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. 2021 Jun 7;16(6):e0252238. doi: 10.1371/journal.pone.0252238

Excess mortality by specific causes of deaths in the city of São Paulo, Brazil, during the COVID-19 pandemic

Gisele Aparecida Fernandes 1, Antonio Paulo Nassar Junior 2, Gulnar Azevedo e Silva 3, Diego Feriani 4, Ivan Leonardo Avelino França e Silva 4, Pedro Caruso 2, Maria Paula Curado 1,*
Editor: Matteo Rota5
PMCID: PMC8184000  PMID: 34097694

Abstract

Background

To investigate the excess of deaths by specific causes, in the first half of 2020 in the city of São Paulo-Brazil, during the COVID-19 pandemic.

Methods

Ecological study conducted from 01/01 to 06/30 of 2019 and 2020. Population and mortality data were obtained from DATASUS. The standardized mortality ratio (SMR) by age was calculated by comparing the standardized mortality rate in 2020 to that of 2019, for overall and specific mortality. The ratio between the standardized mortality rate due to COVID-19 in men as compared to women was calculated for 2020. Crude mortality rates were standardized using the direct method.

Results

COVID-19 was responsible for 94.4% of the excess deaths in São Paulo. In 2020 there was an increase in overall mortality observed among both men (SMR 1.3, 95% CI 1.17–1.42) and women (SMR 1.2, 95% CI 1.06–1.36) as well as a towards reduced mortality for all cancers. Mortality due to COVID-19 was twice as high for men as for women (SMR 2.1, 95% CI 1.67–2.59). There was an excess of deaths observed in men above 45 years of age, and in women from the age group of 60 to 79 years.

Conclusion

There was an increase in overall mortality during the first six months of 2020 in São Paulo, which seems to be related to the COVID-19 pandemic. Chronic health conditions, such as cancer and other non-communicable diseases, should not be disregarded.

Introduction

In March 2020, the World Health Organization (WHO) declared the COVID-19 pandemic [1]. Since then, the disease has spread rapidly across five continents. As of June 30, 2020, more than 10 million cases and around 500,000 deaths had been reported worldwide. Brazil was responsible for more than 1.3 million of these cases and 57,000 deaths [2], while the municipality of São Paulo reported 151,414 cases and 7,123 deaths [3].

It has been well reported in the literature that people with non-communicable diseases (such as cardiovascular, hypertension, diabetes, congestive heart failure, chronic kidney disease, or cancer), males, and those of advanced age have an increased risk of death from COVID-19 [4–6]. The main causes of death worldwide are cardiovascular diseases and cancer [7]. Brazil follows this global pattern, reporting in 2015 a cardiovascular mortality rate of 256 deaths per 100,000 and a cancer mortality rate of 133.5 deaths per 100,000 [8]. In 2018 it was estimated that deaths from cancer in Brazil totaled 243,588 [9].

An excess of deaths during the pandemic has been described in several countries [10–12]. This is likely in part due to the lethality of COVID-19, but can also be a consequence of overloaded health services, resulting in poorer care for patients with chronic diseases such as cancer. In addition, economic and social effects of the pandemic likely worsened the overall health of the population and contributed to increased mortality from all causes. Therefore, investigating the effect of COVID-19 on increased mortality may help elucidate the impact of this disease on various causes of death [13].

In São Paulo, the epicenter of the pandemic in Brazil, the city established a data system in which it is possible to check the basic cause of all deaths in the municipality [14], since June 2020, making it possible to monitor and analyze the pattern of mortality during the period of the Sars-CoV-2 pandemic. Detailed knowledge of the death profile will allow the design of strategies to reduce mortality in the populations at risk. However, there have been few studies on excess overall and specific mortality during the COVID-19 pandemic, using population data in Brazil.

Therefore, this study aims to investigate the excess of deaths by underlying causes, in the first half of 2020 as compared to the same period of 2019, during the COVID-19 pandemic, in the city of São Paulo, Brazil.

Materials and methods

This ecological study was conducted using data on overall and specific mortality, in the period from 01/01 to 06/30 of 2019 and 2020, and population data for the year 2010 from the city of São Paulo–Brazil (date of the last demographic census). The year 2019 was used as a reference, assuming that the number of deaths that occurred in 2019 would be close to that expected in 2020. Mortality data, included data on death certified COVID-19, were obtained from Mortality Information System (SIM) [14] and population data were obtained from the DATASUS [15]. Deaths in which sex and age data were unknown (0.1%) were excluded from the analysis.

