Impact of the COVID-19 pandemic on the incidence and clinical outcomes of diabetic ketoacidosis among male and female children with type 1 diabetes: systematic review and meta-analysis

Background: Some studies suggest that the SARS-CoV-2 pandemic increased the incidence of type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA). However, the impact of this pandemic on pediatric T1DM is still mostly unknown. Therefore, we aimed to assess the effect of the COVID-19 pandemic on clinical outcomes in children with T1DM. Methods: We systematically searched for six databases up to 31 August 2022. We included 46 observational studies, 159,505 children of both sexes with T1DM, and 17,547 DKA events. Results: The COVID-19 pandemic significantly increased, in both sexes, the incidence of 1) DKA (OR 1.68; 95% CI 1.44–1.96), 2) severe DKA (OR 1.84; 95% CI 1.59–2.12), 3) DKA in newly diagnosed T1DM (OR 1.75; 95% CI 1.51–2.03), and 4) ICU admissions (OR 1.90; 95% CI 1.60–2.26). However, we did not find a significant association between this pandemic and 1) the incidence of T1DM, 2) the incidence of DKA in established T1DM, 3) the incidence of KDA complications, 4) the length of hospitalization stay, and 5) mortality. Subgroup analysis showed that the study design and the continent of origin accounted for the heterogeneity. Conclusions: The pandemic SARS-CoV-2 raised, in both sexes, the risk of DKA, severe DKA, DKA de novo, and ICU admissions.


