COVID-19 and Pregnancy

Abstract

It is of greatest concern how COVID-19 is affecting pregnancy, mothers, and babies. Scientists are studying the impact of COVID-19 on pregnant women and babies and are understanding a little more every day. Reports show that there is an increased risk in pregnant women compared to nonpregnant women to get more serious illness due to COVID-19. Researchers are also investigating COVID-19 and its potential impact on a fetus. There are exceedingly rare cases of COVID-19 transmission to the fetus, and newborns can pick up COVID-19 when exposed. Vaccines are proved to be safe for pregnant women and help prevent both mother and the fetus from getting COVID-19 and are also highly effective to prevent COVID-19 infection, critical sickness, and fatalities in general. There are specific guidelines for labor and delivery during the COVID-19 pandemic which are to be imposed and followed to achieve safer and healthier childbirth. In this article, the overall influence of COVID-19 in pregnancy, its pathophysiology, effects on placenta and neonates, maternal and perinatal features and outcomes, the role of vaccination, available treatment options, and the guidelines to be followed during the pandemic are discussed based on the available scientific evidence.

SUMMARY

1. Introduction

2. Pathophysiology

3. Effect on placenta

4. Vertical transmission

5. Fetal and neonatal impact

6. Perinatal outcomes

7. Role of vaccination

8. Currently available treatment options, their efficacy and safety

• 8.1. Antivirals

• 8.2. Immunomodulatory agents

• 8.3. Neutralizing antibodies

• 8.4. Thromboprophylaxis

9. Labor and delivery guidance

10. Conclusion

1. Introduction

SARS-CoV-2 is a novel coronavirus and the cause of the ongoing COVID-19 pandemic. The transmission is mainly through aerosols, respiratory droplets, and fomites. Commonly, it causes fever, dry cough, shortness of breath, headache, and fatigue^1,2. More specific symptoms are also reported, such as anosmia and dysgeusia. Although it usually has a benign course, potential complications including severe pneumonia, respiratory failure, hypercoagulability, shock, and organ failure are also seen³. This novel virus enters the host cell by attaching its viral spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2)⁴. This enzyme is essential for the correct regulation of the physiological renin-angiotensin-aldosterone system (RAAS), and it is expressed in several organs, such as the kidney, lung, heart, and placenta⁵. Although ACE2 is essential for SARS-CoV-2 entry into human cells, it is shown that it has some protective effects on the severity of the disease, mediating mainly against acute severe lung injury and balancing pro-inflammatory and anti-inflammatory function of RAAS. Data shows that ACE2 levels vary between people. Young people and women have higher levels of ACE2 whereas having risk factors, such as diabetes decreases these levels. Genetic phenotype is important as well. For example, East-Asian females have significantly higher expression of ACE2. This may somehow explain why younger people have a milder presentation of the infection, as well as why elderly men with risk factors have the worst outcome⁵. Pregnant women are at higher risk of developing severe symptoms when infected with SARS-CoV-2, with a greater percentage of pregnant women needing ICU admission. The evidence seems to show an extensive immune reaction in the placenta, such as villous hyperplasia, and mural hyperplasia. This is observed as chorioangiosis, fetal thrombosis, chorioamnionitis, and chronic villitis and represents an increased risk of undesirable outcomes during pregnancy and labor such as spontaneous preterm birth and higher maternal mobility⁶. Finally, the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the American Academy of Pediatrics (AAP) recommend breastfeeding while minimizing the risk of transmission such as a good hand wash before contact, and the use of a face mask, will ensure correct nutrition for the baby. Furthermore, studies confirmed that SARS-CoV-2 antibodies are transmitted through breastmilk, while the virus was undetected⁶.

2. Pathophysiology

The response to infections, particularly viruses, may be affected by changes in the maternal immune system during pregnancy. It is considered that, at least in part, the enhanced inflammatory response to viruses during pregnancy is mediated by the following factors: (1) There is a change in the CD4+ T cell population toward the Th2 phenotype rather than the Th1 phenotype. (2) There is a decrease in the number of circulating natural killer (NK) cells. However, whether this decrease in circulating NK cells has clinical ramifications for COVID-19 remains unknown. (3) There is a reduction in plasmacytoid dendritic cells (pDCs) in the circulation. These cells are essential for the generation of type 1 interferon, which protects against viruses. Furthermore, it has been discovered that pDCs from pregnant women have a reduced inflammatory response to the H1N1/09 virus. (4) The innate immune system undergoes changes, including the pattern recognition receptors Toll-like receptors (TLRs)⁷. SARS-CoV-2 infection produces host cell pyroptosis (programmed cell death triggered by inflammation in response to a pathogenic stimulus) and the generation of damage-associated molecular patterns (DAMPs), which can act as TLR ligands and increase inflammation (Figure 1). These changes in the maternal immune system have ramifications for COVID-19's clinical course, as well as its treatment and prevention during pregnancy. However, whether these modifications increase susceptibility and/or morbidity or are protective against COVID-19 must be discovered⁷. In most cases, the placenta acts as a barrier to prevent maternal infection from passing to the fetus (vertical transmission). SARS-CoV-2 expression has been found in midtrimester placenta samples; however, it is unclear if the virus was there owing to primary infection or was aided by placental damage caused by other illnesses. The mechanisms of viral infection of the placenta are still unknown. Given the lack of coexpression of ACE2 and transmembrane serine protease 2 (TMPRSS2) in the placenta, it appears likely that SARS-CoV-2 penetrates the placental tissues through a different route. Other proteases have also been linked to the problem. Both DPP4 and CD147 are extensively expressed in the placenta during pregnancy, suggesting that they may play a role in cell entrance. Although neonatal positivity at birth was inconsistent, SARS-CoV-2 viral RNA was found in the amniotic fluid in case reports of significant maternal sickness. Future research should investigate the inflammatory response, viral load, antibody production, and level of immunity developed in pregnant women at various gestational ages⁷.