The standardized mortality ratio (SMR) by age was calculated as the ratio between the standardized mortality rate of 2020 and that of 2019, for both overall and specific mortality. The ratio between the standardized mortality rate due to COVID-19 in men as compared to women was also calculated for 2020. The same analyses were also performed for each age group (0–9, 10–29, 30–44, 45–59, 60–79, 80 and over) and sex. Crude mortality rates were standardized using the direct method, using the standard “worldwide” population, created by Segi in 1960 and modified in 1966 [16]. The objective of the present analysis was to assess whether in the year 2020 there was an excess of deaths in the municipality of São Paulo, and whether mortality due to COVID-19 was higher among men.

SMRs were calculated for overall mortality and for all cancers, by age groups (0–9, 10–29, 30–44, 45–59, 60–79, 80 and over), sex and such as specific mortality: diabetes mellitus, congestive heart failure, cerebral vascular accident, acute myocardial infarction, cardiovascular diseases, and COVID-19, according to definitions in the international classification of diseases, 10th edition (ICD-10). S1 Table presents the ICD-10 codes for all categories considered in this analyses.

Confidence intervals were calculated at the 95% level (95% CI) and the Fisher’s exact test with a significance level of 5%. All analyses were performed using Excel software (version 10) and OpenEpi [17].

Results

In the first half of 2020, in the municipality of São Paulo, 23,156 deaths were reported among men and 21,782 among women, compared with 17,862 and 18,144, respectively, in the same period of 2019. This represents an increase in overall mortality of 29.6% for men and 20.0% for women. The number of deaths from COVID-19 was 34.3% higher in men (4,830) than in women (3,597). The number of deaths from all cancers decreased from 2019 to 2020, by 14.6% among men (3,762 vs. 3,211) and 10.1% among women (4,059 vs. 3,649) (Tables 1 and 2).

Table 1. Standardized mortality ratios by male vs. female and overall and specific mortality in the municipality of São Paulo, Brazil, from January to June of 2019 vs. 2020.

Male Female
Deaths Deaths
Overall and specific mortality 2019 2020 SMRa CI95%b pc 2019 2020 SMRa CI95%b pc
All causes 17862 23156 1.3 1.17–1.42 <0.001 18144 21782 1.2 1.06–1.36 0.003
Diabetes mellitus 514 553 1.1 0.52–1.85 0.834 558 627 1.1 0.47–2.19 0.638
All cardiovascular diseases 5729 5314 0.9 0.75–1.13 1.000 5864 5280 0.9 0.68–1.15 0.703
Cerebral vascular accident 204 316 1.5 0.62–3.28 0.300 237 345 1.5 0.48–3.88 0.420
Acute myocardial infarction 1787 1599 0.9 0.60–1.26 0.538 377 409 0.8 0.45–1.36 0.476
Congestive heart failure 235 323 1,4 0.55–2.91 0.435 386 404 1.1 0.31–2.54 0.897
All cancers 3762 3211 0.9 0.66–1.09 0.296 4059 3649 0.9 0.67–1.20 1.000
Lung 497 480 1.0 0.44–1.70 0.890 472 408 0.9 0.36–1.95 0.727
Breast - - - - - 85 82 0.9 0.47–1.81 0.865
Colorectum 460 403 0.9 0.40–1.70 0.720 478 440 0.9 0.38–2.03 0.802
Prostate 426 347 0.8 0.56–2.35 0.604 - - - - -
Stomach 336 254 0.8 0.26–1.66 0.566 185 162 0.9 0.11–2.62 0.874
Liver 188 165 0.9 0.31–2.51 0.847 163 124 0.7 0.11–2.75 0.704
Oesophagus 168 139 0.8 0.19–2.27 0.761 38 36 0.9 0.05–7.84 0.930
Cervix uteri - - - - - 132 149 1.1 0.35–4.12 0.844
Thyroid 13 11 0.9 0.11–16.04 0.983 18 16 0.9 0.11–16.77 0.949
Bladder 129 115 0.8 0.10–2.35 0.795 68 41 0.6 0.03–4.72 0.734
Non-Hodgkin lymphoma 115 170 0.6 0.11–2.70 0.577 96 64 0.7 0.02–3.23 0.736
Pancreas 229 218 0.9 0.37–2.39 0.911 302 318 1.1 0.31–2.49 0.881
Leukaemia 140 92 0.6 0.09–2.19 0.551 118 92 0.8 0.16–3.89 0.789
Kidney 67 77 1.2 0.20–4.68 0.797 57 63 1.1 0.03–4.98 0.944
Corpus uteri - - - - - 99 112 1.1 0.18–4.35 0.880
Lip, oral cavity 101 88 0.9 0.12–2.88 0.84 29 33 1.3 0.08–11.9 0.885
Brain, central nervous system 165 108 0.7 0.08–1.89 0.563 164 135 0.8 0.10–2.14 0.737
Ovary - - - - - 187 162 0.9 0.25–2.98 0.847
Melanoma of skin 26 35 1.3 0.05–7.84 0.838 38 43 1.1 0.05–8.01 0.953
Gallbladder 58 46 0.8 0.02–3.54 0.836 95 80 0.9 0.02–4.84 0.888
Larynx 124 124 1.0 0.26–3.08 0.994 25 16 0.6 0.08–11.9 0.829
Multiple myeloma 68 52 0.7 0.02–2.92 0.775 83 52 0.7 0.02–3.88 0.742
Nasopharynx 10 6 0.7 0.14–20.49 0.906 - 4 - - -
Oropharynx 53 41 0.8 0.02–3.68 1.00 14 7 0.6 0.16–24.59 0.876
Hypopharynx 18 15 0.9 0.07–10.54 0.932 4 4 1.1 0.04–6.14 1.00
Hodgkin lymphoma 8 3 0.3 0.18–26.35 0.809 5 4 0.7 0.36–52.7 0.939
Testis 19 11 0.6 0.09–13.17 0.835 - - - - -
Salivary glands 9 10 1.1 0.16–24.59 0.958 4 8 2.1 0.63–92.22 0.764
Vulva - - - - - 19 17 1.0 0.13–19.41 0.981
Penis 4 7 1.7 0.31–46.11 0.859 - - - - -
Open in a new tab

