Effects of This post-hoc analysis used data from the TB APPRISE trial, a multicentre, double-blind, placebo-controlled trial, which randomised women to 28-week IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT) in eight countries with high tuberculosis prevalence. Participants were enrolled between August 2014 and April 2016. Based on modified intent-to-treat analyses, we analysed only live-born babies who had at least one follow-up after birth and compared time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum in overall and sex-stratified multivariable Cox proportional hazards regression. Factors adjusted in the final models include sex of infant, mother's baseline BMI, age in years, ART regimen, viral load, CD4 count, education, and household food insecurity.Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in pregnancy-IPT had a 1.47-fold higher risk of becoming underweight by 12 weeks  than infants in the postpartum-IPT; increased risk persisted to 48 weeks postpartum . Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of low birth weight (LBW) , preterm birth  and becoming underweight by 12 weeks  and 48 weeks . Maternal IPT timing did not influence growth in female infants.Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, particularly male infants. These data add to prior TB APPRISE data, suggesting that IPT during pregnancy impacts infant growth, which could inform management, and warrants further examination of mechanisms.10.13039/100000002National Institutes of Health (NIH)  through the 10.13039/100000060National Institute of Allergy and Infectious Diseases, with cofunding from the 10.13039/100009633Eunice Kennedy Shriver National Institute of Child Health and Human Development  and the 10.13039/100000025National Institute of Mental Health.The TB APPRISE study Supported by the  Pregnancy isoniazid preventive therapy (IPT) has not been associated with adverse pregnancy outcomes in observational studies on pregnant women. A rigorously assessed multicenter randomized control trial in women living with HIV on antiretroviral therapy revealed that pregnancy-IPT was associated with an increased incidence of composite adverse pregnancy outcomes , preterm delivery, and infant congenital anomalies). However, in subsequent secondary analyses of pregnancy cohorts and in a large-scale study of programmatic data in South Africa, antenatal IPT did not appear to be associated with adverse pregnancy outcomes. On the basis of these data, the World Health Organization (WHO) continues to recommend IPT for pregnant women living with HIV, both for their own and their infant's health. In reviewing these studies, we noticed that the long-term and sex-specific effects of pregnancy-IPT on HIV-exposed-uninfected infants were unknown.This post-hoc analysis of the TB APPRISE trial studied the effects of pregnancy-IPT beyond the previously reported composite pregnancy and birth outcomes to include longer term infant growth outcomes and employed sex-stratified analyses. The data shows that maternal IPT during pregnancy was associated with a significantly increased risk of low birth weight and risk of becoming underweight among HEU infants. Male infants exposed to pregnancy-IPT had a significant risk of low birth weight, preterm birth, and longer-term risk of being underweight that persisted over the first year of life.These data add to prior TB APPRISE findings of increased risk of composite adverse pregnancy and birth outcomes associated with IPT during pregnancy, suggesting IPT during pregnancy also impacts the birth size and subsequent infant growth, specifically among male infants. Given that WHO recommended IPT and ART during pregnancy based on data from nonpregnant adults and the absence of harm from observational studies, these data could inform monitoring and management and warrants further examination of potential mechanisms.,Prevention of tuberculosis (TB) among women living with HIV (WLWH) is a high priority in TB endemic areas.,Observational studies on pregnant women, primarily secondary analyses, did not reveal associations of pregnancy IPT with adverse pregnancy outcomes., and growth compromise.Exposure to HIV and ART in-utero may increase the risk of preterm birth, LBW and low birth length, small for gestational age (SGA), stillbirth,12th week postpartum. The postpartum-IPT arm initiated a placebo immediately after trial entry during pregnancy until the 12th week postpartum and then switched to isoniazid daily until the 40th week postpartum. All participants received vitamin B6 and a prenatal multivitamin from week 0 to week 40 postpartum. The randomisation was stratified by the gestational age at trial entry (≥14 weeks to <24 weeks or ≥24 weeks to ≤34 weeks) and was balanced at each site.This post-hoc analysis utilised data from the P1078 TB APPRISE trial – a randomised, double-blind, placebo-controlled, multicentre, non-inferiority study designed to evaluate the effect of pregnancy-IPT vs postpartum-IPT on maternal complications and composite adverse birth outcomes. The trial, as reported in detail previously,As detailed in the parent paper,3, >7.5 g/dL haemoglobin, and >50,000 platelets count/mm3 were eligible. Participants were required to have liver enzymes  at or below 1.25 times the upper limit of the normal range within 30 days prior to study entry. Women with active TB, recent TB exposure, TB treatment for more than 30 days in the previous year, or peripheral neuropathy of grade 1 or higher were excluded. The original study included 956 participants, 477 randomised to pregnancy-IPT and 479 to postpartum-IPT arm. Participants were enrolled between August 2014 and April 2016.Pregnant WLWH, 14–34 weeks of gestation, weighing >35 kg, with >750 absolute neutrophil count cells/mmThis analysis was restricted to HEU infants born to mothers participating in the RCT. Exclusion criteria for this analysis included lack of infant information , HIV infection of the infant, and twin births.Mother-infant pairs were followed up to 48 weeks postpartum. Weight and length of infants were measured at birth, 4th, 8th, 12th, 24th, 36th, 44th, and 48th weeks postpartum to the nearest 0.1 kg and 0.1 cm. The scales were calibrated regularly as per the manufacturer's instructions. Shoes and outer layers of clothing were removed before weight measurements were taken. Infants' lengths were measured with horizontal boards. The data collectors were trained and experienced in weight and length measurement. There was a two-week extension period for mothers who did not attend their last visit. Missing values at the scheduled last visit were replaced by measurements within two weeks after the end of the study.Low birth weight (LBW) was defined as less than 2.5 kg regardless of gestational age. Birth before completion of 37 weeks of pregnancy was regarded as preterm. Small for gestational age (SGA) was defined by weight less than the 10th percentile for gestational age using INTERGROWTH growth standards.Weight-for-age z-score [WAZ], weight-for-length z-score [WLZ], and length-for-age z-score [LAZ]) were defined using WHO child growth standards.3), education, and household food insecurity. Household food insecurity was considered positive if the respondents answered yes to at least one of the following questions: did you experience a lack of resources to get food, have you gone to bed hungry in the last 30 days, and have you passed the entire day and night hungry?Cofactors of growth faltering assessed in the analyses included: Infant sex and maternal characteristics at enrolment, including body mass index (BMI), age, ART regimen, viral non-suppression , CD4 count (cells/mm2 tests (Fisher's exact tests if assumptions were not met) for categorical variables.Means and standard deviations (SDs) were used to describe normally distributed continuous variables, medians and interquartile ranges (IQRs) to describe skewed distributions, and frequencies and percentages to describe categorical variables. Baseline maternal and infant characteristics were compared between pregnancy-IPT and postpartum-IPT randomisation groups using two-sided t-tests (Mann–Whitney U tests if assumptions were not met) for continuous variables and Pearson χIn the primary study, randomisation was carried out on pregnant women. The randomisation groups were compared in modified intent-to-treat analyses adjusted for predetermined potential confounding variables.For the measurement of adverse birth outcomes, the effects of pregnancy-IPT on LBW and preterm birth were examined in the primary trial publication; however, sex-stratified analyses of these outcomes were not conducted. We examined the effects of pregnancy-IPT on birth outcomes  using generalised linear models with a Poisson family and a log link (to estimate relative risks) in overall and sex-stratified analyses. Multivariable generalised linear models were fitted to control potential confounders.For the measurement of growth faltering during infancy, mothers in the postpartum-IPT arm initiated IPT at 12 weeks after delivery, therefore data were censored at 12-weeks postpartum to examine the effect of pregnancy-IPT compared to no IPT during pregnancy and postpartum. In addition, to compare the longer-term effects of pregnancy-IPT on growth faltering, randomised arms were compared up to 48 weeks after birth. Growth faltering was compared between randomised groups using Cox proportional hazards regression models and generalised estimated equations (GEE).th week and after were censored.We used Kaplan–Meier survival analysis to compare, unadjusted, time to the first event of growth faltering  to 12 weeks postpartum and 48 weeks postpartum in overall and sex-stratified analyses. Univariate and multivariable Cox proportional hazards regression models and models including interaction terms between randomisation arm and infants' sex were fit to compare the risk of experiencing the first episode of growth faltering between the randomised groups and any effect modification by infant sex. For these analyses, time zero was the randomisation date, and no failure  was assumed prior to birth. Since participants were randomly assigned to either a treatment or a control group during pregnancy, whatever difference occurred between the two arms, such as gestational age at birth or low birth weight, was assumed to be attributable to the intervention. Infants lost to follow-up or who died prior to failure were censored at their last visit date. Growth data from visits following growth faltering were censored. We used multivariate Cox proportional hazards regression models to identify cofactors , education, and household food insecurity and infant sex) of growth faltering. As fewer than 5% of at-risk participants remained in the study after 60 post-randomisation weeks, the values at 60In multivariable models, we didn't adjust birth characteristics because adjusting for low birth weight, preterm birth, and/or SGA would underestimate the effect of the intervention on the outcome as they are in the causal pathway between pregnancy IPT exposure and long-term growth.Moreover, univariate and multivariable generalised estimated equations (GEE) were fit with a Poisson family and a log link (to estimate relative risk) and exchangeable correlation structure to compare risks of growth faltering  at any time up until 12 weeks postpartum and up to 48 weeks, as well as testing for interaction by infants' sex and analyses stratified by sex. Infants who experienced growth faltering anytime were not censored in this analysis. The multivariate GEE model was used to identify cofactors of growth faltering in HEU infants.We also fitted multivariable linear regression to examine the long-term impact of IPT on growth  at 48 weeks of infant age.We used R version 4.1.0 for analyses.