Figure 1. Mechanism of increased inflammation in SARS-CoV-2 infection.

3. Effect on placenta

The COVID-19 pandemic has had an extreme impact on the population’s health. There are many ongoing investigations and recent studies every day regarding how the SARS-CoV-2 virus behaves in the general population. Studies that analyze pregnant patients and newborns must consider several different variables. Not all mothers are the same, and neither are their pregnancies. Therefore, this virus still presents a challenge to all doctors and researchers. COVID-19 infections in pregnant women have been shown to increase the risk of adverse outcomes during pregnancy such as alterations in perfusion⁸, vasoconstriction, intrauterine growth restriction (IUGR), and eventually preterm birth⁹. Many of the infected women had to go through a preterm emergency cesarean section because of fetal distress^8,9. Studies were conducted on mothers, during pregnancy, and after labor. Most of the trials investigated how the virus could infect the placenta cells and how this would affect the ongoing pregnancy and if this could have an impact on the health of the mother and newborn. Many studies began by taking samples of the placental tissue and focusing on the interaction between the virus and the cellular receptor. Like lung tissue, the placenta also owns ACE2 receptors^8,10. This receptor plays a key role in the entry and replication inside lung tissue and placental tissue as well¹¹. This could be thought to be one of the most important histopathological findings^8,10,11. This receptor is also a component of the ACE-AngII-AT1 axis⁸. There is a theory that if the virus interferes with this placental receptor, it may contribute to the pathological findings of vasoconstriction, fibrosis, inflammation, and thrombo-embolic processes in the placenta⁸. Once pregnant women have been infected with the virus, it can generate a diffuse and severe inflammatory response in the placenta. This ongoing inflammation can lead to what has been shown to be a local inflammatory response, an increase in fibrin deposition, mediated by B-cells, T-cells, and macrophages^12,13. The main target of the virus is considered the syncytiotrophoblast cells that are a component of the placenta¹⁴. These histopathological findings could be compared to the changes found in the lung tissue of patients who are not pregnant and could be considered the counterpart of the diffuse alveolar damage found in patients with pneumonia by SARS-CoV-2^11-14. Other hypotheses propose that a different receptor could play a role in the susceptibility of placental cells to SARS-CoV-2 infection. This receptor, named “caveolin” is thought to endocyte certain viruses¹⁵. Since syncytiotrophoblasts lack this membrane structure, there would not be an inflammatory response that would result in the syncytiotrophoblast remaining intact, with no alteration of its structure and thus SARS-CoV-2 cannot cross into the placental villi¹⁵. In addition, there are many hypotheses that these placental changes could be a result of maternal hypoxemia since the mother has an ongoing infection¹⁵. The SARS-CoV-2 virus has been shown to generate systemic inflammation that could alternate the perfusion and as a result the function of the placental cells. If the placenta is severely damaged, it can lead to diffuse inflammation, chronic intervillositis, and necrosis of the cells¹⁵. In brief, the infection of SARS-CoV-2 during pregnancy can lead to a variety of microscopic changes in the placenta. These changes could interfere with local perfusion, the most important function of the placenta. This would increase the risk of IUGR and eventually preterm birth. Results are still very inconclusive, and there is much more to learn about the effects at the placental level.

