Abstract:OBJECTIVE:  Inequalities contribute substantially to adverse perinatal outcomes; however, data on stillbirth risk and its etiologic diversity across maternal migrant status remain limited in Italy. Understanding these patterns is essential for developing targeted prevention strategies. The aim of the present study was to assess stillbirth risk and evaluate differences in underlying causes between Italian and migrant women in a large population-based cohort. Abstract:STUDY DESIGN:  We conducted a retrospective cohort study including 323,635 births in Emilia-Romagna, Italy (2014-2023). Stillbirth (SB) was defined as fetal death at ≥28 weeks. Maternal origin was categorized as Italian versus migrant according to the citizenship. Risk factors were assessed using multivariable logistic and Cox regression models, and causes of fetal death were classified by Re.Co.De. Abstract:RESULTS:  SB incidence was significantly higher in migrants (0.32%) than Italians (0.21%; OR 1.52; HR 1.55, p < 0.001). Low birthweight, advanced maternal age, obesity, and low number of antenatal visits emerged as significant risk factors for SB irrespective of maternal citizenship. Importantly, fetal deaths related to placental pathologies were significantly more frequent in migrants (n = 150/328, 45.7% in migrants vs. n = 159/464, 34.3% in Italians, p = 0.001), as well as infection/inflammation (n = 33/328, 10.1% in migrants vs. 25/464, 5.4% in Italians, p = 0.019). Abstract:CONCLUSION:  Substantial diversity in SB etiology exists across mothers of different origin, underscoring the need for tailored prevention strategies. Accordingly, ultrasounds and infection screening (i.e., antenatal care) should be implemented, especially in migrants. Such measures, combined with culturally sensitive counseling could reduce preventable stillbirths in the multicultural Italian population.

Background: Nationwide studies described a reduction in preterm birth (PTB) during the Coronavirus disease 19 (COVID-19) pandemic, but this was not confirmed in others. Very few data are available on the trend of PTBs over a longer period, including the post-pandemic period, and on potential risk factors, especially those associated with social disparities. Objective: To investigate the trend in PTB rates and the influence of maternal risk factors in Italy from January 2018 to December 2022, based on 12 Regional Birth Registries covering 86.1% of Italian births. Methods: PTB trend was investigated by an interrupted time series analysis. We assessed the associations of potential risk factors with PTB (Poisson regressions) and calculated their population impact fractions (PIFs). Results: We studied 1,762,422 births; 7.25% were PTB. Before the pandemic, we observed a monthly decrease in PTB rate [−0.2% (95% CI: −0.3; −0.1)]; from July 2020 onwards, the average monthly level of PTBs was 5% lower than before (95% CI: −7.3; −2.7), with a flat trend until December 2022 [−0.02% (95% CI: −0.5; 0.5)]. Socio-economic maternal risk factors (low education, unemployment) and foreign nationality, whose risk ratios were 1.14 (95% CI: 1.04; 1.24), 1.08 (1.05; 1.12), and 1.17 (1.14; 1.21), respectively, showed a decreasing trend after pandemic; their impact on the decrease in PTBs was modest (PIFs between −2.4‰ and −4.2‰). Conclusions: The COVID-19 pandemic changed the pattern of PTB rates in Italy, lowering their average frequency and interrupting a previous decreasing trend. Changes in the trend of socio-economic maternal risk factors marginally explained this pattern.