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BAR, ASC, and GM had access to the dataset. ASC, SML, GJS, AG, and GM were responsible for the final decision on the submission of this manuscript for publication.In this study, 898 infants were included: 448 in the pregnancy-IPT and 450 in the postpartum-IPT arm .Fig. 1FiThe median age of mothers at enrolment was 29 years (IQR 24–33), and median BMI was 26.2 (IQR 23.3–29.7). All mothers were on ART and the majority received either efavirenz-tenofovir-lamivudine ) or efavirenz-tenofovir-emtricitabine ). Almost half (49.2%) of mothers had a CD4 count above 500 cells/mm3, and 37.6% (316/850) of mothers had a viral load of >40 HIV RNA copies/ml. Almost half (447/898) of the infants were female – 228 in the pregnancy-IPT arm and 219 in the postpartum-IPT arm. Baseline maternal and infant demographic and clinical characteristics were similar between randomised arms .Table 1BAs reported in the primary analysis, six mothers (0.4%) and one infant (0.1%) developed TB, and 241 mothers (32.4%) and 41 (5.8%) infants tested positive on a QuantiFERON-TB Gold In-Tube (QGIT) test. There was no significant difference in TB disease or infection incidence in mothers or infants between arms.There was no unadjusted mean difference in WAZ , LAZ , and WLZ  at 48 weeks of infants age between pregnancy-IPT and postpartum-IPT. Similarly, there was no adjusted mean difference in WAZ , LAZ , and WLZ  at 48 weeks of infants age between pregnancy-IPT and postpartum-IPT.Overall, 10.7% of infants were premature, 11.5% were LBW, and 19.2% were SGA at birth. Adjusted for relevant cofactors, infants in the pregnancy-IPT arm had a 1.60-fold higher risk of LBW  than infants in the postpartum-IPT arm . There wIn sex-stratified analyses adjusted for all cofactors, male infants in the pregnancy-IPT arm had a 2.04-fold higher risk of LBW  and 1.81-fold increased risk of preterm birth  than those in the postpartum-IPT arm. Pregnancy-IPT was not associated with LBW or preterm delivery among female infants or SGA among male and female infants .The overall risk of being underweight during the 48-week follow-up period was 22.8 per 100 person-years , risk of stunting was 40.1 per 100 person-years , and risk of wasting was 32.8 per 100 person-years .In univariate analysis, male infants in the pregnancy-IPT had a significantly higher cumulative probability of being underweight , p = 0.041) than male infants in the postpartum-IPT arm a. Fig. 2In multivariable Cox regression models, pregnancy-IPT was associated with infant underweight in analyses to 12 weeks and 48 weeks postpartum. Infants in the pregnancy-IPT arm experienced a 1.47-fold higher risk of becoming underweight in the first 12 weeks  and a 1.34-fold higher risk of becoming underweight in the first 48 weeks  than infants in the postpartum-IPT arm. Maternal IPT timing was not associated with stunting  or wasting  .Table 3RInfant sex significantly modified the effect of pregnancy-IPT on underweight in analyses to 12 weeks  and 48 weeks . Male infants in the pregnancy-IPT arm experienced a 2.02-fold increased risk of becoming underweight in the first 12 weeks  and a 1.82-fold increased risk of becoming underweight in the first 48 weeks  than male infants in the postpartum-IPT arm .There was also a statistically significant differential effect of pregnancy-IPT on wasting in male and female infants by 12 weeks , but not by 48 weeks . Male infants in the pregnancy-IPT arm experienced a 1.61-fold higher risk of becoming wasted in the first 12 weeks , and a 1.43-fold higher risk (nonsignificant) of becoming wasted in the first 48 weeks  than male infants in the postpartum-IPT arm .Among female infants, pregnancy-IPT was not associated with growth faltering – underweight , stunting , and wasting .We also fitted GEE multivariable models to estimate the repeated prevalence of growth faltering during infancy which yielded similar results to Cox regression analyses .2 increase in maternal BMI, infant risk of being underweight decreased by 7% , and wasting risk decreased by 8%   .Table 4CFor every additional year of maternal age, the risk of wasting in infants increased by 4% , while the risk of stunting decreased by 2% . Infants born to mothers who used NVP-regimens experienced 1.6-fold increased risk of being underweight  and 1.34 increased risk of stunting  compared to EFV, TDF, 3TC/FTC regimens. Infants born from mothers who have secondary education have a 21% lower risk of stunting  but a 45% higher risk of wasting  .Multivariable GEE models used to assess cofactors of growth faltering yielded similar results as Cox proportional hazard regression models above .In this post-hoc analysis of a multi-site RCT evaluating maternal IPT in pregnancy versus postpartum, timing of maternal IPT influenced growth outcomes among HEU infants with a significantly higher risk of underweight among infants born to mothers in the pregnancy-IPT arm. There was an effect modification of associations of IPT with growth by infant sex, with significantly increased underweight and wasting in males born to mothers in the pregnancy-IPT versus postpartum-IPT arms. Our findings suggest that the timing of maternal IPT may influence birth size as well as postnatal growth in infants and provide valuable data for policymakers and clinicians considering the optimal timing of IPT in pregnant WLWH.,Our data suggest growth-altering effects of in utero IPT exposure. Infants born to mothers randomised to pregnancy-IPT had a 1.60-fold higher risk of LBW and of becoming underweight during the first year of life than infants born to mothers randomised to postpartum-IPT. During pregnancy, IPT causes embryocidal effects on rats and rabbits, delays neurodevelopment in zebrafish, and affects postnatal growth, development, and cognitive ability in rats.,,,,,,We found that associations between pregnancy-IPT and growth were modified by infant sex. Male infants in the pregnancy-IPT arm had a significantly higher risk of preterm birth, LBW, and longer-term growth faltering than male infants in the postpartum-IPT arm. In contrast, birth outcomes and growth in female infants were not affected by pregnancy-IPT. In utero growth trajectories differ by sex; male foetuses typically grow faster and may not alter their growth trajectory when facing adverse challenges.Pregnancy-IPT was not associated with overall or sex-stratified SGA. The fact that male infants in pregnancy-IPT had a 1.81 higher risk of preterm birth while there was no difference in SGA risk than male infants in postpartum-IPT suggests that the mechanism for LBW in male infants may be through preterm birth.In addition to our primary goal of defining the impact of pregnancy IPT exposure on infant growth, we assessed other cofactors of growth in HEU infants. We found expected associations between maternal BMI and being underweight. Nutritional status during pregnancy affects the Foetus's nutrition, potentially altering its growth. We also found that stunting risk decreased by 2% for every additional year of maternal age. This was consistent with a study using data from 18 countries' Demographic Health Surveys, which found that infants of young mothers had lower heights than infants born to older mothers.This study has multiple strengths, including randomised allocation of IPT timing, excellent retention, and sufficient sample size to investigate growth outcomes. The study also has limitations. This post-hoc analysis was designed after the primary RCT was completed. After 12 weeks of age, infants in the deferred arm received postpartum IPT, so there is not a no-IPT comparator after this time point. However, in analyses that excluded the time period with exposure to postpartum IPT, growth effects of pregnancy-IPT remained similar. Because of the lack of information about infants' growth during pregnancy, we assumed no failure  prior to birth, and birth was assumed as time-one, which could be a limitation. Infants with compromised growth before delivery would have been censored before birth if we had this prior birth information. As a result, it is possible that some infants might have switched categories before birth as a result - from compromised growth to normal growth and vice versa. However, we strongly believe that the design of our study has addressed/minimised the impact of this on the results of our study. Given that randomisation was applied, any difference between the two arms is attributed to IPT exposure during pregnancy. Similarly, the double-blind placebo-controlled randomised controlled trial design has addressed/minimised potential bias and measurement errors. Randomization has addressed selection bias. To reduce measurement error, data collectors were trained in how to measure height and weight in infants. As it was a double-blinded and placebo-controlled design, even if measurement error occurred, there would have been non-differential misclassification, which would attenuate the effect of the exposure on the outcome. Therefore, the design allows us to ensure that our findings are not biased or influenced by measurement errors . And, randomisation was balanced by study site to account for heterogeneity.Breastfeeding is crucial for infant development and growth. We did not include breastfeeding-related variables in our models for the following reasons: 1) to avoid adjusting a potential mediator: Preterm birth and low birth weight are hypothesised pathways to long-term growth effects, and both affect breastfeeding negatively, which make breastfeeding part of the potential causal pathway. As a result, adjusting breastfeeding variables would attenuate intervention effect. 2) Differential censorship: Randomisation date during pregnancy was time zero, and breastfeeding is a time-varying variable that can only be collected after birth. The association between breastfeeding and growth would exclude infants with restricted growth at birth due to censoring in the survival analysis design. 3) Left truncation bias: If adverse birth outcomes affect breastfeeding practice and a large number of infants with adverse birth outcomes are censored at birth (time 1), including breastfeeding in our models to assess its association with growth over each follow-up period would introduce bias. We would be able to fit breastfeeding variables only to infants who survived time one (infants without adverse birth outcomes). For these reasons adding breastfeeding variables to our models would be problematic." As a result of these reasons, and the fact that only a few infants had concurrent infections at each follow-up (on average less than 4 infants had pneumonia), we did not include infection status in the analysis.Other important factors that affect the growth of infants during pregnancy are the drinking and smoking experiences of mothers. Due to the very small number of mothers smoking at enrolment (<2%), we did not include maternal smoking experience as a cofactor in the model. Mothers' drinking experience at enrolment or after was not collected. Nonetheless, the results of the study regarding the effects of IPT on growth would not have been affected by these variables since randomisation would distribute them evenly between the randomisation arms.In conclusion, in this post-hoc analysis, maternal IPT during pregnancy was associated with a significantly increased risk of LBW and risk of becoming underweight among HEU infants. Male infants exposed to pregnancy-IPT had a significant risk of LBW, preterm birth, and longer-term risk of being underweight that persisted over the first year of life. These data add to prior TB APPRISE findings of increased risk of composite adverse birth outcomes associated with IPT during pregnancy, suggesting IPT during pregnancy also impacts birth size and infant growth specifically among male infants. These data could inform monitoring and management and warrants further examination of potential mechanisms.ACH participated in the investigation of the parent study and reviewed and edited this manuscript.AG designed and analysed the parent study. Reviewed and edited this manuscript.ASC∗ participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.AW participated in the investigation of the parent study and reviewed and edited this manuscript.BAR∗ participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.BTM participated in the investigation of the parent study and reviewed and edited this manuscript.DAE participated in all activities of this post-hoc analysis: data management, analysis, writing and editing the manuscript.DW participated in the investigation and validation of the parent study and reviewed and edited this manuscript.EJ participated in the investigation and validation of the parent study and reviewed and edited this manuscript.GM participated in the investigation of the parent study and reviewed and edited this manuscript.GM∗ designed/analysed parent study, data curation, and methodology and reviewed & edited the manuscript.GT participated in the investigation of the parent study and reviewed and edited this manuscript.GJS participated in all activities of this post-hoc analysis: data management analysis, writing and editing the manuscript.HC participated in the investigation of the parent study and reviewed and edited this manuscript.LA participated in the investigation of the parent study and reviewed and edited this manuscript.LSC participated in the investigation of the parent study and reviewed and edited this manuscriptMSR participated in the investigation and validation of the parent study and reviewed and edited this manuscript.NC participated in the investigation of the parent study and reviewed and edited this manuscript.PJP participated in the investigation of the parent study and reviewed and edited this manuscript.SB participated in protocol development and study implementation, and operational support.SML participated in all activities of this post-hoc analysis: data management, analysis, writing and editing manuscript.TN participated in the investigation and validation of the parent study and reviewed and edited this manuscript.TM participated in the investigation and validation of the parent study and reviewed and edited this manuscript.∗ASC, BAR, and GM have accessed and verified the underlying data.sdac.data@fstrf.org) with the agreement of the IMPAACT Network.Due to ethical restrictions in the informed consent documents and in the approved human subjects protection plan of the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, the study's data cannot be made publicly available; public availability could compromise participant privacy. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Center's data access committee (email address: AW declares grants from GSK, Merck, and Janssen; payment for expert testimony from GSK and Merck; and participation on a data safety monitoring board for GSK, Merck, and Seqirus. All other authors declare no competing interests.