4. Vertical transmission

After nearly two years of the ongoing pandemic, research studies have been conducted all over the world regarding the SARS-CoV-2 virus. The transmission of this highly contagious virus via respiratory droplets has been a topic of great discussion regarding vertical transmission from pregnant women infected with SARS-CoV-2 and newborns. Nonetheless, transmission rates from mother to fetus during pregnancy in various studies have shown to be low, transmission rates are thought to be between 0.5% and 2.5%¹⁶. Studies were conducted in order to determine transmission between the mother and the fetus. It is well known that an infected mother can transmit the virus through respiratory droplets during breastfeeding if the appropriate protection measures are not taken. If the correct measures are taken, such as wearing surgical masks when breastfeeding, then breastfeeding and vaginal delivery are unlikely to transmit the virus¹⁷. The transplacental theory is the theory that stands until today over the others. Studies were conducted to determine transplacental infection. In various studies, samples were taken from the mothers and fetal blood and from the placenta. In a single case study conducted in Renmin Hospital blood samples drawn from the baby after delivery showed elevated IgM antibody levels but negative RT-PCR from nasopharyngeal swabs from the newborn¹⁸. The elevated IgM level, that must be produced by the fetus and cannot be passed on from the mother to the neonate, could suggest that the infection occurred in utero¹⁹. The syncytiotrophoblasts are thought to be the main protagonist when it comes to transplacental infection. In fact, they are the barrier between the infections that are passed on from the mother to the fetus in vertical transmissions, not only regarding COVID-19. Controversy arises from the fact that the placenta is often infected, but the infection is not passed on to the fetus. This could suggest a “placental barrier”. Some early studies conducted SARS-CoV-2 cannot enter placental villi for a lack of caveolin. Further studies showed that the placenta expresses ACE2 and TMPRSS2 that may facilitate cell entry of the virus by binding to the viral spike protein²⁰. In the setting of Boston Medical Center, a retrospective and prospective cohort study was conducted with a relatively small sample size from a single clinical site, to determine if the timing in which the maternal infection in pregnancy would change the outcome of the infection in the fetus. Samples were taken from the decidua basalis and analyzed for specific immune cell types dependent on gestational timing of SARS-CoV-2 infection. Results suggest that there is in fact an innate and adaptive immune response mounted at the placental level¹⁶. Varying levels of IL-6, IL-8, IL-10, and TNF-α are present, thought to be synthesized by maternal macrophages at the maternal-fetal interface. Infections during the second trimester showed downregulation of these cytokines suggesting a resolving immune response compared to infections in other trimesters. Likewise, for an infection to occur, there must be an interaction between the host and antigen. In this case it has been shown that mothers may be more susceptible to infections since pregnancy may be considered an immunosuppressed state. Other studies show that different comorbidities may aggravate the course of the infection in pregnant patients. SARS-CoV-2 has been found to have a higher rate of infection in pregnant women with gestational diabetes, hypertension, cardiovascular disease and asthma²¹.

5. Fetal and neonatal impact

Since pregnant women are more susceptible to COVID-related illness and hospitalizations, researchers initially believed the projected miscarriage rate for pregnant women would be 57% based on data from SARS and MERS outbreaks¹⁸. Initial reviews done on the outcome of pregnant women infected with SARS, MERS, and COVID-19 during pregnancy show increased preeclampsia, C-section, perinatal death, and miscarriage due to fetal distress²². This was caused by elevated levels of Il-6, IL-8, and TNF-α, increased hypercoagulation, and systemic inflammation leading to implantation failure and miscarriage²². Earlier systematic reviews also believed that widespread systemic inflammation would cause respiratory dyspnea, nervous system dysplasia, abnormal nervous and respiratory system development, and fetal demise²². Meta-analysis was used to analyze research done between December 1^st, 2019, and March 31^st, 2021, on earlier COVID maternal infections showed that overall, the miscarriage rate was similar between the general population and COVID-19 pregnant women. Miscarriages (<22 weeks) for COVID-19 pregnant women were 15.3% -23.1% with 95% CI, while the overall miscarriage (<20 weeks) rate for normal pregnant women was between 10-26%²³. Contrarily to earlier studies done on COVID-19, there were no associations between COVID-19 infection and miscarriage, and SARS-CoV-2 infection during the first trimester had no impact on early pregnancy loss²³. Initially, there were discrepancies between WHO, CDC, and AAP regarding protocols for mothers and neonates exposed to COVID-19. Studies completed during the past year have given more concise guidance on the management of these patients²⁴. Research shows that although there were cases of horizontal transmission through respiratory droplets when newborns were exposed to infected caregivers, the overall risk of acquired newborn infection was low when infection precautions were implemented. Breastfeeding was encouraged since the transmission of IgA and IgG antibodies helped neutralize SARS-CoV-2 activity, which in turn could provide neonatal immunity²⁴. In addition, the levels of IgG against the virus found only within the cord blood of seropositive women indicated that maternal antibody protection is possible²⁴. In general, if test results are not yet available, it is safe to assume that neonates born to infected mothers are positive for SARS-CoV-2 and should be isolated from other healthy neonates²⁴. Labor and delivery procedures as well as the type of birth (vaginal or C-section) should not be impacted by maternal infection status, and safety precautions should be used for all delivery personnel to ensure protection against maternal virus and aerosol spread²⁴.

