Long-term cardiovascular, cerebrovascular, and thrombotic complications after SARS-CoV-2-Omicron infection: a retrospective cohort study.

OBJECTIVES: Evidence suggests that some COVID-19 survivors experience a wide range of post-COVID-19 sequelae; however, the majority of studies were conducted before the emergence of the milder Omicron variant. We examined the post-acute risk of new-incident cardiovascular complications after SARS-CoV-2 infection in a multi-ethnic Asian population, during Omicron predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals with confirmed SARS-CoV-2 infection during Omicron BA.1/2 transmission and a contemporaneous test-negative group. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular complications using doubly robust competing-risks survival analysis. Risks were reported using two measures: hazard ratio and excess burden. RESULTS: We included 375 903 test-positive, infected individuals (mean age 48 years) and 619 379 test-negative controls (mean age 47 years). The majority (97.5%, 366 593/375 903) of infected individuals had mild infection not requiring hospitalization. There was no overall increased risk of new-incident cardiovascular complications, (adjusted hazards ratio, aHR = 1.01 [0.97-1.07]) amongst COVID-19 survivors when compared against test-negatives. A modestly increased risk and excess burden of dysrhythmias amongst COVID-19 survivors (aHR = 1.09 [1.01-1.19]) was observed. Risk and burdens of new-incident cardiovascular complications predominantly accrued in hospitalized (aHR = 2.81 [2.26-3.50]) and severe COVID-19 cases (aHR = 5.52 [3.76-8.10]). DISCUSSION: No significantly increased overall risk of any cardiovascular complication was observed in the 300 days following COVID-19 infection during the Omicron-dominant period when compared against test-negatives, with the exception of a small increased occurrence of dysrhythmias.

Long-term Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in COVID-19 Survivors: A Retrospective Cohort Study.

BACKGROUND: Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. We examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. RESULTS: We included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069-1.252]) and excess burden (EB, 0.70 [.53-.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02-1.22]) and boosted (HR, 1.10 [.92-1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). CONCLUSIONS: Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting.

Long-term neuropsychiatric sequelae of Delta versus Omicron SARS-CoV-2 infection.

OBJECTIVES: Studies have reported increased rates of long-term neuropsychiatric sequelae after SARS-CoV-2 infection using electronic health-record (EHR) data; however, the majority were conducted before Omicron and booster rollout. We estimated the long-term risks and excess burdens of pre-specified new-incident neuropsychiatric diagnoses after Delta versus Omicron BA.1/2 infection in a highly-vaccinated and boosted cohort of adult Singaporeans. METHODS: The national SARS-CoV-2 testing registry was used to construct cohorts of Singaporean adults infected during periods of Delta and Omicron BA.1/2 predominance and a contemporaneous test-negative control group. New-incident neuropsychiatric diagnoses recorded in the national health care claims database were identified up to 300 days postinfection. Risks and excess burden were estimated using a doubly robust competing-risks survival analysis. RESULTS: 104 179 and 375 903 infected cases were assigned to Delta and Omicron cohorts and compared against test-negative controls (Delta: N = 666 575 and Omicron: N = 619 379). Elevated risk of cognition or memory disorders was consistently reported across Omicron (Adjusted hazards ratio [aHR], 1.24; 95% CI, 1.12-1.38) and Delta cohorts (aHR, 1.63; 95% CI, 1.39-1.92). Delta-variant infection was associated with an increased risk of anosmia or dysgeusia (aHR, 4.53; 95% CI, 2.78-7.41) and psychosis (aHR, 1.65; 95% CI, 1.22-2.22). By contrast, Omicron-variant infection was associated with a risk of abnormal involuntary movements (aHR, 1.93; 95% CI, 1.32-2.83). Risks of neuropsychiatric sequelae predominantly accrued in hospitalized individuals. DISCUSSIONS: A modestly increased risk of cognition and memory disorders at 300 days after SARS-CoV-2 infection was observed among adult Singaporeans infected during the Delta/Omicron BA.1/2 transmission. There was no overall increased risk of neuropsychiatric sequelae observed across other domains. Variant-specific differences were also observed in individual neuropsychiatric sequelae, including an elevated risk of anosmia or dysgeusia after Delta-variant infection.

mRNA SARS-CoV-2 Vaccination Before vs During Pregnancy and Omicron Infection Among Infants.

