SARS-Cov-2 infection during pregnancy: what do we know so far

SARS-CoV-2 causes a respiratory syndrome known as COVID-19^{Reference Liu, Wang, Zhao, Kwak-Kim, Mor and Liao3–Reference Canedo-Marroquín, Saavedra, Andrade, Berrios, Rodríguez-Guilarte, Opazo, Riedel and Kalergis5}, to date, present in almost in all countries around the world with the Americas presenting the higher number of cases compared to Europe and China⁶. This virus has a high contagiousness ratio, 2–4 new cases can appear directly from a single case^{Reference Bar-On, Flamholz, Phillips and Milo7}. SARS-CoV-2 can be transmitted by person-to-person through saliva drops^{Reference Bar-On, Flamholz, Phillips and Milo7}. Its infection induces mild upper respiratory tract infection, fever, cough, and lower respiratory tract infection causing pneumonia with acute respiratory distress syndrome that can be life threatening^{Reference Singhal8}. In general, COVID-19 can affect all age groups including newborns^{Reference Yu and Chen9}. There are two groups with severe risks: older adults¹⁰ and people with previous medical conditions¹¹. Other group that should be considered under risk is pregnant women. During pregnancy, women present an alteration of the immune system with a high tolerance and are susceptibility to infection^{Reference Mor, Aldo and Alvero12}. In relation to SARS-CoV-2, one of four positive diagnosed pregnant women between 15 and 49 years old were hospitalized^{Reference Delahoy, Whitaker and O’Halloran13}. A few studies realized so far showed that they do not develop a more severe illness than not pregnant women^{Reference Delahoy, Whitaker and O’Halloran13–Reference Segars, Katler and Mcqueen15}, most of them were at the third trimester (87%) compared to the 13% were at first and second trimester of pregnancy^{Reference Delahoy, Whitaker and O’Halloran13,Reference Li, Han and Peng14} , this high difference could be explained due to delivery date and not by COVID-19 and more further analyses needs to be done. The principal symptomatology of pregnant women with COVID-19 was cough and fever^{Reference Li, Han and Peng14}. The study by Delahoy et al. reported 598 hospitalized pregnant women, of which 54.5% of them were asymptomatic^{Reference Delahoy, Whitaker and O’Halloran13}. It has been observed that birth can trigger the development of a severe COVID-19 even if is premature birth^{Reference Segars, Katler and Mcqueen15}. In Wuhan, it has been reported that, after delivery, 6 of 118 patients develop a more severe COVID-19, this is suggested by postpartum changes as increased of volume circulation^{Reference Chen, Li and Zheng16}.

Yang et al., studied 27 COVID-19 diagnosed and confirmed pregnant women in Wuhan, China. In total, 3 of the 18 polymerase chain reaction (PCR)-confirmed patients present premature rupture of fetal membranes with one of them presenting preterm premature rupture of fetal membranes at gestational week 30. The offspring present IgG and IgM even though they have a negative PCR for SARS-CoV-2 infection^{Reference Yang, Hu, Zhan, Yang and Xiong17}. This suggests that the newborns were not infected but they are developing an inflammatory response. Immunoglobulins are an important parameter used to evaluate the immune status^{Reference Özdemir, Emsen, Türk Daği and Artaç18}. The origin of the high levels of immunoglobulins is not clear. It is possible that IgG can be transferred from the mother to the fetus. However, IgM does not cross the placental barrier^{Reference Palmeira, Quinello, Ucia Silveira-Lessa, Zago and Carneiro-Sampaio19}. Therefore, the increase in IgM is an interesting fact that needs to be clarified. In this sense, there is one work that intends to analyze this issue; given that, there are high rates of false positivity for the IgM determination this analysis requires more clinical evidence^{Reference Lamouroux, Attie-Bitach, Martinovic, Leruez-Ville and Ville20}. This is suggestive of an in-utero infection^{Reference Fenizia, Biasin and Cetin21}. Evidence related to a pro-inflammatory state was also shown by Dong et al., where a newborn girl which presented increased levels of IgM and IgG together with increased levels IL-6 and IL-10 with no pulmonary signs and negative results for SARS-CoV-2 PCR test. This elevated IgM phenotype was sustained over time being observed until 12 days after birth^{Reference Dong, Tian and He22}. A study performed in six neonates from SARS-CoV-2-infected mothers showed that all were born by C-section and had high levels of IgG, IgM, and cytokines particularly IL-6. Consistently with previous observations, all the newborns were negative in the PCR test^{Reference Zeng, Xu and Fan23}. Another study described neonatal effects observed in the offspring from SARS-CoV-2-infected mothers. Here, neonates with a negative PCR result present premature born accompanied with normal, small for gestational age (SGA), or large for gestational age (LGA) phenotypes and in some cases lower Apgar scores^{Reference Zeng, Xu and Fan23–Reference Trippella, Ciarcià and Ferrari26}. Symptoms as shortness of breath, fever, increased heart rate, feeding intolerance, gastric bleeding^{Reference Zhu, Wang and Fang24}, rashes, and facial ulcerations have also been described^{Reference Chen, Peng and Wang27} showing that SARS-CoV-2 infection during pregnancy may generate several adverse effects in the offspring. There is not complete agreement about the kind of effects of SARS-CoV-2 infection over the offspring during pregnancy. For example the analysis of Yu et al., (2020) showed that after strict control measures no clinical symptoms were observed in four of seven newborns and only one of the rest presented a positive PCR test 36 h after birth and presented only mild symptoms and quickly recovered^{Reference Yu, Li and Kang28}. A deeper analysis on the SARS-CoV-2 effects on the offspring’s immune system was performed by Liu et al., (2020). This study showed a decrease of CD16-CD56 natural killer cells (NK) together with increased levels of IgG, IgM, IL-6, IL-10, and TNF-α in neonates born from mothers infected with SARS-CoV-2 but when the neonates were tested by PCR for SARS-CoV-2 they were negative^{Reference Liu, Zheng and Yang29}. There are few information regarding how neonates could be or not be infected by the virus or if this can be transmitted vertically by the mother. Lesser or no evidence showing that the fetus can clear the virus. The most recent evidences suggest in-utero infection and there is evidence of the presence of viral genetic material at the umbilical cord and also in the newborn nasopharyngeal tract and this issue seems to be dependent of the disease severity because this phenotype is only observed in pregnant patients that develop a severe form of COVID-19^{Reference Fenizia, Biasin and Cetin21}.

