18 July COVID sex and gender PART 1

Sex differences in COVID-19

1. Infection rate in men and women: It is well known that COVID is more severe and deadly in aged men as compared to women, but what about infection rates?  Well a colleague drew my attention to our own Sciensano data, where you clearly see a predominance of women in the 20-59 and the > 80 yrs groups.

I could not find data for European countries on the ECDC site, but via the Gebhard paper (Impact of Sex and gender…), I found this site:  https://globalhealth5050.org/covid19/sex-disaggregated-data-tracker/.  As you can see in the excel, I copied and highlighted in yellow the countries with > 55 % women and in green those with > 55 % men amongst confirmed infections.  There is, in fact a clear pattern: almost all “women-predominant” countries are situated in Western Europe (BE-NL-UK-IRL-Sw-DK-ES-P); Central Europe ( Moldova + Ukrain + Lithuana, Estonia), there is also Canada + New Zealand +South-Korea + South Africa.

The male predominant countries (in green) are in Asia (+ Middle East), Africa and Latin America.  Remarkably, Japan has a slight (55%), but Singapore a heavy (88%) male predominance, in contrast to S-Korea (56.7 % women) and China (balanced).

Another observation is that there are many exceptions on the above “rules”: the “German” countries (D-AU-CH) are “sex-balanced”, Scandinavia is divided between “female predominance” (SW, DK) and balanced (Finl- Norway) countries. Canada is female-predominance (56%), but USA is balanced etc….  

Obviously, for LMIC in Africa, Latin America and Asia, as well as in the Middle East (all “patriarch” societies) the male predominance of COVID infections could be explained by the fact that men are more socially mobile (hence higher chance on infection) and/or have more access to health care. 

But what could be the explanation for the female predominance in many Western countries?  On the site, you find some figures about infection of health care workers (HCW), showing that 68-75 % of infected HCW are female: https://globalhealth5050.org/covid19/healthcare-workers/ .   Obviously, women have a higher contribution to health professions, so that might be in proportion.  However, infections in HCW represented only between 5 (Germany) and 10-11 % (IT-ES) of the total cases at the corresponding dates in those countries  So, female HCW infections cannot be the full explanation for female predominance in the overall ES epidemic for instance…..   

2. The paper about “Sex and Gender impact” provides a nice overview (+ figures) on why men are more vulnerable to COVID complications.  In fact, the biological (sex-related) higher risk, might be due to a more stimulating effect of testosterone on expression of ACE-2 (SARS-CoV-2 receptor) and of TMPRSS-2 (the main enzyme that activates the Spike for binding) as well as the more active innate and adaptive immune system in women.  The “gender” (behavioral) higher risk in men may be due  to a higher frequency of lifestyle-related “co-morbidities” (cardiovascular, pulmonary) and a slower health-seeking behavior.

(The “sex” aspect is similarly discussed in the “Let’s talk about sex” minireview)

3. Pregnancy

3. 1. Prevalence of SARS-CoV-2 in women ready to deliver:

NYC at the height of the epidemic: (March-April) at labor and delivery (L/D) ward: from 161 tested:

• 16 (10 %) symptomatic of whom 5 (31%) tested PCR positive.
• 145 (90 %) asymptomatic of whom 21 (14.5%) positive

Boston at a similar prevalence in general population: on 757 L/D women

• 139 (18.5 %) symptomatic with 11 (8 %) positive.
• 618 (81.5 %) a-symptomatic with  9 (1.5 %) positive  

 3.2. Systematic review on pregnancy outcome  Ultrasound Obstet Gynecol 2020:

Based on consecutive case series of 295 pregnant COVID-19 (+) women (of whom 71.5 PCR-confirmed, other clinical COVID):

• 0-14 %  presented severe pneumonia
• Only 4 cases of spontaneous miscarriage or termination
• 78 %  delivered by Cesarean section,
• Only 8 neonates with birth weight < 2500 g and 1 neonatal asphyxia and death,
• 3 out of 155 tested neonates were PCR + in throat swabs; 

In 9 cases of severe COVID-19 : 7 maternal deaths, 4 intrauterine fetal deaths and 2 neonatal deaths.

3.3. “Invisible enemy”: provides some caveats to this rather positive image:

• Increased ACE2 expression during pregnancy which may favor SARS-CoV2 infection.
• Placental pathology has been observed in all studies thus far, vascular villous lesions including fibrin deposition within and around the villi and infarcts have been reported, suggestive of pre-eclampsia.
• Cytokine storm in pregnant women could potentially impact fetal brain development; thus, increasing the risk for autism, mental health disorders or schizophrenia.

Clearly, more systematic studies are required to answer questions such as:

• Mechanism of SARS-CoV-2 infection, entry in placenta, role of immune cells
• Effect of SARS-CoV-2 during early pregnancy (1st and 2nd trim) on maternal/infant health.
• Direct (vertical transmission) or indirect effect (via placental insufficiency) or inflammatory milieu due to SARS CoV2 infection on the developing fetus.
• Effect of SARS-CoV-2 postnatally in the newborn
• Neonatal impact of SARS-CoV2 infected mother breastfeeding