aSMR: Standardized Mortality Ratio

bCI95%: 95% Confidence Interval

cp: Fisher’s exact test p-value

Table 2. Standardized mortality ratios for COVID-19 by age and male vs. female in São Paulo, Brazil, from January to June 2020.

Deaths 2020
COVID-19 Male Female SMRa CI95%b pc
All age groups 4830 3597 2.1 1.67–2.59 <0.001
0–9 4 5 0.7 0.16–23.06 0.900
10–29 47 30 1.6 0.03–4.72 0.734
30–44 333 166 2.2 0.76–4.80 0.072
45–59 881 501 2.1 1.24–3.47 0.002
60–79 2357 1537 2.2 1.66–2.93 <0.001
80 and over 1208 1358 1.8 1.09–2.80 0.008
Open in a new tab

aSMR: Standardized Mortality Ratio

bCI95%: 95% Confidence Interval

cp: Fisher’s exact test p-value

Among men, the excess of deaths from all causes estimated in the first half of 2020 (5,294) in the city of São Paulo was 9.6% higher than the number of deaths attributed to COVID-19 (4,830). In women, the estimated excess of deaths from all causes (3,638) was 1.1% higher than the number of deaths attributed to COVID-19 (3,597) (Tables 1 and 2).

In 2020, there was an increase in overall age-standardized mortality rates for both men (SMR 1.3, 95% CI 1.17–1.42) and women (SMR 1.2, 95% CI 1.06–1.36). Cancer age-standardized mortality rates on showed a downward trend in both men (SMR 0.9, 95% CI 0.66–1.09) and women (SMR 0.9, 95% CI 0.67–1.20), as well as, all cardiovascular diseases men (SMR 0.9, 95% CI 0.75–1.13) and women (SMR 0.9, 95% CI 0.68–1.15). Similar downward trends were observed for most specific cancer locations, except for kidney, skin melanoma, salivary gland, cervix uteri, corpus uteri, penis, lip, oral cavity (female), and pancreas (female), for which SMRs were higher than one but with non-statistically significant confidence intervals (Table 1).

There was an increase in overall age-standardized mortality rates for males for all age groups above 45 years old. However, for females an increase in overall age-standardized mortality rates was observed only in the age group of 60 to 79 years (SMR 1.3, 95% CI 1.05–1.52). There was a decrease in age-standardized mortality rates for all types of cancer in all age groups in 2020 (Table 3). However, the results of cancer mortality should be interpreted with caution, since the confidence interval included the value 1.