Importance: Infants younger than 6 months are at risk of severe SARS-CoV-2 infection. Data are lacking on the optimum timing for maternal vaccination and estimated effectiveness against Omicron variants, including XBB, for infants. Objective: To investigate maternal vaccination against Omicron variants, including XBB, and the association of vaccination timing during pregnancy vs prior to pregnancy and risks of SARS-CoV-2 infection among infants aged 6 months or younger. Design, Setting, and Participants: This population-based cohort study was conducted between January 1, 2022, and March 31, 2023. Singapore's national dataset was used to study infants born at greater than 32 weeks' gestation between January 1, 2022, and September 30, 2022. The study included infants whose parents had a confirmed SARS-CoV-2 infection from the date of birth up to 6 months of age. Of 21 609 infants born during this period, 7292 (33.7%) had at least 1 parent infected with SARS-CoV-2 before the age of 7 months. Statistical analysis was performed from April to July 2023. Exposure: Infants' mothers were unvaccinated, vaccinated prior to pregnancy, or vaccinated with a messenger RNA (mRNA) SARS-CoV-2 vaccine during pregnancy. Main Outcome and Measure: Infants were considered infected if they had a positive polymerase chain reaction test. Results: Among 7292 infants included in this study, 4522 (62.0%) had mothers who were Chinese, 527 (7.2%) had mothers who were Indian, 2007 (27.5%) had mothers who were Malay, and 236 (3.2%) had mothers who were other ethnicity; 6809 infants (93.4%) were born at full term, and 1272 infants (17.4%) were infected during the study period. There were 7120 infants (97.6%) born to mothers who had been fully vaccinated or boosted as of 14 days prior to delivery. The crude incidence rate was 174.3 per 100 000 person-days among infants born to mothers who were unvaccinated, 122.2 per 100 000 person-days among infants born to mothers who were vaccinated before pregnancy, and 128.5 per 100 000 person-days among infants born to mothers who were vaccinated during pregnancy. The estimated vaccine effectiveness (VE) was 41.5% (95% CI, 22.8% to 55.7%) among infants born to mothers vaccinated during pregnancy. Infants of mothers who received vaccination prior to pregnancy did not have a lower risk for infection (estimated VE, 15.4% [95% CI, -17.6% to 39.1%]). A lower risk for Omicron XBB infection was only observed among mothers vaccinated with the third (booster) dose antenatally (estimated VE, 76.7% [95% CI, 12.8% to 93.8%]). Conclusions and Relevance: In this population-based cohort study, maternal mRNA vaccination was associated with a lower risk of Omicron SARS-CoV-2 infection among infants up to 6 months of age only if the vaccine was given during the antenatal period. These findings suggest that mRNA vaccination during pregnancy may be needed for lower risk of SARS-CoV-2 infection among newborns.

Effectiveness of Monovalent mRNA Vaccines Against Omicron XBB Infection in Singaporean Children Younger Than 5 Years.

