Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth

To the Editors:

We read with great interest the article “Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth.” Sentilhes et al¹ supported with evidence the hypothesis that pregnant women with coronavirus disease 2019 (COVID-19) can have adverse obstetrical outcomes and preterm deliveries. Although the study reported a noncausal association between preterm birth and COVID-19 and that pregnant women with COVID-19 were induced for labor before full term because of their medical conditions, there is a biological evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might cause preterm labor in pregnant women with no medical indication for preterm labor induction. It was reported that the angiotensin-converting enzyme type-2 (ACE-2) receptor (which SARS-CoV-2 uses to enter the cell) is expressed by the female reproductive tract including the uterus, placenta, and ovaries. ACE-2 is highly expressed during pregnancy, at least during mid- to late-gestation, which is speculated to provide a vasodilatory effect driven by its products, namely angiotensin 1 to 7.² Testing for the presence of SARS-CoV-2 is mainly done by a reverse transcription-polymerase chain reaction of a nasopharyngeal swab, and thus women with SARS-CoV-2 viremia might be missed. Once the virus is in the circulation system, it is possible for SARS-CoV-2 to reach the reproductive tract (including the uterus) and to cause down-regulation of the ACE-2 receptors and subsequently low levels of vasodilatory angiotensin 1 to 7, thereby leaving the vasoconstricting effects of angiotensin II unopposed, which might lead to augmented uterine contractions and subsequently preterm birth. Moreover, preeclampsia is associated with low levels of angiotensin 1 to 7. Several reports showed that previously normotensive pregnant women with COVID-19 presented with preeclampsia or preeclampsia-like symptoms (eg, proteinuria).

Moreover, healthy pregnancy is associated with a specific T lymphocytes balance (regulatory T cells [Treg] to T helper 17 cells [Th17]), favoring Treg abundance over Th17. Although Treg lymphocytes maintain fetal tolerance and a reduced local immune response in pregnancy, Th17 is associated with fetal allograft rejection. A low Treg to Th17 ratio was found in pregnant women with preeclampsia, those who aborted, and those who underwent preterm deliveries, which is in accordance with the ratios in severe cases of COVID-19. Although patients with COVID-19 might present with lymphopenia, it is the type of lymphocytes that show disrupted levels (with high Th17 and low Treg levels), which might ultimately alter the Treg to Th17 balance required for a healthy pregnancy.³

The administration of corticosteroids remains the common standard practice in anticipated preterm birth cases; however, corticosteroids was found to be associated with a reduced ACE-2 receptor expression and a subsequent reduction in vasodilatory angiotensin 1 to 7 in animal studies, which might augment preterm birth.⁴ In conclusion, it is important to carefully manage pregnant women with COVID-19, with cautious administration of corticosteroids in those with anticipated preterm deliveries, and to test for viral presence in the circulation system.