The ability to predict the likelihood of a live birth after single fresh embryo transfer is an important part of fertility treatment. While past studies have examined the likelihood of live birth based on the number of oocytes retrieved and cleavage-stage embryos available, the odds of a live birth based on the number of supernumerary blastocysts cryopreserved following a fresh embryo transfer has not been rigorously studied. We performed a retrospective analysis, stratified by age, on patients undergoing their first fresh autologous single day 5 blastocyst transfer to assess relationship between the likelihood of a live birth and number of supernumerary blastocysts cryopreserved. In patients aged <35 years and 35–39 years old, the likelihood of a live birth increased linearly between 1 and 6 supplementary blastocysts and non-linearly if 10 or more blastocysts were cryopreserved. When aged 40 years and above, the likelihood of a live birth increased linearly up to 4 cryopreserved blastocysts and then non-linearly if 10 or more blastocysts were cryopreserved. The present study demonstrated a non-linear relationship between the number of supernumerary blastocysts cryopreserved and the likelihood of a live birth after single blastocyst transfer in the first autologous fresh IVF/ICSI cycle across different age groups. The ability to predict the likelihood of a live birth after single fresh embryo transfer is important for treatment planning and managing patient expectation, particularly in the first in vitro fertilisation (IVF) cycle. Cryopreservation of supernumerary embryos is often regarded as an important prognostic variable and a surrogate marker of IVF success. It increases the cumulative pregnancy rate from a single IVF stimulation  permits The overall reduction in the mean number of embryos transferred over the last decade, in conjunction with improvement in extended embryo culture and cryopreservation techniques, have led to an increase in the availability of surplus embryos for cryopreservation .Previous large studies have examined the association between the number of oocytes retrieved and cleavage-stage embryos available, and the odds of a live birth following a fresh embryo transfer ,5,6,7. HThe aim of this study was to examine the relationship between the number of supernumerary blastocysts cryopreserved and the likelihood of achieving a live birth following elective fresh autologous single blastocyst transfer in patients having their first IVF cycle, stratified according to patient age.Anonymised data on IVF cycles performed at the Assisted Conception Unit, at Guy’s and St Thomas’ Hospital in London, United Kingdom, were collected between July 2006 and June 2018 and retrospectively analysed. This cohort study included records of patients who had their first IVF and intra-cytoplasmic sperm injection (ICSI) cycle culminating in a fresh autologous single blastocyst transfer on day 5 after oocyte fertilisation. All patients included within this study who had at least one supernumerary blastocyst cryopreserved underwent elective single blastocyst transfer.To minimise potential confounders, strict inclusion and exclusion criteria were utilised. Inclusion criteria included women aged between 20 and 45 years old undergoing their first fresh stimulation cycle of IVF or ICSI. Cycles involving pre-implantation genetic testing (PGT), oocyte donation, transfer of cleavage-stage or more than one fresh embryo or total embryo freezing due to increased risk of ovarian hyperstimulation syndrome were excluded.Patient demographics such as female age, body mass index (BMI), previous fertility treatment, previous live birth, period of treatment, and cycle characteristics, including total dose of gonadotrophins administered, method of oocyte fertilisation (IVF vs. ICSI), number of oocytes retrieved and normally fertilised, and number of supernumerary blastocysts cryopreserved in the fresh cycle were analysed.Since age is known to influence the likelihood of achieving a live birth after fresh embryo transfer , we straFollicle stimulating hormone (FSH) injections were started at a dose of 150–450 IU daily for multi-follicular ovarian stimulation in either the mid-luteal long down regulation or the short gonadotropin-releasing hormone (GnRH) antagonist protocol as described previously ,12. The Ovarian response was monitored by transvaginal ultrasound scanning and, where required, serum estradiol level measurements were taken and oocyte maturation was induced using either 10,000 IU of urinary-derived HCG  or 250 µg of recombinant HCG  when at least three 18 mm follicles were seen on ultrasound scan.Transvaginal ultrasound-guided retrieval of cumulus–oocyte complexes was performed using GE Logic V1 portable scanning system  36 h after the HCG injection.Standard IVF or ICSI was used for oocyte fertilisation as clinically indicated and embryos were cultured until day 5 after fertilisation if at least 2 embryos were deemed to be of good quality on day 3 after fertilisation as previously described . On day All patients included in the study had single embryo transfer in accordance with national regulations . All embThe outcomes of each treatment cycle included pregnancy, clinical pregnancy, and live birth. Pregnancy was confirmed by a positive urine hCG test 11 days after blastocyst transfer. A clinical pregnancy was defined as the observation of a gestational sac on ultrasound scanning 5 weeks after embryo transfer. Live birth was defined as the delivery of a live born baby after 23 completed weeks of gestation. For this study, live birth was the primary outcome of interest.The study data were presented as median ± interquartile range (IQR) or percentage. Statistical analysis was performed using STATA version 16 . The pron = 12) had over 15 (16–30) supernumerary blastocysts cryopreserved. The Shapiro–Wilk test was performed to assess and confirm the normality of continuous variables.To assess the association between the number of supernumerary blastocysts cryopreserved and probability of a live birth outcome, fractional logistic regressions  were modEthical approval was received for this study from the local research ethics committee (ref: 01121432/2019). Our study involved neither therapeutic intervention nor change of our routine IVF protocols or data collection. Each couple gave written informed consent for the use of their data anonymously for audit and research purposes upon enrolment into our IVF programme and before starting an IVF cycle in accordance with the UK Human Fertilisation and Embryology Authority (HFEA) regulations.A total of 10,015 fresh autologous non-PGT IVF/ICSI cycles performed in our centre between July 2006 and June 2018 were eligible for inclusion in the study. The mean female age of couples included in the study cohort was 35.1 ± 4.4 years (range 18–45) and was normally distributed throughout the dataset.The mean daily dose of FSH used for ovarian stimulation was 283.8 ± 54.5 IU (range 112.5–450), and the mean duration of ovarian stimulation was 11.2 ± 2.1 days. In 64% of cycles, ICSI was the method used for oocyte fertilisation. The mean number of normally fertilised oocytes was 12.1 ± 7.0. Of the 10,015 first fresh IVF/ICSI cycles included in the study, 5992 (60%) had a single blastocyst transfer with no supernumerary blastocysts available for cryopreservation, whilst 4023 cycles (40%) had between 1 and 30 (mean 3.3 ± 2.5) supernumerary blastocysts cryopreserved. p < 0.0001, p < 0.0001).The overall clinical pregnancy and live birth rates in the study were 36% and 30%, respectively. Cycles in which one or more supernumerary blastocysts were cryopreserved had a significantly higher live birth rate compared to those without blastocyst cryopreservation . p < 0.0001) if six blastocysts were cryopreserved, with an average increase in the live birth rate of 7.8% with each additional blastocyst cryopreserved up to six. The likelihood of having a live birth then increased non-linearly, to 0.95  if 10 or more blastocysts were cryopreserved, with an average increase in the live birth rate of 3.8% with each additional blastocyst cryopreserved after 6 up to 10 or more.For those aged below 35 years, the likelihood of having a live birth increased for each additional blastocyst cryopreserved in a linear progression from 0.33 (95% CI 0.31–0.34) if one supernumerary blastocyst was cryopreserved to 0.80  if six blastocysts were cryopreserved, with an average increase in the live birth rate of 8.6% with each additional blastocyst cryopreserved up to six. The likelihood of having a live birth then increased non-linearly to 0.96  if 10 or more blastocysts were cryopreserved, with an average increase in the live birth rate of 3.5% with each additional blastocyst cryopreserved after 6 up to 10 or more.For those aged between 35–39 years, the likelihood of having a live birth increased for each additional blastocyst cryopreserved in a linear progression from 0.30 (95% CI 0.28–0.32) if one supernumerary blastocyst was cryopreserved to 0.82  if four blastocysts were cryopreserved, with an average increase in the live birth rate of 14.3% with each additional blastocyst cryopreserved up to four. The likelihood of having a live birth then increased non-linearly to 0.99  if 10 or more blastocysts were cryopreserved, with an average increase in the live birth rate of 2.7% with each additional blastocyst cryopreserved after 4 up to 10 or more.The likelihood of having a live birth increased for each additional blastocyst cryopreserved in a linear progression from 0.26 (95% CI 0.19–0.32) if one supernumerary blastocyst was cryopreserved to 0.83  [ [9], whiThe results of the present study contrast with those of a recent report  which suOur study results are clinically relevant as they can be used to improve counselling of couples at the time of their first fresh embryo transfer by providing a realistic perspective of the probability of delivering a baby after single blastocyst transfer based on female age and the number of supernumerary blastocysts cryopreserved. Understanding the association between the probability of a live birth and the number of supernumerary blastocysts cryopreserved could support a practice of single fresh blastocyst transfer when multiple supernumerary blastocysts are cryopreserved irrespective of patient age, and thus help to reduce the temptation to transfer more than one blastocyst, thereby reducing the overall risk of multiple births.The strengths of the present study include the analysis of a large number of IVF/ICSI cycles performed without significant changes in clinical or laboratory protocols. In addition, by only including patients undergoing single blastocyst transfer in their first IVF/ICSI cycle and excluding patients undergoing cleavage-stage embryo transfer, PGT, or receiving donated oocytes, we analysed a relatively homogenous cohort of patients, thereby accounting for potential treatment modality confounders, as well as removing the influence of previous IVF cycles on the utilisation of embryos available in a second or subsequent cycle. Furthermore, we stratified our results by age group to guide clinical practice more precisely and enable clinicians to provide better counselling to patients embarking on their first fresh embryo transfer.However, one distinct limitation of our study was the lack of data on clinical pregnancy loss. We also did not have data reporting on sperm characteristics or the euploid status of the transferred embryos or that of the cryopreserved embryos. While the use of pre-implantation genetic testing for aneuploidy (PGT-A) has been reported to potentially improve live birth rates when used as a tool for embryo selection, embryo selection was carried out solely through morphological evaluation. This study can therefore not be interpreted in the context of having completely euploid embryos cryopreserved. Another limitation of the study is the fact that we could not stratify the results into smaller age brackets as this would have had an impact on the statistical significance of the results produced. It also included results from women undergoing both either the mid-luteal long down regulation or the short gonadotropin-releasing hormone (GnRH) antagonist protocol.In conclusion, the present study results demonstrate that the number of supernumerary blastocysts cryopreserved in the first autologous fresh IVF/ICSI cycle can be a key factor in determining the probability of achieving a live birth after single blastocyst transfer across different age groups. This information can be helpful in patient counselling and promoting single embryo transfer to reduce the risk of multiple births. This study shows that the presence of additional good-quality supernumerary embryos can be used as a reference to determine the likelihood of success following an embryo transfer. Additionally, this study supports a single embryo transfer which is based on embryo quality, maternal age, and the presence or absence of surplus quality embryos.