Importance: Literature on vaccine effectiveness of SARS-CoV-2 messenger RNA (mRNA) vaccines for children younger than 5 years is limited. Objective: To report the effectiveness of monovalent mRNA vaccines against SARS-CoV-2 infection among Singaporean children aged 1 through 4 years during a COVID-19 pandemic wave of the Omicron XBB variant. Design, Setting, and Participants: This was a population-based cohort study, conducted over a 6-month study period from October 1, 2022, through March 31, 2023, after the implementation of community vaccination among all Singaporean children aged 1 through 4 years. The study period was dominated by the Omicron XBB subvariant. Exposure: Receipt of SARS-CoV-2 mRNA vaccines. Main Outcome Measure: Vaccine effectiveness against confirmed SARS-CoV-2 infection. The adjusted incidence rate ratio for confirmed infections using Poisson regression was reported, with the reference group being those who were unvaccinated. Analyses were stratified by prior documented SARS-CoV-2 infection. Results: A total of 121 628 children (median [IQR] age, 3.1 [2.2-3.9] years; 61 925 male [50.9%]) were included in the study, contributing 21 015 956 person-days of observation. The majority of children (11 294 of 11 705 [96.5%]) received the mRNA-1273 COVID-19 vaccine (Moderna). Vaccine effectiveness against confirmed infection was 45.2% (95% CI, 24.7%-60.2%) in partially vaccinated, infection-naive children and 63.3% (95% CI, 40.6%-77.3%) in fully vaccinated, infection-naive children compared with the unvaccinated group. Among previously infected children, vaccine effectiveness against reinfections in those with at least 1 vaccine dose was estimated at 74.6% (95% CI, 38.7%-89.5%). Conclusions and Relevance: Study results suggest that completion of a primary mRNA vaccine series provided protection against SARS-CoV-2 infection in children aged 1 through 4 years. Although incidence of hospitalization and severe illness is low in this age group, there is potential benefit of vaccination in preventing infection and potential sequelae.

Effectiveness of bivalent mRNA vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals: a retrospective cohort study.

BACKGROUND: Emergence of the SARS-CoV-2 omicron (B.1.1.529) variant with high immune evasion has led to the development and roll-out of bivalent mRNA vaccines targeting original and omicron strains. However, real-world observational data on effectiveness of bivalent vaccines are scarce. We aimed to assess the relative effectiveness of a fourth vaccine dose with the BA.1-adapted or BA.4/BA.5-adapted bivalent vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals in Singapore. METHODS: We conducted a retrospective cohort study among Singapore residents aged 18 years and older who had received three monovalent mRNA vaccine doses and were eligible for a fourth dose. Data were collected from official databases on COVID-19 cases and vaccinations maintained by the Singapore Ministry of Health. We analysed the incidence of medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission between Oct 14, 2022, and Jan 31, 2023, by previous infection status and type of fourth vaccine dose received. Inverse probability-weighted Cox regressions were used to estimate hazard ratios (HRs). FINDINGS: 2 749 819 individuals were included in the analysis. For the SARS-CoV-2-naive group, a fourth monovalent vaccine dose did not confer additional protection over three monovalent doses against symptomatic infection (HR 1·09 [95% CI 1·07-1·11]), whereas the bivalent vaccine did provide additional protection (0·18 [0·17-0·19]). Among individuals with previous infection, the HR was 0·87 (95% CI 0·84-0·91) and 0·14 (0·13-0·15) with receipt of the fourth monovalent and bivalent doses, respectively. Against COVID-19-related hospital admission, the bivalent vaccine (HR 0·12 [95% CI 0·08-0·18] in SARS-CoV-2-naive participants and 0·04 [0·01-0·15] in previously infected participants) conferred greater benefit compared with the fourth monovalent dose (0·84 [0·77-0·91] in SARS-CoV-2-naive participants and 0·85 [0·69-1·04] in previously infected participants). INTERPRETATION: A fourth dose with the bivalent vaccine was substantially more effective against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission than four monovalent doses among both SARS-CoV-2-naive and previously infected individuals. Boosters with the bivalent vaccine might be preferred in this omicron-predominant pandemic, regardless of previous infection history. FUNDING: None.

Long-term Real-world Protection Afforded by Third mRNA Doses Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections, Coronavirus Disease 19-related Emergency Attendances and Hospitalizations Amongst Older Singaporeans During an Omicron XBB Wave.

