified data from the Victorian Perinatal Data Collection were analysed for confinements (excluding terminations) from 2003 to 2013 (n = 764 244). Perinatal information for all births ≥20 weeks (or of at least 400 g birthweight if gestation was unknown) were prospectively collected. RESULTS: One in five women (21.8%) who gave birth between 2009 and 2013 experienced a primary postpartum haemorrhage and one in 71 women (1.4%) experienced a severe primary postpartum haemorrhage. The increasing trends in incidence of primary postpartum haemorrhage, severe primary postpartum haemorrhage, blood transfusion, admission to an intensive care or high dependency unit and peripartum hysterectomy were significant (P < 0.001). Women who had an unassisted vaginal birth had the lowest incidence of primary postpartum haemorrhage. The highest incidence was experienced by women who had an unplanned caesarean section birth. Women who had a forceps birth had the highest incidence of severe primary postpartum haemorrhage. CONCLUSIONS: The incidence of primary postpartum haemorrhage, severe primary postpartum haemorrhage and associated maternal morbidities have increased significantly over time in Victoria.

Accuracy of postpartum haemorrhage data in the 2011 Victorian Perinatal Data Collection: Results of a validation study.

BACKGROUND: The postpartum haemorrhage (PPH) rate in Victoria in 2009 for women having their first birth, based on information reported to the Victorian Perinatal Data Collection (VPDC), was 23.6% (primiparas). Prior to 2009 PPH was collected via a tick box item on the perinatal form. Estimated blood loss (EBL) volume is now collected and it is from this item the PPH rate is calculated. Periodic assessment of data accuracy is essential to inform clinicians and others who rely on these data of their quality and limitations. AIMS: This paper describes the results of a state-wide validation study of the accuracy of EBL volume and EBL-related data items reported to VPDC. MATERIALS AND METHODS: PPH data from a random sample of 1% of births in Victoria in 2011 were extracted from source medical records and compared with information submitted to the VPDC. Accuracy was determined, together with sensitivity, specificity, positive predictive value and negative predictive value for dichotomous items. RESULTS: Accuracy of reporting for EBL ≥ 500 mL was 97.2% and for EBL ≥ 1500 mL was 99.7%. Sensitivity for EBL ≥ 500 mL was 89.0% (CI 83.1-93.0) and for EBL ≥ 1500 mL was 71.4% (CI 35.9-91.8). Blood product transfusion, peripartum hysterectomy and procedures to control bleeding were all accurately reported in >99% of cases. CONCLUSIONS: Most PPH-related data items in the 2011 VPDC may be considered reliable. Our results suggest EBL ≥ 1500 mL is likely to be under-reported. Changes to policies and practices of recording blood loss could further increase accuracy of reporting.

What Happens After Menopause? (WHAM): protocol for a prospective, multicentre, age-matched cohort trial of risk-reducing bilateral salpingo-oophorectomy in high-risk premenopausal women.

INTRODUCTION: Women at high inherited risk of ovarian cancer are advised to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) at age 40-45 years or when their families are complete. Most women are premenopausal at this age, so RRBSO will induce surgical menopause. Despite the clear benefits of RRBSO for cancer risk reduction, much less is known about the impact on non-cancer outcomes that contribute to health and well-being and inform surveillance and management strategies. METHODS AND ANALYSIS: This will be a multicentre, prospective cohort study of 105 premenopausal high-risk women undergoing RRBSO and an age-matched comparison group of 105 premenopausal women not planning oophorectomy or pregnancy in the next 2 years. The aim of this study is to measure the impact of RRBSO on sexual function (primary outcome) at 24 months in high-risk premenopausal women compared with the comparison group. Secondary outcomes include menopausal symptoms and menopause-related quality of life, mood, sleep quality, markers of cardiovascular disease and pre-diabetes, bone density and markers of bone turnover, and the impact of hormone replacement therapy use on these outcomes. Data analysis methods will include logistic and linear regression using general estimating equations accounting for the repeated outcome measurements within each participant. ETHICS AND DISSEMINATION: The study has been approved by institutional ethics committees at each participating centre. Findings will be disseminated through peer-reviewed publications and conference presentations, and national and international networks of centres managing high-risk women, and will inform national and international clinical guidelines. TRIAL REGISTRATION NUMBER: The pre-results protocol for this trial is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; registration no: ACTRN12615000082505).

Data accuracy in the Victorian Perinatal Data Collection: Results of a validation study of 2011 data.

