Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

The maternal health study: Study design update for a prospective cohort of first-time mothers and their firstborn children from birth to age ten.

BACKGROUND: Maternal health is critical to the health and well-being of children and families, but is rarely the primary focus of pregnancy and birth cohort studies. Globally, poor maternal health and the exposure of women and children to family violence contribute to the perpetuation and persistence of intergenerational health inequalities. OBJECTIVES: The Maternal Health Study was designed to investigate the contribution of social and obstetric risk factors to common maternal physical and psychological morbidities. Over time, our focus has expanded to include mother-child pairs and investigation of intergenerational trauma and family violence. POPULATION: A total of 1507 first-time mothers were recruited in early pregnancy from six public hospitals in Melbourne, Australia, in 2003-2005. METHODS: Women completed questionnaires or telephone interviews in early pregnancy (≤24 weeks); at 32 weeks' gestation; at three, six, nine, 12 and 18 months postpartum; and at four and ten years. At ten years, women and children were invited to participate in face-to-face interviews, which included direct assessment of children's cognitive and language development. A wide range of obstetric, social and contextual factors have been measured, including exposure to intimate partner violence (IPV) (1-year, 4-year and 10-year follow-up). RESULTS: 1507 eligible women were recruited at a mean gestation of 15 weeks. At one year, four years and ten years postpartum, 90.0%, 73.1% and 63.2% of the original cohort took part in follow-up. One in three women in the study (34.5%) reported exposure to IPV in the first ten years of motherhood: 19% in the first 12 months postpartum, 20% in the year prior to four-year follow-up and 18.3% in the year prior to ten-year follow-up. CONCLUSION: The study affords a unique opportunity to examine patterns of maternal and child health and health service use associated with exposure to IPV.

Evaluation of systems reform in public hospitals, Victoria, Australia, to improve access to antenatal care for women of refugee background: An interrupted time series design.

INTRODUCTION: Inequalities in maternal and newborn health persist in many high-income countries, including for women of refugee background. The Bridging the Gap partnership programme in Victoria, Australia, was designed to find new ways to improve the responsiveness of universal maternity and early child health services for women and families of refugee background with the codesign and implementation of iterative quality improvement and demonstration initiatives. One goal of this 'whole-of-system' approach was to improve access to antenatal care. The objective of this paper is to report refugee women's access to hospital-based antenatal care over the period of health system reforms. METHODS AND FINDINGS: The study was designed using an interrupted time series analysis using routinely collected data from two hospital networks (four maternity hospitals) at 6-month intervals during reform activity (January 2014 to December 2016). The sample included women of refugee background and a comparison group of Australian-born women giving birth over the 3 years. We describe the proportions of women of refugee background (1) attending seven or more antenatal visits and (2) attending their first hospital visit at less than 16 weeks' gestation compared over time and to Australian-born women using logistic regression analyses. In total, 10% of births at participating hospitals were to women of refugee background. Refugee women were born in over 35 countries, and at one participating hospital, 40% required an interpreter. Compared with Australian-born women, women of refugee background were of similar age at the time of birth and were more likely to be having their second or subsequent baby and have four or more children. At baseline, 60% of refugee-background women and Australian-born women attended seven or more antenatal visits. Similar trends of improvement over the 6-month time intervals were observed for both populations, increasing to 80% of women at one hospital network having seven or more visits at the final data collection period and 73% at the other network. In contrast, there was a steady decrease in the proportion of women having their first hospital visit at less than 16 weeks' gestation, which was most marked for women of refugee background. Using an interrupted time series of observational data over the period of improvement is limited compared with using a randomisation design, which was not feasible in this setting. CONCLUSIONS: Accurate ascertainment of 'harder-to-reach' populations and ongoing monitoring of quality improvement initiatives are essential to understand the impact of system reforms. Our findings suggest that improvement in total antenatal visits may have been at the expense of recommended access to public hospital antenatal care within 16 weeks of gestation.

Resumption of sex after a second birth: An Australian prospective cohort.

