The novel coronavirus SARS-CoV-2 and pregnancy: literature review

Since the first case of severe COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in Wuhan (China) in December 2019, the infection has spread rapidly to nearly all of the world’s countries. On March 11, the World Health Organization (WHO) declared COVID19 a pandemic. Previous studies have found that pregnant women are at increased risk for a severe or complicated course of acute respiratory viral infections and influenza [1, 2]. Despite the importance of the problem, the current literature is lacking information related to specific features of COVID-19 in pregnant women. Moreover, the vast majority of relevant studies have been published over the past three months from mid-February to mid-May 2020, which shows that this issue is an increasingly challenging clinical problem worldwide. It is also essential to understand whether there is a risk of vertical transmission of SARS-CoV-2.

Also, there is limited evidence about the dangers of SARS-CoV-2 infection in neonates. This issue requires further investigation, understanding, and development of clinical guidelines. At the same time, preterm infants deserve special attention as a group of newborns with low immunity and often with concomitant diseases.

This review is aimed to survey and analyze the literature reporting characteristic features of COVID-19 in pregnant women and newborns.

Clinical characteristics of COVID-19 in pregnant women

Pregnancy and childbirth seem not to aggravate the clinical course of COVID-19 infection or computed tomography (CT) features of COVID-19 pneumonia. One of the earliest studies by D. Liu et al. analyzed clinical manifestations and CT features of COVID19 pneumonia in a clinic in Wuhan (China) from January 20 to February 10, 2020 [3]. All 15 pregnant women with COVID-19 pneumonia in this study presented with clinical manifestations and CT features of mild pneumonia. No SARS-CoV-2 infection was found in the neonates. Pregnancy and childbirth have not been shown to aggravate the severity of COVID19 pneumonia. Moreover, the researchers raised the question of whether antiviral therapy was necessary for pregnant women with COVID-19 pneumonia, as the symptoms in the pregnant women were mild, and antiviral therapy has been considered as a potential risk to the fetus. A similar study, also conducted in China, also reported no severe maternal and neonatal complications in pregnant women with COVID-19 pneumonia [4]. Only some patients presented respiratory symptoms on admission. Compared to the controls, COV1D-19 pneumonia patients had lower counts of white blood cells, neutrophils, C-reactive protein, and alanine aminotransferase on admission. There are other similar optimistic studies [5–7].

Some articles reported that pregnant women with COVID-19 had a significantly milder clinical course of the disease than non-pregnant patients with similar infection status [8]. However, the authors of this study note that this phenomenon may be attributed to other factors, such as, for example, the younger age of the patients or the mandatory testing of all pregnant women for the novel coronavirus.

Other studies reported that pregnant women with COVID-19 presented with normal body temperature and mild respiratory symptoms before childbirth, but had post-partum fever [9]. In a study by H. Chen et al., nine pregnant women with COVID-19 underwent a cesarean section in their third trimester [10]. Of them, seven patients presented with a fever. Other COVID-19 symptoms, including cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two), were also observed. In two cases, fetal distress was observed. Five out of nine women had increased concentrations of aminotransferase. It was concluded that clinical characteristics of COVID-19 pneumonia in pregnant women were similar to those reported for non-pregnant adult patients who developed COVID-19 pneumonia.

There are published data investigating pregnancy complications after infections with other respiratory syndrome coronaviruses, such as SARS-CoV and MERSCoV. These studies suggest that these coronaviruses have the potential to cause severe maternal and perinatal complications; therefore, pregnant women with SARSCoV-2 infection should be treated with some caution. Other authors suggest that SARS- CoV-2 infection has less potential to cause adverse pregnancy outcomes than SARS-CoV and MERS-CoV coronaviruses [11–13].

However, more recent studies are less optimistic. They suggest that although pregnancy does not worsen the clinical course of COVID-19, conversely, the COVID19 during pregnancy can cause complications for both the mother and the fetus. A review by L. Panahi et al. analyzed 13 relevant articles and revealed that COVID19 could cause fetal distress, miscarriage, respiratory distress, and preterm delivery in pregnant women [14]. On the other hand, it has been found that clinical symptoms of COVID-19 in pregnant women are not different from those of non-pregnant women. A review by E. Mullins et al. reported that 15 (47%) out of 32 pregnant women with COVID-19 delivered preterm, and two had severe pregnancy complications [12]. Some reviews reported perinatal [15] and maternal mortality [16] associated with COVID-19.