Table 3. Standardized mortality ratios by age and male vs. female in São Paulo, Brazil, from January to June of 2019 vs. 2020.

Male Female
Deaths Deaths
2019 2020 SMRa CI95%b pc 2019 2020 SMRa CI95%b pc
Overall Mortality
0–9 606 479 0.8 0.46–1.31 0.372 464 401 0.9 0.48–1.46 0.604
10–29 527 688 1.3 0.69–2.19 0.374 319 366 1.1 0.52–2.45 0.762
30–44 1108 1558 1.4 0.92–2.11 0.108 757 968 1.3 0.71–2.15 0.377
45–59 3176 4198 1.3 1.04–1.66 0.020 2104 2593 1.2 0.88–1.71 0.214
60–79 7677 10216 1.3 1.16–1.52 <0.001 6510 8250 1.3 1.05–1.52 0.008
80 and over 4768 6017 1.3 1.02–1.54 0.027 7990 9204 1.2 0.89–1.45 0.250
Cancer Mortality
0–9 13 6 0.5 0.07–10.54 0.761 12 11 0.9 0.07–10.85 0.972
10–29 58 53 0.9 0.02–3.72 0.935 62 40 0.7 0.02–3.58 0.73
30–44 135 115 0.8 0.12–2.82 0.814 245 240 1,0 0.34–2.75 0.982
45–59 724 587 0.8 0.40–1.43 0.51 817 689 0.8 0.43–1.54 0.608
60–79 2081 1807 0.9 0.63–1.19 0.405 1925 1751 0.9 0.61–1.34 0.649
80 and over 809 696 0.9 0.45–1.53 0.628 998 918 0.9 0.39–1.83 0.831
Open in a new tab

aSMR: Standardized Mortality Ratio

bCI95%: 95% Confidence Interval

cp: Fisher’s exact test p-value

The age-standardized mortality rates due to COVID-19 for men in São Paulo was twice that observed for women (SMR 2.1, 95% CI 1.67–2.59). When stratifying these data by age group, there was an excess of deaths among men compared to women for all age groups from 45 years onwards (Table 2).

Discussion

In the municipality of São Paulo, the excess of deaths in the first half of 2020 was 24.9%, and of these, 94.4% had COVID-19 as the specific mortality. There was an increase in overall mortality for both sexes, particularly in men aged 45 and over and among women aged 60–79 years.

The present findings revealed that in the municipality of São Paulo the excess of deaths from all causes was 9.6% (men) and 1.1% (women) greater than the number of deaths attributed to COVID-19. This is a small margin compared to those reported in similar studies elsewhere; in Portugal, for example, the increase in mortality was 3 to 5 times higher than that explained by deaths from COVID-19 [10]. In Italy and Germany the excess of deaths was also greater than that officially registered by the disease [11, 12]. Another study carried out in Italy revealed an increase in mortality 60% greater than the number of deaths attributed to COVID-19 [18].

For malignant neoplasms there was a trend towards decreased mortality. The increase in all-cause mortality during the pandemic highlights the consequences of the overload of COVID-19 on health systems [11].

A Brazilian study identified an excess of deaths from all causes among both men and women, reaching 24% in men and 14% in women [19]. In this study, the largest increases were seen in states in the North and Northeast regions. In the city of São Paulo, the month of May showed a 42% excess of deaths among men and 33% in women, results similar to those of the present study (30% and 20%, respectively).

It is noteworthy that, in this study, no cause other than COVID-19 showed an increase in deaths in 2020, but it should be expected that patients with COVID-19 will evolve with serious and lethal cardiovascular outcomes [20]. In the study by Azevedo e Silva et al. [19], however, it was found that 33.5% more deaths in the country, from March to May 2020, were not registered as having been due to COVID-19. This may reflect the worsening of chronic health problems as medical monitoring was discontinued due to the pandemic.

On the other hand, we cannot rule out the hypothesis that the number of deaths with an specific mortality of COVID-19 in São Paulo may be over-registered in the mortality system. There may have been a greater trend in the notification of deaths by COVID-19 and, as a result, the other causes may have been underreported. Such excessive attribution of cause of death are expected at critical times such as the COVID-19 pandemic [21].