BACKGROUND: Few longitudinal studies have examined women's experiences of sex after childbirth. Much of the advice given to couples about what to expect in relation to sex after childbirth is based on cross-sectional studies. OBJECTIVE: To investigate timing of resumption of sex after a second birth and assess associations with obstetric factors (method of birth and perineal trauma) and time interval between first and second births. METHOD: Prospective cohort of 1507 nulliparous women recruited before 25 weeks' gestation in Melbourne, Australia followed up at 3, 6, 9, and 12 months after first births, and 6 and 12 months after second births. Measures include: obstetric factors and resumption of vaginal sex after first and second births. RESULTS: By 8 weeks after their second birth, 56% of women had resumed vaginal sex, compared with 65% after their first birth. Women were more likely to resume sex later than 8 weeks postpartum if they had a spontaneous vaginal birth with episiotomy or sutured perineal tear (aOR: 2.21, 95% CI: 1.5-3.2), operative vaginal birth (aOR: 2.60, 95% CI: 1.3-5.3) or cesarean delivery (aOR: 2.15, 95% CI: 1.4-3.3) compared with a vaginal birth with minimal or no perineal trauma. There was no association between timing of resumption of sex and the time interval between births. CONCLUSION: For almost half of the cohort, sex was not resumed until at least 8 weeks after the second birth. Timing of resumption of sex was influenced by obstetric factors, but not the time interval between births.

Physical, sexual and social health factors associated with the trajectories of maternal depressive symptoms from pregnancy to 4 years postpartum.

PURPOSE: Few studies have examined the course of maternal depressive across pregnancy and early parenthood. The aim of this study was to identify the physical, sexual and social health factors associated with the trajectories of maternal depressive symptoms from pregnancy to 4 years postpartum. METHOD: Data were drawn from 1102 women participating in the Maternal Health Study, a prospective pregnancy cohort study in Melbourne, Australia. Self-administered questionnaires were completed at baseline (<24 weeks gestation), and at 3-, 6-, 12-, and 18 months, and 4 years postpartum. RESULTS: Latent class analysis modelling identified three distinct classes representing women who experienced minimal depressive symptoms (58.4%), subclinical symptoms (32.7%), and persistently high symptoms from pregnancy to 4 years postpartum (9.0%). Risk factors for subclinical and persistently high depressive symptoms were having migrated from a non-English speaking country, not being in paid employment during pregnancy, history of childhood physical abuse, history of depressive symptoms, partner relationship problems during pregnancy, exhaustion at 3 months postpartum, three or more sexual health problems at 3 months postpartum, and fear of a partner since birth at 6 months postpartum. CONCLUSIONS: This study highlights the complexity of the relationships between emotional, physical, sexual and social health, and underscores the need for health professionals to ask women about their physical and sexual health, and consider the impact on their mental health throughout pregnancy and the early postpartum.

Consultation about Sexual Health Issues in the Year after Childbirth: A Cohort Study.

BACKGROUND: Postnatal sexual health remains underresearched. The main aims of this study were to investigate the prevalence of postnatal sexual health issues, and the extent to which primary care practitioners routinely inquire about sexual health issues. METHOD: 1,507 first time mothers were recruited in early pregnancy and followed up at 3, 6, and 12 months postpartum. Sexual health issues were assessed at every follow-up using a checklist. RESULTS: Eighty-nine percent of women reported sexual health issues in the first 3 months postpartum. The most common sexual health issues at 3 months postpartum were: loss of interest in sex, pain during sex, vaginal tightness, and lack of lubrication. Fifty-one percent continued to report loss of interest in sex at 12 months postpartum, and around 30 percent reported persisting pain. Although most women had contact with primary care practitioners during the first 3 months postpartum, only 24 percent recalled being asked about sexual health issues by general practitioners and 14 percent by maternal and child health nurses. Women who had a cesarean delivery had equivalent or higher odds of reporting persisting sexual health issues, but had lower odds of being asked directly about sexual problems (OR 0.58 [95% CI 0.4-0.9]). CONCLUSIONS: Sexual health issues are extremely common after childbirth. There was no evidence that women who had a cesarean delivery experienced fewer sexual health problems. Despite frequent contact with health professionals, women rarely discussed sexual health issues unless health professionals asked them directly. Given the high prevalence of postpartum sexual health issues routine inquiry is warranted.

Changes to sexual and intimate relationships in the postnatal period: women's experiences with health professionals.