BACKGROUND: Literature on long-term real-world vaccine effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) booster vaccines (up to and beyond 360 days) is scarce. We report estimates of protection against symptomatic infection, emergency department (ED) attendances and hospitalizations up to and beyond 360 days post-receipt of booster messenger RNA (mRNA) vaccines among Singaporeans aged ≥60 years during an Omicron XBB wave. METHODS: We conducted a population-based cohort study including all Singaporeans aged ≥60 years with no documented prior SARS-CoV-2 infection who had previously received ≥3 doses of mRNA vaccines (BNT162b2/mRNA-1273), over a 4-month period during transmission of Omicron XBB. We reported the adjusted incidence-rate-ratio (IRR) for symptomatic infections, ED attendances and hospitalizations at different time-intervals from both first and second boosters, using Poisson regression; with the reference group being those who received their first booster 90 to 179 days prior. RESULTS: In total, 506 856 boosted adults were included, contributing 55 846 165 person-days of observation. Protection against symptomatic infections among those who received a third vaccine dose (first booster) waned after 180 days with increasing adjusted IRRs; however, protection against ED attendances and hospitalizations held up, with comparable adjusted IRRs with increasing time from third vaccine doses (≥360 days from third dose: adjusted IRR [ED attendances] = 0.73, 95% confidence interval [CI] = .62-.85; adjusted IRR [hospitalization] = 0.58, 95% CI = .49-.70). CONCLUSIONS: Our results highlight the benefit of a booster dose in reducing ED attendances and hospitalizations amongst older adults aged ≥60 years with no documented prior SARS-CoV-2 infection, during an Omicron XBB wave; up to and beyond 360 days post-booster. A second booster provided further reduction.

BNT162b2 vaccine protection against omicron and effect of previous infection variant and vaccination sequence among children and adolescents in Singapore: a population-based cohort study.

BACKGROUND: Information on variant-specific vaccine protection and the effect of previous infection variant is scarce in children. We aimed to ascertain the level of protection conferred by BNT162b2 COVID-19 vaccination against omicron variant infection (BA.4 or BA.5, and XBB) in a previously infected national paediatric cohort. We also explored the association between sequence of previous infection (variant) and vaccination on protection. METHODS: We did a retrospective, population-based cohort study using the national databases of all confirmed SARS-CoV-2 infections, vaccines administered, and demographic records maintained by the Ministry of Health, Singapore. The study cohort consisted of children aged 5-11 years and adolescents aged 12-17 years who had a previous SARS-CoV-2 infection from Jan 1, 2020, to Dec 15, 2022. People who were infected during the pre-delta period or were immunocompromised (received three vaccination doses [children 5-11 years old] and four vaccinations doses [adolescents 12-17 years old]) were excluded. Those who had multiple episodes of infection before the study start date, were not vaccinated before infection but completed three doses, received bivalent mRNA vaccine, or received non-mRNA vaccine doses were also excluded. All SARS-CoV-2 infections confirmed by reverse transcriptase polymerase chain reaction or rapid antigen testing were grouped into delta, BA.1, BA.2, BA.4 or BA.5, or XBB variants using a combination of whole-genome sequencing, S-gene target failure results, and imputation. For BA.4 or BA.5, the study outcome period was June 1-Sept 30, 2022, and for XBB variants the outcome period was Oct 18-Dec 15, 2022. Incidence rate ratios between vaccinated and unvaccinated were derived using adjusted Poisson regressions and vaccine effectiveness was estimated as (1-risk ratio) × 100%. FINDINGS: 135 197 people aged 5-17 years (79 332 children and 55 865 adolescents) were included in the cohort for the vaccine effectiveness analysis against omicron BA.4 or BA.5, and 164 704 people aged 5-17 years (97 235 children and 67 469 adolescents) were included for the analysis against omicron XBB. Approximately 47% of participants were female and 53% were male. Among those previously infected, vaccine effectiveness against BA.4 or BA.5 infection in fully vaccinated children (two doses) was 74·0% (95% CI 67·7-79·1) and in adolescents (three doses) was 85·7% (80·2-89·6). Against XBB, protection conferred with full vaccination was lower at 62·8% (95% CI 42·3-76·0) in children and 47·9% (20·2-66·1) in adolescents. In children, receipt of two-dose vaccination before first SARS-CoV-2 infection provided them with the highest protection against subsequent BA.4 or BA.5 infection at 85·3% (95% CI 80·2-89·1); however, this was not shown to be the case for adolescents. First infection variant had an effect on vaccine effectiveness against omicron BA.4 or BA.5 reinfection in the following descending order: BA.2 conferred the highest protection (92·3% [95% CI 88·9-94·7] in children and 96·4% [93·5-98·0] in adolescents) followed by BA.1 (81·9% [75·9-86·4] in children and 95·0% [91·6-97·0] in adolescents), and delta which conferred the lowest protection (51·9% [5·3-75·6] in children and 77·5% [63·9-86·0] in adolescents). INTERPRETATION: In previously infected children and adolescents, BNT162b2 vaccination provided additional protection against omicron BA.4 or BA.5 and XBB variants compared with those who remained unvaccinated. Hybrid immunity against XBB was lower than against BA.4 or BA.5, especially in adolescents. Early vaccination of previously uninfected children before their first SARS-CoV-2 exposure could potentially strengthen population immunity resilience against future variants. FUNDING: None.

Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study.

BACKGROUND: Despite a large proportion of the population having been vaccinated and infected, Singapore had SARS-CoV-2 waves driven by the BA.5 and XBB sublineages of the omicron (B.1.1.529) variant. Data on the protective immunity against medically attended, symptomatic reinfections with omicron BA.4, BA.5, and XBB conferred by previous SARS-CoV-2 infections and vaccinations are scarce. We therefore aimed to derive information from Singapore's experience as one of the first countries with an XBB-driven wave. METHODS: For this retrospective national cohort study, we used information from official databases of the Ministry of Health of Singapore to assess hybrid immunity (obtained from previous infection and vaccination) against medically attended, symptomatic BA.4 and BA.5 reinfections from Oct 1, 2022, to Nov 1, 2022, and medically attended, symptomatic XBB reinfections from Oct 18, 2022, to Nov 1, 2022, among Singapore citizens and permanent residents aged at least 18 years. All individuals with acute respiratory symptoms who presented at any health-care facility in Singapore between the stated dates were tested for SARS-CoV-2. Individuals were grouped into SARS-CoV-2-naive, pre-omicron, omicron BA.1, and omicron BA.2 groups according to their previous infection status. Data were also stratified by time from first infection to analyse the waning of immunity. Incidence rate ratios (IRRs) were measured by generalised linear Poisson regressions, with SARS-CoV-2-naive individuals as the reference group, and protective immunity was calculated as one minus the risk ratio multiplied by 100. FINDINGS: 2 456 791 individuals were included in the study, contributing 53·1 million person-days of observation for the SARS-CoV-2-naive group, 3·4 million person-days for the pre-omicron group, 6·6 million person-days for the BA.1 group, and 13·7 million person-days for the BA.2 group between Oct 1, 2022, and Nov 1, 2022. Compared with SARS-CoV-2-naive individuals, first infections with pre-omicron variants did not confer protection against reinfection with BA.4 or BA.5 (IRR 0·87 [95% CI 0·73-1·05] for pre-omicron infection with booster vaccination) or XBB (IRR 1·29 [1·23-1·35] for pre-omicron infection with booster vaccination). Previous BA.2 infection with booster provided the greatest protection against reinfection, but this was lower against reinfection with XBB (protective immunity 51%; 95% CI 49-53) than against reinfection with BA.4 or BA.5 (78%; 74-82). Protection conferred by previous BA.2 infection against XBB reinfection waned faster over time from first infection (from 74% [72-75] at 3-6 months to 49% [47-52] at 7-8 months) than protection against BA.4 or BA.5 reinfection (from 87% [82-90] at 3-6 months to 74% [66-80] at 7-8 months). INTERPRETATION: Protection against XBB reinfection conferred by a previous omicron infection with vaccination was lower and waned faster than protection against BA.4 or BA.5 reinfection, which is indicative of the greater immune evasiveness of the XBB sublineage. Although severe COVID-19 is uncommon, populations remain vulnerable to future reinfection waves from emerging SARS-CoV-2 variants despite high rates of vaccination and infection, as reflected by substantially higher reinfection rates during Singapore's XBB wave than during the previous BA.5-driven wave. Policy makers could consider emerging public health interventions, such as omicron-adapted bivalent vaccines, to maintain population immunity against COVID-19. FUNDING: None.

