Introduction

On December 31, the first case of pneumonia caused by a new corona- virus (SARS-CoV-2) was announced in the city of Wuhan, Hubei province, China. Since then, new cases have appeared all around the world, to such a degree that the World Health Organization (WHO) declared it a global pandemic on March 13^1,2.

The available information suggests that the infection was originally zoo- notic, but current transmission is through close person-to-person con- tact (less than 2 meters) through respiratory droplets, or by direct contact with surfaces contaminated with infected secretions. Transmission could also occur by contaminated stool. The usual incubation period is 4 to 6 days, but it can vary from 2 to 14 days.

As the number of infected increases, cases of pregnant women with COVID-19 rise. Currently, there are no controlled studies of this disease in pregnant patients, but we have found case studies, case series and reviews³⁾ informing that pregnant women with COVID-19 do not tend to present serious symptoms. Until now, one maternal death has been reported, despite viral pneumonia being a leading cause of maternal mortality worldwide(4). In pregnant women, COVID-19 is usually characterized by fever (77 to 85%), followed by respiratory symptoms (dry cough and dyspnea in 23%), fatigue and/or muscle pain and, less frequently, gastrointestinal symptoms like diarrhea. Leukopenia and especially lymphopenia have also been reported³. It remains unclear if the pulmonary compromise or the pneumonia pattern among infected pregnant women differs from the other patients. A study of 15 cases in China⁵ found that most infected pregnant women had mild pneumonia with the same imaging findings as the general population, which are pavement pattern and consolidations mainly in the inferior lobes from both lungs⁶.

As in the general population, diagnosis is done by detecting viral genome (RT-PCR)^1-4).

Vertical transmission is highly unlikely; it has not been shown in any case during the current COVID-19 outbreak in China(3), nor in previous epidemics by similar coronaviruses (SARS-CoV and MERS-CoV)(7). Available studies have not found the virus in genital secretions, amniotic fluid nor breast milk³. Reported cases of infection in newborns are probably due to horizontal transmission.

This review summarizes the findings of studies and analyses in pregnant women with COVID-19, to contribute to the knowledge and management of this group of patients.

Methodology of the revIew

We performed a systematic review in the databases PubMed and Google Scholar until April 25, 2020, searching for published articles about pregnant women infected with SARS-CoV-2, without language restriction, and extending the search to the references of the retrieved articles. The review also included pregnancy outcomes after COVID-19 was diagnosed, as well as newborn’s birth, progress and outcomes. Relevant data were extracted to a dedicated database. The protocol was registered in the research database of Panama.

Diagnosis

Current methods to detect SARS-CoV-2 include:

Nucleic acid detection technology (RNA)

This diagnostic technology works with nucleic acid and is currently available as commercial kits. However, it has the following disadvantages: false negatives and false positives, samples for detection are easily contaminated and they require precision instruments and technical professionals. It is inconvenient to study the population at a large scale, and the technique is not viable for all hospitals. Besides, the positive rate for mild cases and for samples taken more than one week ago is low.

Immunodiagnostics techniques

Enzyme-linked immunosorbent assay (ELISA). The ELISA method is a fast, simple test that has a high sensitivity and does not require special instruments. It is particularly adequate for the serological detection of a large number of samples. Nevertheless, the purity of the antigen or of the coated antibody can seriously affect its specificity.

Immunogold labelling technology has become a trend in in vitro diagnostics in the last years because of its simple process that does not require special equipment nor specific operator training. Test results are intuitive and convenient for basic units and field work.

Molecular Methods

Routine confirmation of COVID-19 cases is based on detecting viral nucleic acid (RNA) by RT-PCR assays.

RNA can be extracted from the samples using any standard protocol or extraction kit. In general, the lysis step in RNA extraction inactivates any living virus, so lysates are usually considered non-infectious. Inactivation of SARS-CoV-2 by sample lysis has been confirmed in some commercial kits^8,9.

The protocol is based on detecting two targets in the viral genome: the E gene as a first line screening assay and the RdRp gene as the confirmatory assay using probes P1 and/or P2. The E gene is specific for all viruses related to SARS-CoV-2 (SARS-CoV and bat coronaviruses), while the RdRp gene is specific for SARS-CoV-2 when tested with probe P2. The PAHO/WHO has distributed specific reagents (primers, probes and positive controls) and protocols for these assays^8,9.

Although it is recommended to test for two different genetic targets (the E gene, followed by the RdRp gene) in order to obtain laboratory confirmation, once there is sustained transmission of coronavirus-19 within an area or country, it is not necessary to perform PCR for both genes. Diagnosis can use either the E or the RdRp gene. However, PCR for the E gene has a greater sensitivity, so the E gene is preferred for diagnosis.

Many reasons can explain a negative result in a person infected with COVID-19:

Poor sample quality, handling, transportation

Sampling failure, insufficient sample, presence of PCR inhibitors in the extracted RNA

Sample collection taking place when the patient is shedding undetectable levels of the virus, for example, too early or too late in the infectious disease process.

As with any other molecular assay, viral mutations in the regions targeted by the probes can affect detection sensitivity.

We must remember that, although this type of test is the most precise way to determine disease, its sensitivity does not exceed 60 to 70%.