It has been previously described that the risk of death from COVID-19 among men is twice that in women, despite the number of cases being similar; the results of the present study are in alignment. In contrast, a study conducted in the USA did not identify any difference in mortality between the sexes [22]. It should be noted that sex differences in mortality due to COVID-19 are not consistent across all age groups. The excess of deaths due to COVID-19 reported here was identified in men aged 45 and over, which is in line with what has been reported elsewhere [23].

The excess of deaths due to COVID-19 in men is possibly associated with a greater number of comorbidities and exposure to risk factors (alcoholism, smoking, and occupational exposures) which are risk factors related to male behavior [24]. In addition, there seems to be an interaction between gender and age, with males of advanced age having the highest risk of death by COVID-19. This association should be studied further in order to understand the clinical evolution of the disease.

During the COVID-19 pandemic in the city of São Paulo, a 30% increase in overall and specific mortality was identified among men over 45 and women in the 60 to 79 age group, which is consistent with other studies [10–12]. This increase in overall mortality in elderly individuals is possibly a result of the excess of deaths related to COVID-19.

SMRs for the cancer set and for most of the cancer groups analyzed were lower not significant. A study carried out at twenty health institutions in the USA revealed that cancer incidence rates declined as COVID-19 advanced in the country. Breast, prostate, and melanoma cancer showed the greatest decline in incidence, while lung, colorectal, and hematological cancers were the least impacted [25]. It is critical to monitor the effects of the COVID-19 pandemic on the profile of cancer mortality in Brazil. Some reports have shown that the impact may be important, such as in the reduced number of oral biopsies in the Brazilian Unified Health System, especially in the southeast region (-75.6%). This may ultimately result in the diagnosis of tumors in more advanced stages and with poorer prognosis [26].

The COVID-19 pandemic has driven patients with other diseases away from health services, which impacted on the screening, diagnosis, and treatment of diseases such as cancer [27]. The results of the present study should serve as an alert for the need to implement cancer surveillance measures. It is essential to investigate how cancer patients are being assisted. Social distancing measures may on the one hand protect against exposure to the virus and other infections, but on the other hand can delay cancer treatment and surveillance.

The findings of this study illustrate the situation in the municipality of São Paulo and cannot be extrapolated to the rest of Brazil. This, the largest city in Brazil, was where SARS-CoV-2 first entered and remains the place that accumulates the largest number of COVID-19 cases in the country. The strength of this study is in its use of official mortality data provided by the DATASUS Mortality Information System (SIM) and the finding that they offer powerful tools for the implementation of health surveillance in monitoring excess of deaths in Brasil.

In conclusion, in order to avoid an excess of deaths in the coming months, it is necessary for health systems to remain alert and prepared for future peaks of COVID-19. The increase in overall mortality during the pandemic period seems to be related to Sars-CoV-2. However, likely that a share of the deaths classified as COVID-19 may also have a diagnosis of cancer and cardiovascular diseases listed in the death certificate, and this may account for the apparent decrease in cancer and cardiovascular diseases mortality. It is suggested that individuals with comorbidities associated with risk of death by COVID-19 pursue preventive actions and continuous treatment adjustments, as many uncertainties about COVID-19 still remain.

Supporting information

S1 Table. Causes of deaths and corresponding ICD-10 codes.

(DOCX)

Click here for additional data file. (15.8KB, docx)

Data Availability

The data underlying the results presented in the study are available from: http://tabnet.saude.prefeitura.sp.gov.br/cgi/deftohtm3.exe?secretarias/saude/TABNET/SIM_PROV/obitop.def http://tabnet.datasus.gov.br/cgi/deftohtm.exe?popsvs/cnv/popbr.def.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Matteo Rota

24 Feb 2021

PONE-D-21-00780

Excess mortality by underlying causes of deaths in the city of São Paulo, Brazil, during the COVID-19 pandemic

PLOS ONE

Dear Dr. Curado,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript has been sent out to an outstanding reviewer with a strong background and competence in the study of cause-specific excess mortality. The manuscript is interesting but there are several issues that should be addressed. One of the major comments raised up by the reviewer is related to the authors’ choice to include hypertension as a cause of deaths, without considering chronic cardiovascular conditions, leaving aside an important share of cardiovascular deaths. Please find attached the comments.

In addition to the reviewers’ comments, I would ask to:

  • Clarify if the DATASUS website (page 4 line 100) also included data on certified COVID-19 mortality.

  • Clarify Table 1 and Table 2 by putting in a top row the label “Male” or “Female”;

  • Specify within Table 3 that the SMR is computed for Male vs Female, and not “by gender” as specified in the table caption.