Objective:Stillbirth represents a tragic event, affecting families as well as caregivers. Evidence suggests that a portion of stillbirths is preventable. The audit cycle is a method to improve healthcare. This study evaluates the effectiveness of this methodology applied within a Perinatal Surveillance System in improving the quality of care and its association with a lower proportion of potentially preventable stillbirths. Methods:We conducted a prospective evaluation of the quality of assistance and compared two 5-year periods (2014-2018 and 2019-2023) in the Emilia-Romagna Region (North of Italy). The audit cycle was implemented, as detailed in the text, in two steps: at local and central levels. In addition to temporal trends in its rate, stillbirth causes and their preventability were evaluated. Population features were also recorded. Univariable logistic regression models were used. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were reported. Results:In the study period, 1041 stillbirths occurred. These stillbirths underwent the same diagnostic work-up and audit evaluation. The overall stillbirth rate was 0.33%. When comparing the two 5-year periods, the proportion increased slightly (0.313% vs. 0.354%). We observed a significant reduction in maternal conditions as the primary cause of stillbirth (OR, 0.34; 95% CI, 0.16-0.66) as well as unexplained cases (OR, 0.62; 95% CI, 0.16-0.66) during the second 5-year period (2019-2023). The quality of assistance also improved over time, with the proportion of inadequate care decreasing from 9.92% in 2014-2018 to 6.71% in 2019-2023 (OR, 0.63; 95% CI, 0.40-0.98). Conclusion:The audit cycle was associated with fewer preventable and unexplained stillbirths. The overall proportion increased slightly between periods, likely due to changing maternal risk factors, but the audit helped maintain a low rate and improve the quality of care.

PURPOSE:The aim of this work is to assess cervical length (CL) distribution in a low-risk population in order to evaluate the applicability of a possible universal CL screening in the second trimester, aimed at preventing preterm birth (PTB). METHODS:In a multicentric, prospective cohort study, singleton pregnant women attending second trimester anatomy scan between 18 + 0 to 22 + 6 weeks of gestation were eligible. Teenage pregnancy and women with previous PTB were excluded. The recruitment occurred from February 2020 to December 2022. TVU CL was measured by expert sonographers, in 12 National Health Service (NHS) care clinics of Modena and Parma districts (Emilia-Romagna Region, Italy). Internal quality check of images was performed. Personal and obstetric history, as well as gestational age were collected. Primary outcomes were to define CL curves and the incidence of CL ≤25 mm in low-risk pregnant women Secondary outcomes were the incidences of PTB <37, <34, and <32 weeks. RESULTS:Among 3226 screened women, mean and median CL were 40.8 and 40 mm, respectively. The 10th centile was equal to 33 mm while 25 mm represented the 2nd centile of the distribution. The incidence of CL ≤25 mm (short cervix) was 1.25%. Among those women, 7.5% were shorter than 150 cm, opposed to 2.1% in the normal CL group (p = .02); in addition there were more nullipara, women ≥ 40 and smokers (p = .03). Women with short cervix were at higher risk of PTB (23.6 vs 4.3%; RR: 4.6, 95%CI 2.49-8.48). At multivariate analysis, both CL ≤ 25 mm (RR: 5.51, 95%CI: 2.45-12.3) and stature ≤150 cm (RR: 2.54, 95%CI: 1.11-5.79) resulted independent predictors for PTB, once adjusted for other risk factors (fibroids, cervical surgery, obesity, low education, older age, smoking habit). CONCLUSION:Although our study confirmed that women with short cervix are more likely to deliver preterm, the low incidence of such risk factor means that most of the preterm births occurred among women with normal cervical length. Thus, in a low-risk Italian population, ineffectiveness of universal screening is forecast.

BACKGROUND:The aim of the study is to perform an overview of intrapartum stillbirth (SB) at term, assessing risk factors, causes of death and quality of pregnancy care. METHODS:This is an area-based, prospective cohort study on pregnant women at ≥37 weeks from 2014 to 2021. We compared intrapartum SB' information to alive birth and to antepartum deaths of the same period. Results of logistic regression are reported as the Odds Ratio (OR) with 95% confidence interval (95% CI) and the P value. A descriptive analysis about the causes of death and quality of pregnancy care is performed. RESULTS:The overall rate of SB at term in Emilia-Romagna was 1.06 ‰ births. Among the 260 cases, 27 (10.4%) occurred during labor, with an intrapartum SB rate of 0.11‰. This SB rate was stable during years. SGA newborn (P=0.005, 95% CI 1.47-9.04, OR 3.63), low level of education (P<0.0001, 95% CI 2.98-16.11, OR 6.93), pre pregnancy BMI ≥ 25 kg/m2 (P<0.0001, 95% CI 6.61-31.74, OR 14.50) are independent risk factors for intrapartum SB when compared to alive newborns. Compared with antepartum SB, excessive weight gain in pregnancy (RR 2.91, 1.43-3.98, P=0.001) represents a risk factor for intrapartum ones. CONCLUSIONS:Preventing intrapartum SB at term in developed country should be based on both the appropriate antenatal management of fetal growth and the avoidance of maternal excessive weight gain. An effort toward pre conceptional intervention of improving maternal shape could be of value.