Antigen Detection

During the first days after symptom onset (between 1 and 5), viral proteins that can be detected with several tests, such as ELISA and immunofluorescence, are generated. These assays have a generally acceptable specificity (depending on the assay). Thus, a positive result can be used as a diagnostic criterion, together with case definition and the clinical and epidemiological history; it can also be used to make public health decisions, such as social isolation. Nevertheless, the dynamics of production and secretion of these proteins (antigens) has not been established, so a negative result should not be used to rule out disease, and other criteria must be taken into account¹⁰. Besides, as days after infection and peak viral load pass by, sensitivity decreases.

Serologic Methods

Assays based on the detection of IgM/IgG antibodies can be of use in the investigation of outbreaks and seroprevalence studies. Many assays that detect IgM/IgG antibodies, such as ELISA and rapid diagnostic tests, are available and commercialized for diagnosing infection by coronavirus-19. These tests can be limited by cross-reaction with other coronaviruses normally present in the community, which makes the results difficult to interpret. Besides, response and antibody production dynamics during the different phases of infection is not fully established yet, which further limits the use of these tests.

Some studies have shown that during the first 6 to 7 days since symptom onset, less than 40% of patients have detectable antibodies¹¹. In the same way, antibody detection after day 7 only indicates previous contact with the virus, but it does not confirm presence and active shedding of it. Detected antibodies could be the result of a previous infection and not of an acute one, which is the problem that requires diagnosis.

Many products that detect antibodies (IgM and/ or IgG) induced by COVID-19 infection are being commercialized, including rapid diagnostic tests (RDT). Any test of this kind must be validated and its performance evaluated in terms of specificity and sensitivity.

These are the tests that will certainly help us assess population immunity and the duration of protection against the virus. Even today, they can help us know if there are people who were infected and did not present any symptoms.

Cesarean section

Delivery in a patient with COVID-19 should preferably take place when tests are negative. Because of this, infection with COVID-19 should not be an indication for patients with a gestational age under 39 weeks; however, there are some scenarios to discuss.

For patients in the 39th week or more with history of a C-section or an obstetric indication of cesarean delivery and COVID-19, either mild or severe, C-section must take place with all the required care regarding personal protection and follow-up of mother and newborn.

In pregnancies under 39 weeks with a previous C-section or obstetric indication of C-section and COVID-19, with criteria of mild disease, the team must wait until clinical findings disappear or improve and tests for SARS-CoV-2 turn negative.

In pregnancies under 39 weeks with a previous C-section or an obstetric indication for it and COVID-19, with criteria of severe disease, the decision to operate must be discussed with the neonatologist, the specialist in infectious diseases, the pulmonologist and the gynecologist-obstetrician. If the patient has less than 37 weeks and the clinical scenario allows it, corticoids must be administered as previously described. In some cases, the obstetric indication for C-section is a maternal condition, which may worsen during the active phase of labor.

There is no evidence that early or delayed clamping is associated with a higher risk of infection. As such, we consider that the attending professional should wait at least one minute to clamp the umbilical cord, until there is evidence suggesting the contrary. Vertical transmission of the virus has not been proven^3,15.

Breastfeeding

There is currently no evidence of the virus being found in breast milk, so this would not be a reason to suspend breastfeeding; further research is still required. It is clear that, in the scenario of an infected mother in close contact with her newborn, there is a risk of infection for the baby. Consensus among most organizations^17,22,28 is that breastfeeding should not be forbidden as long as mother and child are in normal conditions. This is a decision that should be discussed and agreed upon with the mother²².

If breastfeeding is decided and mother-child contact cannot take place, milk should be expressed following all hygiene measures and avoiding any possible contagion, and a relative or a third person should feed the milk to the infant.

Asymptomatic cases

When there is sustained community transmission in a city or country, the chance of having asymptomatic cases is higher; among pregnant women, this probability persists. To date, we have identified three publications^29-31 that demonstrate the existence of asymptomatic pregnant patients. Combined, they present 48 cases initially admitted to the hospital without any symptoms, who later developed signs for COVID-19 and were diagnosed with the disease, during vaginal or cesarean delivery or during the immediate postpartum. Interestingly, Sutton et al^.(31 tested 215 patients in a maternity ward, of which 33 (15%) were positive for COVID-19. An outstanding finding of this study was that out of the 33 positive patients, 29 of them were asymptomatic on admission; in other words, 88% of COVID-19 cases had no symptoms.

Given the findings of these studies, it is necessary to attend all obstetric patients as suspect cases and to perform confirmatory tests for SARS-CoV-2 whenever possible.

Conclusions

SARS-CoV-2 is a new coronavirus that started infecting humans by the end of 2019. It has caused the WHO to declare it a global pandemic and it has affected over 3 million people, causing approximately 200 000 deaths. Pregnant women are vulnerable to infection.

Most infected patients develop a mild form. In pregnant women, less than 10% develop the severe form, and less than 2% is admitted to an ICU. Only one case of maternal death has been published.

A significant proportion of cases of COVID-19 in the third trimester result in preterm birth (25%), mainly due to maternal instability and the attending healthcare team’s decision, as well as a higher frequency of premature membrane rupture. Perinatal mortality is very low. Vertical transmission has not been shown yet and cases of infected newborns seem to be caused by horizontal transmission.

There is a significant amount of asymptomatic cases seeking routine obstetric attention, so obstetric patients have to be treated as possible cases, providing the necessary protection for the healthcare team, the newborn and their families.