Health Literacy, Individual and Community Engagement, and Cardiovascular Risks and Disparities: JACC: CardioOncology State-of-the-Art Review.

Cardiovascular and cancer outcomes intersect within the realm of cardio-oncology survivorship care, marked by disparities across ethnic, racial, social, and geographical landscapes. Although the clinical community is increasingly aware of this complex issue, effective solutions are trailing. To attain substantial public health impact, examinations of cancer types and cardiovascular risk mitigation require complementary approaches that elicit the patient's perspective, scale it to a population level, and focus on actionable population health interventions. Adopting such a multidisciplinary approach will deepen our understanding of patient awareness, motivation, health literacy, and community resources for addressing the unique challenges of cardio-oncology. Geospatial analysis aids in identifying key communities in need within both granular and broader contexts. In this review, we delineate a pathway that navigates barriers from individual to community levels. Data gleaned from these perspectives are critical in informing interventions that empower individuals within diverse communities and improve cardio-oncology survivorship.

A retrospective evaluation of inter-fraction motion in prostate cancer patients with involved nodes receiving prostate and pelvic ± para-aortic nodal irradiation.

INTRODUCTION: The inter-fraction motion of pelvic ± para-aortic (PA) nodal volumes in prostate cancer patients with involved nodes is yet to be quantified and the optimal IGRT strategy for these patients is currently unknown. METHODS: A single-centre retrospective evaluation was performed investigating inter-fraction motion in the prostate and involved nodal volumes of patients receiving pelvic ± PA nodal irradiation. Patients were selected for inclusion if they; were undergoing prostate + pelvic node +/- PA node radiation for prostate cancer with involved lymph nodes and had received daily online CBCT scans. The planning CT and subsequent CBCT images from each treatment fraction were selected for analysis. RESULTS: Out of 567 CBCTs, from 20 patients, there were no incidences where independent lymph node displacement was >0.5 cm from planning volumes. Lymph node motion relative to prostate was >0.5 cm on 15 occasions out of 567 scans (2.6%). Where the difference between prostate and lymph nodes was >0.5 cm, this was always a result of the rectum causing variation in the prostate position, not a change in nodal position. DISCUSSION: These results suggests that there is limited independent displacement between the involved pelvic ± PA nodal volumes and bony anatomy. Therefore, bony anatomy could be used as a lymph node match surrogate for prostate patients receiving nodal irradiation for active disease. The results also suggest additional emphasis should be placed on bowel preparation in these patients to reduce the risk of geographical miss. CONCLUSION: In conclusion, the results of this evaluation suggests that there is limited independent displacement between the involved pelvic ± PA nodal volumes and bony anatomy. This provides evidence to trials investigating the role of pelvic ± PA nodal irradiation to ensure appropriate margins and IGRT strategies are used when investigating this further.

Preoperative inflammatory biomarkers reveal renal involvement in postsurgical mortality in hip fracture patients: an exploratory study.

Background: Hip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients. Methods: In a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers. Results: Of the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76-40.51], and with both markers plus estimated glomerular filtration rate (eGFR)- cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI. Conclusion: High postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group.

Decision-Making in Surgery.

Surgeons face unique challenges in perioperative decision-making and communication with patients and families. In cardiothoracic surgery, the stakes are high, life and death decisions must be made quickly, and surgeons often lack a longstanding relationship with patients and families prior to intervention. This review considers specific challenges in the preoperative period followed by those faced postoperatively. While preoperative deliberation and informed consent focus on reaching a decision between 2 or more alternative approaches, the most vexing postoperative decisions often involve the patient's discontent with the best-case outcome or how to ensure goal-concordant care when complications arise. This review explores the preoperative ethical and legal requirement for informed consent by describing the contemporary preferred method, shared decision-making. We also present a framework to optimize surgeon communication and promote patient and family engagement in the setting of high-risk surgery for older patients with serious illness. In the postoperative period the family is often tasked with deciding what to do about major complications when the patient has lost decision-making capacity. We discuss several examples and offer strategies for surgeons to navigate these challenging situations. We also explore the concepts of clinical heroism and futility in relation to communicating with patients and families about the outcomes of surgery. Persistent ethical challenges in decision-making suggest that surgeons should improve their skills in communicating with patients to better engage with them, both before and after surgery.

Children's physical activity and sedentary behaviour in before school care: An observational study.

