The coronavirus disease 2019 (COVID-19) is caused by a RNA-virus, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), with genetic similarities with other coronaviruses such as the bat coronavirus (Bat-CoV), the SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV).1 The latter two have the ability to infect humans. Cases of SARS-CoV-1 were initially diagnosed between 2002 and 2004 and is currently considered as an eradicated virus, whereas the MERS-CoV-1 was initially identified in 2012, and some cases are still reported in Saudi Arabia.2 None of these viruses have reached pandemic category, but in 2013 the WHO declared MERS-CoV as a global threat.3 Although the new virus is more contagious than previous ones, the average mortality is lower in SARS-CoV-2 (3-4%) as compared to SARS-CoV-1 (10%) and MERS-CoV (37%).4-6
We are currently facing a very rapid spread and a continuous increase in the worldwide number of COVID-19 cases, although some countries, such as China, South Korea and Japan, are controlling new cases and are beginning to lift restrictions. Contrary to this, other countries are just starting to report an increase in the number of cases, such as USA and Central and South America and the Caribbean. Despite this, the number of cases does not seem to be the most reliable parameter to measure the magnitude of viral spread, since up to 86% of virus carriers are asymptomatic and were probably not reported as a clinical problem.7 Furthermore, the lack of reliable tests, the low capacity of each country to perform tests, and the rate of false negatives due to low quality test reagents, do not allow a precise estimation of the pandemic evolution.8,9
2.General aspects of COVID-19
COVID-19 pneumonia has similar clinical characteristics to that produced by bacteria or other viruses. The faster spread of the SARS-CoV-2, as compared to other coronaviruses such as the SARS-CoV-1, appears to be related to the fact that it is thousands of times more contagious, with a basic reproduction ratio of 2.5.10,11 Interestingly, it not only multiplies in the lungs like the SARS-CoV-1, but also replicates actively in the throat during the first week when symptoms initiate.12
The SARS-CoV-2 has an incubation period of 5-6 days,13 after which various complaints may occur: anosmia, headache, myalgia, gastro-intestinal symptoms, cough, fever, dyspnea and neumonia among the most important.14 Severe disease occurs more frequently in patients with associated comorbidities (obesity, hypertension, chronic obstructive pulmonary disease, diabetes mellitus) and with higher mortality rates (up to 15%) observed in men aged 80 or more.15-17 Mortality rates will also depend on available local health resources at a given moment, which in turn will depend on the speed of action regarding its prevention or control.18 The clinical picture is associated by a cytokine storm with overproduction of tumor necrosis factor, interleukin (IL) 6, and IL-1β. The massive inflammatory response is associated with multiorgan lesions that at the same time potentiates the inflammatory reaction and impairs anticoagulant mechanisms. In severe pneumonia cases, there are microthrombosis, disseminated intravascular coagulation, and multiorgan failure with raised D-dimer concentrations (a poor prognostic feature). Disseminated intravascular coagulation is common in non-survivors.19
Although the most prevalent general COVID-19 symptoms include respiratory difficulty, cough, myalgia, and loss of appetite, some mild to moderate cases may frequently report olfactory and gustatory dysfunction. A multinational European study analyzed these symptoms in the general population using olfactory and gustatory questionnaires based on the smell and taste component of the Questionnaire of Olfactory Disorders-Negative Statements.20 Facial pain and nasal obstruction were the most frequent disease-related otolaryngological symptoms. An 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders. Olfactory dysfunction appeared before the other symptoms in 11.8% of cases. Among the 18.2% of patients who did not present nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0% and sudden anosmia or ageusia may be suggestive COVID-19. However, there is no information about those symptoms in pregnant women.