Chlamydia trachomatis and Neisseria gonorrhoeae, that may cause permanent damages. The use of ophthalmic prophylaxis varies widely around the world, according to the different health and socio-economic contexts. To date in Italy there is no a clear legislation regarding ophthalmia neonatorum prophylaxis at birth.Ophthalmia neonatorum is an acute conjunctivitis that occurs in newborns within the first month of life. The most serious infections are due to Chlamydia trachomatis and Neisseria gonorrhoeae vaginal infections.We invited all birth centers in Italy to carry out a retrospective survey relating the last three years. We collected data regarding demographics of neonates, drugs used for ophthalmic prophylaxis and results of the screening of pregnant women for Neisseria, 9,6% only for Chlamydia and 25,8% for both germs.Among 419 birth centers, 302  responded to the survey. Overall 1041384 neonates, 82,3% of those born in the three years considered, received ophthalmic prophylaxis. Only 4,585  of them received one of the drugs recommended by the WHO. The Centers that participated to the survey reported 12 episodes of Chlamydial conjunctivitis and no Gonococcal infection in the three years. Only 38% of the Centers performed vaginal swabs to pregnant women: 2,6% screened only for Neisseria gonorrhoeae or Chlamydia trachomatis in Italy. Due to the lack of legislation regulating the prophylaxis of ophthalmia neonatorum in newborns, the Italian Society of Neonatology, the Italian Society of Obstetrics and Gynecology and the Italian Society of Perinatal Medicine have recently issued new recommendations on this topic.The data obtained from the survey showed a low incidence of neonatal conjunctivitis due to either  Neisseria gonorrhoeae, but currently it includes any conjunctivitis in this age group. Neisseria gonorrhoeae and Chlamydia trachomatis cause the most serious infections, with possible severe complications such as corneal ulceration, corneal perforation or permanent blindness. Neisseria gonorrhoeae conjunctivitis now accounts for less than 1% of reported cases of ON in the United States, while Chlamydia trachomatis infections ranges from 2 to 40%. Other bacteria such as Staphylococcus, Streptococcus, Hemophilus and some Gram-negative bacteria account for 30% to 50% of cases . Among the centers assisting less than 500 births/year, 50/103  answered to the survey, among those assisting between 500 to 999 births/year 123/170  centers answered, among those assisting between 1000 to 2499 births/year 112/127  centers answered and those assisting more than 2500 births year 17/19 . We did not observe any difference in terms of adherence to the survey between centers of North, Centre, and South of Italy nor between regions. Figure During the study period all neonates born in the centers participating to the survey  undeThe WHO recommendation invites to use a single-use antibiotic ointment. The medications used for prophylaxis of the Italian newborns included in the survey were in double antibiotic solution, in multi-use packaging and not prepared as single-use antibiotic ointment Fig. . TherefoChlamydia trachomatis conjunctivitis were reported , all occurring in only six neonatal units (2%) out of 302 participating to the survey reported Neisseria gonorrhoeae infection was never reported.Overall, 12 cases of One hundred and fifteen centers  performed screening of sexually transmitted diseases via vaginal swabs: 8  centers for gonococcal infections, 29 (10%) for chlamydial infections and 78  for both germs Fig. .Fig. 4InIn Italy there is no clear legislation regarding ophthalmia neonatorum prophylaxis at birth. The law regulating the administration of antibiotic prophylaxis to newborns at birth dates back to 1940  and has In Italy, the National Surveillance System of the National Health Institute does not collect data on the incidence of chlamydial or gonococcal conjunctivitis in the neonatal period. The data from our national survey shed a light on the incidence of neonatal conjunctivitis and on the current prophylactic practices in Italy, at the same time underpinning an urgent need to update the Italian scientific societies’ recommendations regarding the administration of ophthalmic prophylaxis.It is somewhat concerning that in Italy 99,6% of all newborns did not receive at birth the ophthalmic prophylaxis according to WHO recommendations, despite an extremely wide use of ophthalmic prophylaxis. Although this clear inconsistency, no cases of gonococcal and very few cases of chlamydial conjunctivitis in newborns have been reported period of the study. These low incidences of conjunctivitis recorded by our survey may be a limitation of our report. However, it must be considered that a high number of birth points participated in our survey, in most of which infants are followed up for routine checkups even after discharge. This allows the identification of conjunctivitis at least in the first 10 days of life. In addition, the severe conjunctivitis may require hospitalization, and in Italy all infants must be admitted to Neonatal Units. Surely, more complete data would have been obtained by involving all primary care pediatricians and all pediatric ophthalmology units; in contrast, we would have had a lower survey participation rate.Several European countries no longer administer universal ocular prophylaxis but recommend the screening and treatment of sexually transmitted diseases in pregnant women at high risk. The Canadian Pediatric Society does not recommend universal prophylaxis with erythromycin but promote epidemiological investigations to estimate the incidence of ON . HoweverNeisseria gonorrhoeae at the first prenatal visit [To prevent ON, the Center for Disease Control and Prevention (CDC), recommends that all pregnant women with risk factors for sexually transmitted diseases and their partners should be screened for al visit . Pregnanal visit .Chlamydia trachomatis and Neisseria gonorrhoeae, and the current national shortage of drugs recommended by the CDC and the WHO, the Italian Society of Neonatology (SIN), the Italian Society of Gynecology and Obstetrics (SIGO) and the Italian Society of Perinatal Medicine (SIMP), have deemed necessary to issue a position statement [In the light of the above mentioned evidence, and taking into account the scenario that our data have disclosed, the low incidence in Italy of neonatal conjunctivitis from tatement , with thTo standardize the prophylactic procedures throughout Italy, at the same time assessing the actual need to perform ophthalmic prophylaxis to all birth cohorts based on the data coming from Italian birth centersTo avoid administering useless antibiotics to infants, which may be in turn harmful when used without a precise indication.The two objectives of the position statement are the following:For this initiative to be successful, it is essential to have a multidisciplinary approach, with the obstetrical, neonatological and nursing staff working together to have primary prevention activities to be started from the earliest stages of pregnancy.The Intersociety document does not recommend anymore the administration of the ophthalmic antibiotic prophylaxis at birth to all newborns, but only to neonates born from unattended pregnancies (defined as less than three visits performed during pregnancy) or unscreened pregnant women at risk for sexually transmitted diseases. Neonates requiring ophthalmic prophylaxis should receive immediately after birth, either 0,5% erythromycin or 1% tetracycline or 1% chloramphenicol ophthalmic ointment.Neisseria gonorrhoeae and Chlamydia trachomatis is recommended for all pregnant women at risk for sexually transmitted diseases at the first prenatal care visit. The document recommends against administering ophthalmic antibiotic prophylaxis at birth to neonates born from a mother with a vaginal swab positive for Chlamydia trachomatis regardless of treatment during pregnancy or with a vaginal swab positive for Neisseria gonorrhoeae, but adequately treated during pregnancy.Moreover, a vulvovaginal swab for Chlamydia trachomatis, regardless of treatment during pregnancy, and asymptomatic/symptomatic neonates born to a mother positive for Neisseria gonorrhoeae not treated or inadequately treated during pregnancy should be treated with systemic antibiotic therapy.Finally, symptomatic neonates born to a mother positive for


Birth is a significant event in women’s lives. As Mansfield notes (2008) many women aim for a birth that avoids pharmacological pain relief because they are advised it is better for them and their baby. For women having their first baby, this may not be realistic as 3/4 of primiparous women in Australia will use pharmacological pain relief. This study examines the expectations that a group of women had regarding pain relief, how these expectations developed and what happened to requests for pain relief in labour.N = 43 interviews). Interviews were recorded and transcribed and coded by ES using NVivo software with hierarchical thematic analysis used.A longitudinal prospective study design was used to recruit 15 women who were having their first baby. Women having low risk pregnancies, hoping for a ‘natural birth’  were eligible. A semi-structured interview tool was used across all three interviews that asked women about their expectations, then actual labour experience, pain management requests and how these were responded to by carers. Fifteen women were interviewed – at 36 weeks gestation; as soon after delivery of their baby as possible, then six months post-delivery (The study found that women appear to experience a mismatch between expectations they had developed pre-birth, versus actual experience. This appears to cause a specific form of dissonance – which we have termed ‘birth dissonance’ leaving them feeling traumatised post birth. This is because what women expected to happen in birth was often not realised. In particular, some women requested pain relief in birth and felt that their request was not responded to as hoped, and also seemed to develop post-birth trauma. We proposed that this may have resulted from dissonance arising from their expectations about being able to birth without significant pain relief. Interventions and technology may also contribute to this sense of mismatch and post-birth trauma.Low risk birthing women birthing in a hospital may have to engage with higher levels of technology, intervention and pain relief than that which they expected pre-birth. This could possibly be avoided with four simple changes. Firstly, better pre-birth education