OBJECTIVE: In Australia, less than one quarter of children aged 5-12 years meet national physical activity (PA) guidelines. Before school care operates as part of Out of School Hours Care (OSHC) services and provide opportunities for children to meet their daily PA recommendations. The aim of this study was to explore factors associated with children meeting 15 min of moderate-to-vigorous-intensity physical activity (MVPA) while attending before school care. METHODS: A cross-sectional study was conducted in 25 services in New South Wales, Australia. Each service was visited twice between March and June 2021. Staff behaviours and PA type and context were captured using staff interviews and the validated System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN) time sampling tool. Child PA data were collected using Actigraph accelerometers and associations between program practices and child MVPA analysed. RESULTS: PA data were analysed for 654 children who spent an average of 39.2% (±17.6) of their time sedentary; 45.4% (±11.4) in light PA; and 14.9% (±11.7) in MVPA. Only 17% of children (n = 112) reached ≥15 min MVPA, with boys more likely to achieve this. Children were more likely to meet this recommendation in services where staff promoted and engaged in PA; PA equipment was available; children were observed in child-led free play; and a written PA policy existed. CONCLUSIONS: Before school care should be supported to improve physical activity promotion practices by offering staff professional development and guidance on PA policy development and implementation practices.

Surgical Resection in Nontuberculous Mycobacterial Pulmonary Disease.

Rates of nontuberculous mycobacterial pulmonary disease are increasing worldwide, particularly in the United States and other developed countries. While multidrug antimicrobial therapy is the mainstay of treatment, surgical resection has emerged as an important adjunct. In this article, we will review the indications for surgery, preoperative considerations, surgical techniques, and postoperative outcomes.

Weight Gain in People with HIV: The Role of Demographics, Antiretroviral Therapy, and Lifestyle Factors on Weight.

We explored factors associated with weight gain among people with HIV (PWH) on antiretroviral therapy (ART) at The Ohio State University Wexner Medical Center (OSUWMC). This was a retrospective cohort study of adult PWH on ART for ≥3 months. Patients with CD4+ T cell count <200 cells/mm3, viral load >200 copies/mL, history of malignancy, or pregnancy were excluded. Eight hundred seventy patients met criteria. The primary outcome was percent weight change over the follow-up period (Δ = relative effects). The secondary outcome was the odds of ≥5 kg weight gain over the study period. The effects of concurrent medications, medical comorbidities, ART combinations, and lifestyle behaviors on these outcomes were modeled using mixed effects regression analyses. Over a mean follow-up of 1.86 years, the study population gained a mean percent weight of 2.12% ± 0.21% (p < .001) with the odds of ≥5 kg weight gain of 0.293 (p < .001). Males gained an average of 1.88% ± 0.22% over follow up, while females gained an average of 3.37% ± 0.51% over follow up (p = .008 for the difference). In regression models, combination therapy with tenofovir alafenamide (TAF) and integrase strand transfer inhibitor (INSTI) containing regimens was associated with an increase in weight over the study period (Δ = 2.14% ± 0.45%, p < .001 and Δ = 1.09% ± 0.39%, p = .005, respectively). Increasing age was significantly associated with a decrease in percent weight change over the study period (Δ = -0.68% ± 0.18% per year, p < .001). Self-reported improvement in diet was associated with a decrease in weight change (Δ = -1.99% ± 0.47%, p ≤ .001) and reduced odds of ≥5 kg weight gain (odds ratio = 0.70, 95% confidence interval = 0.50-0.97, p = .03). Factors associated with weight gain include therapy with TAF and INSTI. Diet may play an influential role in attenuating weight gain in PWH.

Early posthospitalization recovery after extracorporeal membrane oxygenation in survivors of COVID-19.

OBJECTIVE: We sought to determine the influence of venovenous extracorporeal membrane oxygenation (ECMO) on outcomes of mechanically ventilated patients with COVID-19 during the first 120 days after hospital discharge. METHODS: Five academic centers conducted a retrospective analysis of mechanically ventilated patients with COVID-19 admitted during March through May 2020. Survivors had access to a multidisciplinary postintensive care recovery clinic. Physical, psychological, and cognitive deficits were measured using validated instruments and compared based on ECMO status. RESULTS: Two hundred sixty two mechanically ventilated patients were compared with 46 patients cannulated for venovenous ECMO. Patients receiving ECMO were younger and traveled farther but there was no significant difference in gender, race, or body mass index. ECMO patients were mechanically ventilated for longer durations (median, 26 days [interquartile range, 19.5-41 days] vs 13 days [interquartile range, 7-20 days]) and were more likely to receive inhaled pulmonary vasodilators, neuromuscular blockade, investigational COVID-19 therapies, blood transfusions, and inotropes. Patients receiving ECMO experienced greater bleeding and clotting events (P < .01). However, survival at discharge was similar (69.6% vs 70.6%). Of the 217 survivors, 65.0% had documented follow-up within 120 days. Overall, 95.5% were residing at home, 25.7% had returned to work or usual activity, and 23.1% were still using supplemental oxygen; these rates did not differ significantly based on ECMO status. Rates of physical, psychological, and cognitive deficits were similar. CONCLUSIONS: Our data suggest that COVID-19 survivors experience significant physical, psychological, and cognitive deficits following intensive care unit admission. Despite a more complex critical illness course, longer average duration of mechanical ventilation, and longer average length of stay, patients treated with venovenous ECMO had similar survival at discharge and outcomes within 120 days of discharge.