There is a difficulty in discriminating common complications encountered in high-risk pregnancies with comorbidities, such as preeclampsia, from COVID-19. S. Gidlöf et al. described a clinical case of dichorionic twin pregnancy with severe preeclampsia complicated by COVID-19 [17]. A 34-year-old primipara with hypertension and proteinuria was diagnosed with gestational diabetes mellitus at 29 weeks of gestation. Since she presented with signs of pneumonia, a nasopharyngeal COVID-19 RNA test was taken, and its result was positive. The woman had severe preeclampsia complicated by COVID-19. She underwent emergency cesarean delivery. Both twins had negative nasopharyngeal COVID-19 tests. The difficulty lies in the possibility to confuse the manifestations of severe pregnancy complications with the signs of COVID-19.

The possibility of mother-to-child transmission of SARS-CoV-2

The problem of mother-to-child transmission of SARS-CoV-2 is two-fold, including transfer either in utero or by breastfeeding. Also, newborns could become infected with COVID-19 after birth if they come into contact with infected respiratory droplets. There is no doubt about the possibility of this mode of SARSCoV-2 transmission. Therefore, it is not considered in this paper. Let’s review each of these transmission modes in more detail.

There is currently no evidence of intrauterine transmission of COVID-19 from the mother to the fetus through the placenta. Of significant interest is the review article by L. Panahi et al. published in March 2020 [14]. The authors searched for all articles published in various databases, including PubMed, Scopus, Embase, Science Direct, and Web of Science from December 2019 to March 18, 2020. A review of 13 final articles published in this area revealed that there were no reports of vertical transmission of SARS-CoV-2 in pregnancy and clinical symptoms of COVID-19 in pregnant women were not different from those of non-pregnant women.

Similar results were obtained in other studies carried out almost at the same time as the above review. A review by E. Mullins et al. analyzed 23 case reports or series of cases and identified 32 women affected by COVID-19 in pregnancy, delivering 30 babies [12]. In 25 babies, no cases of vertical transmission were reported. An article by H. Chen et al. reported that clinical symptoms of COVID-19 in nine pregnant women at Wuhan University were similar to those of non-pregnant women, and no cases of transmission to children were identified [10, 18].

No cases of mother-to-child transmission of SARSCoV-2 were reported in later studies [4, 6, 7, 17, 19, 20]. However, there are rare reports of mother-to-child transmission of coronavirus [21, 22]. In two cases, it remains unclear whether the transmission was before or shortly after the birth of the baby. In the discussion, researchers are inclined to believe that the baby acquired COVID-19 after birth. The study by D. Chen et al. reported of a neonate who tested positive for SARSCoV-2 infection on real-time PCR 36 hours after birth [23]. Whether the newborn was infected with SARSCoV-2 in utero or after delivery remains unknown.

Besides, no studies have detected SARS-CoV-2 RNA in the placenta of mothers with confirmed COVID-19 [7, 19].

Mother-to-child transmission of SARS-CoV-2 by breastfeeding is apparently also impossible [10, 24]. Guidelines suggest that either COVID-19 positive mothers may breastfeed their neonates under strict measures of infection control, or the neonates may be fed with freshly expressed breast milk [24, 25].

Clinical characteristics of COVID-19 in newborns

There is a lack of studies examining the course of COVID-19 in newborns. Few cases have been observed in newborn babies, and those infected with SARSCoV-2 had a mild course of the disease, and none developed severe neonatal complications [23, 26, 27].