Vaccine effectiveness against Delta, Omicron BA.1, and BA.2 in a highly vaccinated Asian setting: a test-negative design study.

OBJECTIVES: We compared the vaccine effectiveness over time of the primary series and booster against infection and severe disease with the Delta, Omicron BA.1, and BA.2 variants in Singapore, an Asian setting with high vaccination coverage. METHODS: We conducted a test-negative case-control study on all adult residents in Singapore who underwent PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in acute hospitals. Individuals with a negative PCR from 1 September, 2021, to 30 November, 2021, and 1 December, 2021, to 25 April, 2022, served as controls for the Delta and Omicron variants respectively, and PCR-positive individuals within these two time periods served as cases. Associations between vaccination status and SARS-CoV-2 infection and severe disease with the Delta or Omicron variants were measured using Poisson regressions. Vaccine effectiveness was calculated by taking 1 minus risk ratio. RESULTS: There were 68 114 individuals comprising 58 495 controls and 9619 cases for the Delta period, of whom 53 093 completed the primary series and 9161 were boosted. For the Omicron period, 104 601 individuals comprising 80 428 controls, 8643 BA.1 cases, and 15 530 BA.2 cases were included, of whom 29 183 and 71 513 were vaccinated with the primary series and boosted, respectively. The primary series provided greater protection against infection with Delta (45%, 95% CI 40-50%) than against infection with Omicron (21%, 95% CI 7-34% for BA.1; 18%, 95% CI 6-29% for BA.2) at <2 months from vaccination. Vaccine effectiveness of the booster was similar against infection with BA.1 (44%, 95% CI 38-50%) and BA.2 (40%, 95% CI 35-40%). Protection against severe disease by the booster for BA.1 (83%, 95% CI 76-88%) and BA.2 (78%, 95% CI 73-82%) was comparable to that by the primary series for Delta (80%, 95% CI 73-85%). CONCLUSION: Our findings support the use of a booster dose to reduce the risk of severe disease and mitigate the impact on the healthcare system in an Omicron-predominant epidemic.

National Rates of Lower Extremity Amputation in People With and Without Diabetes in a Multi-Ethnic Asian Population: a Ten Year Study in Singapore.

OBJECTIVE: Population level data from Asia on amputation rates in people with and without diabetes are extremely limited. Hence it is unclear how the rising diabetes prevalence in Asia has affected the amputation burden. The present study examined national amputation rates in people with and without diabetes in Singapore from 2008 to 2017 in the context of increasing diabetes prevalence and health system changes. METHODS: This was a retrospective observational study using national population data for ages 16 - 100 years obtained from the Ministry of Health Singapore administrative datasets. Age sex standardised major and toe/ray amputation rates per 100 000 people with diabetes and per 100 000 people without diabetes were calculated. Rates were calculated overall and in each ethnic group (Chinese, Malay, Indian, Others), with trends over time calculated using joinpoint trend analysis. In addition, age specific rates, relative risk (RR) of amputation in diabetics compared with non-diabetics and proportion of amputations in the population attributable to diabetes were also calculated. RESULTS: Between 2008 and 2017, the database included 3.6 million unique individuals, of whom 75% were Chinese, 8.6% Malay, 7.9% Indian, and 8.4% Others. Of those, 413 486 (11%) had diabetes. Major amputation rates in people with diabetes remained stable (2008: 99.5/100 000; 2017: 95.0/100 000 people with diabetes, p = .91) as did toe/ray amputation rates. Rates in people without diabetes were substantially lower, with major amputation rates decreasing significantly (2008: 3.0/100 000; 2017: 2.1/100 000 people without diabetes, 3% annual reduction, p = .048). Diabetes related amputation rates were highest in Malays and lowest in Chinese. Diabetes related major amputation rates declined significantly among Chinese (3.1% annual reduction, p < .038). While the RR for amputations in diabetes remained stable, the proportion of major amputations attributable to diabetes increased from 63.6% in 2008 to 81.7% in 2017 (3% annual increase, p = .003). CONCLUSION: Diabetes related major and toe/ray amputation rates have remained stable but relatively high in Singapore compared with other countries, and the proportion of amputations attributable to diabetes has increased over time. More research is needed to understand the aetiopathological, sociocultural, and health system factors that may underlie the continued high rates of diabetes related amputations in this population.