Factors Associated With Provision of Nonbeneficial Surgery: A National Survey of Surgeons.

OBJECTIVE: We tested the association of systems factors with the surgeon's likelihood of offering surgical intervention for older adults with life-limiting acute surgical conditions. BACKGROUND: Use of surgical treatments in the last year of life is frequent. Improved risk prediction and clinician communication are solutions proposed to improve serious illness care, yet systems factors may also drive receipt of nonbeneficial treatment. METHODS: We mailed a national survey to 5200 surgeons randomly selected from the American College of Surgeons database comprised of a clinical vignette describing a seriously ill older adult with an acute surgical condition, which utilized a 2×2 factorial design to assess patient and systems factors on receipt of surgical treatment to surgeons. RESULTS: Two thousand one hundred sixty-one surgeons responded for a weighted response rate of 53%. For an 87-year-old patient with fulminant colitis and advanced dementia or stage IV lung cancer, 40% of surgeons were inclined to offer an operation to remove the patient's colon while 60% were inclined to offer comfort-focused care only. Surgeons were more likely to offer surgery when an operating room was readily available (odds ratio: 4.05, P <0.001) and the family requests "do everything" (odds ratio: 2.18, P <0.001). CONCLUSIONS: Factors outside the surgeon's control contribute to nonbeneficial surgery, consistent with our model of clinical momentum. Further characterization of the systems in which these decisions occur might expose novel strategies to improve serious illness care for older patients and their families.

Are E-cigarettes associated with postpartum return to smoking? Secondary analyses of a UK pregnancy longitudinal cohort.

OBJECTIVES: Postpartum return to smoking (PPRS) is an important public health problem. E-cigarette (EC) use has increased in recent years, and in a contemporary UK pregnancy cohort, we investigated factors, including ECs use, associated with PPRS. DESIGN: Secondary analyses of a longitudinal cohort survey with questionnaires at baseline (8-26 weeks' gestation), late pregnancy (34-36 weeks) and 3 months after delivery. SETTING: 17 hospitals in England and Scotland in 2017. PARTICIPANTS: The cohort recruited 750 women who were current or recent ex-smokers and/or EC users. A subgroup of women reported being abstinent from smoking in late pregnancy (n=162, 21.6%), and of these 137 (84.6%) completed the postpartum questionnaire and were included in analyses. OUTCOME MEASURES: Demographics, smoking behaviours and beliefs, views and experience of ECs and infant feeding. RESULTS: 35.8% (95% CI 28% to 44%) of women reported PPRS. EC use in pregnancy (adjusted OR 0.34, 95% CI 0.13 to 0.85) and breast feeding (adjusted OR 0.06, 95% CI 0.02 to 0.24) were inversely associated with PPRS, while household member smoking at 3 months post partum was positively associated with PPRS (adjusted OR 11.1, 95% CI 2.47 to 50.2). CONCLUSION: EC use in pregnancy could influence PPRS. Further research is needed to confirm this and investigate whether ECs could be used to prevent PPRS.

The Association Between Factors Promoting Nonbeneficial Surgery and Moral Distress: A National Survey of Surgeons.

OBJECTIVE: To assess the prevalence of moral distress among surgeons and test the association between factors promoting non-beneficial surgery and surgeons' moral distress. SUMMARY BACKGROUND DATA: Moral distress experienced by clinicians can lead to low-quality care and burnout. Older adults increasingly receive invasive treatments at the end of life that may contribute to surgeons' moral distress, particularly when external factors, such as pressure from colleagues, institutional norms, or social demands, push them to offer surgery they consider non-beneficial. METHODS: We mailed surveys to 5200 surgeons randomly selected from the American College of Surgeons membership, which included questions adapted from the revised Moral Distress Scale. We then analyzed the association between factors influencing the decision to offer surgery to seriously ill older adults and surgeons' moral distress. RESULTS: The weighted adjusted response rate was 53% (n = 2161). Respondents whose decision to offer surgery was influenced by their belief that pursuing surgery gives the patient or family time to cope with the patient's condition were more likely to have high moral distress (34% vs 22%, P < 0.001), and this persisted on multivariate analysis (odds ratio 1.44, 95% confidence interval 1.02-2.03). Time required to discuss nonoperative treatments or the consulting intensivists' endorsement of operative intervention, were not associated with high surgeon moral distress. CONCLUSIONS: Surgeons experience moral distress when they feel pressured to perform surgery they believe provides no clear patient benefit. Strategies that empower surgeons to recommend nonsurgical treatments when they believe this is in the patient's best interest may reduce nonbeneficial surgery and surgeon moral distress.