An important increase of IL-6 was observed in one of the analyzed neonates who develop a severe necrotizing enterocolitis which is consistent with other author that observed gastric bleeding^{Reference Zhu, Wang and Fang24,Reference Li, Han and Peng25,Reference Yu, Li and Kang28} . Increased levels of IL-6 have been proposed as an earlier marker for neonatal sepsis in newborns^{Reference Delanghe and Speeckaert30}. A similar observation was made in neonates from human immunodeficiency virus (HIV) and hepatitis B-infected mothers which also present an increased blood levels of pro-inflammatory cytokines such as IL-6, among others, altering the immune response of the fetus^{Reference Lohman-Payne, Gabriel and Park31,Reference Yockey and Iwasaki32} . CD16-CD56 NK cells are the first line of defense by lysing viral-infected or tumor cells which are present in higher levels in the neonate^{Reference Lee and Lin33}. A similar phenotype is observed in non-infected infants born from HIV infected mothers, here samples taken at birth showed a decreased proportion of NK cells^{Reference Smith, Jalbert and de Almeida34}. NK cells are able to modulate the adaptative immune response, playing a key role in controlling viral infections so alterations in NK cells could alter the anti-viral defense in the neonate^{Reference Ackermann, Verleden and Kuehnel35}.

Regarding the effects of SARS-CoV-2 infection, it has been observed in autopsies from patients died from COVID-19, the presence of SARS-CoV-2 inside the endothelial cells^{Reference Ackermann, Verleden and Kuehnel35,Reference Varga, Flammer and Steiger36} , which can be a predictable result considering the presence of ACE2 in endothelium cells^{Reference Hoffmann, Kleine-Weber and Schroeder37}, but it has also been observed that ACE2 expression on infected patient’s endothelial cells is higher than control healthy patients^{Reference Ackermann, Verleden and Kuehnel35}. This phenotype is associated with vasculitis in tissues like skin, liver, kidney, among others^{Reference Varga, Flammer and Steiger36,Reference Colmenero, Santonja and Alonso-Riaño38} . Moreover, pulmonary tissue presents an increased angiogenesis^{Reference Ackermann, Verleden and Kuehnel35} that can be explained by two mechanisms: one of them is growing by vessels sprouting where capillaries start to extend and the second growing by intussusceptive angiogenesis which is when one vessel is divided to form two new vessels, this phenotype has been observed in patients with chronic lung disease^{Reference Voelkel, Douglas and Nicolls39}.