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this manuscript Dr Fernandes et al. presented the results of an ecologic study showing the differences in cause-specific mortality between the first half of the 2020 and 2019 in the city of Sao Paulo, Brazil. They found an excess in overall mortality in 2020 that they attributed to the Covid-19 pandemic.

The topic is interesting and the manuscript is well written. However, I have some points that I think need to be addressed.

1. Line 97: It is not clear why the authors needed the 2010 population data to compute mortality rates over the first half of 2019 and 2020.

2. Line 104. I would say “…overall and specific mortality”. Mortality statistics are usually based on the underlying cause of death.

3. Line 113-117. The selection of the causes of death is quite unusual and I disagree with the choices made by the authors. In particular, I would not include hypertension since it is a risk factor rather than an underlying cause of death, and it is selected as an underlying cause of death only when there are no other more specific causes mentioned on the death certificate, such as cerebrovascular and renal diseases. Moreover, I cannot understand why the authors did not consider chronic cardiovascular conditions, leaving aside an important share of cardiovascular deaths. Finally, I do not think it is worth reporting data on obesity, since it is rarely mentioned on death certificates.

4. Results. Text and tables are difficult to follow since tables are not commented in the order they were presented.

5. Results. When the authors refer to an increase or decrease in mortality they should specify if they refer to a change in the absolute numbers or age-standardized rates.

6. Table 1. Some SMR are emphasized in bold, with apparent no reason, or at least I did not get it. In any case, I would avoid it and leave the reader judge the relevance of the result.

7. Table 2. How did the authors compute the age-standardized mortality ratio by age groups if the age groups presented have the same wide of those used to get the weights from the standard population? Please clarify.

8. Table 2. Please avoid bold emphasis.

9. Table 3. See the above comment on age groups.

10. Lines 205-206. The increase in overall mortality was also observed in younger men, aged 30-44 years, and among women aged 60-79 years. Please revise the sentence accordingly.

11. Conclusions: The authors concluded that the increase in overall mortality during the pandemic period is related to SARS-CoV-2 and other health conditions such as cancer. However, cancer deaths in Sao Paolo decreased from 3762 in 2019 to 3211 in 2020. Thus, the pandemic does not seem to have directly increased cancer mortality. It is, however, likely that a share of the deaths classified as COVID-19 may also have a diagnosis of cancer listed in the death certificate, and this may account for the apparent decrease in cancer mortality.

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Reviewer #1: No

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PLoS One. 2021 Jun 7;16(6):e0252238. doi: 10.1371/journal.pone.0252238.r002

Author response to Decision Letter 0

22 Apr 2021

Reviewers' comments:

Manuscript Number: PONE-D-21-00780

Title: Excess mortality by specific causes of deaths in the city of São Paulo, Brazil, during the COVID-19 pandemic

Response to Editor

Point 1: Clarify if the DATASUS website (page 4 line 100) also included data on certified COVID-19 mortality.

Response 1: Thank you for your comment. Data on certified COVID-19 mortality were obtained from the SIM. We included the following sentence in line 102: “Mortality data, included data on death certified COVID-19, were obtained from SIM [14] and population data were obtained from the DATASU [15].”

Point 2: Clarify Table 1 and Table 2 by putting in a top row the label “Male” or “Female”

Response 2: Thank you for your suggestion. The changes were made to the tables.

Point 3: Specify within Table 3 that the SMR is computed for Male vs Female, and not “by gender” as specified in the table caption

Response 3: Thank you for your suggestion. The changes were made to the tables caption.

Response to Reviewer 1 Comments

Point 1: Line 97: It is not clear why the authors needed the 2010 population data to compute mortality rates over the first half of 2019 and 2020.

Response 1: Thank you for your comment. We used population data from 2010 to calculate mortality rates in the first half of 2019 and 2020, because it was the date of the last demographic census conducted in Brazil. We included the following sentence in line 97 and 98: “(date of the last demographic census)”

Point 2: Line 104. I would say “…overall and specific mortality”. Mortality statistics are usually based on the underlying cause of death.

Response 2: Thank you for your comment. We deleted the sentence “due to underlying cause” from the manuscript.