6. Perinatal outcome

The normal physiologic changes that occur during pregnancy are like COVID symptoms; rhinitis, dyspnea, and changes in lung volume, making it harder to differentiate between the two diagnoses²⁵. Overall, the cardiovascular and pulmonary changes that occur during pregnancy increase the potential for infection and hypoxia. During pregnancy, Th1 helper cells decrease while Th2 helper cells increase causing a decrease in cell-mediated immunity and increasing maternal predisposition to infection²⁵. Influenza studies done on mouse colonies showed that pregnancy increased the Th1 inflammatory response pathway causing more physiological stress in the lungs. During COVID-19 infection, these same pregnant mouse colonies showed an increase in the Th2 pathway, activating an earlier protective immune response that leads to milder infections²⁵.

The gold standard diagnosis for COVID-19 is RT-PCR which gives a quantitative value for the viral load. Although COVID assays provide faster results and are more widely available, they do report a low false-negative rate possibly due to undetected viral loads. It is difficult to expand the use of RT-PCR since it requires specific equipment and reagents, a colder temperature, and can only be done in a biosafety level 2 lab (BSL-2)²⁵. Current pregnancy-specific treatment includes management of sepsis and respiratory distress which are common complications of COVID infection. For nonpregnant patients, higher sequential organ failure assessment (SOFA) scores and D-dimer (a small protein fragment found in the blood following fibrinolysis) levels >1 μg/mL on admission correlates with increased mortality. Using D-dimer levels to predict outcomes is difficult in pregnant patients since this value is generally higher and it is rare to find normal values within this population²⁵. Changes in renal perfusion and the increase in oxygen demand to support placental perfusion should be considered when calculating SOFA scores to account for normal physiologic changes during pregnancy²⁵. Per WHO guidelines, the use of systemic corticosteroids is not recommended since it delays viral clearance and has no impact on survival²⁶.

There is conflicting information on predicting the course of SARS-CoV-2 infection in pregnant women and newborns. While some studies show fluctuations in the clinical presentation of symptoms, the consensus is that it is still not clear whether the infection causes pregnancy complications²⁷. A study done at New-Jahra Hospital in Kuwait using retrospective chart data from 185 patients between March 15^th, 2020, to May 31^st, 2020, was used to analyze the clinical outcomes of pregnancy, maternal and fetal health for COVID-19 positive mothers²⁷. Out of 185 women, 1.1% had severe pneumonia while most (88%) had mild symptoms- fever being the most common seen in 58% followed by cough seen in 50.65%, and rhinorrhea/sore throat in 24.3%. Out of the 185, 1.6% had a miscarriage, 0.54% had fetal demise (not due to COVID), and 89% had live births, leaving 8.6% with ongoing pregnancies at the time of analysis. The most common lab finding (42.1%) was elevated lactate dehydrogenase, followed by 37.1% with elevated C-reactive protein (CRP), 24.2% with elevated alanine transaminase, and 15.7% with lymphopenia²⁷. The majority (97.3%) of patients who tested positive with PCR were given Oseltamivir, 24.3% received ceftriaxone, and 96.7% received Low Molecular Weight Heparin (LMWH). The patients with pneumonia were treated in the ICU without the use of extracorporeal membrane oxygenation and were eventually discharged²⁷.

Out of 165 deliveries, 26.6% were preterm and 47.8% (79) were born via cesarean section. 78 of the 79 C-sections were done because of fetal distress, and one was done because of fetal hypoxia caused by maternal pneumonia. While there were no neonatal deaths, 3% of neonates presented with hyaline membrane disease, and 1.2% tested positive for COVID. As well, COVID-19 infection in mother gives rise to risks of having small for gestational age (SGA) and low birth weight infants. Most preliminary studies noted fever and cough as most seen in COVID positive pregnant patients²⁷. In addition, most studies showed that COVID infections occur most commonly during the 2nd and 3rd trimesters and have a positive correlation with gestational diabetes²⁸. Since pregnancy naturally causes a hypercoagulable state, monitoring D-dimer levels is encouraged to prevent maternal mortality, especially when COVID infections are involved²⁷. Overall, the ICU admission rates among COVID pregnant women were about the same as the healthy population and experienced positive outcomes for both their own health and the health of their newborns²⁷. Figure 2 presents the effects of SARS-CoV-2 infection in pregnancy.

Figure 2. Impact of COVID-19 on pregnancy.

7. Role of vaccination

Maternal immunization is a public health strategy that tries to protect both the woman and her fetus or newborn infant from specific illnesses. Vaccination of pregnant women causes the production of vaccine-specific antibodies, which are then passed on to the children via the placenta or nursing²⁹. Due to the efforts of the scientific community and collaboration between the federal government and the pharmaceutical industry, multiple viable and safe COVID-19 vaccines have been created at an unprecedented pace. However, because pregnant and breastfeeding women are still excluded from COVID antiviral and vaccination trials, there is a contradiction of a lack of empirical evidence in a high-risk population³⁰.