Diabetes-related lower extremity complications in a multi-ethnic Asian population: a 10 year observational study in Singapore.

AIMS/HYPOTHESIS: Diabetes progression and complication risk are different in Asian people compared with those of European ancestry. In this study, we sought to understand the epidemiology of diabetes-related lower extremity complications (DRLECs: symptomatic peripheral arterial disease, ulceration, infection, gangrene) and amputations in a multi-ethnic Asian population. METHODS: This was a retrospective observational study using data obtained from one of three integrated public healthcare clusters in Singapore. The population consisted of individuals with incident type 2 diabetes who were of Chinese, Malay, Indian or Other ethnicity. We examined incidence, time to event and risk factors of DRLECs and amputation. RESULTS: Between 2007 and 2017, of the 156,593 individuals with incident type 2 diabetes, 20,744 developed a DRLEC, of whom 1208 underwent amputation. Age- and sex-standardised incidence of first DRLEC and first amputation was 28.29/1000 person-years of diabetes and 8.18/1000 person-years of DRLEC, respectively. Incidence of both was highest in individuals of Malay ethnicity (DRLEC, 36.09/1000 person-years of diabetes; amputation, 12.96/1000 person-years of DRLEC). Median time from diabetes diagnosis in the public healthcare system to first DRLEC was 30.5 months for those without subsequent amputation and 10.9 months for those with subsequent amputation. Median time from DRLEC to first amputation was 2.3 months. Older age (p < 0.001), male sex (p < 0.001), Malay ethnicity (p < 0.001), Indian ethnicity (p = 0.014), chronic comorbidities (nephropathy [p < 0.001], heart disease [p < 0.001], stroke [p < 0.001], retinopathy [p < 0.001], neuropathy [p < 0.001]), poorer or missing HbA1c (p < 0.001), lower (p < 0.001) or missing (p = 0.002) eGFR, greater or missing BMI (p < 0.001), missing LDL-cholesterol (p < 0.001) at diagnosis, and ever-smoking (p < 0.001) were associated with higher hazard of DRLEC. Retinopathy (p < 0.001), peripheral vascular disease (p < 0.001), poorer HbA1c (p < 0.001), higher (p = 0.009) or missing (p < 0.001) LDL-cholesterol and missing BMI (p = 0.008) were associated with higher hazard of amputation in those with DRLEC. Indian ethnicity (p = 0.007) was associated with significantly lower hazard of amputation. CONCLUSIONS/INTERPRETATION: This study has revealed important ethnic differences in risk of diabetes-related lower limb complications, with Malays most likely to progress to DRLEC. Greater research efforts are needed to understand the aetiopathological and sociocultural processes that contribute to the higher risk of lower extremity complications among these ethnic groups.

Trends in the incidence of diagnosed diabetes: a multicountry analysis of aggregate data from 22 million diagnoses in high-income and middle-income settings.

BACKGROUND: Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. METHODS: In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995-2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. FINDINGS: Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from -1·1% to -10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. INTERPRETATION: The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Risk Prediction Scores for Mortality, Cerebrovascular, and Heart Disease Among Chinese People With Type 2 Diabetes.

