Interpretation
According to the data of 118 cases of COVID-19 pregnancy in Wuhan2, 64% of the cases occurred during late pregnancy, and the rate of severe disease in all patients with COVID-19 pregnancy was 8%, which was lower than the average level of the general population (15.7%). There were no deaths reported. It has been suggested that pregnancy might confer potential immunity. This was consistent with our study wherein even severe COVID-19 improved after proper treatment (Case A).
Among the three confirmed patients (Case A, B, C), only two (Case A and C) showed elevated liver enzymes possibly because of COVID-19-related hypoxia augmenting the inflammatory factors. Additionally, we found a pro-inflammatory state in COVID-19 (elevated CRP and IL-6 levels). The liver was also affected as seen from the abnormal liver function tests. Finally, after the administration of antiviral therapy (umifenovir and interferon atomisation) and liver supplements,liver function profile improved.
None of the patients showed significant foetal malformation or foetal or placental virus infection. Even Case C, which was prematurely terminated, had crown-lump length (CRL) at 12 weeks at par with age.
Placental pathology suggest chronic placental injury, hence has the possibility of decreasing maternal blood perfusion into the villi, thus, hindering maternal-foetal exchange2. This may be secondary to the hypoxic and inflammatory condition during COVID-19 affecting the placenta. Massive perivillous fibrin deposition and large agglomeration of necrotic villi suggested placental infarction was also found in Case B. The preterm premature rupture of membrane in Case B may be not only due to transverse presentation but also associated with the chronic ischemia and increased cytokines. Fortunately, only significant placental infarction was associated with SGA foetuses13. In the present study, although placental damaged was noted, the outcomes of were relatively ideal. The placental potency may be enough to overcome the villi impairment. However, if a mother had some complications associated with placental dysfunction (preeclampsia, fetal growth retardation, et al), COVID-19 may severely affect the placenta and foetus and result to adverse pregnancy outcome. These studies indicated that pregnancy with COVID-19 during the first and second trimester may result to full recovery allowing the continuation of pregnancy to term with good maternal and foetal outcomes.
All the placenta tests were negative for SARS-CoV-2 nucleic acid. In our previous study, same negative results were found in the three cases who had COVID-19 just before delivery9. The recent study cannot provide definite evidence to support intrauterine infection with COVID-19.
Vertical transmission includes intrauterine infection during pregnancy, intrapartum infection, and transmission through close contact and breastfeeding after delivery. ACE2 is a functional receptor for SARS-CoV-2 infection14. Theoretically, ACE2 provides the opportunity for SARS-CoV-2 infection. SARS-CoV-2 attaches to the cells using S protein and enter cells through binding to ACE2. It was suggested that the distribution and expression of ACE2 may be critical for the target organs affected by SARS-CoV-215,16. The available evidence suggests that ACE2 is widely expressed in female reproductive system and the maternal-foetal interface, which includes the stromal cells and perivascular cells of decidua, cytotrophoblasts and syncytiotrophoblasts14,17. Our results showed that both the placenta and decidua expressed ACE2 during early pregnancy with significantly higher levels than those during late pregnancy. However, the histologic and real-time PCR of the placenta had the negative results. Therefore, organs with high ACE2 expression may not always be the target of SARS-CoV-2.
During vertical transmission, high viral loads of SARS-CoV-2 is necessary. The placental villi may have more opportunities for SARS-CoV-2 to enter the maternal blood allowing the virus to infect the trophoblast cells. SARS-CoV-2 may then pass through the placental villous lobules to enter the foetal capillaries and infect the foetus. According to some reports, the lungs and the intestine may be major viral target organs of SARS-CoV-218. Studies have shown a high expression of ACE2 and TMPRSS2 in the lungs of newborns19. This places neonates at high risk for SARS-CoV-2 infection.
A Lamouroux et al20 reported three swabs positive for SARS-CoV-2 in 11 placental or membrane swabs sent following delivery in women with moderate to severe COVID-19. None of the infants tested positive for SARS-CoV-2 on days 1 to 5 of life, and none demonstrated COVID-19 symptoms. While there were no clinical signs of vertical transmission, they postulated on possible intrapartum viral exposure. For infants delivered vaginally, viral contamination may be from room air, vaginal secretions, maternal blood, or amniotic fluid. In our study, no virus or viral infection was found in the placenta. Wang et al21 reported a case of positive SARS-CoV-2 throat swab test in a newborn 36 hours after delivery. Airborne transmission possibility after delivery cannot be excluded. The risk of neonatal infection from postpartum exposure via respiratory secretions and close contact should be avoided. The neonate throat swab tests and placenta tests were negative in our cases. This reminds obstetricians that although there is no clear evidence of intrauterine infection, careful attention to protect the neonate from exposure to SARS-CoV-2 during and after delivery should be observed.
In clinical studies, most of the neonates were negative of SARS-CoV-22,4. The placenta may not be the main target organ of SARS-CoV-2. There is no clear evidence of intrauterine infection, which requires further study regarding the specific mechanisms involved.