Introduction
Type 1 diabetes (T1DM) is an autoimmune disease traditionally associated with viral infections. 1,2The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus shows a great affinity for the angiotensin-converting enzyme (ACE) 2 receptor and other receptors present in the islets of Langerhans in the pancreas.Therefore, the SARS-CoV-2 virus could induce insulin resistance, hyperglycemia, and diabetes mellitus (DM) decompensation.On the contrary, hyperglycemia could worsen the prognosis of the COVID-19 disease. 3,4There seems to be, in fact, a bidirectional relation between COVID-19 and DM. 5,61][12] Besides, people with DM are disproportionately affected by COVID-19.For example, they are more susceptible to be admitted to an intensive care unit (ICU) than those non-diabetic patients. 13In addition, patients with T1DM have 3.5 times higher mortality rates from COVID-19 than those without T1DM. 14However, data are still controversial.Some studies found no differences in the percentage of newly diagnosed T1DM complicating with DKA in COVID-19 and non-COVID-19 periods. 15,16Therefore, it is maybe due to more difficult access to healthcare systems. 15In fact, despite the advantages of telemedicine during the pandemic, several reports have shown that a considerable quantity of T1DM patients has presented complications, probably associated with fear and delay in seeking medical help. 17Another factor that could increase the incidence of T1DM, diabetic ketoacidosis (DKA), and severe DKA is the widespread use of steroids during the pandemic due to their ability to induce insulin resistance, hyperglycemia, and de novo DM. 18,19 An international multicenter study in Europe and the USA aimed to examine the impact of the COVID-19 pandemic on the prevalence of DKA in pediatric type 1 diabetes.The researchers noted that the DKA prevalence at T1DM diagnosis during the pandemic years was 39%, significantly higher than the estimated prevalence of 33% for the two previous years.However, they did not find significant differences by sex or age. 20ype 1 diabetes mellitus"; exposure: "COVID-19" OR "SARS-CoV-2"; comparator: "NOT COVID-19" OR "NOT SARS-CoV-2"; outcome: "diabetic ketoacidosis" OR "DKA" OR "incidence" OR "hospital stay" OR "intensive care unit admission" OR "mortality" (Extended data).We did not limit searches by date or language.
The eligibility criteria followed the PECO question.We included studies that evaluated pediatrics'new-onset T1DM during the COVID-19 pandemic and during the same pre-pandemic period, which reported at least one of the following outcomes: children with new-onset and established T1DM, DKA among children with newly diagnosed and established T1DM, DKA, and severe DKA among newly diagnosed and established children with T1DM, ICU admissions, DKA complications, length of hospitalization stay, and mortality due to DKA.We excluded case reports, case series, duplicated publications, and papers in which more than 50% of patients were >18 years old or had other types of diabetes mellitus.This cutoff ensures that most participants in the included studies are children, which increases the likelihood that the results are relevant to them. 21Three reviewers (FEL-J, BADT-H, and GAV-T) independently.Three independent reviewers (FEL-J, BADT-H, and GAV-T) examined articles, and a fourth researcher (EDM-R) resolved discrepancies.We screened references from retrieved documents for additional articles.We reviewed the papers found and verified the compliance of the components of the PECO framework and the inclusion and exclusion criteria.In addition, we extracted and recorded the essential information from each article in a spreadsheet: authors' names, year and country of publication, type of study, number of patients, sex of the patients, number of events, the measure of association, and adjusted confounders if reported.
Initially, we planned to perform subgroup analyses according to DKA severity, mortality, length of hospitalization, and sex.However, as the protocol stipulated, these subgroup analyses would be executed if feasible regarding information and data.In addition, in concordance with the SAGER guidelines, 24 we defined sex as the biological attributes associated with physical and physiological features separated as mutually exclusive and complementary categories (male or female); that is, the sum of both is equal to the total number of cases.
We pooled the number of patients and events of interest in the quantitative synthesis and calculated odds ratios (ORs) with 95% confidence intervals (95% CIs) using the Mantel-Haenszel method.We considered the risk ratio (RR) equivalent to OR if the incidence of the event evaluated was fewer than 10 percent. 25We used forest plots to represent the quantitative synthesis and assessed heterogeneity among studies with Cochran's Q test and Higgins I 2 statistic.We predefined that if heterogeneity was not significant (p > 0.05, I 2 statistics < 40%), we would use a fixed-effects model.We carried out sensitivity and subgroup analyses and assessed the risk of bias with the Newcastle-Ottawa Scale (NOS) tool. 26Finally, we examined the publication bias using a funnel plot.
In addition, we compare the incidence per 10 5 children/year of T1DM between the pre-pandemic and pandemic period using medians and interquartile ranges (IQRs) and the Mann-Whitney test.We calculated the mean difference (MD) measures as the absolute difference between the means in the two (pre-pandemic and pandemic) groups.In the case of those studies that did not report the means or the standard deviation (SD) of the samples, we estimated it from the data provided by the authors.As long as the data are not significantly skewed away from normality, 27 it is possible to estimate MD and SD if we know the size, the minimum, median, and maximum of the sample (scenario 1); 28,29 the size, first quartile, median, third quartile (scenario 2); 28,29 or the size, minimum, first quartile, median, third quartile, and maximum of the sample (scenario 3). 28,30

Results
We collected 112 studies, 98 in the primary screening and 14 in the secondary examination.Following the removal of duplicated articles, there were 87 articles left that we examined in title and abstract.Subsequently, we found and analyzed 46 papers in full text.We considered these 46 papers for qualitative and quantitative synthesis (Figure 1).
Of the 46 studies included in this review, six studies were cross-sectional studies (CSS), two papers were case-control studies (CCS), and thirty-eight documents were prospective or retrospective cohort studies (PCS, RCS).This review includes a total of 159,505 children with T1DM, 17,547 events of DKA-5,792 episodes of severe DKA, 15,600 episodes of DKA in de novo T1DM, and 521 episodes of DKA in established T1DM, 791 ICU admissions, 822 DKA related complications, and one death (Table 1).
Following the approach of most studies, we analyzed outcomes comparing the pre-pandemic and the pandemic periodsregardless of their COVID-19 status (positive or negative)-instead of reporting events in children with COVID-19 positive or negative.Consequently, we only included papers that reported both groups of children (a pre-pandemic and a pandemic cohort).The lack of a pre-pandemic group was the leading cause of the exclusion of most studies (Extended data).
We analyzed nine outcomes (pre and during the COVID-19 pandemic) in children: 1) the incidence of T1DM, 2) the incidence of DKA in T1DM, 3) the incidence of severe DKA in T1DM, 4) the incidence of DKA in de novo T1DM, 5) the incidence of DKA in established T1DM, 6) the incidence of ICU admissions due to DKA in T1DM, 7) the incidence of DKA complications in T1DM, 8) the length of hospitalization stay, and 9) the risk of mortality due to DKA.T1DM: type 1 diabetes mellitus, DKA: diabetic ketoacidosis, RCS: Retrospective cohort study, PCS: Prospective cohort study, CSS: Cross-sectional study, ISPAD: International Society for Pediatric and Adolescent Diabetes, ADA: American Diabetes Association, DCCP: Diabetes Canada Clinical Practice, WHO: World Health Organization, ICU: admission to the intensive care unit, UC: unicenter, MC: multicenter, ND: not described.

