Incidence and Outcomes Associated with Menopausal Status in COVID-19 Patients: A Systematic Review and Meta-analysis

Akbari, Abolfazl; Zarifian, Ahmadreza; Hadizadeh, Alireza; Hajmolarezaei, Ezat

doi:10.1055/s-0043-1772595

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet 45 (12) • 2023 • https://doi.org/10.1055/s-0043-1772595 copy

Incidence and Outcomes Associated with Menopausal Status in COVID-19 Patients: A Systematic Review and Meta-analysis

Incidência e resultados associados ao estado da menopausa em pacientes com COVID-19: Uma revisão sistemática e metanálise

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective

Menopause causes several changes in the body that may affect the response to COVID-19. We aimed to investigate the possible association between menopausal status and incidence and outcomes in COVID-19 patients.

Methods

Combinations of keywordsCOVID-19, menopause, and estrogen were used to search the PubMed, Embase, Web-of-Science, and Scopus databases for articles reporting the incidence and outcomes of COVID-19 (discharge, length-of-admission, intensive care, or mortality) in premenopausal women, available through December 29, 2022. Data from studies comparing the incidence of COVID-19 infection with the age-matched male population were pooled and meta-analyzed using a random-effects model.

Results

Overall, 1,564 studies were retrieved, of which 12 were finally included in the systematic review to compare disease outcomes, and 6 were meta-analyzed for the incidence of COVID-19 in premenopausal and postmenopausal women. All studies reported better COVID-19-associated outcomes in premenopausal women compared with postmenopausal women. After adjusting for confounding factors, three studies found better outcomes in postmenopausal women, and two found no association between menopausal status and COVID-19 outcomes. Our meta-analysis found a higher incidence of COVID-19 infection among premenopausal women than postmenopausal women, when compared with age-matched men (odds ratio = 1.270; 95% confidence interval: 1.086–1.486; p = 0.003).

Conclusion

The incidence of COVID-19 was significantly higher in premenopausal women than in postmenopausal women when compared with age-matched men. Although premenopausal women may have more favorable COVID-19-associated outcomes, the presumed preventive effect of estrogens on the incidence and related outcomes of COVID-19 in premenopausal women cannot be proven at present. Further longitudinal studies comparing pre- and post-menopausal women are required to provide further insight into this matter.