SARS, MERS, H1N1, and related viruses during pregnancy

Viral infections are able to cause detrimental effects over the offspring. The knowledge obtained from the most recent pandemics like SARS and MERS will allow us to understand the possible effects of SARS-CoV-2 during pregnancy. According the World Health Organization (WHO), vertical transmission of SARS-CoV-2 is still a controversial topic^{Reference Li, Zhao and Zheng58,Reference Guan, Chen and Zhong59} . However, vertical transmission in respiratory viruses is common, in months with high frequencies of respiratory viruses. This notion changed the “sterile womb dogma” which described that unborn organs like the lungs are protected from any external agent during gestation^{Reference Piedimonte, Walton and Samsell60,Reference Perez-Muñoz, Arrieta, Ramer-Tait and Walter61} . In the next paragraph, we analyzed the effects of other respiratory viruses in pregnancy and newborns.

In the case of SARS, there is no evidence of vertical transmission between mother and fetus, SARS-infection is produced after birth. Nevertheless, SARS-illness in pregnancy is associated to preterm births, growth retardation in the unborn, gastrointestinal complications in the fetus, and miscarriages^{Reference Li and Ng62–Reference Wong, Chow and Leung64}. Consistently, no evidence of vertical transmission has been shown for the middle east respiratory syndrome (MERS). However, the consequences of MERS infection in gestating women are severe, even more than SARS. It has been described cases of perinatal death of women, stillbirth, neonate deaths short time after birth, preterm birth, and also there are cases of pregnant women with successful deliveries of healthy newborns^{Reference Payne, Iblan and Alqasrawi65–Reference Schwartz and Graham70}.

In the case of influenza virus, the transmission is unusual. Specifically, avian influenza A subtype H1N1 the mother-to-fetus transmission was determinate in some cases reports, but it was infrequent^{Reference Liu, Sha and Yu71}. Similar to other respiratory viruses, H1N1 influenza produces miscarriages, prematurity birth, and even death^{Reference Liu, Sha and Yu71,Reference Liu72} . In Perú, was detected a case with congenital pneumonia and positive infection of H1N1 in a child that birth at 36 weeks of gestation^{Reference Vásquez, Chávez and Gamio73}. In addition in Japan, the 2% of a cohort of neonates were positive for H1N1 and the symptoms were alleviated by oseltamivir^{Reference Takahashi, Kitajima, Kusuda, Morioka and Itabashi74}. In the case of another avian influenza A (H5N1) vertical transmission has been studied, viral genetic material was determinate in the placenta and the respiratory tract of the unborn^{Reference Gu, Xie and Gao75,Reference Korteweg and Gu76} . In another case, an analysis of the placenta of a women death due to an influenza-infection showed the presence of necrosis and analysis of the 4 months fetus showed the presence of edema and immune cells infiltration in the lung^{Reference Shu, Yu and Li77}.

Studies in pneumoviruses such as human metapneumovirus (hMPV) have shown that women infected during pregnancy present pre-term birth or children with low birth weight^{Reference Lenahan, Englund and Katz78}. In the case of hRSV, pregnant women infected with hRSV can present febrile illness, pneumonia, or both. Women who were positive cases for hRSV had preterm birth and 57% of their progeny were positive for the virus^{Reference Regan, Klein and Langley79,Reference Chu, Katz and Tielsch80} . Also, it has been demonstrated through a preclinical model that vertical transmission of the virus can be detected after the birth^{Reference Manti, Cuppari and Lanzafame81}. hRSV-infected neonates can show pneumonia, a symptom related to acute low respiratory tract infection (ALRTI), and blood and serum samples analysis showed the presence of antibodies and viral RNA^{Reference Manti, Cuppari and Lanzafame81}. In this line, it has been determinate hRSV particles in the cord blood^{Reference Fonceca, Chopra and Levy82} reinforcing the concept of transmission from the mother to the fetus. Several consequences can be associated to this transmission like hyperreactivity associated to develop asthma, reinfections, and respiratory dysfunctions during infancy^{Reference Piedimonte and Harford83}. A comprehensive resume about the effects of the different respiratory viruses is shown in Table 1.

Table 1.

Effects of viral infections during pregnancy

Concluding remarks

Immune response during pregnancy is a very well-controlled process which is in constant adaptation due to environmental changes. So far, little is known about the effects of viral infections over the offspring, a fact that is today even more relevant because of the fast spreading of SARS-CoV-2. Even though SARS-CoV-2 and other viruses can or not be vertically transmitted, the above-described information highlights the importance of tracing pregnant women and their newborns given that the illness induced by the infection could have detrimental effects over the fetus or even worst produce death of the mother and the unborn, which is why it is needed more focus in pregnant women. For this reason, it is important to learn those mechanisms that are underling viral infections in order to develop strategies that can prevent mother–fetal damage.