Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death

Geldsetzer P; Mukama T; Jawad N; Riffe T; Rogers A; Sudharsanan N

doi:10.1101/2021.02.23.21252314

Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death

Geldsetzer P ^{1,

2},

Affiliations

1. Division of Primary Care and Population Health, Department of Medicine, Stanford University, Stanford, California, USA.
Authors
Geldsetzer P^{1,

2}
(1 author)
2. Heidelberg Institute of Global Health, Heidelberg University, Heidelberg, Germany.
Authors
Geldsetzer P^{1,

2}
Mukama T²
Sudharsanan N²
(3 authors)
3. Stanford University School of Medicine, Stanford, California, USA.
Authors
Jawad N³
(1 author)
4. Laboratory of Population Health, Max Planck Institute for Demographic Research, Rostock, Germany.
Authors
Riffe T⁴
(1 author)
5. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Authors
Rogers A⁵
(1 author)

Preprint from medRxiv, 26 Feb 2021
https://doi.org/10.1101/2021.02.23.21252314 PPR: PPR289354

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Abstract

Men are more likely than women to die due to coronavirus disease 2019 (COVID-19). This paper sets out to examine whether the magnitude of the sex differences in the COVID-19 mortality rate are unusual when compared to other common causes of death. In doing so, we aim to provide evidence as to whether the causal pathways for the sex differences in the mortality rate of COVID-19 likely differ from those for other causes of death. We found that sex differences in the age-standardized COVID-19 mortality rate were substantially larger than for the age-standardized all-cause mortality rate and most other common causes of death. These differences were especially large in the oldest age groups.

One Sentence Summary

The sex difference in the mortality rate of coronavirus disease 2019 is substantially larger than for other common causes of death.

Free full text

PPRID: PPR289354
EMSID: EMS117713medRxiv preprint, version 1, posted 2021 February 26
https://doi.org/10.1101/2021.02.23.21252314

Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death

P. Geldsetzer ^1, ² , T. Mukama ^2, ^3, ⁴, N. Jawad ⁵, T. Riffe ⁶, A. Rogers ⁷, and N. Sudharsanan ²

Affiliations

1. Division of Primary Care and Population Health, Department of Medicine, Stanford University, Stanford, California, USA.
2. Heidelberg Institute of Global Health, Heidelberg University, Heidelberg, Germany.
3. Division of Preventive Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
4. Department of Disease Control and Environmental Health, School of Public Health, College of Health Sciences, Makerere University, Kampala, Uganda.
5. Stanford University School of Medicine, Stanford, California, USA.
6. Laboratory of Population Health, Max Planck Institute for Demographic Research, Rostock, Germany.
7. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

Copyright and license information

This preprint is made available via the Europe PMC open access subset, for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original preprint source.

This article is a preprint. A journal published article is available.

Abstract

Introduction

Males have a higher risk of death from coronavirus disease 2019 (COVID-19) than females ^1–6. This difference has been observed for both the case fatality rate (CFR; i.e., deaths among those diagnosed with a SARS-CoV-2 infection) and infection fatality rate (IFR; i.e., deaths among all those who were infected with SARS-CoV-2) ¹. This higher risk of death from COVID-19 in males has been highlighted both in the academic literature and the media ^7–9.

Understanding why these disparities by sex exist has become an active area of research. However, given that the risk of death from COVID-19 is strongly related to one’s expected remaining life expectancy ⁶, it is unclear whether the observed sex differences in the COVID-19 fatality rate are simply a reflection of men’s shorter life expectancy ¹⁰, which is at least in part due to their poorer health status at any given age. This study aimed to determine if sex differences in COVID-19 mortality are larger when compared to the all-cause mortality rate, mortality rates for other common causes of death, and – given SARS-CoV-2’s common respiratory manifestations – other respiratory causes of death, including respiratory infections. This information is crucial, as it begins to elucidate whether the higher COVID-19 mortality risk among males reflects the survival advantage among females compared to males, and is, thus, likely a result of the biological, behavioral, and social pathways that cause this survival advantage as opposed to causal pathways that are specific to COVID-19. Understanding these causal pathways could help in the development of therapeutics and preventive measures for COVID-19 and future coronavirus disease outbreaks.