D. Chen et al. reported a case of transmission of the COVID-19 from mother to neonate in Wuhan (China) [23]. The neonate was transferred to a designated hospital for children with SARS-CoV-2 infection. After hospitalization, the newborn had no fever and cough, but mild shortness of breath was observed. A chest x-ray revealed a mild lung infection. Neonatal care and observation resulted in the rapid resolution of these symptoms. The newborn was discharged home two weeks later after two consecutive negative test results for SARS-CoV-2 RNA. Another study described three cases of infection SARS-CoV-2 in newborns, who also had mild disease [26].

There are isolated reports of severe bacterial complications in newborns with COVID-19 [28]. Therefore, in such cases, newborns should be tested for SARS-CoV-2.

General guidelines for the management of pregnant women and newborns

Currently, available research evidence is based on small-sized studies with an inadequate duration of follow-up. Therefore, it is essential to conduct further studies to investigate the safety and health of pregnant women and newborns with COVID-19. Pregnant women are susceptible to respiratory infections and the development of severe pneumonia, which may make them more susceptible to COVID-19 disease than the general population, especially if pregnant women have chronic illnesses or postpartum complications. Therefore, in strategies focused on the prevention and treatment of COVID-19 infection, pregnant women and newborns should be considered as critical groups with risk factors.

The guidelines provided by the National Health Commission of China suggest that neonates born to women with confirmed or suspected COVID-19 infection the neonate needs to be isolated in a separate room for at least 14 days after birth and should not be fed with the breast milk from mothers [29].

The American College of Obstetricians and Gynecologists (ACOG) and the Society for MaternalFetal Medicine have developed an algorithm to aid practitioners in promptly evaluating and treating pregnant women with a confirmed or suspected COVID-19 [30]. The algorithm notes that, unlike the flu and other acute respiratory infections, concerning COVID-19, limited data currently available do not indicate that pregnant women are at an increased risk of severe morbidity. However, given the lack of published cases and little experience of treating patients with other coronaviruses, such as SARS-CoV and MERSCoV, special care must be taken when evaluating and treating pregnant women. The algorithm was designed to aid practitioners in promptly evaluating and treating pregnant women with known exposure and/or those with symptoms consistent with COVID-19 (patients with suspected COVID-19). It should be remembered that if an influenza virus circulates in an institution, it also may cause symptoms compatible with COVID19. The algorithm for practitioners for evaluating and managing pregnant women with confirmed or suspected COVID-19 allows pregnant women to be categorized into groups, including patients who do not require special prenatal care, and groups of high, moderate, and low risk.

The Centers for Disease Control and Prevention (CDC) in the United States recommends that healthcare providers obtain a detailed travel history for all categories of patients, including pregnant women with high fever or ARI [31]. Health care providers should immediately notify infection control personnel at their facility of the presence of individuals suspected of having COVID-19.

CDC published Considerations for Inpatient Obstetric Healthcare Settings [32]. They were designed for healthcare facilities providing obstetric care for pregnant women with confirmed or with suspected COVID-19 in inpatient obstetric healthcare settings, including obstetrical triage, labor, and delivery, recovery, and inpatient postpartum settings.

Key recommendations include the following:

• Healthcare providers should promptly notify infection control personnel at their facility of the anticipated arrival of a pregnant patient who has confirmed or suspected COVID-19.
• Patients with confirmed COVID-19 or suspected COVID-19 should be looked after in a separate room with a closed door. For patients undergoing aerosol procedures, cabinets should be reserved for isolation from airborne infections.
• Infants born to mothers with known 19 or suspected COVID-19 at the time of delivery should be monitored.

To reduce the risk of mother-to-child transmission of coronavirus, obstetric care facilities should consider temporary separation of a mother with known or suspected COVID-19 and her infant (for example, providing separate rooms).

Also, the CDC has developed Interim Guidance on Breastfeeding, and Breast Milk Feeds in the Context of COVID-19 [33]. Occasionally, breastfeeding or feeding with breast milk is not recommended. The question of whether and how to start or continue breastfeeding should be determined by the mother in coordination with her family and healthcare providers. A mother with confirmed COVID-19 should be counseled to take all possible precautions to avoid spreading the virus to her infant, including hand hygiene and wearing a cloth face covering. When expressing breast milk either by hand expression or with a breast pump, the mother should clean her hands before touching any pump or bottle parts and wear a cloth face covering. Also, she should properly clean and sanitize breast pumps after each use.