The Food and Drug Administration (FDA) suggested undertaking developmental and reproductive toxicology studies before enrolling pregnant people or those who are not actively avoiding pregnancy in clinical trials, in acknowledgment of the necessity of including pregnant women in COVID-19 vaccination clinical trials. CDC has also developed a free smartphone app called "v-safe" that allows people, including pregnant women, to report adverse events after receiving the COVID-19 vaccine. Over 50,000 pregnant women have been studied so far, and no major vaccine-related side events have been reported. The United Kingdom has likewise established a comparable register for its inhabitants, with identical results and no safety issues with the COVID-19 vaccine³⁰.

Despite the potentially fatal implications of COVID-19 infection in pregnant women and the availability of safe and effective (in nonpregnant populations) COVID-19 immunization, there is a paucity of published data on the safety and efficacy of any COVID-19 vaccine in human pregnancy. Shimabukuro et al. reviewed data from safety surveillance registries, such as “v-safe” and the Vaccine Adverse Event Reporting System (VAERS), on the safety of mRNA COVID-19 immunizations in pregnant women³¹. A total of 35,691 pregnant v-safe participants were enrolled and the most common local and systemic effects following immunization were injection-site pain, weariness, headache, and myalgia, which were more common after the second dose³⁰.

Vaccination during pregnancy has been shown to protect both the mother and the baby from infectious diseases such as influenza and pertussis. COVID-19 vaccination based on mRNA nanoparticles and adenovirus vector, according to many expert committees, poses no major harm to pregnant or breastfeeding newborns. Shimabukuro et al. observed pregnancy loss in 13.9% of individuals who had completed pregnancy, based on an examination of safety surveillance registries such as “v-safe” and VAERS (i.e., live-born infant, spontaneous abortion, induced abortion, or stillbirth). They also mention preterm birth (9.4%) and small size for gestational age as negative neonatal outcomes (3.2%). There were no neonatal deaths reported. Many scientists believe that vaccine-stimulated immunoglobulin A can transfer through breast milk and provide further protection against COVID-19 to newborns³⁰. Golan et al. found the presence of vaccine-derived IgA antibodies in breastmilk 3-4 weeks post-vaccination with mRNA COVID-19 vaccine (n=23). Moreover, discovered that the IgA antibody titers in the breastmilk of participants who received COVID-19 vaccination and COVID-19 infection were identical³².

COVID-19 vaccine is the most promising method of containing the global pandemic of COVID-19. It is critical to protect our vulnerable pregnant and nursing women while also emphasizing their participation in vaccination and antiviral therapy, clinical studies, and vaccine administration³⁰.

8. Currently available treatment options, their efficacy and safety

Preferably, pregnant women with COVID-19 should be hospitalized irrespective of the severity of the disease³³. General treatment remains the same for pregnant women and the general population. It includes (1) monitoring vitals, symptoms, FiO2, complete blood count, liver and renal function, CRP, and chest imaging, (2) oxygen therapy with achieving oxygen saturation over 95 percent, and (3) antibiotics for secondary bacterial infection (4) maintaining fluid and electrolyte balance³⁴.

8.1 Antivirals

Limited data is available for antiviral drugs used in pregnant women with COVID-19³⁵. Below, some of the most useful ones are briefly described.

Lopinavir/Ritonavir (LPV/r)

Protease inhibitors are known for their use in the treatment of the Human Immunodeficiency Virus (HIV)³⁶. It reduces mortality when used in the treatment of COVID-19 during pregnancy³⁶. The potential adverse event includes hepatotoxicity, which exaggerates COVID-19-related liver dysfunction³⁷. Roberts SS et al. conducted a study using an antiretroviral pregnancy registry to estimate birth defects due to exposure to LPV/R in HIV-positive pregnancies showing the safety profile of LPV/R used during pregnancy³⁸. The dosage required is LPV/r (200mg/50mg), two capsules orally with alpha interferon (5 million IU in 2 mL of sterile water for injection), and nebulized inhalation twice a day³⁹.

Remdesivir

It is a nucleoside analog, acting by inhibiting viral RNA-dependent RNA polymerase⁴⁰. It is the first drug approved by FDA for the treatment of COVID-19 (October 22, 2020)⁴¹. In 2020, Burwick et al., through a remdesivir compassionate use program in pregnant women with severe COVID-19 showed increased recovery and decreased adverse events with a remdesivir treatment course of 10 days (200 mg on day 1 and 100 mg from 2-10 days, given intravenously) during pregnancy⁴². Contraindications included (1) glomerular filtration rate < 30 L/min, and (2) alanine aminotransferase level > 5 times the upper limit of normal³⁷. Certain studies have identified remdesivir to be effective and safe during pregnancy, and its efficacy reached up to 68%³³.