Results

We extracted the latest available country-level data on COVID-19 deaths from the COVerAGE-DB for countries for which age- and sex-disaggregated data were available (as of 09 February 2021) ¹¹. We then obtained age- and sex-disaggregated data on all-cause mortality and population size for each of these countries from the Human Mortality Database (HMD) ¹² and, for countries not included in the HMD, from the United Nation’s World Population Prospects (WPP) ¹⁰. The latest available mortality data for specific causes of death were drawn from the World Health Organization’s (WHO) mortality database ¹³. We then calculated the ratios for the sex difference in the COVID-19 mortality (i.e., the ratio of the number of COVID-19 deaths in men divided by the male mid-year population to the number of COVID-19 deaths in women divided by the female mid-year population) and compared these ratios to those for i) all-cause mortality, ii) each of the six most common causes of death groups globally for adults (excluding injuries) ¹⁴, and iii) each major respiratory cause of death.

Age- and sex-disaggregated data on COVID-19 deaths were available for 59 countries (Table 1).

Table 1. Population, all-cause deaths, and COVID-19 cases and deaths by sex and country

				All-cause mortality			COVID-19 mortality
		Population (000s)		Deaths (000s)			Deaths
Country	Period/year†	Female	Male	Female	Male	Date*	Female	Male
Afghanistan	2015-2020	18,952	19,976	549	646	28.11.2020	381	1,130
Argentina	2015-2020	23,147	22,049	802	878	15.01.2021	19,648	26,539
Australia	2018	12,495	12,298	76	82	07.02.2021	468	441
Belgium	2018	5,794	5,630	57	54	07.02.2021	10,880	10,479
Brazil	2015-2020	108,124	104,436	2,901	3,790	01.02.2021	84,023	111,936
Canada	2018	18,513	18,249	139	144	22.09.2020	4,516	4,672
Chad	2015-2020	8,226	8,200	445	490	21.10.2020	27	65
Chile	2017	8,923	8,573	51	56	13.01.2021	7,449	9,986
Colombia	2015-2020	25,898	24,985	617	742	07.02.2021	22,852	40,064
Croatia	2018	2,124	1,982	27	26	20.12.2020	345	332
Cuba	2015-2020	5,703	5,623	239	266	24.05.2020	33	49
Cyprus	2015-2020	604	604	20	22	29.11.2020	40	103
Czechia	2018	5,390	5,220	56	57	07.02.2021	7,167	9,327
Denmark	2019	2,917	2,889	27	27	02.02.2021	995	1,165
Ecuador	2015-2020	8,819	8,824	188	243	31.07.2020	3,590	7,025
Estonia	2019	699	626	8	7	13.12.2020	131	97
Eswatini	2015-2020	590	570	24	29	30.12.2020	78	106
Finland	2019	2,795	2,723	27	27	20.12.2020	270	402
France	2018	33,419	31,324	300	297	28.01.2021	22,052	30,657
Germany	2017	41,824	40,697	475	458	07.02.2021	29,827	31,839
Greece	2017	5,549	5,222	61	63	16.01.2021	2,241	3,199
Hungary	2017	5,122	4,675	68	64	29.11.2020	296	293
Iceland	2018	171	178	1	1	29.11.2020	45	60
India	2015-2020	662,903	717,101	22,515	26,158	02.10.2020	30,987	69,888
Iraq	2015-2020	19,865	20,358	417	492	24.05.2020	50	110
Ireland	2017	2,413	2,365	15	15	20.12.2020	971	1,029
Israel	2016	4,268	4,195	22	22	09.12.2020	1,260	1,672
Italy	2017	31,121	29,404	340	311	05.01.2021	32,481	42,567
Japan	2019	63,705	60,392	674	707	18.08.2020	294	531
Jordan	2015-2020	5,037	5,166	84	104	07.02.2021	1,557	2,822
Kenya	2015-2020	27,053	26,719	641	761	11.10.2020	72	208
Latvia	2017	1,054	896	15	14	29.11.2020	49	40
Lithuania	2019	1,499	1,296	20	18	29.11.2020	120	171
Luxembourg	2019	305	309	2	2	20.12.2020	162	178
Malawi	2015-2020	9,696	9,434	274	333	27.12.2020	45	143
Malta	2015-2020	220	221	9	9	20.12.2020	84	243
Mexico	2015-2020	65,861	63,071	1,688	2,058	13.01.2021	50,228	86,689
Nepal	2015-2020	15,788	13,348	437	460	26.09.2020	101	259
Netherlands	2018	8,654	8,527	79	75	14.02.2021	6,595	7,808
Nigeria	2015-2020	101,670	104,470	5,546	6,038	17.01.2021	306	840
Pakistan	2015-2020	107,220	113,672	3,364	3,974	02.06.2020	435	1,253
Panama	2015-2020	2,155	2,160	44	61	04.07.2020	219	501
Paraguay	2015-2020	3,508	3,624	85	104	16.01.2021	912	1,408
Peru	2015-2020	16,593	16,379	374	491	04.02.2021	13,506	28,432
Philippines	2015-2020	54,552	55,029	1,249	1,836	04.02.2021	4,404	6,713
Poland	2018	19,840	18,593	201	214	20.12.2020	1,385	2,057
Portugal	2018	5,425	4,869	56	57	02.02.2021	6,367	6,890
Romania	2015-2020	9,884	9,354	621	654	29.11.2020	362	490
Slovakia	2017	2,784	2,652	26	27	20.12.2020	964	1,047
Slovenia	2017	1,041	1,025	10	10	31.01.2021	1,964	1,795
South Korea	2018	25,680	25,595	138	161	28.06.2020	134	148
Spain	2018	23,776	22,881	210	215	04.02.2021	27,559	33,065
Switzerland	2018	4,278	4,206	35	32	08.02.2021	4,121	4,747
Togo	2015-2020	4,159	4,119	164	170	02.02.2021	18	59
Turkey	2015-2020	42,703	41,636	997	1,201	26.10.2020	3,541	6,258
Ukraine	2013	24,407	20,961	338	325	06.02.2021	7,568	9,827
United Kingdom	2018	33,554	32,687	312	304	01.01.2021	40,282	48,960
Uruguay	2015-2020	1,795	1,678	81	82	18.01.2021	74	236
USA	2018	165,365	160,460	1,381	1,458	26.12.2020	192,335	228,829