for women about how painful labor is likely to be. Secondly, pre-birth education which includes a detailed explanation of the utility of pharmacological and non-pharmacological pain relief. Thirdly, more egalitarian decision-making during labour and finally delivering upon women’s requests for pain relief in labor, at the time that they ask for it. Further research is required to determine the extent of birth dissonance and how women making the transition to motherhood can avoid it.The online version contains supplementary material available at 10.1186/s12884-023-06066-7. Childbirth may be a painful experience for women hoping to have a baby vaginally without pain relief – especially for first births. As in the UK, Canada and parts of the United States, nearly all Australian women (96%) deliver their baby in a hospital  and thusNon-pharmaceutical analgesia may include movement, warm water, breathing techniques aromatherapy and massage, many of which lack high quality evidence to support their efficacy –10. ThisPharmaceutical interventions have been subjected to numerous randomized controlled trials and other studies –15. ManyThe experience of childbirth, however, is different to other pain related events . Pain inhttps://mamanaturalbirth.com) often encourage women to avoid pharmacological pain relief so that they can avoid complications from pain relief, but also come to understand the power of their bodies in new ways ”. And I just kept saying to my partner, “You need to make them do it….I was like I don't care about that woman [midwife], it's making me really angry”. I was “No, I don't care, she needs to [organise an epidural]”, because she was pretty active in trying to convince me otherwise…..Another woman Louise – talks about how her pain relief request for an epidural was deferred and she then entreats her partner to act on her behalf. She says that after a number of refusals for an epidural, she tells her carers:Louise’s initial requests were not met, so in order to strengthen her position, she asked her partner to advocate on her behalf. The description of a midwife who was “pretty active in trying to convince” her not to have an epidural is informative of the limited power some women perceive that they have in labor. This is particularly so when we consider that Louise is in the midst of labor, is a patient in a hospital, and has no other way to access pain relief other than via her midwife, who has thus far refused her requests. She felt disempowered, hence implored her partner to strengthen her claim.Many women are committed to the idea of a ‘drug free’ vaginal birth – because they consider this is the best type of birth for their baby as espoused by various authors , 54, 55.Part of the trauma experienced by these nulliparous women is that they perceive an expectation that it is better to aim for a natural birth, because women’s bodies are designed to do this and therefore they can and should , 23, 26.The study findings presented here challenge this broadly promulgated assumption that pain in labor as part of a ‘natural birth’ is an essential element of the process of the ‘rendering’ of a mother. Women’s choices for pain relief in labor need to be respected, regardless of others’ opinions about an apparent need to experience pain to become a mother at one extreme, through to freely promoting routine use of one or more of the numerous forms of pharmacological or non-pharmacological analgesia. The mismatch that women in our study had between what they expected versus their lived experience appeared to result in a dissonance. This particular form of dissonance seems to arise in women post-birth as a result of the expectations that they construct prior to birth regarding the birth experience and their bodily ability to manage that pain without pain relief, and ultimately, needing to use pain relief to manage that pain. For women in this study who asked for pain relief and had this request denied or deferred, their distress appeared to be greater than in/for women who had their pain relief request met.The discrepancy between expectation and reality of birth has not previously been distilled into a single term, but rather described as a ‘mismatch between expectation and reality’ –46, 56. even if they experienced unexpected intervention. This may be because they felt that they had at least a degree of control over some aspect of their birth experience, when other elements of it had deviated from their original plans. This study did not investigate why interventions were instigated, but rather focused on pain relief requests and how these requests were responded to by their carers. These results suggest that, despite their low-risk healthy status, few of the women in this study were realistically prepared for the actual experience of childbirth. This includes them not being aware of the possibility of interventions and pain and having pain relief deferred. It also suggests that within this setting, improvements might be made by medical staff and midwives as explained below, to better respond to women’s requests during labor.Our findings suggest that when women’s pain was managed as and when they requested, they were less likely to develop post-birth trauma type symptoms Midwives, as the primary caregivers during labour and birth in many countries, bring their own philosophies and beliefs about the use or avoidance of interventions, including analgesia, to the birthing room. They are well placed to work ‘with woman’ to navigate the multitude of ways that pregnancy, labor and birth may be experienced. This includes providing comprehensive pre-birth education that more accurately reflects the many ways that labour and birth may deviate from the expectations that they may have developed from the various sources to which they have been exposed while pregnant.This study was a single site study conducted over a period of several years. The findings here are representative of the culture of that birthing unit and the birthing experience that women are having in that unit. Each birthing unit culture varies, and other studies in other units are required for comparative purposes. A larger study involving multiple interviewers and double coding of themes may be instructive in relation to other themes or reasons for post-birth trauma appearing in women post-birth. Two women did not complete all three interviews, but did complete two of the three. Only women who spoke English were able to be included owing to no interpreters being available for interviews in the study budget.The researchers have had varied experiences of birth themselves, and bring their own experiences to this study. Two researchers have children which they birthed, one researcher has two children who are adopted; one researcher has worked extensively with birthing women but does not have children of her own. We acknowledge that these experiences impact the interpretation of the data.This study shows that even women with low-risk birthing profiles who choose to give birth in a hospital may have to engage with higher levels of technology, intervention and pain relief than that which they expected pre-birth. It also suggests that when these women request pain relief in birth and that request is not responded to as they had anticipated, they may be more likely to develop post-birth trauma. For women who asked for pain relief and had this request denied or deferred, their distress appeared to be greater and resulted in a particular form of trauma – namely birth dissonance. We are compelled to ask whether this trauma could be avoided by the use of improved pre-birth education for women about how painful labor is likely to be. Secondly, that education pre-birth needs to include a detailed explanation of the utility of pain relief, including the results of a recent Cochrane systematic review which shows that it does not lead to increased interventions. Thirdly more egalitarian decision-making during labor, and finally delivering upon women requests for pain relief in labor, at the time that they ask for it.Additional file 1. Attachment A - Interview schedule for women having their first baby (Pre-Birth/Post Birth Interview).Additional  file 2. Particpants were advised in the consent process that their data would be anonymised, and be used to create a thesis and may be used in publications.


Glandular odontogenic cyst (GOC) is a rare, aggressive odontogenic lesion that presents in the jaws. It is a diagnostically challenging entity due to its ability to mimic intraosseous mucoepidermoid carcinoma, botryoid cyst, surgical ciliated cyst, and radicular cyst. Treatment ranges from conservative to aggressive surgical interventions due to its varied clinical and radiological appearance and also its potential for recurrence. Aggressive surgical interventions result in the need for surgical site reconstruction, thus increasing patient morbidity. We report a case of GOC in the anterior mandible that was conservatively treated by the application of 5-Fluorouracil (5-FU). Topical application of 5-FU was selected in the management of this lesion as it has shown to be effective in reducing recurrence rates of other aggressive odontogenic lesions such as odontogenic keratocysts. To our knowledge, this is the first case reported in the literature that was successfully treated by the combination of cyst enucleation, curettage, peripheral ostectomy and application of 5-FU. No recurrence was detected after 14-month follow-up. Key words:Odontogenic cysts, Fluorouracil, Recurrence. Glandular odontogenic cyst (GOC) is a rare, aggressive odontogenic cyst with a recurrence rate as high as 21.6%  scan revealed a well circumscribed, multilocular radiolucency in the anterior mandible that extended from the first left premolar to the right canine  and subsequently the term glandular odontogenic cyst was adopted  as a cyst of odontogenic origin in 1992 . Precedi adopted .GOCs are exceedingly rare and literature reports that it makes up approximately 0.2% of all odontogenic cysts . GOCs arHistologically, GOC has similar features to both benign and malignant neoplasms of the jaws. The lesion can mimic mucoepidermoid carcinoma, botryoid cyst, surgical ciliated cyst, radicular cyst or dentigerous cyst6. Clinically, they present as slow growing, asymptomatic swellings of the jaw and less frequently present with pain and paraesthesia. GOC’s occur more frequently in the mandible 70%) than the maxilla (30%). It is most commonly found in the anterior regions of the jaws with no gender predilection . The mea0% than tSurgical management of GOC includes curettage, enucleation, marginal and segmental resection . Enuclea5-FU is a chemotherapeutic agent that has been in use since 1957 for the management of colonic and breast cancers as well as skin cancers in the head and neck region. It functions by inducing cytotoxicity via reducing the production of deoxythymidine mono-phosphate which is a key intracellular molecule required for DNA repair and replication .The advantages of 5-FU have been well documented in the management of OKCs. A recent study demonstrated that the use of 5-FU is superior to Carnoy’s solution . The stuThe benefits of 5-FU in the management of aggressive odontogenic cysts are well established, however there are no recorded cases of GOC being managed with 5-FU as an adjuvant treatment option. This report documents the first case of GOC being successfully treated with 5-FU as an adjuvant medicament with no recurrence after 14-month follow-up. In conclusion, this report demonstrates that GOC, in addition to enucleation, curettage and peripheral ostectomy, can be successfully managed by the application of 5-FU. This conservative method of treatment may result in reduced recurrence rates without significant morbidity to the patient.