Keywords
COVID-19; menopause; estrogen; climacteric

First author	Study design	Country	Patients	Date	Menopausal criteria	Sample size	Age (years old)	Crude findings	Further analysis	Corrected confounding variables
Ding et al.	Cross-sectional	China	Patients hospitalized at 3 branches of Tongji Hospital	28 January - 8 March, 2020	Amenorrhea > 1 year	1,730	60.33 ± 14.36	Severity (premenopause: 46% versus postmenopause: 58%) and clinical outcomes including discharge (premenopause: 23% versus postmenopause: 6%), remained in hospital (premenopause: 77% versus postmenopause: 92%), and death (premenopause: 0% veersus postmenopause: 2%) were significantly different between premenopausal women and postmenopausal women.	Age-match comparison Severity (p = 0.83) and clinical outcomes (p = 0.49) including discharge, remained in hospital, and death did not differ significantly between menopausal women and age-matched men, whereas premenopausal women had significantly better clinical outcomes and fewer severely ill patients than age-matched men (p < 0.01 for both).	Age and comorbidities
Wang XW. et al.	Retrospective cohort	China	COVID-19 inpatients at the Taikang Tongji Hospital	15 February - 30 April, 2020	Amenorrhea > 1 year	300	65.3 ± 14.8	Postmenopausal women had higher rates of severe disease (41.7 versus 0%), bilateral pulmonary infiltration (91.7 versus 64.7%), and mortality (2.0 versus 6.0%) than premenopausal women.	Age-match comparison Men had higher rates of severe disease (23.7% versus 0%; p = 0.003) and bilateral pulmonary infiltration (86.1% versus 64.7%; p = 0.04) than premenopausal women. However, there was no significant difference in mortality (2.0% versus 0%; p = 1.00) between the 2 groups. Men and postmenopausal women had the same percentage of severe disease (32.7% versus 41.7%; p = 0.21), bilateral lung infiltration (86.1% versus 91.7%; p = 0.24), and mortality (2.0% versus 6.0%; p = 0.25).	Age, body mass index, comorbidities, treatment, and laboratory results
Mishra et al.	Retrospective cohort	India	Females admitted at tertiary care dedicated COVID hospital	May – August, 2020	Amenorrhea > 1 year	147	39.05 ± 15.42	Length of hospital stay (premenopause: 8.6 ± 3.9; postmenopause: 14.1 ± 8.9; p < 0.01), severe disease (premenopause: 7.3%; postmenopause: 23.5%; p < 0.01), and mortality (premenopause: 0%; postmenopause: 9.8%; p < 0.01) were significantly different between groups.	Multivariate logistic regression: Menopausal status is not associated with length of hospital stay (p = 0.057) or severity progression (p = 0.262).	Age, obesity, comorbidities, oxygen/ventilator requirement, hemoglobin, and neutrophil to lymphocyte ratio
O'Brien et al.	Retrospective cohort	Canada	Canadian COVID-19 dataset	Up to 27 July 2020	More than 60 years/o	101,121	NR	Women had a lower COVID-19 incidence rate than men unless they were 80 years of age or older. Premenopausal women had a lower incidence rate than men of the same age.	–
Seeland et al.	Retrospective cohort	17 countries	Electronic health records in a TriNetX Real-World database	Up to 16 July 2020	> 50	68,466	NR	Premenopausal women had higher incidence rates than men of the same age. Mortality rates increased steadily with age in both sexes, but the increase was steeper in men at 50 years old.	–
Sha et al.	Retrospective cohort	China	Jinan Infectious diseases Hospital in Shandong, Shandong Provincial Chest Hospital in Shandong, and Huanggang Central Hospital in Hubei	31 January - 17 April, 2020	> 55	413	57.25 ± 3.75	Postmenopausal women had a higher mortality rate than premenopausal women (5.2% versus 3.8%).	Age-match comparison Premenopausal women had the same in-hospital mortality rate as men of the same age (3.8 versus 4.0%, p = 0.918). Postmenopausal women had a considerably lower mortality rate than men in the same age group (5.2 versus 21.0%, p = 0.007).	Age and comorbidities
Garg et al.	Retrospective cohort	India	A COVID-19 facility	April – July, 2020	Amenorrhea > 1 year	720	60.15 ± 6.39	Postmenopausal women and men had a higher risk of death than premenopausal women (premenopause: 8.6%; postmenopause: 19.4%)	Age-match comparison Risk of death in men ≤ 48 years old was 12.8% and in men > 48 it was 25.9%	Age and comorbidities
Liu et al.	Retrospective cohort	China	Renmin Hospital of Wuhan University (Wuhan, China) and Xiangyang Central Hospital (Xiangyang, China)	20 January - 1 April, 2020	> 55	459	63.25 ± 3.50	Postmenopausal women had a higher risk of death and longer length of hospitalization than premenopausal women (premenopause: 3; postmenopause: 7, premenopause: 18 (9–28); postmenopause: 13 (7–24)	Age-match comparison The difference in incidence between men and women was not observed in patients > 55 years old. 141 patients were < 55 years old, of whom 19 died (16 men versus 3 women; p < 0.005). Of the 318 cases > 55 years old, 115 died (47 women versus 68 men, p = 0.149).	Age and comorbidities
Wang M. et al.	Retrospective cohort	China	The Central Hospital of Wuhan, Wuhan Red Cross Hospital, the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, and Lichuan People's Hospital in Hubei Province	31 December, 2019–31 March, 2020	Amenorrhea >1 year	2,501	56.18 ± 4.32	–	Multivariable logistic regression analysis and age-match comparison There is no significant differences between premenopausal and postmenopausal females after propensity score matching by age (odds ratio of severe disease: 0.63 [0.32–1.24] and odds ratio of death: 1.83 [0.16–21.5]).	Age and comorbidities
Ferretti et al.	Retrospective cohort	Italy	Patients hospitalized at IRCCS San Matteo Foundation (Pavia, Italy) for COVID-19	February - December, 2020	> 50	1,764	70.10 ± 4.05	Postmenopausal women had higher incidence and mortality rates than premenopausal.	Age-match comparison Premenopausal women had higher incidence and mortality rates than men of the same age. However, incidence and mortality rates were higher in age-matched men than in postmenopausal women.	Age and comorbidities
Costeira et al.	Retrospective cohort	United Kingdom	Female users of the COVID Symptom Study application	7 May-15 June, 2020	Amenorrhea > 1 year	152,637	53.8	Menopausal women had higher rates of predicted COVID-19 (p < 0.01), but tested COVID-19 patients and severity of disease were not significantly different with postmenopausal women (p > 0.05).	–
Toure et al.	Retrospective cohort	USA	Nonpregnant women admitted to the Hospital System in Rhode Island	March 1-June 30, 2020 and July 1, 2020 - February 28, 2021	> 55	1,863	67.57 ± 18.0	Postmenopause was associated with higher mortality (OR = 8.6 [2.7–27.6]), readmission (OR = 1.5 [1.04–2.2]), severe illness (OR = 5.7 [1.3–23.9]), and longer length of hospitalization (OR 1.6 = [1.2–2.2]).