† Year for which population and deaths data are available in the HMD. Population and mortality projections for the 2015-2020 period from the UN’s World Population Prospects (WPP) were used for countries not in the HMD.

* Date when latest sex-disaggregated data were available for each country.

Caption: We extracted latest available population and deaths count data for each country. Population and deaths count data were available for 32 countries from the Human Mortality Database (HMD): Australia, Belgium, Canada, Chile, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Luxembourg, Netherlands, Poland, Portugal, Slovakia, Slovenia, South Korea, Spain, Switzerland, Ukraine, United Kingdom and USA. For countries not in the HMD, we obtained the standard projections of population numbers and deaths for the 2015-2020 period from the United Nation’s World Population Prospects (WPP) (https://population.un.org/wpp/Download/Standard/Population/).

From this data, we calculated the age-standardized male-to-female rate ratios of mortality from COVID-19 and all-causes. The age standardization, conducted separately for each country, was carried out to ensure that differences in the male-to-female mortality rate ratio between COVID-19 and all causes were not confounded by sex differences in the age distribution. Point estimates greater than one in Figure 1 indicate that men had a higher rate of death than women. We found that in most countries, the male disadvantage for COVID-19 mortality was substantially larger than their all-cause mortality disadvantage (Figure 1 and Figure S1).

Open in new tabFigure 1: Male-to-female rate ratios of mortality from COVID-19 and all causes.

Caption: Rate ratios for the sex differences in COVID-19 and all-cause mortality were calculated for each country by dividing the age-standardized mortality rate in males by the age-standardized mortality rate in females.

Next, we investigated whether the degree of the male disadvantage in the COVID-19 compared to the all-cause mortality varied by age group. To do so, we divided – separately by ten-year age group – the age-standardized male-to-female rate ratio for the COVID-19 mortality by the age-standardized male-to-female rate ratio for all-cause mortality. Point estimates greater than one in Figure 2, thus, indicate that the sex differences in the mortality rate for COVID-19 were greater than expected based on the sex differences in the all-cause mortality rate. We found that among the older age groups, especially the group aged 80 years and older, the higher rate of death for men than woman exceeded (in relative terms) that for all-cause mortality for most countries. Among younger age groups, especially those aged less than 50 years, the direction and magnitude of these differences varied greatly by country. These patterns are similar when adjusting these estimates for remaining life expectancy (Figure S2).

Open in new tabFigure 2: Relative difference in the male-to-female rate ratios of COVID-19-specific and all-cause mortality, by age group.

Caption: The relative difference in the rate ratio was calculated by dividing (separately among each age group shown) the male-to-female rate ratio for the COVID-19-specific mortality rate by the male-to-female rate ratio for the all-cause mortality rate.

Using the same metric as for Figure 2, we then compared the relative magnitude of sex differences in the mortality for COVID-19 to that for other major causes of mortality (circulatory diseases, cancer, chronic respiratory diseases, respiratory infections and tuberculosis, diabetes, and neurologic disorders). We found that in most countries the relative sex differences for COVID-19 were larger than for each of the other common causes of death (Figure 3 and Figure S3). However, this was not true for chronic respiratory conditions for which countries were spread approximately equally across the vertical dashed line drawn at one (i.e., the number indicating that the relative sex difference for the COVID-19 mortality was the same as for chronic respiratory diseases). Implementing the same analysis as in Figure 3 for each common respiratory cause of death (the ICD-10 codes used for categorization are shown in Table S2) revealed that the similar male disadvantage in mortality for chronic respiratory diseases as for COVID-19 is largely driven by a high male disadvantage in mortality from bronchitis and emphysema (Figure S4) and, thus, likely the higher prevalence of smoking (especially in the past) among men than women ^15,16.