Retinopathy of prematurity (ROP) is a leading cause of blindness in children and an ROP epidemic is predicted this decade in sub-Saharan Africa. With the increasing survival rate of preterm babies in Uganda, and no data on ROP prevalence, there is a need to assess the burden of ROP to inform preventive strategies and targeted screening.We conducted a two-center cross-sectional study of preterm  infants from the neonatal units of Kawempe National Referral Hospital (KNRH) and Mulago Specialised Women and Neonatal Hospital (MSWNH) from August 2022 to October 2022. An ophthalmologist examined all participants using an indirect ophthalmoscope with a + 20D convex lens and captured digital images using a Volk iNview™ Fundus Camera. The collected data were entered into Epidata 4.2 and exported to Stata 14.0 for analysis.331 preterm infants enrolled in this study. The oxygen received was unblended. The mean gestational age was 30.4 ± 2.7 weeks, and the mean birth weight was 1597 ± 509 g. 18/101 (17.8%) were found to have any ROP amongst the preterm infants recruited from MSWNH, 1/230 (0.4%) from KNRH [95% CI] had any stage of ROP (i.e. stage 5). Of these, 8 (42.1%) had stage 2 ROP. Infants with a birth weight below 1500 g were 10 times more likely to have ROP than those among infants with a birth weight more than 1500 g [AOR: 10.07 (2.71–37.44)]. Infants who were not fed exclusively on breast milk had higher odds of having ROP than those exclusively fed on breast milk [AOR: 7.82(1.92–31.82)].6% of preterm infants born in two tertiary hospitals in Uganda were found to have ROP. Lack of exclusive feeding on breast milk and birth weight of less than 1500 g were strong predictors of ROP. The higher prevalence of ROP in MSWNH calls for cautious use of oxygen among preterms. We recommend targeted ROP screening for those at risk.The online version contains supplementary material available at 10.1186/s12886-023-03195-7. More infants born preterm are surviving and thriving than ever before. Some preterm infants will have developmental disability, including visual complications , 2. RetiThe rising incidence of ROP in developing countries is largely attributable to the improvement of neonatal care and the subsequent improvement in survival of preterm infants as well as increased exposure to potentially modifiable risk factors. . PreviouThe World Health Organization (WHO) recommends that all babies at risk of retinopathy of prematurity have a fundus examination by a trained observer 4–7 weeks after birth . This reThe challenges are lack of awareness amongst health workers, parents and health policy makers as regards to ROP, its detrimental effects to a child, the need for a regular nationwide ROP screening program and the inevitable need to offer affordable treatment for ROP to those preterm babies found to have vision-threatening ROP .Uganda has a preterm birth rate of 13.6 births per 1000 live births yearly but no data on ROP prevalence and no formal ROP screening program . TherefoWe conducted a two-center cross-sectional prevalence study, from August to October 2022.≈ 40 US Dollars).This study was conducted at the Neonatal Units of Kawempe National Referral Hospital (KNRH) and Mulago Specialised Women and Neonatal Hospital (MSWNH), located in the Kawempe division in Uganda’s capital, Kampala. Both hospitals serve as the teaching hospitals of Makerere University College of Health Sciences. KNRH offers free health services to patients while MSWNH offers free and private health services. During the study period, the noted cost for admission of a preterm infant at MSWNH was about 150,000 Uganda Shillings per night  ward of KNRH admits about 20 neonates daily, with 80–100 preterm babies cared for at a given time in the NICU. A minority (about ten or fewer) stay on the ward for over four weeks, but the numbers vary. The neonatal follow-up clinic of KNRH is integrated within the pediatric Acute Care Unit) clinic, reviewing approximately 100 preterm babies weekly. Around 80 of these preterm infants are four or more weeks old.MSWNH is a component of Mulago National Referral Hospital (MNRH), the largest hospital in Uganda. The NICU ward of MSWNH admits about five neonates per day, with 50–60 preterm babies cared for at a given time in this NICU. About five or fewer stay on the ward for four weeks or longer, but the numbers also vary. The neonatal follow-up clinic of MSWNH reviews approximately 30 neonates a week. Around 15 of these preterm infants are four weeks old and older. MSWNH receives preterm babies referred in from KNRH, other health facilities around Kampala, and a few from different regions of Uganda.The NICU of MSWNH is well equipped with more advanced neonatal care services than that of KNRH. For example, preterm babies at KNRH receive basic unblended oxygen therapy on a ‘shared-basis’ via improvised ‘Y-connectors’. The babies at MSWNH have ready supply of unblended oxygen for low-flow and continuous positive airway pressure (CPAP), with every bed having direct connection to the central oxygen supply pipes embedded within the walls and each preterm infant having its own oxygen saturation monitor 24/7. Anecdotal reports indicate that KNRH refers most very preterm infants, especially those with birthweight below 1000 grams and other neonatal risks, to MSWNH for further management.NICUs of both facilities have an appended space for Kangaroo Care for stable preterm infants and admit to the NICU if they have or are at risk of complications or danger after birth. The neonatal follow-up clinic receives preterm babies discharged from the NICU, reviewing regularly until they have attained 2.5 kg, then discharging to the preterm/LBW clinic for subsequent review until one year of age. Upon discharge from the NICU, the patient’s data is summarized on a discharge form carried by the mother when she comes to the outpatient neonatal follow-up clinic. The preterm infants who were discharged early were followed-up via the Preterm Review clinics and ROP screening done for those found to fit in the inclusion criteria during the study duration, irrespective of birth weight.In these facilities, the neonates are reviewed and managed by qualified paediatricians, medical officers and trained neonatal nurses.Preterm babies managed at KNRH and MSWNH during the study period.All pre-term neonates who were admitted to the neonatal wards, and those who attended the neonatal follow-up clinics during the study period with this description:Born less than 37 weeks gestational age with post-menstrual age (PMA) < 49 weeks.if GA > 30 weeks, neonates who were at least four weeks old.if GA < 30 weeks, neonates who were at least 4–9 weeks old (as long as the PMA reaches a minimum of 31 weeks).Those whose parents/ guardians consented to enrolment in the study.The gestational age was assessed by reviewing the Ballard score recorded in the patient’s file or the last normal menstrual cycle data reported by the mother, or by ultrasound scan measurements done within the first trimester of pregnancy.Very sick neonates deemed too unstable for eye examination by neonatal clinical staff (5 babies).Very hazy corneas that could not be seen through using an indirect ophthalmoscope and the Volk iNview Fundus Camera .Sample size calculation for the prevalence was determined using the Kish Leslie formula at 95% confidence interval and error within 5% of one proportion for the prevalence (ref). Sample size calculation for factors associated with ROP was done using the difference in two independent proportions formula by Fleiss (ref). Assuming 50% of preterm infants undergoing treatment in neonatal care units were at risk of developing ROP whilst basing on estimates by Onyango et al., 2018 (ref), the minimum sample size for this study was calculated as 385 participants ) infants in MSWNH and1/230 (0.4% [0.1–3.1]) infants from KNRH.Among those with ROP, 736.8%) had Stage 2 Zone II in either the left or the right eye. One neonate examined at KNRH was found with Stage 5 ROP (i.e. end-stage ROP) in both eyes and no other infant was seen to have ROP in KNRH. Of the preterm neonates with ROP, 210.5%) presented with stage 1, 8(42.1%) with stage 2, 3(15.8%) with stage 3, 2(10.5%) with stage 4, 1(5.3%) with stage 5 and 3(15.3%) with A-ROP (Table 6.8% had 0.5% presSix (1.8%) had tortuous blood vessels, while one neonate (0.3%) had leukocoria.On univariate analysis, the following factors were associated with ROP: gestational age, birth weight, intraventricular hemorrhage, patent ductus arteriosis, respiratory distress, oxygen therapy, history of phototherapy, APGARS, and anemia. After checking for collinearity, the following factors remained significant in the multivariate analysis; low birth weight, chronological age and type of feeding were significantly associated with retinopathy of prematurity Table .We assessed the prevalence of ROP in 2 tertiary units in Uganda. Out of 331 preterm babies, 19 (5.7%) had ROP of any stage, with 18 of these cases from one hospital (i.e. MSWNH).Our findings suggest that the burden of undiagnosed ROP in Uganda is significant. Point estimates of prevalence will depend on factors associated with context , quality and level of care , and study design . Previous studies from comparable settings in Botswana and Rwanda have reported similar prevalence of 7.3–11% when screening infants < 34 weeks and < 35 weeks. The difference in prevalence between the two hospitals is multifactorial. MSWNH offers free and privatized services, is a training centre for neonatology, and is a referral centre that receives infants from surrounding facilities including KNRH. This may reflect the higher risk patients that survive at MSWNH vs. KNRH. The gestational age and birthweight of infants screened in MSWNH was therefore lower than KNRH, with a higher proportion with sepsis, RDS, and blood transfusions. One postulation would be the smaller KNRH patients may not survive long enough to get ROP. Overall, the difference in prevalence likely reflects baseline differences in the patient populations. Data points from both sites are definitely important. Oxygen therapy contributes to ROP by affecting retinal vascularization through regulating vascular endothelial growth factor . In lineAll the babies with ROP identified in this study will need ongoing follow-up. We found stage 2 ROP in 42% of those with ROP. At least 13 (68.4%) were treatment-requiring ROP. The current cost of an intravitreal injection for avastin (bevacizumab) is 600,000/= (about $ 158). Families would also have to pay for travel and accommodation costs. Treatment is currently only offered in very few facilities in Kampala, Uganda’s capital which include Mengo Hospital, Nsambya Hospital and Dr. Agarwal’s Eye Hospital. By the time of doing this study, and even currently in Uganda, laser therapy is unavailable for treatment of ROP. Laser therapy, the gold standard for ROP treatment, is surely a possible treatment of ROP in preterm infants with large birth weight and mature Gestational Age. Besides, such a treatment might decrease the follow-up burden for the families. Lack of access to this important treatment option remains a problem throughout sub-Saharan Africa .Three (15.8%) babies with ROP had advanced ROP (Stage IV and V), that even with treatment has a poor outcome of only minimal ambulatory vision. The preterm baby who had Stage 5 ROP was the only one found to have ROP amongst all the 230 screened at KNRH during the study period. This child was rendered blind as per treatment capabilities in Uganda. The surgical techniques needed for Stage 5 ROP are unique and very demanding, with successful