Molnupiravir

It is an FDA-approved Emergency use authorization (EUA) antiviral medication for the treatment of COVID-19⁴³. However, molnupiravir is not authorized to be used during pregnancy due to its teratogenic potential, until further studies⁴³.

Nirmatrelvir-Ritonavir (Paxlovid)

It is the first FDA-approved oral antiviral drug for EUA in the treatment of COVID-19 disease⁴⁴. Paxlovid is a combination of nirmatrelvir, which stops the virus from replicating, and ritonavir, which prolongs its duration of action⁴⁵. As Vitiello, Antonio, et al. in his review mentioned about embryo-fetal developmental toxicity studies in the rat or rabbit, (1) no teratogenic effects were seen except (2) reduction in fetal body weight in the rabbit⁴⁶. So, it is not recommended to use during pregnancy until further clinical trials⁴⁶.

Chloroquine and Hydroxychloroquine

The emergency use authorization of chloroquine and hydroxychloroquine for the treatment of COVID-19 was revoked by FDA on June 15, 2020⁴⁷. These antimalarial drugs were used in the treatment of COVID-positive pregnancies due to their safety profile, especially with hydroxychloroquine compared to other antimalarials⁴⁸. In 2020, Sisti et al. conducted a case report of a middle-aged woman G6P4014 at 26 weeks of gestation with COVID-19, treated with the combination of hydroxychloroquine (started on 400 mg on day 2 of hospitalization and 400 mg for the next 5 days, orally) and azithromycin (500 mg on day 1 of hospitalization and 250 mg for the next 4 days, orally) showing clinical improvement with low adverse outcomes except for QTc prolongation which got resolved with magnesium therapy⁴⁹. Vincent et al. reported that chloroquine terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2 affected virus receptor binding, these inhibitory effects were present before and after exposure to the virus⁵⁰. Thus, the authors concluded the potency of chloroquine in preventing and treating SARS-CoV-2⁵⁰. Despite that, high dose chloroquine can cause systolic hypotension exaggerating supine hypotension in pregnancy due to aortocaval compression by the gravid uterus³³. The recommended dose for hydroxychloroquine is 400mg, twice a day on day 1 followed by 200mg, twice a day from 2-4 days, given orally, and chloroquine 1 g on day 1 followed by 500mg from 2-7 days depending on recovery³⁷.

8.2 Immunomodulatory Agents

Interferon-alpha

Interferon-alpha has also been suggested for use during pregnancy in women suffering from COVID-19³⁹. Interferon-alpha inhibits viral synthesis through its immunomodulatory effects⁵¹. Certain studies have shown that a combination of interferon-alpha with lopinavir/ritonavir or favipiravir works effectively against SARS-CoV2 when administered via nebulization in a negative pressure room to prevent the dissemination of the virus through aerosol⁵¹. The recommended dosage is 5 million units twice per day⁵¹. The use of IFN-α during pregnancy is assumed to have abortifacient effects⁵¹. Therefore, IFN-α aerosol inhalation therapy should be used during pregnancy only if the benefits outweigh the potential risks to the fetus⁵¹.

Baricitinib (Olumiant)

The first immunomodulatory medication, baricitinib (Olumiant), was authorized by FDA on May 10, 2022, for the treatment of COVID-19⁵². It is the Janus Kinase (JAK) inhibitor, previously used in combination with remdesivir to treat COVID-19⁵³. Animal embryo-fetal development studies in pregnant rats and rabbits at the maximum recommended human dose (MRHD) showed (1) reduced fetal body weight and skeletal malformations (2) embryo lethality in rabbits (3) No developmental toxicity during organogenesis at approximately 5 and 13 times MRHD respectively⁵⁴. However, more clinical studies are required to establish the efficacy and safety profile of baricitinib use during COVID-19 pregnancy⁵⁴.

Tocilizumab

It is an FDA-approved EUA medication for the treatment of COVID-19⁵⁵. In 2020, Naqvi et al. mentioned a case report of 35-year-old primigravida at 22 weeks of pregnancy with COVID-19 treated with remdesivir (200mg on day 4 followed by 100 mg from 5-8 days of hospitalization, intravenously) and tocilizumab, and IL-6 monoclonal antibody (400mg, intravenously on day 3 of hospitalization), combination showing normalization of serum inflammatory markers (IL-6, C-reactive protein), decrease in oxygen requirement, and improvement in the clinical course of infection with less adverse events⁵⁶.