Objective. To compare the estimates of preterm birth (PTB; 22-36 weeks gestational age, GA) and stillbirth rates during COVID-19 pandemic in Italy with those recorded in the three previous years. Design. A population-based cohort study of liveborn and stillborn infants was conducted using data from Regional Health Systems and comparing the pandemic period (March 1st, 2020-March 31st, 2021, N= 362,129) to an historical period (January 2017- February 2020, N=1,117,172). The cohort covered 84.3% of the births in Italy. Methods. Logistic regressions were run in each Region and meta-analyses were performed centrally. We used an interrupted time series regression analysis to study the trend of preterm births from 2017 to 2021. Main Outcome Measures. The primary outcomes were PTB and stillbirths. Secondary outcomes were late PTB (32-36 weeks’ GA), very PTB (<32 weeks’ GA), and extreme PTB (<28 weeks’ GA), overall and stratified into singleton and multiples. Results. The pandemic period compared with the historical one was associated with a reduced risk for PTB (Odds Ratio: 0.90; 95% Confidence Interval, CI: 0.87, 0.93), late PTB (0.91; 0.87, 0.94), very PTB (0.87; 0.84, 0.91), and extreme PTB (0.88; 0.82, 0.94). In multiples, point estimates were not very different, but had wider CIs. No association was found for stillbirths (1.01; 0.90, 1.13). A linear decreasing trend in PTB rate was present in the historical period, with a further reduction after the lockdown. Conclusions We demonstrated a decrease in PTB rate after the introduction of COVID-19 restriction measures, without an increase in stillbirths.

From the Obstetrics and Gynecology Unit, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy (Drs Salerno, Melis, Donno, Guariglia, Facchinetti, and Monari); International Doctorate School in Clinical and Experimental Medicine, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy (Dr Menichini); Emilia-Romagna Health and Welfare Directorate, Community Care Department, Bologna, Italy (Dr Perrone)

Objective To investigate the effect of a quality improvement project with an educational/motivational intervention in northern Italy on the implementation of the trial of labor after cesarean section (CS). Method A pre-post study design was used. Every birth center (n = 23) of the Emilia-Romagna region was included. Gynecologist opinion leaders were first trained about Italian CS recommendations. Barriers to implementation were discussed and shared. Educational/motivational interventions were implemented. Data of multipara with previous CS, with a single, cephalic pregnancy at term, were collected during two periods, before (2012-2014) and after (2017-2019) the intervention (2015-2016). The primary outcome was the rate of vaginal birth after CS (VBAC) and perinatal outcomes. Results A total of 20 496 women were included. The VBAC rate increased from 18.1% to 23.1% after intervention (P < 0.001). The likelihood of VBAC-adjusted for age 40 years or older, Caucasian, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) at least 30, previous vaginal delivery, and labor induction-was increased by the intervention by 42% (odds ratio 1.42, 95% confidence interval 1.31-1.54). Neonatal well-being was improved by intervention; neonates requiring resuscitation decreased from 2.1% to 1.6% (P = 0.001). Conclusion Educating and motivating gynecologists toward the trial of labor after CS is worth pursuing. Health quality improvement is demonstrated by increased VBAC even improving neonatal well-being.

Abstract Objectives Data collected worldwide on stillbirth (SB) rates during the Covid-19 pandemic are contradictory. Variations may be due to methodological differences or population characteristics. The aim of the study is to assess the changes in SB rate, risk factors, causes of death and quality of antenatal care during the pandemic compared to the control periods. Methods This prospective study is based on the information collected by the Emilia-Romagna Surveillance system database. We conducted a descriptive analysis of SB rate, risk factors, causes of death and quality of cares, comparing data of the pandemic (March 2020–June 2021) with the 16 months before. Results During the pandemic, the SB rate was 3.45/1,000 births, a value in line with the rates of previous control periods. Neonatal weight >90th centile was the only risk factor for SB that significantly changed during the pandemic (2.2% vs. 8.0%; p-value: 0.024). No significant differences were found in the distribution of the causes of death groups. Concerning quality of antenatal cares, cases evaluated with suboptimal care (5.2%) did not change significantly compared to the control period (12.0%), as well as the cases with less than recommended obstetric (12.6% vs. 14%) and ultrasound evaluations (0% vs. 2.7%). Conclusions During the COVID-19 pandemic, no significant differences in SB rates were found in an area that maintained an adequate level of antenatal care. Thus, eventual associations between SB rate and the COVID-19 infection are explained by an indirect impact of the virus, rather than its direct effect.