Incidence of T1DM
During the pre-COVID-19 era, the median incidence of DKA among children with T1DM was 17.28 per 10 5 patients/ year (IQR 10.87-26.9),and during the COVID-19 era, the incidence of DKA among children with T1DM was 19.35 per     2a) among children with T1DM.

Length of hospital stay among T1DM pediatric patients
Compared with the pre-COVID-19 era, the COVID-19 era did not significantly affect the duration of hospital stay due to DKA (MD 0.18; 95% CI -0.11-0.46)(Figure 2g) among children with T1DM.

Risk of mortality due to DKA
We found two studies 37,43 evaluating this outcome.Unfortunately, only one 43 of these two studies reported events during the pandemic.Consequently, we decided not to conduct a meta-analysis for this clinical outcome.Of the 46 studies included, 40 had a low risk of bias and six had a high risk of bias according to assessment with the Newcastle-Ottawa Scale (NOS) tool (Table 2).
The funnel plot suggested publication bias (Figure 3).

Discussion
To our knowledge, this is the first systematic review and meta-analysis that asses nine outcomes associated with the effect of COVID-19 on pediatric T1DM and DKA.According to our results, the COVID-19 pandemic significantly increased the incidence of DKA (OR 1.68; 95% CI 1.44-1.96),severe DKA (OR 1.84; 95% CI 1.59-2.12),DKA in newly diagnosed T1DM (OR 1.75; 95% CI 1.51-2.03),and ICU admissions (OR 1.90; 95% CI 1.60-2.26).Conversely, we found no association between the COVID-19 pandemic and the incidence of T1DM, DKA in established T1DM, DKA complications, the length of hospitalization stay, and mortality (Figure 2a-g).These findings are in agreement with other meta-analyses.
Nassar M et al. 76 conducted a systematic review to identify the prevalence, clinical presentation, and outcomes of T1DM in patients with COVID-19.They searched for observational studies in four databases.The results evaluated were the duration of hospital stay, general ward admission, ICU admission, frequency of DKA, serious hypoglycemia, and mortality.They included 15 papers in the qualitative analysis.They had reports that included information from both children and adults with COVID-19.The frequency of T1DM among patients with COVID-19 varied between 0 and 30%, while the prevalence of COVID-19 among patients with T1DM varied between 0 and 17%.The assessed outcomes ranged widely among the studies.Furthermore, the study's duration of hospital stay, general ward admission, ICU admission, frequency of DKA, and serious hypoglycemia varied significantly among the included studies.The systematic review by Nassar M et al. 76 has several limitations reported by the authors.First, they could not perform a meta-analysis because of the lack of studies with appropriate information.Besides, the characteristics of the participants differed widely among the studies.Therefore, in our meta-analysis, we excluded 13 of the 15 studies of the paper by Nassar M et al. because these studies combined adults with pediatric patients or did not have a control (pre-pandemic) group.
Rahmati M et al. 12 systematically explored the occurrence of de novo T1DM in children and its complications, such as diabetic ketoacidosis, previously and in the times of the pandemic of COVID-19.First, they carried out a systematic search of four databases.Then, they performed a quantitative synthesis comparing the probabilities of developing T1DM and diabetic ketoacidosis in children with T1DM before (the year 2019) and during (the year 2020) the pandemic.They also examined glycemic and glycated hemoglobin levels in pediatric participants with de novo T1DM previously and at the time of this pandemic.They found that the overall incidence ratio of T1DM in 2019 was 19.73 per 10 5 children and 32.39 per 10 5 in 2020.During 2020 the cases of de novo T1DM, diabetic ketoacidosis, and serious diabetic ketoacidosis raised significantly.Similarly, in 2020, the median glycemic and glycated hemoglobin levels in pediatric participants with de novo T1DM during the COVID-19 era increased notably.They concluded that the pandemic raised the likelihood of developing de novo T1DM, diabetic ketoacidosis, and serious diabetic ketoacidosis in children.
Rahmati M et al. 12 conducted heterogeneity and sensitivity analysis and assessed the possibility of publication bias.However, their paper only included studies covering the first wave of the SARS-CoV-2 pandemic.Conversely, our study includes more recent studies that covered subsequent waves.In addition, we excluded two studies of the review by Rahmati M et al., one because it did not report DKA cases nor a numerator to calculate an incidence ratio, and the other because there was no control (pre-pandemic) group.