Corticosteroids (prednisone, dexamethasone, hydrocortisone)

Corticosteroids are used commonly for fetal lung maturation (betamethasone- 12 mg, given intramuscularly 24 hours apart) during pregnancy⁵⁷. Corticosteroids such as dexamethasone can be administered to COVID-19 pregnant patients with an increased risk of complications such as premature survival and the need for oxygen and mechanical ventilation³⁷. However, the use of Dexamethasone during the 1st trimester and after 37 weeks of gestation is contraindicated³⁵. In 2020, Zhou et al. performed a decision analysis in preterm prelabor rupture of membranes (PPROM) and COVID-19 positive pregnancies, showing the effectiveness of the administration of antenatal corticosteroids before 31 weeks of gestation as it increased maternal and infant quality-adjusted life years⁵⁷. Despite the benefits, corticosteroids with their immunosuppression effects can cause worsening infection in critically ill patients³⁷. The treatment course is of short duration with methylprednisolone 1-2 mg/kg/day³⁹. High doses of dexamethasone should also be avoided during pregnancy due to its negative effects on the fetus³⁷.

8.3 Neutralizing Antibodies

Bamlanivimab-Etesevimab/Casirivimab-Imdevimab (REGEN-COV)/Tixagevimab-Cilgavimab (Evsheld)

FDA revoked EUA for bamlanivimab (a monoclonal antibody that blocks the virus attachment and entry into human cells) in the treatment of COVID-19⁵⁸. However, it gave emergency use authorization to bamlanivimab and etesevimab/casirivimab and imdevimab/tixagevimab, and cilgavimab, when used in combination for prevention against SARS CoV-2^59-61. These antibodies work by preventing the binding of the spike protein of SARS-CoV-2, to its receptor on target host cells, thereby decreasing viral load⁶². In February 2022, Richley, Michael, et al. conducted a retrospective case series on monoclonal antibodies (bamlanivimab plus etesevimab or casirivimab plus imdevimab) use in pregnant persons with COVID-19 concluding favorable outcomes in pregnant women with its use⁶².

Sotrovimab

Its EUA for treatment of COVID-19 was revoked by FDA on April 5, 2022, due to its ineffectiveness against the Omicron subvariant⁶³.

Bebtelovimab

On February 11, 2022, FDA authorized a EUA against the Omicron subvariant⁶⁴. The infusion-related infections including anaphylaxis have been seen as adverse events with infusion of bebtelovimab⁶⁵. It is not recommended during pregnancy unless potential benefits outweigh risks, despite cross-reactivity studies using human fetal tissue showing no significant binding of clinical concern⁶⁵.

Convalescent Plasma Transfusion (CPT)

FDA has authorized high titer COVID-19 CPT for Emergency Use Authorization against SARS CoV-2⁶⁶. Convalescent Plasma (CP) therapy includes using blood plasma from recently recovered COVID-19 patients containing antibodies targeting SARS-CoV-2⁶⁷. In 2020, Grisolia et al. reported a case of a 29-year-old woman with G2P1 24 2/7 weeks of gestation with COVID-19 transfused with 300 mL of CP on day 7 and day 12 from the onset of symptoms resulting in (1) improvement in lymphocyte count (2) decrease in C-reactive protein and ferritin (3) decrease in oxygen requirement and resolution of inflammatory lung damage and acute respiratory distress syndrome (ARDS) (4) rapid recovery with no adverse outcomes⁶⁸. Thus, the authors concluded an improved clinical response with CP therapy in COVID-19 positive pregnancies⁶⁸. In 2021, Franchini et al. conducted a systemic review involving 12 case reports related to CP therapy administered between 21-36 (+/- 2) weeks of pregnancy with COVID-19 results showed that (1) two CP units at the first on day 2 of hospitalization showed clinical improvement in the majority of cases⁶⁹. Moreover, CP therapy efficacy is greater when administered within 72 hours of hospitalization (2) one case showed neutralization of SARS CoV-2 (3) improved maternal and fetal outcomes with decreased maternal morbidity in the majority of cases (4) no adverse outcomes in the majority of cases proved the safety of CP therapy⁶⁹. Thus, the authors concluded the efficacy and safety of CP therapy in COVID-positive pregnancies⁶⁹. Despite that, CP therapy may cause infection with blood-borne pathogens, Hepatitis B Virus, Hepatitis C Virus, and HIV⁶⁷. The treatment protocol is administrating CP in a single dose of 200 mL³⁷.

8.4 Thromboprophylaxis

Pregnancy is a hypercoagulable state; infection with COVID-19 can exaggerate the risk for venous thromboembolism (VTE)^70,71. According to The Royal College of Obstetricians and Gynecologists (RCOG), all pregnant women with COVID-19 should be assessed for VTE and receive prophylactic Low Molecular Weight Heparin (LMWH) unless birth is expected within 12 hours^70,71. Prophylaxis with LMWH (4000 IU/day) requires to be continued through the puerperium until the patient is diagnosed with COVID-19³⁷. Long-term adverse effects are heparin-induced thrombocytopenia and osteoporosis³⁷. Table 1 summarizes currently available therapeutic options for the treatment of COVID-19 during pregnancy.

Table 1. Table title.