Open in new tabFigure 3: Relative difference in the male-to-female rate ratios of COVID-19-specific mortality and six major causes of mortality

Discussion

The degree to which men are more likely to die from COVID-19 than women is substantially larger than would be expected merely based on the fact that men are generally more likely to die at any given age than women. Thus, the probability of succumbing to a SARS-CoV-2 infection does not appear to be fully explained by the remaining life expectancy of the person who was infected. This observation suggests that the causal pathways that link male sex to a shorter life expectancy may not fully explain the unusually high male disadvantage in COVID-19 mortality. Our findings, therefore, lend support to hypotheses that posit that the causal pathways that link male sex to a higher mortality from a SARS-CoV-2 infection are specific to SARS-CoV-2 rather than shared with the pathways responsible for the shorter life expectancy among men than women or the causal pathways for sex differences for other common causes of death.

This study has several limitations. First and foremost, this study can only provide suggestive (as opposed to conclusive) evidence as to whether or not the causal pathways underlying the male disadvantage for COVID-19 mortality are shared with those underlying the all-cause mortality disadvantage for men. Second, our mortality rate calculations for COVID-19 use the total population (by sex) as the denominator. Thus, the assumption underlying the validity of our calculation is that there are no substantial differences in the probability of being infected with SARS-CoV-2 between males and females. To date, evidence from seroprevalence studies suggests that this assumption is reasonable ^17,18. An alternative approach is to use the number of identified cases of SARS-CoV-2 infections as the denominator (i.e., calculating the case fatality rate). This approach, however, assumes that the degree of underdetection of SARS-CoV-2 infections is the same among men as among women. This assumption would, for example, be violated if males are more likely to develop symptoms from a SARS-CoV-2 infection than females and are, therefore, more likely to seek out a COVID-19 test, or if men have better access to testing than women. Although both choices for the denominator (total population or number of cases) rely on untestable assumptions, our analyses in which we use the number of cases instead of the total population as denominator found that the choice of denominator does not substantially change our conclusions.

Studies have hypothesized that the sex differences in COVID-19 mortality exist due to behavioral and social risk factors (e.g., higher incidence of smoking and drinking among men than women) that place men at a greater risk of mortality from health complications associated with COVID-19 ^19–24. Other studies have cited a higher rate of comorbidities, such as diabetes and heart disease, as the reason for the higher COVID-19 fatality rate among men ^4,25–28. Finally, some studies suggest biological factors that may explain these disparities. One potential factor is a higher expression among men than women of the angiotensin-converting enzyme 2 receptor, which is used by SARS-CoV-2 to enter the host cell ^3,29,30. Other possible biological factors relate to immunological differences between males and females ^31–33. Ultimately a combination of biological, behavioral, and social pathways may be responsible for the high male disadvantage in COVID-19 mortality. Elucidating these causal chains is an important research area given that it may assist in the development of therapeutics and preventive measures for COVID-19 and future outbreaks of coronavirus diseases.

One Sentence Summary

The sex difference in the mortality rate of coronavirus disease 2019 is substantially larger than for other common causes of death.

Supplementary Material

Supplemental Figures Download source data

Funding

PG was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR003143

Author Information

Correspondence to: Pascal Geldsetzer, Division of Primary Care and Population Health, Department of Medicine, Stanford University, 1265 Welch Road, Stanford, California 94305, USA, ude.drofnats@reztesdlegp

Author contributions: Pascal Geldsetzer: conceptualization, methodology, writing – original draft preparation; Trasias Mukama: methodology, data analysis, writing – reviewing and editing; Nadine Jawad: methodology, writing – original draft preparation; Tim Riffe: conceptualization, methodology, writing – reviewing and editing; Angela Rogers: methodology, writing – reviewing and editing; Nikkil Sudharsanan: conceptualization, methodology, writing – reviewing and editing;

Competing interests: The authors declare no competing interests;

Data and materials availability

All the data used in the study are publicly available. COVID-19 mortality data are available from the COVerAGE-DB (https://osf.io/mpwjq/). Data on population size by age and sex are available from the HMD (www.mortality.org) and the United Nation’s WPP (https://www.who.int/healthinfo/mortality_data/en/).

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