Cutaneous manifestations of COVID-19 have also been reported.21 Vesicular eruptions appear early in the disease developing, even in some cases, before other symptoms. Other patterns appear later in the disease evolution, as acral areas of erythema-edema, usually asymmetrical, with some vesicle or pustules with small red or purple spots caused by bleeding under the skin. Other lesions include small macropapules, sometimes around hair follicles or similar to pityriasis rosea. Itching was very common for urticariform lesions (92%) and for maculopapular (57%).21
3.SARS-CoV-2 during pregnancy
Women have more compromise of the respiratory system than the general population22 and can also be infected with both SARS-CoV-1 and 2, and MERS-CoV.23,24 However, more susceptibility to coronavirus infection has not been demonstrated during pregnancy25 and the clinical evolution is similar to that of non-pregnant women of similar age.26 During pregnancy, maternal dominant T-helper (Th) 2, protects the fetus, and the Th1 response (increase of interleukin 1) is associated with higher mortality risk among those with COVID-19.27 Respiratory failure progresses rapidly among pregnants with compromise of the cardiorespiratory system.22 Despite the fact that we have more and more data on this, there is no specific information on what is the real incidence of COVID-19 during pregnancy.
3.1. Clinical characteristics during pregnancy and perinatal outcomes
A high rate of maternal fatalities has been described in pregnants infected with SARS-CoV-1 and MERS-CoV (up 25% and 35% respectively).28,29 This figure seems to be much higher than what is currently described for SARS-CoV-2. The clinical course of pregnant women with COVID-19 has been reported generally mild to moderate, being fever and cough the two most frequent.23,30 Only a 5% of cases were severe.31,32 So far, no maternal mortality associated to SARS-CoV-1 has been reported but some cases have already been described for SARS-CoV-2.33 Therefore, pregnant women do not seem more susceptible to COVID-19 or to develop severe pneumonia.34 In general, the perinatal prognosis will depend on prematurity, often due to iatrogenesis, and on maternal well-being at the end of the pregnancy.
Qiancheng et al.26 reported a retrospective study regarding the severity of COVID-19 in pregnant (n = 28) and non-pregnant (n=54) women of similar reproductive age that occurred during two months of 2020 at the Central Hospital of Wuhan. They determined that there was no risk of viral vertical transmission during the third trimester of pregnancy including vaginal delivery. Also co-morbidities were not frequently reported in both groups. The majority of women were classified as having moderate pneumonia, 85.7% in pregnant women, and 98% in non-pregnant ones. Only 2 pregnant women and 1 non-pregnant had severe pneumonia. The authors recognized among the limitations that (i) more severe patients might have been admitted to other hospitals, other than the study center, and (ii) studied pregnant women were infected with SARS-CoV-2 in the late stage of pregnancy, and the probability of vertical transmission during the first half of pregnancy could not be assessed.
A retrospective study analyzed the clinical records of pregnant women with COVID-19 pneumonia treated at 25 hospitals in China between January 20 and March 24, 2020. The possible vertical transmission of the virus was studied by testing SARC-CoV-2 in amniotic fluid, cord blood, and neonatal pharyngeal swab.35 All tests resulted negative and there were no cases of fetal deaths. In addition, vaginal secretion samples were collected from the lower-third of the vagina upon admission and were negative.
Zaigham and Andersson30 performed a systematic review of peer-reviewed publications both in English and Chinese to summarize the clinical manifestations of 108 pregnancies with COVID-19, as well as maternal and perinatal outcomes. Cases of SARS-CoV-2 infection were confirmed by a laboratory test (reported in 18 articles). Women started to have symptoms in the third trimester of gestation, being fever (68%) and coughing (34%) the most frequent. Women presented lymphocytopenia (59%) and elevated C-reactive protein (CRP) (70%). A 91% of gravids delivered by cesarean section. Three maternal intensive care unit admissions were noted but there were no maternal deaths. One neonatal death and one intrauterine death were also reported. The authors concluded that although the majority of mothers were discharged without major complications, severe maternal morbidity and perinatal deaths as a result of COVID-19 were also reported. Vertical transmission of the COVID-19 could not be ruled out. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are required.
Di Mascio et al.23 performed another systematic review of pregnancy and perinatal outcomes of 79 coronavirus spectrum infections, and particularly SARS-COV-2. There was a diagnosis of pneumonia in 91.8% of cases, being the most common symptoms fever (82.6%), cough (57.1%) and dyspnea (27.0%). For all coronavirus infections, the rate of miscarriage was 39.1%; preterm birth < 37 weeks (24.3%); premature prelabor rupture of membranes (20.7%), preeclampsia (16.2%), and fetal growth restriction (11.7%). An 84% of women were delivered by cesarean section, perinatal death occurred in 11.1% and 57.2% of newborns were admitted to the neonatal intensive care unit. When focusing on COVID-19, the most common adverse pregnancy outcome was preterm birth < 37 weeks, occurring in 41.1% (95% CI 25.6-57.6) of cases, while the rate of perinatal death was 7.0% (95% CI 1.4-16.3). None of the 41 assessed newborns showed clinical signs of vertical transmission.