Worse survival in patients with right ventricular dysfunction and COVID-19-associated acute respiratory distress requiring extracorporeal membrane oxygenation: A multicenter study from the ORACLE Group.

OBJECTIVE: We sought to determine the impact of right ventricular dysfunction on the outcomes of mechanically ventilated patients with COVID-19 requiring veno-venous extracorporeal membrane oxygenation. METHODS: Six academic centers conducted a retrospective analysis of mechanically ventilated patients with COVID-19 stratified by support with veno-venous extracorporeal membrane oxygenation during the first wave of the pandemic (March to August 2020). Echocardiograms performed for clinical indications were reviewed for right and left ventricular function. Baseline characteristics, hospitalization characteristics, and survival were compared. RESULTS: The cohort included 424 mechanically ventilated patients with COVID-19, 126 of whom were cannulated for veno-venous extracorporeal membrane oxygenation. Right ventricular dysfunction was observed in 38.1% of patients who received extracorporeal membrane oxygenation and 27.4% of patients who did not receive extracorporeal membrane oxygenation with an echocardiogram. Biventricular dysfunction was observed in 5.5% of patients who received extracorporeal membrane oxygenation. Baseline patient characteristics were similar in both the extracorporeal membrane oxygenation and non-extracorporeal membrane oxygenation cohorts stratified by the presence of right ventricular dysfunction. In the extracorporeal membrane oxygenation cohort, right ventricular dysfunction was associated with increased inotrope use (66.7% vs 24.4%, P < .001), bleeding complications (77.1% vs 53.8%, P = .015), and worse survival independent of left ventricular dysfunction (39.6% vs 64.1%, P = .012). There was no significant difference in days ventilated before extracorporeal membrane oxygenation, length of hospital stay, hours on extracorporeal membrane oxygenation, duration of mechanical ventilation, vasopressor use, inhaled pulmonary vasodilator use, infectious complications, clotting complications, or stroke. The cohort without extracorporeal membrane oxygenation cohort demonstrated no statistically significant differences in in-hospital outcomes. CONCLUSIONS: The presence of right ventricular dysfunction in patients with COVID-19-related acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation was associated with increased in-hospital mortality. Additional studies are required to determine if mitigating right ventricular dysfunction in patients requiring veno-venous extracorporeal membrane oxygenation improves mortality.

Survey of plastic surgery trainee attitudes to a career as a burns surgeon: A potential workforce dilemma.

AIM AND METHOD: The aim of this study was to gain insight into potential pitfalls in workforce planning for future consultant burns surgeons. An anonymous online survey was sent to current plastic surgery registrars in the UK to assess their subspecialty career choices, the perceived barriers to a career in burns surgery and possible solutions to these. RESULTS: The response rate was 33%. Of 44 respondents, burns surgery was the primary subspecialty of choice for 2% (n = 1) and the secondary choice for 9% (n = 4). Reasons given for not selecting burns surgery included a lack of exposure to the subspecialty, a perceived narrow scope of clinical practice and a concern about the potential negative impact on personal lifestyle. DISCUSSION AND CONCLUSION: Our results may be extrapolated to demonstrate a potential shortfall in the workforce for burns surgery in the future. To address the perceived barriers highlighted by trainees, a coordinated response at a national and international level is most likely to be successful through the cooperation of burns associations. Possible solutions include increasing burns subspecialty exposure during training, incorporating experience in intensive care into surgical training, and highlighting the numerous research opportunities in burns surgery.

Self-assembly of a trigonal bipyramidal architecture with stabilisation of iron in three spin states.