Alfayez OM et al. 10 conducted a systematic review aiming to study the characteristics of DKA before and during the pandemic of SARS-CoV-2 in children with T1DM.First, they searched for observational and found 20 documents on DKA.Then, they performed a random model analysis and reported that the pandemic, compared to the period before, significantly raised the probability of developing DKA and serious DKA.Similarly, pediatric patients with de novo T1DM presented a substantially greater risk of developing DKA during the pandemic than those patients during the pre-COVID-19 era.However, the heterogeneity was significant in all of these estimates (I 2 = 44%-71%).Two papers mentioned the likelihood of DKA among children with previously diagnosed T1DM, and this probability was not statistically increased during the COVID-19 era.The authors concluded that their research evidenced that DKA likelihood, particularly the chance of developing serious DKA, raised significantly during the COVID-19 period.
Alfayez OM et al. 10 reported subgroup and sensitivity analysis, and explored the possibility of publication bias.Although their systematic review collected fewer than half as many studies as ours, all included studies had an adequate control group.Consequently, their conclusions are closer to ours.Nevertheless, we highlight that of the studies included by these authors, one is a case-control study, 39 and four follow a cross-sectional design. 40,50,57,64In studies of cross-sectional and case-control design, we only are able to assess odds, not risk.Therefore, a better measure of the effect size would have been to report odds ratios instead of risk ratios, 77,78 as the authors estimated.
Elgenidy A et al. 11 conducted a meta-analysis to investigate the increase of DKA in pediatrics at the time of the SARS-CoV-2 pandemic.In three databases, they looked for papers evaluating the frequency of diabetic ketoacidosis.The researchers reported 24 studies, including 124,597 pediatric patients with T1DM.Their main finding was that the pandemic raised statistically significantly the likelihood of developing DKA in children with de novo T1DM (RR 1.41; 95% CI 1.19-1.67;p < 0.01), particularly of those with serious DKA (RR 1.66: 95% CI 1.30-2.11)compared with the pre-COVID-19 era.Statistical heterogeneity was substantial (I 2 = 86% and 59%, respectively).They found no important rise in the probability of developing DKA during the pandemic in pre-existing T1DM or combined-de novo and preexisting T1DM children compared with the pre-COVID-19 era.They concluded that the likelihood of DKA in children with de novo T1DM had risen in the time of the SARS-CoV-2 pandemic and tended to present in more serious forms.
Elgenidy A et al. performed subgroup and sensitivity analysis and evaluated the risk of publication bias.However, in our meta-analysis, we excluded 5 of the 17 studies quantitatively analyzed by Elgenidy A et al. because they did not report any of the events of interest or the lack of a control group.Moreover, these authors also included two case-control studies 39,59 and cross-sectional studies 40,50,57,64 and reported relative risks instead of odds ratios.Therefore, the same considerations previously mentioned for the meta-analysis of Alfayez OM et al. should apply.
The heterogeneity was significant in this systematic review and meta-analysis (I 2 > 90%, p < 0.05).According to the subgroup examination, the type of study design and the provenance region of the studies explained this lack of homogeneity among studies (test for subgroups difference I 2 = 83.2%,p = 0.003; I 2 > 49.4%, p = 0.11; respectively).
Sensitivity analysis did not alter the global size estimate, showing good consistency.Because of the limited data among studies, we decided not to carry out subgroup analysis and meta-regression according to other variables.Unlike the study by Elgenidy A et al., because most studies do not provide complete information, we did not perform subgroup according to the type of onset of diabetes (de novo, established, or combined-de novo and established-T1DM) or the degree of diabetic ketoacidosis (serious, moderate, or mild).On the contrary, following Rahmati M et al. and Alfayez OM et al., we analyzed the diabetes onset and the degree of DKA as an independent outcome.
We highlight several strengths in our meta-analysis: 1) the strategy search was comprehensive and compiled a more significant number of papers than any other previous systematic review or meta-analysis, 2) all the studies that we included involved a control (pre-pandemic) group, 3) all the papers that we included examined clinical-not surrogateoutcomes, and 4) we carried out sensitivity and subgroup analysis and examined for possible publication bias.Then, our conclusions are stronger than those previously reported by any other meta-analysis.
This study has important limitations: 1) heterogeneity was significant, 2) we were not able to carry out subgroup analyses regarding other essential factors such as age or sex, 3) it is possible that there exists a publication bias, as was suggested by our funnel plot, and finally, 4) we could not establish definite conclusions on other important outcomes such as the likelihood of T1DM, DKA complications, the duration of hospitalization stay, and mortality due to DKA.In addition, although we initially planned to perform subgroup analyzes according to sex, due to the scarcity of data (most studies combined information for both sexes), it was not possible to achieve this sub-analysis.In fact, none of the previously cited systematic reviews could perform a subgroup analysis according to sex.