Point 3: Line 113-117. The selection of the causes of death is quite unusual and I disagree with the choices made by the authors. In particular, I would not include hypertension since it is a risk factor rather than an underlying cause of death, and it is selected as an underlying cause of death only when there are no other more specific causes mentioned on the death certificate, such as cerebrovascular and renal diseases. Moreover, I cannot understand why the authors did not consider chronic cardiovascular conditions, leaving aside an important share of cardiovascular deaths. Finally, I do not think it is worth reporting data on obesity, since it is rarely mentioned on death certificates.

Response 3: Thank you for your comment. We excluded mortality from obesity and arterial hypertension from the article and included mortality from congestive heart failure and all cardiovascular diseases.

Point 4: Results. Text and tables are difficult to follow since tables are not commented in the order they were presented

Response 4: Thank you for your comment. We organized the tables in the order in which they were commented on in the text.

Point 5: Results. When the authors refer to an increase or decrease in mortality they should specify if they refer to a change in the absolute numbers or age-standardized rates.

Response 5: Thank you for your comment. We refer to the age-standardized mortality rates. We included this information all over the manuscript to clarify.

Point 6: Table 1. Some SMR are emphasized in bold, with apparent no reason, or at least I did not get it. In any case, I would avoid it and leave the reader judge the relevance of the result.

Response 6: Thank you for your comment. We excluded the emphasized in bold the Table 1.

Point 7: Table 2. How did the authors compute the age-standardized mortality ratio by age groups if the age groups presented have the same wide of those used to get the weights from the standard population? Please clarify.

Response 7: Thank you for your comment. First we calculate the crude mortality rate for all age groups in 2019 and 2020, stratified as described in the method session. The crude mortality rate result was multiplied by age groups from the standard Segi population. The SMR was calculated by dividing the standardized mortality rate by 2020 age group by the standardized mortality rate by the same age group of 2019, in order to compare the differences that occurred. We included the following sentence in lines 115, 116 and 117: “SMRs were calculated for overall mortality and for all cancers, by age groups (0–9, 10–29, 30–44, 45–59, 60–79, 80 and over), sex and such as specific mortality:”

Point 8 : Table 2. Please avoid bold emphasis.

Response 8 : Thank you for your comment. We excluded the emphasized in bold.

Point 9 : Table 3. See the above comment on age groups.

Response 9 : Please, see answer in response 7 above.

Point 10 : Lines 205-206. The increase in overall mortality was also observed in younger men, aged 30-44 years, and among women aged 60-79 years. Please revise the sentence accordingly

Response 10 : Thank you for your comment. We included the following sentence in line 212: “and among women aged 60-79 years”

Point 11 : Conclusions: The authors concluded that the increase in overall mortality during the pandemic period is related to SARS-CoV-2 and other health conditions such as cancer. However, cancer deaths in Sao Paolo decreased from 3762 in 2019 to 3211 in 2020. Thus, the pandemic does not seem to have directly increased cancer mortality. It is, however, likely that a share of the deaths classified as COVID-19 may also have a diagnosis of cancer listed in the death certificate, and this may account for the apparent decrease in cancer mortality.

Response 11: Thank you for your comment. We added part of your comment to the article in lines 294, 295, 296,297 and 298: However, likely that a share of the deaths classified as COVID-19 may also have a diagnosis of cancer and cardiovascular diseases listed in the death certificate, and this may account for the apparent decrease in cancer and cardiovascular diseases mortality.

Decision Letter 1

Matteo Rota

12 May 2021

Excess mortality by underlying causes of deaths in the city of São Paulo, Brazil, during the COVID-19 pandemic

PONE-D-21-00780R1

Dear Dr. Curado,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Matteo Rota, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing my comments.

I have only one further minor point: the authors emphasized in the abstract that mortality from cancer tended to be lower in 2020 than in 2019. However, similar results were found for CVD deaths, although none of the differences were statistically significant. Therefore, I rather would say that there were not significant differences in cause specific mortality.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Matteo Rota

28 May 2021

PONE-D-21-00780R1

Excess mortality by specific causes of deaths in the city of São Paulo, Brazil, during the COVID-19 pandemic

Dear Dr. Curado:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Matteo Rota

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Causes of deaths and corresponding ICD-10 codes.

    (DOCX)

    Click here for additional data file. (15.8KB, docx)

    Data Availability Statement

    The data underlying the results presented in the study are available from: http://tabnet.saude.prefeitura.sp.gov.br/cgi/deftohtm3.exe?secretarias/saude/TABNET/SIM_PROV/obitop.def http://tabnet.datasus.gov.br/cgi/deftohtm.exe?popsvs/cnv/popbr.def.

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