Women navigate many social changes when they become a mother, often including considerable changes to intimate and sexual relationships. This paper draws on data collected in an Australian multicentre prospective nulliparous pregnancy cohort study and a nested qualitative substudy exploring women's experiences of sex and intimacy after the birth of their first child. In all, 1507 women were recruited in early pregnancy (mean gestation 15 weeks) and completed self-administered questionnaires at 3, 6 and 12 months and 4.5 years postpartum. Eighteen participants were interviewed 2.5-3.5 years after the birth of their first child regarding sex and intimacy after having a baby. Interviews were transcribed verbatim and analysed using interpretive phenomenological analysis. Cohort data reveal a considerable drop in both emotional satisfaction and physical pleasure in intimate relationships after birth, with emotional satisfaction continuing to fall up until 4.5 years postpartum. Less than one-quarter of participants reported that their general practitioner had asked directly about sexual health or relationship problems in the first 3 months postpartum (23% and 18%, respectively). In contrast, 13% of women reported that a maternal and child health nurse had asked directly about sexual problems since the birth, and 31% had asked directly about relationship problems. In-depth interviews revealed that relationships with intimate partners were important issues for women following childbirth, and women were seeking reassurance from health professionals that their changing experiences of sex and intimacy after childbirth were 'normal'. Some women felt they had 'fallen through the gaps' and there was not an opportunity provided by health professionals for them to discuss changes affecting their sexual and intimate relationships. The findings suggest that intimate relationships are significantly strained in the years following childbirth and women want more information from primary health care professionals regarding changes to intimate and sexual relationships after childbirth.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Factors influencing adverse events following COVID-19 vaccination.

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p = 0.02) or CoronaVac (26/262, 10%; p < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p < 0.001) or CoronaVac (23/262, 9%; p < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: Insights from prospectively collected data in the BRACE trial.

BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Group Pregnancy Care for refugee background women: a codesigned, multimethod evaluation protocol applying a community engagement framework and an interrupted time series design.

INTRODUCTION: Pregnancy and early parenthood are key opportunities for interaction with health services and connecting to other families at the same life stage. Public antenatal care should be accessible to all, however barriers persist for families from refugee communities to access, navigate and optimise healthcare during pregnancy. Group Pregnancy Care is an innovative model of care codesigned with a community from a refugee background and other key stakeholders in Melbourne, Australia. Group Pregnancy Care aims to provide a culturally safe and supportive environment for women to participate in antenatal care in a language they understand, to improve health literacy and promote social connections and inclusion. This paper outlines Froup Pregnancy Care and provides details of the evaluation framework. METHODS AND ANALYSIS: The evaluation uses community-based participatory research methods to engage stakeholders in codesign of evaluation methods. The study is being conducted across multiple sites and involves multiple phases, use of quantitative and qualitative methods, and an interrupted time series design. Process and cost-effectiveness measures will be incorporated into quality improvement cycles. Evaluation measures will be developed using codesign and participatory principles informed by community and stakeholder engagement and will be piloted prior to implementation. ETHICS AND DISSEMINATION: Ethics approvals have been provided by all six relevant authorities. Study findings will be shared with communities and stakeholders via agreed pathways including community forums, partnership meetings, conferences, policy and practice briefs and journal articles. Dissemination activities will be developed using codesign and participatory principles.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial).

INTRODUCTION: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. METHODS AND ANALYSIS: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. ETHICS AND DISSEMINATION: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Urinary incontinence in nulliparous women before and during pregnancy: prevalence, incidence, and associated risk factors.

INTRODUCTION: Few studies have examined associations of prepregnancy urinary incontinence (UI). METHODS: Multicentre prospective pregnancy cohort study (n = 1,507) using standardised measures to assess frequency and severity of UI. RESULTS: Prevalence of UI increased from 10.8% in the 12 months before the index pregnancy to 55.9% in the third trimester. Stress incontinence (36.9%) and mixed incontinence (13.1%) were more common during pregnancy than urge incontinence alone (5.9%). UI before pregnancy was associated with childhood enuresis (adjusted odds ratio (AdjOR) = 2.4, 95% confidence interval (CI) 1.6-3.4), higher maternal body mass index (AdjOR = 2.3, 95% CI 1.4-3.8), and previous miscarriages or terminations (AdjOR = 1.6, 95% CI 1.1-2.3). The strongest predictor of incident UI in pregnancy was occasional leakage (less than once a month) before pregnancy (AdjOR = 3.6, 95% CI 2.8-4.7). CONCLUSIONS: Further research is needed to elucidate the complex interplay of prepregnancy and pregnancy-related factors in the aetiology of UI in nulliparous women.

Fear of an intimate partner and women's health in early pregnancy: findings from the Maternal Health Study.