Conclusions
Our systematic review shows that the SARS-CoV-2 pandemic significantly impacted T1DM and DKA outcomes in pediatric patients.This pandemic increased 1) the risk of DKA, 2) the risk of serious DKA, 3) the risk of DKA in children with de novo T1DM, and 4) ICU admissions due to DKA.Conversely, the relation of the SARS-CoV-2 pandemic with other outcomes such as 1) the incidence of pediatric T1DM, 2) the incidence of DKA in established pediatric T1DM, 3) the incidence of complications due to DKA, 4) the length of hospitalization stay, and 5) the risk of mortality due to DKA, were not statistically significant.Nonetheless, clinicians should interpret these findings with caution due to several limitations.Consequently, more research is still necessary to improve knowledge of the relationship between SARS-CoV-2 and diabetic ketoacidosis.Nevertheless, our results imply that healthcare systems should be alert and prepared for a potential rise in diabetic ketoacidosis cases, especially severe DKA cases, in future waves of viral respiratory pandemics.This project contains the following underlying data:

Reporting guidelines
Figshare: PRISMA checklist for "Impact of the Covid-19 pandemic on the incidence and clinical outcomes of diabetic ketoacidosis among children with type 1 diabetes: systematic review and meta-analysis", https://doi.org/10.6084/m9.figshare.21625790. 81gshare: Figshare2: PRISMA Flowchart, https://doi.org/10.6084/m9.figshare.21625775.82 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).Introduction "Another factor that could increase the incidence of T1DM, diabetic ketoacidosis (DKA), and severe DKA is the widespread use of steroids during the pandemic due to their ability to induce insulin resistance, hyperglycemia, and de novo DM. " In this article, we discuss Type 1 DM.There is no need to discuss the treatment protocols for COVID-19 that increase diabetes secondary to drugs.Also, our focus should be on children.