Self-assembly and characterisation of a supramolecular trigonal bipyramidal iron cage containing an [FeIII(µ2-F)6(FeII)3]3+ star motif at its core is reported. The complex can be formed in a one step reaction using an heterotopic ligand that supports site-specific incorporation of iron in three distinct electronic configurations: low-spin FeII, high-spin FeII and high-spin FeIII, with iron(II) tetrafluoroborate as the source of the bridging fluorides. Formation of a µ2-F bridged mixed-valence FeII-FeIII star is unprecedented. The peripheral high-spin FeII centres of the mixed-valence tetranuclear star incorporated in the iron cage are highly anisotropic and engage in F-mediated antiferromagnetic exchange with the central FeIII ion.

Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases.

OBJECTIVE: To assess the risks of developing dementia associated with different types and durations of menopausal hormone therapy. DESIGN: Two nested case-control studies. SETTING: UK general practices contributing to QResearch or the Clinical Practice Research Datalink (CPRD), using all links to hospital, mortality, and social deprivation data. PARTICIPANTS: 118 501 women aged 55 and older with a primary diagnosis of dementia between 1998 and 2020, matched by age, general practice, and index date to 497 416 female controls. MAIN OUTCOME MEASURES: Dementia diagnoses from general practice, mortality, and hospital records; odds ratios for menopausal hormone treatments adjusted for demographics, smoking status, alcohol consumption, comorbidities, family history, and other prescribed drugs. RESULTS: Overall, 16 291 (14%) women with a diagnosis of dementia and 68 726 (14%) controls had used menopausal hormone therapy more than three years before the index date. Overall, no increased risks of developing dementia associated with menopausal hormone therapy were observed. A decreased global risk of dementia was found among cases and controls younger than 80 years who had been taking oestrogen-only therapy for 10 years or more (adjusted odds ratio 0.85, 95% confidence interval 0.76 to 0.94). Increased risks of developing specifically Alzheimer's disease were found among women who had used oestrogen-progestogen therapy for between five and nine years (1.11, 1.04 to 1.20) and for 10 years or more (1.19, 1.06 to 1.33). This was equivalent to, respectively, five and seven extra cases per 10 000 woman years. Detailed risk associations for the specific progestogens studied are also provided. CONCLUSION: This study gives estimates for risks of developing dementia and Alzheimer's disease in women exposed to different types of menopausal hormone therapy for different durations and has shown no increased risks of developing dementia overall. It has shown a slightly increased risk of developing Alzheimer's disease among long term users of oestrogen-progestogen therapies.

Analysis of Recent Literature on Lung Volume Reduction Surgery.

Publication of the National Emphysema Treatment Trial (NETT) in 2003 established lung volume reduction surgery (LVRS) as a viable treatment of select patients with moderate to severe emphysema, and the only intervention since the availability of ambulatory supplemental oxygen to improve survival. Despite these findings, surgical treatment has been underused in part because of concern for high morbidity and mortality. This article reviews recent literature generated since the original NETT publication, focusing on physiologic implications of LVRS, recent data regarding the safety and durability of LVRS, and patient selection and extension of NETT criteria to other patient populations.

Role of procedural intervention and acute illness in veterans affairs smoking cessation program referrals: A retrospective study.

INTRODUCTION: Tobacco use remains pervasive amongst veterans. Unfortunately, the negative impact on postoperative outcomes may preclude surgeons from offering operative intervention to veterans who smoke. As such, a major health event may provide added incentive to quit. We sought to describe the role of acute illness and interventional specialist involvement in Veterans Affairs Smoking Cessation Program referrals compared to primary care wellness initiatives. METHODS: We retrospectively reviewed consultations to the pharmacy-led Smoking Cessation Program (SCP) at the Middleton Memorial VA Hospital from 2017 to 2019. Consultations placed during the last three months were categorized based on the source of referral: primary care, acute care, and interventional specialties. Descriptive statistics were used to assess rates of veteran engagement based on referral source. Consultation completion was used as a proxy for veteran engagement. RESULTS: A total of 2993 new SCP consultations were placed during the study period. Overall, veteran engagement rose from 43% in 2017 to 53% in 2019. In recent months, there were 282 SCP referrals. While only 19 (7%) of these referrals were placed by interventional specialties - primarily cardiology and thoracic surgery - the rate of veteran engagement was 63%. The majority of referrals (65%) were placed by primary care providers with an engagement rate of 68%. In contrast, only 42% of consultations placed in the context of an acute illness were completed. CONCLUSIONS: In our study, primary care directed smoking cessation referrals were most prevalent and resulted in the highest completion rates. The presence of an acute illness in isolation failed to impact program success. However, while surgeon-initiated referrals were meager in number, the engagement rate approached that of primary care. This finding suggests that surgeons play a powerful role in influencing patient behavior that may be harnessed to augment success of existing smoking cessation programs.

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.