The CDC recommends that all healthcare providers who enter a room of a mother or infant with suspected or confirmed COVID-19 should follow recommended infection prevention and control measures, including the use of recommended personal protective equipment. Detailed recommendations are published in the Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) [31].

The Royal College of Obstetricians and Gynecologists (RCOG, UK) has published Guidance for healthcare professionals on COVID-19 infection in pregnancy [34]. General recommendations for the provision of healthcare services to pregnant women are as follows:

• Given the risks to pregnancy-associated with COVID-19, pregnant women should ensure compliance with social distancing measures.
• It is recommended that, whenever practicable, all contacts should be made by telephone or using video conferencing.

In antenatal care for pregnant women with confirmed COVID-19, who are currently in a period of selfisolation, scheduled appointments should be delayed; no additional tests are required; even if a woman tested negative for COVID-19, but she has COVID-19 symptoms, COVID must be assumed.

For women with confirmed COVID before birth:

• The neonatal team should be informed of the imminent birth of a baby to a woman with moderate to severe COVID-19 as early as possible.
• Regarding the mode of delivery, an individualized decision should be made. Cesarean delivery should be performed according to indications based individualized assessment according to usual practice.
• Given the association of COVID-19 with acute respiratory distress syndrome, women with mild to severe symptoms of COVID-19 should be closely monitored. Efforts should be targeted towards achieving neutral fluid balance in labor.

Besides, the Royal College of Obstetricians and Gynecologists offers an algorithm to aid practitioners in assessing and managing pregnant women with confirmed and suspected COVID-19.

The website of the Ministry of Health of Russia provides Interim Guidelines for Prevention, Diagnosis, and Treatment of the Novel Coronavirus Infection (COVID-19), which is generally similar to the Interim Clinical Guidance of CDC [35]. At the time of writing (04.24.2020), it was version 6 of the guidelines. The provision of obstetric care to COVID-19 patients is addressed in chapter 5.5 of the guidelines. Besides, there are subsections addressing the management of pregnant women, parturient, and puerperal women. Obstetric management strategies are determined by several aspects, including the severity of the patient’s condition, the condition of the fetus, and gestational age. In patients with a moderate and severe course of the COVID-19 presenting before 12 weeks of gestation, termination of pregnancy is possible after the cure of the disease. Regional anesthesia is the preferred method of anesthesia in the absence of contraindications. Antiviral, antibacterial, detoxification therapy, and respiratory support are carried out according to indications. The prognosis for the mother and fetus depends on the gestational age at which the disease occurred, the presence of premorbid background (smoking, obesity, comorbidities including respiratory tract and ENT diseases, diabetes mellitus, and HIV infection), the severity of the infection process, the presence of complications and timeliness of antiviral therapy. A separate block describes the management of newborns in the contest of the coronavirus COVID-19 pandemic.

Conclusion

Pregnant women are at increased risk for developing a severe or complicated course of acute respiratory viral infections and influenza. Therefore, the management of COVID-19 infection in pregnant women requires a careful weighing of risks and benefits for mother and fetus. Pregnancy and childbirth do not seem to aggravate the clinical course of COVID-19 infection or CT features of COVID-19, and the clinical characteristics of COVID-19 pneumonia are generally similar to those for non-pregnant adult patients with COVID-19. However, COVID-19 during pregnancy can cause complications for both the mother and the fetus, including fetal distress, miscarriage, respiratory distress, and preterm delivery. Also, there is a problem of discriminating between the manifestations of severe pregnancy complications and the signs of COVID-19. There is currently no evidence of in utero mother-to-child transmission of SARS-CoV-2. It is also unlikely that mothers with COVID-19 can transmit the virus to their newborns via breast milk. Many generally similar guidelines for the management of pregnant women with COVID-19 have been published since the beginning of the outbreak, including Interim Guidelines for Prevention, Diagnosis, and Treatment of the Novel Coronavirus Infection (COVID-19), available on the website of the Russian Ministry of Health.