OBJECTIVE: Public health data sets such as the Victorian Perinatal Data Collection (VPDC) provide an important source for health planning, monitoring, policy, research and reporting purposes. Data quality is paramount, requiring periodic assessment of data accuracy. This article describes the conduct and findings of a validation study of data on births in 2011 extracted from the VPDC. METHOD: Data from a random sample of one percent of births in Victoria in 2011 were extracted from original medical records at the birth hospital and compared with data held in the VPDC. Accuracy was determined for 93 variables. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for dichotomous items. RESULTS: Accuracy of 17 data items was 99% or more, the majority being neonatal and intrapartum items, and 95% or more for 46 items. Episodes of care with the highest proportion of items with accuracy of 95% or more were neonatal and postnatal items at 80 and 64%, respectively. Accuracy was below 80% for nine items introduced in 2009. Agreement between medical records and VPDC data ranged from 48% to 100%, the exception being two highly inaccurate smoking-related items. Reasons for discrepancies between VPDC data and medical records included miscoding, missing and inconsistent information. CONCLUSION: This study found high levels of accuracy for data reported to the VPDC for births in 2011; however, some data items introduced in 2009 and not previously validated were less accurate. Data may be used with confidence overall and with awareness of limitations for some new items.

Pharmacological interventions for promoting smoking cessation during pregnancy.

BACKGROUND: Smoking in pregnancy is a public health problem. When used by non-pregnant smokers, pharmacotherapies (nicotine replacement therapy (NRT), bupropion and varenicline) are effective for smoking cessation, however, their efficacy and safety in pregnancy remains unknown. Electronic Nicotine Delivery Systems (ENDS), or e-cigarettes, 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 (including NRT, varenicline and bupropion), other medications, or ENDS when used for smoking cessation in pregnancy. SEARCH METHODS: We searched the Pregnancy and Childbirth Group's Trials Register (11 July 2015), checked references of retrieved studies, and contacted authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) conducted in pregnant women with designs that permit the independent effects of any type of pharmacotherapy or ENDS on smoking cessation to be ascertained were eligible for inclusion.The following RCT designs are included.Placebo-RCTs: any form of NRT, other pharmacotherapy, or ENDS, with or without behavioural support/cognitive behaviour therapy (CBT), or brief advice, compared with an identical placebo and behavioural support of similar intensity.RCTs providing a comparison between i) any form of NRT, other pharmacotherapy, or ENDS added to behavioural support/CBT, or brief advice and ii) behavioural support of similar (ideally identical) intensity.Parallel- or cluster-randomised trials were eligible for inclusion. Quasi-randomised, cross-over and within-participant designs were not, due to the potential biases associated with these designs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias and also 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 11 outcomes (principally birth outcomes) that indicated neonatal and infant well-being; and we also collated data on adherence with trial treatments. MAIN RESULTS: This review includes a total of nine trials which enrolled 2210 pregnant smokers: eight trials of NRT and one trial of bupropion as adjuncts to behavioural support/CBT. The risk of bias was generally low across trials with virtually all domains of the 'Risk of bias' assessment tool being satisfied for the majority of studies. We found no trials investigating varenicline or ENDS. Compared to placebo and non-placebo controls, there was a difference in smoking rates observed in later pregnancy favouring use of NRT (risk ratio (RR) 1.41, 95% confidence interval (CI) 1.03 to 1.93, eight studies, 2199 women).  However, subgroup analysis of placebo-RCTs provided a lower RR in favour of NRT (RR 1.28, 95% CI 0.99 to 1.66, five studies, 1926 women), whereas within the two non-placebo RCTs there was a strong positive effect of NRT, (RR 8.51, 95% CI 2.05 to 35.28, three studies, 273 women; P value for random-effects subgroup interaction test = 0.01). There were no differences 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. Compared to placebo group infants, at two years of age, infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' (one trial). Generally, adherence with trial NRT regimens was low. Non-serious side effects observed with NRT included headache, nausea and local reactions (e.g. skin irritation from patches or foul taste from gum), but these data could not be pooled. AUTHORS' CONCLUSIONS: NRT used in pregnancy for smoking cessation increases smoking cessation rates measured in late pregnancy by approximately 40%. There is evidence, suggesting that when potentially-biased, non-placebo RCTs are excluded from analyses, NRT is no more effective than placebo. There is no evidence that NRT used for smoking cessation in pregnancy has either positive or negative impacts on birth outcomes. However, evidence from the only trial to have followed up infants after birth, suggests use of NRT promotes healthy developmental outcomes in infants. Further research evidence on NRT efficacy and safety is needed, ideally from placebo-controlled RCTs which achieve higher adherence rates and which monitor infants' outcomes into childhood. Accruing data suggests that it would be ethical for future RCTs to investigate higher doses of NRT than those tested in the included studies.

Pharmacological interventions for promoting smoking cessation during pregnancy.

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. OBJECTIVES: 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. SEARCH 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN 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. AUTHORS' 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.