Elshafeey et al.36 reported a systematic review and meta-analysis regarding COVID-19 during pregnancy and childbirth. They summarized the clinical presentation and obstetric outcomes of 33 studies including data from 385 cases of which 14 (3.6%) were severe and 3 (0.8%) were critical. These 17 women were admitted to the intensive care unit, and 6 out of 17 were mechanically ventilated and one case died. A total of 252 women gave birth, 175 (69.4%) by cesarean section and 77 (30.6%) through vaginal delivery. Outcomes for 256 newborns included four reverse-transcription polymerase-chain-reaction (PCR) positive cases, two stillbirths, and one neonatal death. The authors concluded that the clinical characteristics and severity was similar to non-pregnant women or men. In addition, the review of 256 newborns, 8 were admitted to the NICU (3.1%), 3 needed neonatal mechanical ventilation (1.2%), 12 had respiratory distress syndrome (4.7%), 3 had pneumonia (1.2%), and 3 disseminated intravascular coagulation (1.2%). Mortality occurred in 3 cases and there were two stillbirths of two critical women (one maternal mortality and one woman on extracorporeal membrane oxygenation. In addition, there was one early neonatal death occurred due to complications of prematurity following cesarean delivery at 34 weeks due to antepartum hemorrhage.
3.2. Respiratory assessment
Chest radiography, computed tomography (CT) and/or chest ultrasound of patients with COVID-19 pneumonia are very important for early diagnosis and follow-up. Radiographic images of these patients show increased opacities with bilateral lower lobe predominant distribution, whereas lung ultrasound shows thickened pleural lines and patchy consolidations, and computed tomography shows consolidations.14,37-39 These findings were consistent with the experience provided by Peng et al.40 and Poggiali et al.,41 confirming the important role of lung ultrasound on the management of patients with SARS-CoV-2 that allows to rapidly diagnose and monitor COVID-19 pneumonia and its evolution toward acute respiratory distress syndrome (ARDS), in critically ill patients.
Ultrasound chest exam may be preferred in pregnant women, showing as mentioned above thickened pleural lines and patchy consolidations. These type of images have repeatedly been reported by radiologist as a fundamental part of the early diagnosis and the monitoring of the effects of treatment of the COVID-19 pneumonia.37,38
3.3. Laboratory findings and diagnostic test during pregnancy
Laboratory test findings include lymphocytopenia, thrombocytopenia, leukopenia, and the elevation of D-dimer and ferritin.14 Lymphocytopenia (59%) and elevation of CRP (70%) are among the most frequent laboratory abnormalities observed in gravids-30 In pregnancy, D-Dimer cannot be considered a marker of severity due to its physiological elevation during gestation.42
Xu et al.17 reported retrospective results of five pregnant women > 34 weeks’ gestation with a positive PCR test for SARS-CoV-2. These women displayed lymphopenia (<1.1 × 109/L) and eosinopenia (<0.02 × 109/L) at the onset of fever. The timing of eosinopenia largely matched that of lymphopenia. Lymphopenia and eosinopenia persisted until patients’ illness clinically and radiographically improved after antiviral/ antibacterial treatment. In contrast, leukopenia was observed in only one patient and all women had anemia, decreased albumin, and increased CRP and D-dimer levels
Carrying out diagnostic tests for SARS-CoV-2, antibodies and/or PCR, whether antepartum, intrapartum or postpartum will depend on the possibilities of each center or healthcare system, although we must bear in mind the possibility of false negatives so it is important to also take into account the symptoms of the patient.43 This would allow us to classify them as confirmed, possible, improbable, or uninfected, and act accordingly.