The lowest incidence of perinatal morbidity and mortality occurs around 39–40 weeks. Therefore, a policy of elective induction of uncomplicated singleton once pregnancy reaches full‐term become cau...

The new coronavirus emergency spread to Italy when little was known about the infection’s impact on mothers and newborns. This study aims to describe the extent to which clinical practice has protected childbirth physiology and preserved the mother–child bond during the first wave of the pandemic in Italy. A national population-based prospective cohort study was performed enrolling women with confirmed SARS-CoV-2 infection admitted for childbirth to any Italian hospital from 25 February to 31 July 2020. All cases were prospectively notified, and information on peripartum care (mother–newborn separation, skin-to-skin contact, breastfeeding, and rooming-in) and maternal and perinatal outcomes were collected in a structured form and entered in a web-based secure system. The paper describes a cohort of 525 SARS-CoV-2 positive women who gave birth. At hospital admission, 44.8% of the cohort was asymptomatic. At delivery, 51.9% of the mothers had a birth support person in the delivery room; the average caesarean section rate of 33.7% remained stable compared to the national figure. On average, 39.0% of mothers were separated from their newborns at birth, 26.6% practised skin-to-skin, 72.1% roomed in with their babies, and 79.6% of the infants received their mother’s milk. The infants separated and not separated from their SARS-CoV-2 positive mothers both had good outcomes. At the beginning of the pandemic, childbirth raised awareness and concern due to limited available evidence and led to “better safe than sorry” care choices. An improvement of the peripartum care indicators was observed over time.

Objectives To describe a cohort of Italian women with confirmed COVID-19 infection admitted during pregnancy for out or inpatient hospital care, in order to provide rapid feedback for clinicians and policymakers. Design National population-based cohort study. Setting 297 Italian public and private maternity units. Population Pregnant women with COVID-19 infection confirmed by RT-PCR testing through nasopharyngeal swab and/or chest RX or CT findings and/or antibody response from maternal blood. Exclusion criteria: age <18 years, refusal to participate and inability to give consent to participation. Methods A network of 351 trained reference clinicians enrols eligible women after acquiring an informed consent and completes a data entry form through a secure web-based system. Main outcome measures COVID-19 pneumonia, invasive respiratory support, ICU admission, women’s severe morbidity and mortality Results Over 80% of the 65 cases occurred in Northern Italy. Women’s mean age is 33.8 years. Gestational age at presentation is ≤14 weeks in 15.6% of the cases, 15-27 weeks in 51.6% and ≥28 weeks in 32.8% women. Pneumonia affects 41.5% of the cohort; three women have severe complications and are admitted to ICU. None has died. Conclusions The study describes the course of COVID-19 infection in a cohort of pregnant women, providing valuable information to improve clinical and logistical management of these cases. Questions arising from the study deserve further research.

The lowest incidence of perinatal morbidity and mortality occurs around 39–40 weeks. Therefore, a policy of elective induction of uncomplicated singleton once pregnancy reaches full‐term become cau...