results after surgery seen in about 20–50% of the cases, however, this is currently not available in Uganda , 20. SucOur data have reproduced the higher risk of ROP in infants with low birth weight (independent of gestation), consistent with an Ethiopian study on infants attending an eye clinic in Minilk-11 hospital found that infants born with a very low birth weight below 1000 g or between 1000 and 1500 g were 39 times and 12 respectively more likely to develop ROP compared to those with greater than 1500 g . Our stuThis is the very first study on the prevalence, pattern (stages) and associated factors of ROP among preterm infants in Uganda. It provides strong evidence of the undiagnosed burden of ROP in Uganda, and a strong basis for advocating for screening and treatment programs. The risk factors for ROP identify critical areas for intervention and prevention. In our study, these areas included the prevention of low-birth-weight, the promotion of exclusive breastfeeding, and interventions to improve the quality of care for preterm newborns, especially the safe and rational use of oxygen.The current capacity in Uganda for ROP screening is still very low given the fact that this was the very first study of ROP burden in two of the largest public hospitals which are even national referral hospitals managing preterm infants in the country.The challenges are lack of awareness amongst health workers, parents and health policy makers as regards to ROP, its detrimental effects to a child, the need for a regular Nation-wide ROP screening program and the inevitable need to offer affordable treatment for ROP to those preterm babies found to have treatment-requiring ROP.Since ending the study, the principal investigator (NI) has continued to reinforce the ROP screening program he commenced in these two tertiary hospitals MSWNH and KNRH. The principal investigator (NI) also approached various NICUs both private and public as well as those in the urban and in the rural areas to inform them of the crucial need of initiating an ROP screening program in their centres and is willing to help them in this.The authors of this paper recommend a collaboration between ophthalmology, neonatology, nursing, paediatrics and health policy makers so as to establish a robust nation-wide ROP screening program in Uganda, then subsequently draft the much-needed ROP national guidelines for Uganda.The large difference in prevalence between the two sites highlights the importance of context. Our findings are therefore not generalizable to all facilities caring for preterm newborns in Uganda, and our findings underline the importance of conducting larger prevalence surveys to inform the design of a screening program. Our study did not collect detailed information on risk factors , and this will be important in future studies to help inform interventions for prevention of ROP.The prevalence of ROP among infants born < 37 weeks gestational age in tertiary hospitals in Uganda is significant at 5.7%. Prevalence was significantly different between the two facilities with MSWNH having a higher prevalence than KNRH (17.8% Vs 0.4%). 7 infants (36.8%) had Stage 2 of ROP and 13 (68.4%) had treatment-requiring ROP The most significant risk factors for ROP were long duration of oxygen therapy, pretems not being exclusively fed on breast milk and low birth weight less than 1500 g.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4Supplementary Material 5Supplementary Material 6Supplementary Material 7


Editorial on the Research TopicTopic opportunities, barriers and pitfall of current nutritional practice in preterm infantsIn the past few decades, significant changes have been made to the nutritional practices for preterm infants. These changes mainly include people's increasing attention to the benefits of nutrient density on the health of preterm infants, immunobiology of human milk, and discussion of nutritional indicators.Lin et al. conducted a cohort study with infants who had a gestational age of less than 28 weeks or a birth weight of less than 1,000 g, and they concluded that a higher proportion of enteral feeding/total fluid intake is associated with a lower risk of BPD. Therefore, preterm infants who do not have feeding intolerance should be encouraged to receive early and rapid enteral nutrition.Pulmonary edema is commonly observed in infants with bronchopulmonary dysplasia (BPD). However, while limiting fluid intake helps to prevent this condition, it can also limit energy intake . This hiZhu et al. found that the first MOM feeding time in infants with very low birth weight (VLBW) >72 h after birth was a high-risk factor for moderate and severe BPD, suggesting that MOM feeding within 72 h of the birth of infants with VLBW reduces the risk of moderate and severe BPD. However, disputes remain regarding the type and form of enteral feeding , lactoferrin, and lysozyme, which can regulate immunity, infection, and sterilization. However, clinical instability typically precludes enteral feeding in the first few days of life. Oropharyngeal administration is a potential alternative method for improving colostrum quality . To evalZ-score related to birth status. In 2021, a multicenter study from Jiangsu Province, China, found that the change in weight Z-score was closely related to the time to regain birth weight, birth weight, and gestational age  because EUGR is a static process. At present, an increasing number of studies focus on dynamic EUGR, which refers to the change in body weight onal age . To reduonal age . These aThis research topic on opportunities, barriers, and pitfalls of current nutritional practice in preterm infants presents the current progress in the nutritional practice of preterm infants. These studies have highlighted the importance of nutritional practices. However, in the field of preterm infant nutrition, there is still a long way to go in improving breastfeeding rates, effectively carrying out enteral nutrition, and reducing parenteral nutrition infusion time. Consequently, further discussion is required.


What is the association between using sodium-glucose contransporter-2 inhibitors (SGLT2i) and the risk of recurrent gout flares among adults with gout and type 2 diabetes?In this cohort study of 5931 patients with gout and type 2 diabetes, initiation of SGLT2i treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality than initiation of active comparator treatments.These findings suggest that SGLT2i may reduce the burden of recurrent gout flares and narrow the mortality gap between patients with gout and the general population. This cohort study compares the risk of recurrent gout flares and all-cause mortality between patients with gout and type 2 diabetes who initiate treatment with sodium-glucose cotransporter-2 inhibitors and those who initiate treatment with glucagonlike peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors. Recurrent flares are the hallmark of clinical manifestation of gout. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a lower risk of incident gout; however, their association with recurrent flares is unknown.To examine the association of SGLT2i vs active comparators  with the risk of recurrent gout flares and all-cause mortality among patients with gout and type 2 diabetes.This population-based retrospective cohort study was performed from January 1, 2013, to March 31, 2022, using a UK primary care database. Participants included patients with gout and type 2 diabetes with visits to their general practitioners.Initiation of treatment with SGLT2i or active comparators.The primary outcome was the number of recurrent gout flares ascertained using recorded codes and prescription records. Secondary outcomes were the first recurrent gout flare and all-cause mortality. The association of SGLT2i compared with active comparators for the risk of recurrent flares, the first recurrent flare, and all-cause mortality was assessed using Poisson regression or the Cox proportional hazards model with propensity score overlap weighting.Of a total of 5931 patients included in the analysis , 1548 initiated SGLT2i treatment and 4383 initiated treatment with active comparators during the study period. The relative rate of the recurrent flares with SGLT2i vs active comparators was 0.79 . Similar results were observed in the association of SGLT2i with the rate of recurrent flares when compared with DPP-4i or GLP-1 RA. For the first recurrent flare for SGLT2i vs active comparators, rate difference was −8.8  per 1000 person-years and the hazard ratio was 0.81 . All-cause mortality per 1000 person-years was 18.8 for SGLT2i and 24.9 for active comparators, with rate difference of −6.1  per 1000 person-years and hazard ratio of 0.71 .The findings of this cohort study suggest that SGLT2i were associated with a lower risk of recurrent gout flares and mortality than their active comparators in patients with gout and type 2 diabetes. These findings further suggest that SGLT2i could help reduce the burden of recurrent gout flares and could also narrow the mortality gap between patients with gout and the general population. The prevalence and incidence of gout have risen worldwide for decades.11 However, previous studies have shown that management of gout is still suboptimal, as many patients either do not receive ULT or do not receive the proper dose of ULT.13 In addition, adherence to ULT is low,14 resulting in recurrent gout flares.18Current rheumatology guidelines recommend that patients with gout receive long-term therapy for lowering of urate levels (ULT) to achieve crystal dissolution, ultimately preventing recurrent gout flares.19 reduce the major adverse cardiovascular events and all-cause mortality in individuals with or without diabetes.21 Studies also found that SGLT2i lower serum urate levels and reduce the risk of incident gout.29 However, to date, no study has specifically examined the association of SGLT2i with the risk of recurrent gout flares and all-cause mortality in patients with gout. Using an electronic medical records database from the UK, we conducted a population-based cohort study to compare the risk of recurrent gout flares and all-cause mortality between patients initiating SGLT2i treatment and those initiating 2 other antidiabetic medications  in patients with gout and type 2 diabetes.Sodium-glucose cotransporter-2 inhibitors (SGLT2i), which treat type 2 diabetes,STROBE) reporting guideline.In this cohort study, we used data from the IQVIA Medical Research Database (IMRD), which incorporated data from The Health Improvement Network, a Cegedim database from general practitioners (GPs) in the UK. The IMRD contains health information on approximately 19 million patients from 839 general practices in the UK. The computerized information includes sociodemographic characteristics, anthropometric characteristics, lifestyle factors, details from visits to GPs, diagnoses from specialist referrals and hospital admissions, as well as results of laboratory tests. The Read classification system is used to code specific diagnoses, whereas a dictionary based on the Multilex classification system is used to code drugs. This study received approval from the medical ethical committee of Xiangya Hospital, with a waiver of informed consent owing to the use of deidentified data, and was approved by the IMRD Scientific Review Committee. The study followed the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology  and all-cause mortality during the follow-up period.The primary outcome was the total number of recurrent gout flares (hereinafter referred to as recurrent flares) during