Maternal and Placental Immune Responses to SARS-CoV-2 Differ by Fetal Sex

Perinatal vulnerability to infectious disease and other pregnancy exposures has long been known to be greater in males than females. In addition, males have demonstrated to have increased risk for severe COVID-19 illness compared to females.

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Extending that line of inquiry, Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology and in the Department of Obstetrics and Gynecology at Massachusetts General Hospital, and colleagues have demonstrated fetal sex–specific maternal and placental adaptive and innate immune responses to SARS-CoV-2. Their report appears in Science Translational Medicine.

Study Methods

The team analyzed maternal and cord blood samples drawn at delivery from 38 women who were infected with SARS-CoV-2 during pregnancy and their 19 male and 19 female neonates (no neonates were infected). The control group was 30 women who were not infected and their 15 male and 15 female neonates.

Placental Transfer of SARS-CoV-2 Antibodies

Newborn antiviral immunity relies heavily on the placental transfer of maternal immunoglobulin G (IgG) to the fetal circulation. IgG titers against all SARS-CoV-2 antigens tested (the spike protein and its subunits, receptor-binding domain and nucleocapsid protein) were significantly lower in women carrying a male fetus.

In contrast, the transfer of influenza and pertussis antibodies was similar across pregnancies.

Placental Fc Receptor Expression

The efficient transfer of maternal antibodies across the placenta depends on a higher quantity of Fc receptors. Also important is the co-localization of Fcγ receptors with the neonatal Fc receptor, which has a lead role in transferring maternal IgG to fetal circulation.

In this study, Fc receptor expression was upregulated in male placentas in response to SARS-CoV-2 infection, perhaps as compensation for low maternal antibody titers.

However, co-localization of Fcγ receptor III with the neonatal Fc receptor was significantly increased in male placentas. This receptor pattern resulted in the preferential transfer of inflammatory antibodies, which might promote a more inflammatory immune response in male fetuses.

Placental Expression of Interferon-stimulated Genes

The expression of several interferon-stimulated genes and proteins and interleukin-10 was significantly higher in male placentas exposed to SARS-CoV-2 than in male control placentas. In contrast, female placentas exposed to SARS-CoV-2 had lower expression of interferon-stimulated genes and proteins compared to female controls. Interferon responses inhibit viral infection but can also drive inflammatory pathology.

Looking Ahead

This study suggests several questions for future research:

• Is the male-specific upregulation of interferon-stimulated genes beneficial (protective against viral infection) or harmful (resulting in increased placental inflammation, increased risk of fetal growth restriction or poor placental function)?
• Does the male-associated impairment in placental SARS-CoV-2–specific antibody transfer make male infants more vulnerable to early-life SARS-CoV-2 infection?
• When coupled with previously identified sex differences in the transfer of maternal humoral immunity, what insights can these findings provide into male infants' generally increased vulnerability to morbidity and mortality?

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