This paper aims to describe the Italian obstetric surveillance system (ItOSS) preparedness as an element for a timely response to the new Coronavirus pandemic. ItOSS is a surveillance network that has been collecting data on maternal mortality and conducting population studies on obstetric near misses since 2013. At the beginning of the pandemic, ItOSS launched a new population-based project to monitor SARS-CoV-2 infection during pregnancy and post-partum and promptly give back information useful to clinicians and decision-makers. All the regions and autonomous provinces, for a total of 289 birth units (PN), joined the study. Data relating to pregnant or post-partum women with a confirmed SARS-CoV-2 infection diagnosis addressing the maternities for outpatient visits or hospitalization were collected. The project methodology entails that each participating maternity reports the cases to ItOSS uploading data through an open-source platform. The on-line form includes sociodemographic and clinical data and maternal-neonatal outcomes. Biological samples to detect possible vertical transmission are also collected voluntarily. A total of 534 incident cases were reported from February 25th to July 10th 2020; 7 regions also collected biological samples for 227 cases; data collection is still ongoing.A preliminary analysis of the first 146 SARS-CoV-2 positive women who gave birth between February 25th to April 22nd shows an incidence rate of the infection equal to 2.1/1,000 in Italy and 6.9/1,000 in the Lombardy Region (Northern Italy). The brief time needed to setting up and operating the project, the national coverage, the adoption of shared tools for data collection, the quality and completeness of the information collected show how the availability of active networks like ItOSS represents a crucial element to hold a high level of preparedness in case of a health emergency.

There is evidence that preterm infants of migrant mothers are at a higher risk of adverse perinatal outcomes than those of native-born mothers, and that human milk feeding is beneficial to infants’ neurodevelopment. Using the United Nations Human Development Index (HDI) to classify mother’s country of origin, we investigated whether type of neonatal feeding (human milk vs. mixed milk vs. exclusive formula milk) affected preterm newborn neurodevelopment varying across different HDI categories (Italian native-born vs. high HDI migrant vs. low HDI migrant) up to 2 years of age. Neurodevelopment of 530 infants born in Italy at ≤32 weeks of gestational age and/or weighing <1500 g was measured at 3-, 6-, 9-, 12-, 18-, and 24-months corrected age (CA) using the revised Griffiths Mental Development Scale 0–2 years. The trajectories of the general developmental quotient and its five subscales were estimated using mixed models. At 24-months CA only preterm infants of low HDI migrant mothers and fed exclusive formula milk showed moderate neurodevelopment impairment, with lower developmental trajectories of eye-hand coordination, performance, and personal-social abilities. Migrant mothers from low HDI countries and their preterm infants should be targeted by specific programs supporting maternal environment, infant development, and human or mixed milk neonatal feeding. Future research should focus on a deeper understanding of the mechanisms through which type of feeding and mother migrant conditions interact in influencing preterm infants’ neurodevelopment.

This paper aims to describe the Italian obstetric surveillance system (ItOSS) preparedness as an element for a timely response to the new Coronavirus pandemic. ItOSS is a surveillance network that has been collecting data on maternal mortality and conducting population studies on obstetric near misses since 2013. At the beginning of the pandemic, ItOSS launched a new population-based project to monitor SARS-CoV-2 infection during pregnancy and post-partum and promptly give back information useful to clinicians and decision-makers. All the regions and autonomous provinces, for a total of 289 birth units (PN), joined the study. Data relating to pregnant or post-partum women with a confirmed SARS-CoV-2 infection diagnosis addressing the maternities for outpatient visits or hospitalization were collected. The project methodology entails that each participating maternity reports the cases to ItOSS uploading data through an open-source platform. The on-line form includes sociodemographic and clinical data and maternal-neonatal outcomes. Biological samples to detect possible vertical transmission are also collected voluntarily. A total of 534 incident cases were reported from February 25th to July 10th 2020; 7 regions also collected biological samples for 227 cases; data collection is still ongoing.A preliminary analysis of the first 146 SARS-CoV-2 positive women who gave birth between February 25th to April 22nd shows an incidence rate of the infection equal to 2.1/1,000 in Italy and 6.9/1,000 in the Lombardy Region (Northern Italy). The brief time needed to setting up and operating the project, the national coverage, the adoption of shared tools for data collection, the quality and completeness of the information collected show how the availability of active networks like ItOSS represents a crucial element to hold a high level of preparedness in case of a health emergency.

BACKGROUND:Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. OBJECTIVES:To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. SEARCH METHODS:In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. SELECTION CRITERIA:We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. DATA COLLECTION AND ANALYSIS:We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. MAIN RESULTS:We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I2 = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I2 = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I2 = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I2 = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I2 = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I2 = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women). AUTHORS' CONCLUSIONS:Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.