Impacts of pregnancy and menopause on COVID-19 severity: a systematic review and meta-analysis of 4.6 million women

Background: Corona Virus Disease 2019 (COVID-19) pandemic is still a public health emergency of international concern. However, whether pregnancy and menopause impact the severity of COVID-19 remain unclear. Aim: This study is performed to investigate the truth. Design: Study appraisal and synthesis follows PRISMA guideline. Meta-analysis is performed in random-effects model. Methods: PubMed, Embase, Cochrane database, Central, CINAHL, ClinicalTrials.gov, WHO COVID-19 database and WHO-ICTRP are searched until 28 March 2023. Results: In total, 57 studies (4640275 COVID-19 women) were analyzed. Pregnant women were at a lower risk of severe COVID-19, intensive care unit (ICU) admission and disease mortality compared to those nonpregnant women with comparable comorbidities. In contrast, pregnant women with more prepregnancy comorbidities were at a higher risk of severe COVID-19, ICU admission and invasive mechanical ventilation (IMV). In addition, pregnant women with pregnancy complications had a significantly increased risk of severe COVID-19 and ICU admission. Menopause increased COVID-19 severity, IMV requirement and disease mortality. Hormone replacement therapy inhibited COVID-19 severity in postmenopausal women. Premenopausal and postmenopausal women had a lower chance of severe illness than age-matched men. The impact of pregnancy on COVID-19 severity was significant in Americans and Caucasians, whereas the effect of menopause on COVID-19 severity was only significant in Chinese. Conclusions: Pregnancy and menopause are protective and risk factors for severe COVID-19, respectively. The protective role of pregnancy on COVID-19 is minimal and could be counteracted or masked by prepregnancy or pregnancy comorbidities. The administration of estrogen and progesterone may prevent severe COVID-19.