PubMed (29 December)
Search	Query	Results
#1 (Menopause)	(post-menopausal [title/abstract] OR postmenopausal [title/abstract] OR Postmenopause [title/abstract] OR Post-menopause [title/abstract] OR peri-menopausal [title/abstract] OR perimenopausal [title/abstract] OR peri-menopause [title/abstract] OR perimenopause [title/abstract] OR premenopausal [title/abstract] OR pre-menopausal [title/abstract] OR pre-menopause [title/abstract] OR premenopause [title/abstract] OR Climacteric [title/abstract] OR Menopause[title/abstract] OR menopausal [title/abstract] OR Menstrual [title/abstract] OR Menses[title/abstract] OR Menstruation[title/abstract] OR Hypoestrogenic[title/abstract] OR Hypo-estrogenic[title/abstract] OR Estrogenic[title/abstract])	178,597
#2 (COVID-19)	(“severe acute respiratory syndrome coronavirus 2” OR “Wuhan coronavirus” OR “Wuhan seafood market pneumonia virus” OR “COVID19 virus” OR “COVID-19 virus” OR “coronavirus disease 2019 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” OR “2019 novel coronavirus” OR “COVID-19” OR “2019 novel coronavirus infection” OR “COVID19” OR “coronavirus disease 2019” OR “coronavirus disease-19” OR “2019-nCoV disease” OR “2019 novel coronavirus disease” OR “2019-nCoV infection” OR “Coronavirus Infections” OR “Coronavirus Infection” OR “Infection, Coronavirus” OR “Infections, Coronavirus” OR “novel coronavirus” OR Covid* OR “sars 2”)	332,066
Final	#1 AND #2	399
SCOPUS (7 October)
#1 (Menopause)	TITLE-ABS-KEY(post-menopausal OR postmenopausal OR Postmenopause OR Post-menopause OR peri-menopausal OR perimenopausal OR peri-menopause OR perimenopause OR premenopausal OR pre-menopausal OR pre-menopause OR premenopause OR Climacteric OR Menopause OR menopausal OR Menstrual OR Menses OR Menstruation OR Hypoestrogenic OR Hypo-estrogenic OR Estrogenic)	291,187
#2 (COVID-19)	TITLE-ABS-KEY(“severe acute respiratory syndrome coronavirus 2” OR “Wuhan coronavirus” OR “Wuhan seafood market pneumonia virus” OR “COVID19 virus” OR “COVID-19 virus” OR “coronavirus disease 2019 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” OR “2019 novel coronavirus” OR “COVID-19” OR “2019 novel coronavirus infection” OR “COVID19” OR “coronavirus disease 2019” OR “coronavirus disease-19” OR “2019-nCoV disease” OR “2019 novel coronavirus disease” OR “2019-nCoV infection” OR “Coronavirus Infections” OR “Coronavirus Infection” OR “Infection, Coronavirus” OR “Infections, Coronavirus” OR “novel coronavirus” OR Covid* OR “sars 2”)	417,588
Final	#1 AND #2	583
Embase (30 July)
#1 (Menopause)	(post-menopausal:ti,ab,kw OR postmenopausal:ti,ab,kw OR Postmenopause:ti,ab,kw OR Post-menopause:ti,ab,kw OR peri-menopausal:ti,ab,kw OR perimenopausal:ti,ab,kw OR peri-menopause:ti,ab,kw OR perimenopause:ti,ab,kw OR premenopausal:ti,ab,kw OR pre-menopausal:ti,ab,kw OR pre-menopause:ti,ab,kw OR premenopause:ti,ab,kw OR Climacteric:ti,ab,kw OR Menopause:ti,ab,kw OR menopausal:ti,ab,kw OR Menstrual:ti,ab,kw OR Menses:ti,ab,kw OR Menstruation:ti,ab,kw OR Hypoestrogenic:ti,ab,kw OR Hypo-estrogenic:ti,ab,kw OR Estrogenic:ti,ab,kw)	244,423
#2 (COVID-19)	(“severe acute respiratory syndrome coronavirus 2”:ti,ab,kw OR “Wuhan coronavirus”:ti,ab,kw OR “Wuhan seafood market pneumonia virus”:ti,ab,kw OR “COVID19 virus”:ti,ab,kw OR “COVID-19 virus”:ti,ab,kw OR “coronavirus disease 2019 virus”:ti,ab,kw OR “SARS-CoV-2”:ti,ab,kw OR “SARS2”:ti,ab,kw OR “2019-nCoV”:ti,ab,kw OR “2019 novel coronavirus”:ti,ab,kw OR “COVID-19”:ti,ab,kw OR “2019 novel coronavirus infection”:ti,ab,kw OR “COVID19”:ti,ab,kw OR “coronavirus disease 2019”:ti,ab,kw OR “coronavirus disease-19”:ti,ab,kw OR “2019-nCoV disease”:ti,ab,kw OR “2019 novel coronavirus disease”:ti,ab,kw OR “2019-nCoV infection”:ti,ab,kw OR “Coronavirus Infections”:ti,ab,kw OR “Coronavirus Infection”:ti,ab,kw OR “Infection, Coronavirus”:ti,ab,kw OR “Infections, Coronavirus”:ti,ab,kw OR “novel coronavirus”:ti,ab,kw OR Covid*:ti,ab,kw OR “sars 2”:ti,ab,kw)	295,859
Final	#1 AND #2	390
WOS (30 July)
#1 (Menopause)	(TI = (post-menopausal OR postmenopausal OR Postmenopause OR Post-menopause OR peri-menopausal OR perimenopausal OR peri-menopause OR perimenopause OR premenopausal OR pre-menopausal OR pre-menopause OR premenopause OR Climacteric OR Menopause OR menopausal OR Menstrual OR Menses OR Menstruation OR Hypoestrogenic OR Hypo-estrogenic OR Estrogenic) OR AB = (post-menopausal OR postmenopausal OR Postmenopause OR Post-menopause OR peri-menopausal OR perimenopausal OR peri-menopause OR perimenopause OR premenopausal OR pre-menopausal OR pre-menopause OR premenopause OR Climacteric OR Menopause OR menopausal OR Menstrual OR Menses OR Menstruation OR Hypoestrogenic OR Hypo-estrogenic OR Estrogenic))	158,610
#2 (COVID-19)	(TI = (“severe acute respiratory syndrome coronavirus 2” OR “Wuhan coronavirus” OR “Wuhan seafood market pneumonia virus” OR “COVID19 virus” OR “COVID-19 virus” OR “coronavirus disease 2019 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” OR “2019 novel coronavirus” OR “COVID-19” OR “2019 novel coronavirus infection” OR “COVID19” OR “coronavirus disease 2019” OR “coronavirus disease-19” OR “2019-nCoV disease” OR “2019 novel coronavirus disease” OR “2019-nCoV infection” OR “Coronavirus Infections” OR “Coronavirus Infection” OR “Infection, Coronavirus” OR “Infections, Coronavirus” OR “novel coronavirus” OR Covid* OR “sars 2”) OR AB = (“severe acute respiratory syndrome coronavirus 2” OR “Wuhan coronavirus” OR “Wuhan seafood market pneumonia virus” OR “COVID19 virus” OR “COVID-19 virus” OR “coronavirus disease 2019 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” OR “2019 novel coronavirus” OR “COVID-19” OR “2019 novel coronavirus infection” OR “COVID19” OR “coronavirus disease 2019” OR “coronavirus disease-19” OR “2019-nCoV disease” OR “2019 novel coronavirus disease” OR “2019-nCoV infection” OR “Coronavirus Infections” OR “Coronavirus Infection” OR “Infection, Coronavirus” OR “Infections, Coronavirus” OR “novel coronavirus” OR Covid* OR “sars 2”))	277,897
Final	#1 AND #2	190