Based on data from several publications, Sethuraman et al.44have described how to interpret diagnostic tests for SARS-CoV-2 over time; although time intervals should be considered approximately. The proposal is only applicable if patients are proactively followed from the time of exposure, which is not easy in clinical practice and expensive when all techniques are to be required and all settings be taken into account. The most commonly used and reliable test for diagnosis of COVID-19 has been the reverse-transcription polymerase PCR test, performed from nasopharyngeal swabs or other upper respiratory tract specimens, including throat or, more recently, saliva. The virus can be detected at day 1 of symptoms and peaks within the first week of symptom onset; the positivity declines by 3 weeks and then on it becomes undetectable. A “positive” PCR result reflects only the detection of viral RNA and does not necessarily indicate the presence of viable virus.
3.4. Management of COVID-19 and pregnancy
The initial management of COVID-19 pregnant cases were not associated with severe maternal morbidity or mortality. However, more recent reports suggest that a subset of pregnant women may suffer organ failure or even die. Pregnants have a state of increased thrombin and prothrombin secretion that enhances the thrombosis risk when affected by COVID-19. Hospital management should be focused on treating the mother and protecting the newborn and health personnel. In general, management is also extrapolated from that used for the general population, monitoring vital signs, oxygen therapy, monitoring fetal well-being and prophylactic antibiotic use for bacterial pneumonia Some centers have used antiviral therapy (i.e. lopinavir, ritonavir and hydroxychloroquine) but, to date, there is no clear evidence of the effectiveness.
Prophylactic dose of a low molecular weight heparin (LMWH) is recommended for hospitalized patients with COVID-19 to prevent venous thromboembolism and treatment dose of LMWH is contemplated for those with significantly raised D-dimer concentrations due to concerns of thrombin in the pulmonary circulation; but LMWH also has anti-inflammatory properties that might be beneficial in COVID-19 patients. The International Society of Thrombosis and Hemostasis has generated a simple algorithm for the management of COVID-19 coagulopathy45 The use of low molecular weight heparin has been recommended in all such patients46 This body of evidence should be considered by obstetricians caring for pregnant women affected by COVID-19. A coagulation profile to detect the presence of subclinical disseminated intravascular coagulation and the use of low molecular weight heparin for the prevention of thromboembolic disorders should be considered and discussed between clinicians and patients.46
4.Miscarriage and preterm birth risk
Although miscarriage and second trimester losses have been described in SARS-CoV-1 and MERS-CoV infected pregnants,28, 47 direct association could not be demonstrated.47 48 To date, relationship with SARS-CoV-2 also has not been demonstrated,32 although the first case of perinatal mortality in a premature newborn has already been described.30 A recent systematic review of Di Mascio et al.23 reported that coronavirus infected pregnant women (including SARS-CoV-1, SARS-CoV-2 and MERS-CoV) present miscarriages, prematurity, probably due to iatrogenesis, and perinatal death among the > 90% who also had pneumonia. Regarding the relationship between SARS-CoV-2 and preterm birth, this has been mainly associated to iatrogenesis due to the termination of pregnancy to maintain maternal well-being.23,49 The risk of fetal hypoxia is probably secondary to maternal hypoxia due to COVID-19 pneumonia, rather than to the direct viral involvement which has not been demonstrated.
New information arises from a single pregnant woman with symptomatic COVID-19 associated with severe preeclampsia and placental abruption, demonstrating viral presence by molecular and immunohistochemical assay and electron microscopy.50 The SARS-CoV-2 was localized in the maternal interphase of syncytiotrophoblastic cells, suggesting that in some gravids the virus can affect the placenta.
During the pandemic, it is important to perform a PCR screening at delivery in order to know who is virally active for SARS-CoV-2; thus, to improve the clinical care of the pregnants, the newborn and protect health personnel with personal protective equipment (PPE). If screening is not possible, the decision to take these protective measures would have to rely on the symptoms compatible with the disease. Caution should also be taken with asymptomatic cases who had symptoms in the past two weeks, who had recently had a risky contact or are under viral screening.
At the time of delivery, pregnant women with COVID-19 may have evident clinical symptoms of the respiratory syndrome and must be assisted with personal protective equipment (PPE). However, there are also those without clinical symptoms or signs of the disease who may be subsequently diagnosed with COVID-19. To manage each prototype of patient, as a common high risk case, may create a huge cost for the clinical assistance. It is not clear which percentage of gravids are at risk of severe complications during delivery and those that will not develop the SARS-CoV-2.