Methods
A peer review whose field is statistics is the most appropriate situation.

Discussion
The discussion and conclusion are sufficient and comprehensive.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.

Stefano Passanisi
University of Messina, Messina, Italy I have carefully reviewed the manuscript.The authors conducted a systematic review and metaanalysis to evaluate the incidence of new T1D cases, DKA incidence, severity, and associated outcomes during the COVID-19 pandemic.Despite the end of the pandemic, the topic remains relevant.The study is methodologically well-conducted, but some revisions are needed, particularly in language and the discussion section.Here are my specific comments: The first sentence regarding T1D definition should acknowledge viral infections as potential triggers for T1D onset.

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The description of the risk of bias assessment should be moved to the upper part of the results section, after presenting the final number of studies in the SR.

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In Table 1, consider using "non-specified" instead of "other" in the DKA criteria column.
○ Figure 2, while separated into subgroups, is busy and may be challenging to read.Evaluate options for revision.
○ Appreciate the analysis of T1D incidence based on different geographic areas in Figure 2b.Briefly describe this in the text.

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The discussion section needs expansion.Instead of describing other systematic reviews, delve into potential explanations for increasing T1D incidence and DKA, insights into the SARS-CoV-2 and T1D association, and the diabetogenic action of SARS-CoV-2.Refer to this recent literature review [1].

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A thorough revision by a native English speaker is recommended for text fluency.

3.
The process of how four independent reviewers examined the articles and a fifth investigator resolved discrepancies is unclear, especially given that there are only four authors listed in total.Please note that only three authors are listed on PROSPERO.

4.
The eligibility criteria need to be more precisely defined.The PECO question seems more oriented towards assessing whether having COVID-19 is associated with any of those outcomes, and not whether the incidence of each of the outcomes increased during the pandemic vs. pre-pandemic.In this sense, rather than formulating a PECO, it may be more useful to describe the inclusion criteria for studies in detail (as some previous systematic reviews have done).

5.
Please clarify why you preferred to use OR instead of RR. 6.
The statistical procedure for obtaining MD for the duration of hospital stay is not mentioned.Could you provide more detail on this? 7.
I strongly recommend presenting the complete results of the NOS, not just the final outcome.

Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly
Are sufficient details of the methods and analysis provided to allow replication by others?Partly

Are the conclusions drawn adequately supported by the results presented in the review? Partly
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Partly Competing Interests: I know two authors as they are researchers from universities in my home country; however, we have never worked together.I confirm I am able to review this article the results are relevant to children.Then, In the new version of the manuscript, we have included a small paragraph indicating that we considered a >50% cutoff for excluding studies.
The process of how four independent reviewers examined the articles and a fifth investigator resolved discrepancies is unclear, especially given that there are only four authors listed in total.Please note that only three authors are listed on PROSPERO.Replay: Thank you for this insightful comment.You are right.Consequently, we have made the pertinent corrections in this revised manuscript version.Furthermore, we have updated the protocol in PROSPERO, including the four authors.
The eligibility criteria need to be more precisely defined.The PECO question seems more oriented towards assessing whether having COVID-19 is associated with any of those outcomes, and not whether the incidence of each of the outcomes increased during the pandemic vs. pre-pandemic.In this sense, rather than formulating a PECO, it may be more useful to describe the inclusion criteria for studies in detail (as some previous systematic reviews have done).Replay: Thank you for this accurate comment.We have made the following modifications in our manuscript: 1) we have modified the Population component of our PECO question, and 2) described with more detail the inclusion criteria following the example of previous similar systematic reviews.