Study	1. Were the two groups similar and recruited from the same population?	2. Were the exposures measured similarly to assign people to both exposed and unexposed groups?	3. Was the exposure measured in a valid and reliable way?	4. Were confounding factors identified?	5. Were strategies to deal with confounding factors stated?	6. Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?	7. Were the outcomes measured in a valid and reliable way?	8. Was the follow-up time reported and sufficient to be long enough for outcomes to occur?	9. Was follow-up complete, and if not, were the reasons to loss to follow-up described and explored?	10. Was appropriate statistical analysis used?
Wang et al.	Y	Y	Y	N	N	Y	Y	Y	Y	Y
Mishra et al.	N	Y	Y	N	N	Y	Y	Y	Y	Y
O'Brien et al.	Y	Y	N	Y	Y	Y	Y	Y	N	Y
Seeland et al.	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
Sha et al.	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
Garg et al.	Y	Y	Y	N	N	Y	Y	Y	Y	Y
Liu et al.	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
Wang et al.	Y	Y	Y	Y	Y	Y	Y	Y	N	Y
Ferretti et al.	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
Costeira et al.	U	Y	Y	N	N	Y	Y	Y	N	Y
Toure et al.^* * only the abstract was available.	U	U	U	N	N	U	Y	Y	U	U

Study	Were the criteria for inclusion in the sample clearly defined?	Were the study subjects and the setting described in detail?	Was the exposure measured in a valid and reliable way?	Were objective, standard criteria used for measurement of the condition?	Were confounding factors identified?	Were strategies to deal with confounding factors stated?	Were the outcomes measured in a valid and reliable way?	Was appropriate statistical analysis used?
Ding et al.	Y	Y	Y	Y	Y	Y	Y	Y

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[1] Address for correspondence Ezat Hajmolarezaei, Mashhad, 91778 99191Razavi Khorasan Province, Iran (e-mail: hajmollarezaeie@mums.ac.ir).