Vintzileos et al.51 screened for the COVID-19 immune status in 161 pregnants admitted to the labor and delivery area. They found that 19.9% were COVID-19 positive (32/161 patients), and of these 34% (n=11) were asymptomatic and 21 (66%) were symptomatic. The authors drew several conclusions related to routine COVID-19 testing: (i) routine testing would increase PPE use in 21 asymptomatic patients; (ii) there were 5 patients with clinical symptoms who had a negative test; (iii) testing would increase 10% the identification of infected gravids (16/161); and (iv) all 32 COVID-19 positive mothers had negative COVID-19 tested neonates. Maternal testing during labor allows the identification of gravids that need PPE, allocate clinical resources such as chest imaging, oxygen use, and the transference to negative-pressure rooms. In addition, testing may neutralize the trend of mothers to “reduce”/deny symptoms in order to prevent them from being separating from their newborns. This type of study should be confirmed in different clinical scenarios and countries.
All healthcare personnel attending women in active labor should wear full personal PPE. Ashokka et al.45 have given some general/standard recommendations about maternal care during delivery to reduce risk of infection. Due to the possibility of viral dissemination during intense exhaling related to pain of active labor, early epidural analgesia for pain control should be considered. Advanced ventilatory and circulatory support, in an intensive care unit, should be provided by specialists for cases presenting with severe complications such as pneumonia, ARDS, and multi-organ dysfunction syndrome.
Up to 93% of described COVID-19 pregnancy cases have delivered by cesarean section, the majority due to the effects of COVID-19 over gestation and the risk of fetal well-being compromise.30,52 Another indication for cesarean section has been the maintenance of maternal well-being that can lead to iatrogenic prematurity.23, 24, 49, of which, in some elective cases its justification should be questioned.53
6.Puerperium and vertical transmission
First series of pregnant SARS-CoV-2 cases have not been able to demonstrate vertical transmission to the fetus; neither intrauterine, nor through the birth canal. Furthermore, the virus has not been detected in vaginal fluid nor in maternal milk;24, 54, 58 although it appears to have been detected in stool.9
Six newborn cases with elevated IgG antibodies in the blood and cases with elevated IgM have been described; although none of these cases yielded a positive PCR test.59,60 There is a need for more correlational studies. There is one case in which SARS-CoV-2 was diagnosed by PCR in a newborn at 36 hours of life, but the authors themselves indicated that although this could be a case of vertical transmission confirmation was not possible and still need to be confirmed.61 Rodrigues et al.62 carried out a systematic review of 30 original studies without language restriction, irrespective of study quality or language, reporting 182 deliveries resulting in one stillbirth and 185 live births. In all cases amniotic fluid, placenta and/or cord blood were analyzed and resulted negative for COVID-19. In addition, breast milk samples from 13 mothers had no evidence of the presence of the virus in breast milk.
Breastfeeding may be allowed depending on maternal and neonatal health status and prohibiting should be decided on an individual case basis, after discussion with an infectious expert physician and neonatologist.63
The COVID-19 has change the way medicine should be addressed in the near future. There is no specific treatment for COVID-19 and the current management is focused on maintaining ventilatory and cardiovascular functions and prevent thromboembolism. For the moment, there is no clear evidence for any specific coronavirus antiviral therapy. Future progress may be related to the development of a specific vaccine to prevent the infection.
This review was partially supported by the Sistema de Investigación y Desarrollo and the Vice-Rectorado de Investigación & Postgrado of the Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador.
“Furthermore, the lack of reliable tests, the low capacity of each country to perform tests, and the rate of false negatives due to low quality test reagents, do not allow a precise estimation of the evolution of the pandemic [8,9].”
“been delivered by cesarean section, the majority due to the effects of COVID-19 during gestation and the risk of impaired fetal well-being [30,51-52]. In other cases cesarean section has been indicated for maintenance of maternal well-being, which can lead to iatrogenic prematurity [23-24,48]. In some elective cases its justification should be questioned .
Conflict of Interest