the follow-up period. A gout flare was defined as a recorded Read code of gout plus a recorded prescription of colchicine; a recorded Read code of gout together with at least 1 of intra-articular corticosteroids, nonsteroidal anti-inflammatory drugs, or corticosteroid or adrenocorticotropic hormone within 1 week; or having Read codes specific for gout flare.Covariates included age, sex, socioeconomic deprivation index score , region, body mass index , alcohol use, smoking, gout duration (year from the first gout diagnosis to the index date), type 2 diabetes duration (year from the first type 2 diabetes diagnosis to the index date), Charlson Comorbidity Index, comorbidities at any time since enrolment to the index date, medication use, and use of health care services  during the 1 year before the index date. The details of comorbidities and medication use are listed in 30 The overlap weight is defined as 1 minus the propensity score for a treated unit and a propensity score for a comparison unit. Thus, patients with a propensity score of 0.5 make the largest contribution to the effect estimate, and patients with a propensity score close to 0 or 1 make the smallest contribution, therefore smoothly reducing the influence of patients at the tails of the propensity score distribution without making any exclusions and eliminating the potential bias that can arise from the multiplication of scores of the few patients with extremely high or low propensity scores. We assessed the distribution of baseline characteristics between 2 comparison cohorts before and after overlap weighting using the absolute standardized differences. Participants were followed up from the day of initiating medication under the study to the first of the following events to occur: disenrolled from a GP, age of 90 years, death, or the end of the study . We calculated the weighted incidence rate for the recurrent flares and estimated the weighted absolute rate difference (RD) between 2 comparison cohorts. We calculated the relative rate (RR) and its 95% CI using a Poisson regression model. Missing values of BMI, smoking status, alcohol consumption, and socioeconomic deprivation index score were imputed using a sequential regression method. To minimize random error, we imputed 5 data sets using Rubin rules.37Participants were allocated into one of the nine 1-year blocks  based on the date of initiation of either SGLT2i or active comparator treatment. Within each 1-year time block, we assembled a cohort of SGLT2i initiators and a cohort of initiators of active comparators. In each 1-year time block, we calculated propensity scores for SGLT2i initiation conditional on the aforementioned baseline characteristics. We applied overlap weighting of the propensity scores to balance baseline characteristics between the comparison groups.We performed several sensitivity analyses to assess the robustness of the study findings. First, we compared the rate of recurrent flares between patients who initiated SGLT2i treatment and each of the active comparators . Second, we conducted an as-treated analysis to account for nonadherence to medications under investigation. Specifically, we censored the follow-up at the time when participants either changed  or discontinued  their initiated medication. Third, we conducted a complete data analysis by excluding participants who had missing data values of covariates to assess whether the missing data affect the study findings. Fourth, we performed 3 subgroup analyses stratifying the study sample according to sex, the ULT use during the 1 year before the index date (yes and no), and the baseline serum urate level (<360 μmol/L and ≥360 μmol/L). Fifth, we assessed the risk of recurrent gout flares during 1 year after initiating allopurinol in patients with gout. Sixth, we performed an analysis by including the level of serum urate at baseline in the propensity score estimation.38 Finally, we examined the association of SGLT2i vs active comparators with the risk of all-cause mortality using the Cox proportional hazards model. We also compared the risk of all-cause mortality between SGLT2i initiators and each of the active comparators separately.To examine whether the risk of the recurrent flares increased during the early period after initiating either SGLT2i or its active comparators, we estimated the monthly risk of the recurrent flares over the first 12 months. For the first recurrent flare analysis, the follow-up ended at the first of the following events: the occurrence of the first recurrent flare, disenrolled from a GP, age of 90 years, death, or the end of the study. We calculated the weighted incidence rate for the first recurrent flare and estimated the RD between 2 comparison cohorts. We performed a Cox proportional hazards model analysis to obtain a hazard ratio (HR) and its 95% CI of the first recurrent flare. We adopted the subdistribution hazard function to account for the competing event of death.P values were 2-sided, and P < .05 was considered statistically significant for all tests. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute Inc).All Among the 5931 patients included in the analysis , we identified 1548 patients (26.1%) who initiated SGLT2i treatment  and 4383 (73.9%) who initiated of treatment with active comparators . Before propensity score overlap weighting, compared with those initiating treatment with active comparators, those initiating SGLT2i treatment were younger and more likely to be men; had higher BMI and lower levels of serum urate; had a lower prevalence of hypertension, stroke, osteoarthritis, venous thromboembolism, chronic kidney disease, and prescriptions of antihypertensive medicine, other antidiabetic medicine, aspirin, and diuretics; and less use of health care services. After propensity score overlap weighting, the distribution of the characteristics of the 2 comparison cohorts was well balanced  . The floAs shown in As shown in As shown in eFigure 5 in Using the UK population-based database, we found that initiating SGLT2i treatment was associated with a lower risk of recurrent gout flares among the patients with gout and type 2 diabetes. Unlike other ULT medications, we did not observe an apparent transient increase in the risk of gout flares shortly after initiating SGLT2i therapy. In addition, SGLT2i initiators had lower all-cause mortality than DPP-4i initiators.27 showed that SGLT2i reduced serum urate level, incident hyperuricemia, and incident gout in patients with type 2 diabetes or chronic heart failure, compared with placebo. Several observational studies29 also reported that initiation of SGLT2i treatment was associated with a lower risk of incident gout than initiation of DPP-4i or GLP-1 RA treatment in patients with type 2 diabetes. However, to our knowledge, no study has previously assessed whether SGLT2i reduces the risk of recurrent gout flares. Our study fills this knowledge gap and demonstrates that initiating SGLT2i treatment was associated with a lower rate of recurrent flares than initiating DPP-4i or GLP-1 RA treatment in patients with gout and type 2 diabetes.Previous post hoc analyses of randomized clinical trials39 This effect is attributed to the glucose in the urine competing with soluble urate for glucose transporter 9–mediated reabsorption in the proximal tubule due to the reduced transport function of SGLT2.40 Additionally, SGLT2i enhance sirtuin-1, an enzyme that inhibits xanthine oxidase and decreases serum urate levels.41 Second, SGLT2i may suppress pyrin domain–containing 3 inflammasome activation and attenuate interleukin 1β secretion42 and thus may lower the risk of gout flares. Finally, studies have shown that SGLT2i could improve kidney function and heart failure and reduce the use of loop or thiazides diuretics,43 which may indirectly lower the risk of recurrent gout flares.Several biological mechanisms may explain our findings. First, SGLT2i could reduce serum urate concentration by increasing kidney urate elimination.21 enhancing the credibility of our findings regarding the risk of gout flares. Third, we used the sequential overlap-weighting method to control for confounding; and the age- and sex-adjusted effect estimates are similar to those generated from the overlap-weighted method, indicating that any residual confounding, if present, is unlikely to explain away the association of SGLT2i with either the risk of recurrent gout flares or all-cause mortality.Several strengths of our study are worth noting. First, we implemented an active-comparator new-user design to assess the risk of recurrent flares associated with SGLT2i use. This design helps minimize the confounding by indication and prevalent user biases. Second, no ULT medications have shown a protective effect on all-cause mortality in patients with gout. Although we did not observe a significant reduction of all-cause mortality during the early years of follow-up after initiating SGLT2i treatment, our findings suggest that SGLT2i may be associated with a reduced risk of all-cause mortality. This finding is consistent with previous studies that have shown a similar association,44 In addition, we demonstrated that the risk of gout flares increased during the first 3 months after initiating allopurinol and then leveled off, which is comparable to the findings of the previous randomized clinical trials.45 All this evidence suggests a reasonable level of ascertainment for gout flares. Furthermore, if gout flares were misclassified, such misclassification is likely nondifferential and biases the results toward the null. Second, we could not evaluate the association of SGLT2i with the risk of recurrent gout flares and mortality among the population who seek care outside the GP system included in IMRD; however, this limitation should not affect the internal validity of the current findings. Third, physician-ordered prescriptions may not reflect the actual medication taken by the patients. However, we found that the results from the intention-to-treat analysis did not differ materially from those of the as-treated analysis, suggesting that the potential bias from nonadherence may not be substantial.This study also has some limitations. First, the IMRD does not contain hospitalization data, and some patients may not seek care from GPs for recurrent gout flares. Additionally, the ascertainment of gout flares using a pragmatic approach may lead to a misclassification. As a result, the risk of recurrent gout flare might be underestimated. Nevertheless, it is worth noting that, for gout flares identified by a recorded Read code of gout along with treatments within 1 week, approximately 86% of patients in our study had a documented code for gout on the same date as a prescription of nonsteroidal anti-inflammatory drugs or corticosteroids, and the remaining patients had a recorded code for gout within 7 days before the prescription. Although the therapeutic use of colchicine has extended to other disorders , we would expect patients to take colchicine continuously. When colchicine is prescribed for a discrete episode, it is more often to patients who experienced gout flares.In this cohort study of patients with gout and type 2 diabetes, initiating SGLT2i treatment was associated with a reduced risk of recurrent gout flares compared with initiating DPP-4i or GLP-1 RA treatment. Furthermore, SGLT2i initiators had a lower all-cause mortality than initiators of DPP-4i. These findings suggest that SGLT2i might hold potential in reducing the burden of recurrent gout flares and potentially narrowing the mortality gap between patients with gout and the general population.