Please clarify why you preferred to use OR instead of RR.
Replay: Thank you for this insightful comment.Of the 46 studies included in this review, six studies were cross-sectional studies (CSS), two papers were case-control studies (CCS), and thirty-eight documents were prospective or retrospective cohort studies (PCS, RCS).The only measure of association that these study designs have is the OR.Consequently, we used OR, not RR.
The statistical procedure for obtaining MD for the duration of hospital stay is not mentioned.Could you provide more detail on this?Replay: Thank you for this valuable comment.In this revised version of our manuscript, we have modified the respective paragraph detailing the statistical method used for obtaining MD and SD.Furthermore, we have included the corresponding references that support these statements.
I strongly recommend presenting the complete results of the NOS, not just the final outcome.Replay: Thank you for this important.In this revised version of our manuscript, we have modified "Table 2. Bias assessment of the included studies," presenting the complete Newcastle-Ottawa Scale (NOS) tool.

Figure 1 .
Figure 1.Flow chart of the selection process of the included studies.
1 diabetes mellitus, DKA: diabetic ketoacidosis, RCS: Retrospective cohort study, PCS: Prospective cohort study, CSS: Cross-sectional study, ISPAD: International Society for Pediatric and Adolescent Diabetes, ADA: American Diabetes Association, DCCP: Diabetes Canada Clinical Practice, WHO: World Health Organization, ICU: admission to the intensive care unit, UC: unicenter, MC: multicenter, ND: not described.
Incidence of severe DKA among newly diagnosed children with T1DM Compared with the pre-COVID-19 era, the COVID-19 era increased the odds of DKA by 75% (OR 1.75; 95% CI 1.51-2.03)(Figure 2c) among children with newly diagnosed T1DM.Incidence of severe DKA among children with established T1DM Compared to the pre-COVID-19 era, the COVID-19 era did not significantly increase the odds of developing DKA (OR 0.98; 95% CI 0.79-1.21)(Figure 2d) among children with established T1DM.

Figure 2 .
Figure 2. (a) Incidence of DKA in pediatric T1DM before and during the COVID-19 era according to the type of study design; (b) Incidence of DKA in pediatric T1DM before and during the COVID-19 era according to the continent of origin of the study; (c) Incidence of severe DKA in pediatric T1DM before and during the COVID-19 era; (d) Incidence of DKA in newly diagnosed pediatric T1DM before and during the COVID-19 era; (e) Incidence of DKA in established pediatric T1DM before and during the COVID-19 era; (f) Incidence of ICU admissions due to DKA in pediatric T1DM before and during the COVID-19 era; (g) Incidence of complications due to DKA in pediatric T1DM before and during the COVID-19 era.

Figure 3 .
Figure 3. Funnel plot of the studies regarding the incidence of DKA in pediatric T1DM.

Table 1 .
General characteristics of the included studies.

Table 2 .
Bias assessment of the included studies according to NOS tool.

Table 2 .
Continued PCS: prospective cohort study, RCS: retrospective cohort study, CCS: case-control study, NOS: Newcastle-Ottawa Scale tool.Note: An asterisk (*) represents a star in each domain of the Newcastle-Ottawa scale (NOS) tool.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified? ('Living Systematic Review' or a variation of this term should be included in the title
References 1. Bombaci B, Passanisi S, Sorrenti L, Salzano G, et al.: Examining the associations between COVID-19 infection and pediatric type 1 diabetes.Expert Rev Clin Immunol.2023; 19 (5): 489-497 PubMed Abstract | Publisher Full Text ." .)Partly Competing Interests: No competing interests were disclosed.Reviewer Expertise: Pediatrics, diabetes, allergy I confirm that I

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Version 1
Reviewer Report 25 July 2023 https://doi.org/10.5256/f1000research.141300.r172554incidenceand clinical outcomes of diabetic ketoacidosis among male and female children with type 1 diabetes: systematic review and meta-analysis".Below are my comments and suggestions for improving your submission:The objective of evaluating the incidence of T1D is not clearly stated, especially since the title mentions that your population is children with T1D.It would seem this is not a variable as all subjects already have this diagnosis.Could you clarify this further?