BACKGROUND: Intimate partner violence affects 1 in 4 women at some stage in their lives. Exposure to violence has short- and long-term consequences for women themselves and their children. The objective of this study was to examine associations between fear of an intimate partner and maternal physical and psychological morbidity in early pregnancy. METHOD: This paper reports baseline measures from a prospective pregnancy cohort study of 1,507 nulliparous women recruited at six public hospitals in Melbourne, Australia. RESULTS: The study showed that 18.7 percent (280/1,497) of women reported being afraid of an intimate partner at some stage in their lives; 3.1 percent (47/1,497) were afraid in early pregnancy and 15.6 percent (233/1,497) had been afraid before but not during the current pregnancy. Compared with women who had never been afraid of an intimate partner, women who reported being afraid of an intimate partner in early pregnancy (< or = 24 wk gestation) were at increased risk of urinary incontinence (adjusted OR = 1.64, 95% CI 0.9-3.1), fecal incontinence (adjusted OR = 3.32, 95% CI 1.2-9.2), vaginal bleeding (adjusted OR = 2.84, 95% CI 1.5-5.5), anxiety (adjusted OR = 10.22, 95% CI 5.0-21.2), and depression (adjusted OR = 4.43, 95% CI 2.1-9.7). Women afraid of an intimate partner before but not during pregnancy experienced a similar pattern of morbidity. CONCLUSIONS: Women afraid of an intimate partner both before and during pregnancy have poorer physical and psychological health in early pregnancy.

Sexual pleasure and emotional satisfaction in the first 18 months after childbirth.

OBJECTIVE: to investigate the experiences of first time mothers with regard to emotional and sexual intimacy in the period from birth to 18 months postpartum. DESIGN: prospective pregnancy cohort, with follow-up at 3, 6, 12 and 18 months postpartum. SETTING AND PARTICIPANTS: first-time mothers were recruited in early pregnancy at 6 public maternity hospitals in Melbourne, Australia. FINDINGS: 1239 women who completed the baseline questionnaire and all follow up questionnaires were included in the sample for analysis: 78% resumed vaginal sex by 3 months postpartum, 94% by 6 months and 98% by 12 months postpartum. Emotional satisfaction with intimate partner relationships declined over time, from 67.3% reporting high satisfaction at 3 months to 53.9% at 18 months postpartum. In contrast, sex was described as extremely or very pleasurable by 40.1% of women at 3 months postpartum, compared with 49.1% at 18 months postpartum. There was a strong association between emotional satisfaction and the degree to which women experienced physical pleasure in their sexual relationship. Women who were happy with their partner's contribution to household tasks were markedly more likely to report high emotional satisfaction (OR 10.31, 95% CI6.7-15.9) and somewhat more likely to report greater physical pleasure in their sexual relationship (OR 2.32, 95% CI 1.5-3.5). KEY CONCLUSIONS: women experience profound changes in their sexual and intimate relationships in the first 18 months postpartum. While sex appears to improve over time, emotional satisfaction appears to decline. Partner involvement in household tasks is associated with greater emotional satisfaction. IMPLICATIONS FOR PRACTICE: pregnant women and their partners may benefit from information and discussion about the likelihood of changes to their emotional and sexual relationships after childbirth.

Maternal health study: a prospective cohort study of nulliparous women recruited in early pregnancy.

BACKGROUND: In the first year after childbirth, 94% of women experience one or more major health problems (urinary incontinence, faecal incontinence, perineal pain, back pain). Difficulties in intimate partner relationships and changes affecting sexual health are also common. The aim of this study is to investigate changes in women's health from early pregnancy until four years after the birth of a first child. METHODS/DESIGN: The Maternal Health Study is a longitudinal study designed to fill in some of the gaps in current research evidence regarding women's physical and psychological health and recovery after childbirth. A prospective pregnancy cohort of >1500 nulliparous women has been recruited in early pregnancy at six metropolitan public hospitals in Melbourne, Australia between April 2003 and December 2005. In the first phase of the study participants are being followed up at 30-32 weeks gestation in pregnancy, and at three, six, nine, 12 and 18 months postpartum using a combination of self-administered questionnaires and telephone interviews. Women consenting to extended follow-up (phase 2) will be followed up six and 12 months after any subsequent births and when their first child is four years old. Study instruments incorporate assessment of the frequency and severity of urinary and bowel symptoms, sexual health issues, perineal and abdominal pain, depression and intimate partner violence. Pregnancy and birth outcome data will be obtained by review of hospital case notes. DISCUSSION: Features of the study which distinguish it from prior research include: the capacity to identify incident cases of morbidity and clustering of health problems; a large enough sample to detect clinically important differences in maternal health outcomes associated with the method of birth; careful exposure measurement involving manual abstraction of data from medical records in order to explore mediating factors and possible causal pathways; and use of a variety of strategies to improve ascertainment of health outcomes.