CONTEXT: Risk scores for cardiovascular and mortality outcomes have not been commonly applied in Chinese populations. OBJECTIVE: To develop and externally validate a set of parsimonious risk scores [University of Hong Kong-Singapore (HKU-SG)] to predict the risk of mortality, cerebrovascular disease, and ischemic heart disease among Chinese people with type 2 diabetes and compare HKU-SG risk scores to other existing ones. DESIGN: Retrospective population-based cohorts drawn from Hong Kong Hospital Authority health records from 2006 to 2014 for development and Singapore Ministry of Health records from 2008 to 2016 for validation. Separate five-year risk scores were derived using Cox proportional hazards models for each outcome. SETTING: Study participants were adults with type 2 diabetes aged 20 years or over, consisting of 678,750 participants from Hong Kong and 386,425 participants from Singapore. MAIN OUTCOME MEASURES: Performance was evaluated by discrimination (Harrell C-index), and calibration plots comparing predicted against observed risks. RESULTS: All models had fair external discrimination. Among the risk scores for the diabetes population, ethnic-specific risk scores (HKU-SG and Joint Asia Diabetes Evaluation) performed better than UK Prospective Diabetes Study and Risk Equations for Complications Of type 2 Diabetes models. External validation of the HKU-SG risk scores for mortality, cerebrovascular disease, and ischemic heart disease had corresponding C-indices of 0.778, 0.695, and 0.644. The HKU-SG models appeared well calibrated on visual plots, with predicted risks closely matching observed risks. CONCLUSIONS: The HKU-SG risk scores were developed and externally validated in two large Chinese population-based cohorts. The parsimonious use of clinical predictors compared with previous risk scores could allow wider implementation of risk estimation in diverse Chinese settings.

Trends and predictors of cesarean birth in Singapore, 2005-2014: A population-based cohort study.

BACKGROUND: Rates of cesarean birth have continued to rise in many high-income countries. We examined the temporal trends and predictors of cesarean birth in Singapore. METHODS: Linked hospitalization and Birth Registry data were used to examine all live births to Singaporean citizens and permanent residents between January 1, 2005 and December 31, 2014 (n = 342 932 births). We calculated cesarean rates and age-adjusted average annual percent change (AAPC) in those rates and used sequential multivariable regression modeling to assess the contribution of changes in predictors to the change in cesarean rates over time. RESULTS: The overall cesarean rate in Singapore rose from 32.2% in 2005 to 37.4% in 2014. Among singleton, cephalic, term pregnancies, the two major predictions of cesarean were nulliparity and previous cesarean, each accounting for just over one-third of all cesareans. Higher AAPC was observed in nulliparous women of Indian ethnicity (0.74% [95% confidence interval 0.68-0.80]) compared with Chinese (0.62% [0.60-0.65]) or Malay women (0.63% [0.59-0.68]), and in women who delivered in private hospitals (0.62% [0.60-0.64]) compared with those delivered under subsidized care in public hospitals (0.58% [0.52-0.63]). Parity and education had the largest influences on cesarean birth trend (attenuation of AAPC from 0.62% [0.59-0.66] to 0.39% [0.38-0.40] after adjustment). CONCLUSION: Cesarean birth has continued to rise at a steady rate in Singapore. Strategies to curb this temporal increase include avoidance of medically unnecessary primary cesarean and attempts at trial of labor and vaginal delivery among women with a history of prior cesarean.

Avoidable Hospital Admissions From Diabetes Complications In Japan, Singapore, Hong Kong, And Communities Outside Beijing.

Improving the quality of primary care may reduce avoidable hospital admissions. Avoidable admissions for conditions such as diabetes are used as a quality metric in the Health Care Quality Indicators of the Organization for Economic Cooperation and Development (OECD). Using the OECD indicators, we compared avoidable admission rates and spending for diabetes-related complications in Japan, Singapore, Hong Kong, and rural and peri-urban Beijing, China, in the period 2008-14. We found that spending on diabetes-related avoidable hospital admissions was substantial and increased from 2006 to 2014. Annual medical expenditures for people with an avoidable admission were six to twenty times those for people without an avoidable admission. In all of our study sites, when we controlled for severity, we found that people with more outpatient visits in a given year were less likely to experience an avoidable admission in the following year, which implies that primary care management of diabetes has the potential to improve quality and achieve cost savings. Effective policies to reduce avoidable admissions merit investigation.