Table caption

No.	Therapeutics option	Mechanism of action	Efficacy	Safety
Antivirals
1	Lopinavir/Ritonavir (LPV/r)	Antiretroviral, protease inhibitors	Decreases mortality	Safe
2	Remdesivir	Nucleoside analog, inhibits SARS-CoV2 RNA- dependent RNA polymerase	Increases recovery and decreases adverse events	Insufficient data to determine its safety
3	Molnupiravir	Mutagenesis, interferes with viral replication	No data	No data
4	Nirmatrelvir-Ritonavir (Paxlovid)	Nirmatrelvir is a SAR-CoV-2 protease inhibitor whereas ritonavir prolongs its duration of action	No data	No data
5	Chloroquine and Hydroxychloroquine	Interferes with terminal glycosylation of ACE2, in vitro activity against SARS-CoV-2	FDA revoked its EUA against SARS-CoV-2	May lead to systolic hypotension with high dose chloroquine and QTc prolongation when hydroxychloroquine is combined with azithromycin
Immunomodulatory Agents
6	Interferon-alpha	Immunoregulatory effects	Effective when used in combination with LPV/r	Insufficient data to determine its safety
7	Baricitinib (Olumiant)	JAK inhibitor, intracellularly inhibits the release of pro-inflammatory cytokines	No data	No data
8	Tocilizumab	IL-6 monoclonal antibody, inhibiting the pro-inflammatory activity of IL-6	Normalize inflammatory markers, decreases oxygen requirement, faster recovery, and decreases adverse events when used in combination with remdesivir	Insufficient data to determine its safety
9	Corticosteroids	Anti-inflammatory effects	Improves clinical course and decreases maternal and fetal mortality as well as morbidity	Safe, generally used for preterm lung maturation during pregnancy
Neutralizing Antibodies
10	Bamlanivimab-Etesevimab/Casirivimab-Imdevimab (REGEN-COV)/Tixagevimab-Cilgavimab (EVUSHELD)	Prevents receptor binding of the spike protein of SARS-CoV2, decreases viral load	Favorable outcomes are seen in pregnancy	Insufficient data to determine its safety
11	Sotrovimab	FDA revoked its use, ineffective against Omicron sub-variant
12	Bebtelovimab	Binds to spike protein of SARS CoV-2, decreases virus replication	Effective against Omicron sub-variant	Insufficient data to determine its safety
13	Convalescent Plasma Transfusion	High titer antibodies against SARS-CoV-2 from recently recovered patients	Increase in lymphocyte count, decrease in inflammatory markers, decrease in oxygen requirement, and decrease in maternal mortality	Insufficient data to determine its safety
Thromboprophylaxis
14	Low Molecular Weight Heparin	Anti-coagulant properties	Prevents venous thromboembolism (VTE)	Safe

However, pregnant women with COVID-19 should be alert while using these drugs. Physicians should only prescribe these drugs if the benefits outweigh the risks in this population. Moreover, they should also be monitored for adverse effects and possible toxicity to decrease maternal-fetal morbidity and mortality³³. Emphasis should be made to include pregnant women in clinical trials for the treatment of COVID-19 leading to the development of efficacious treatment with improved maternal and fetal outcomes in this population⁷².

9. Labor and delivery guidance

During the COVID-19 pandemic, labor and delivery come with its own unique guidelines. The hospital admission for these patients is planned and therefore patients are required to follow certain protocols to protect the health of the mother and the baby. The recommendations are as follows:

1. Take off from work 2 weeks prior to the date of delivery and maintain strict isolation⁷².

3. Labor and delivery triage patients and partners undergo verbal screening for upper respiratory infection symptoms⁷³.

a. If patients are positive for symptoms, provide a mask and further evaluate by the obstetric provider⁷³.

b. If the partner is positive for symptoms, refer to a medical care provider⁷³.

c. If a patient is COVID-19 positive, personal protective equipment should be utilized including a surgical mask and/or N95 mask, protective eyewear, gloves, and gown. Practice strict hand hygiene⁷².

d. Precautions should be taken to avoid the use of aerosolized oxygen⁷³.

5. Recommendations of labor induction vary with current protocols of the region delivery is taking place⁷².

a. During the first stage of labor, general management should occur as usual, including necessary intrapartum antibiotic use and oxytocin⁷³.To reduce the risk of COVID-19 spread, oxygen use in fetal resuscitation and nitrous oxide use are not recommended^74,75_,

b. The use of anesthesia during COVID-19 is not contraindicated⁷⁵. Regional anesthesia is encouraged since it reduces maternal respiratory distress due to pain and anxiety during labor⁷⁶.

6. Care in labor:

a. Aim to keep oxygen saturation >94% and titrate accordingly⁷⁷.

b. If women have signs of sepsis, investigate and treat as per guidance on sepsis in pregnancy but also consider active COVID-19 as the cause⁷⁷.

c. The mode of birth should not be influenced by COVID-19 unless the woman's respiratory condition demands urgent delivery⁷⁷.

d. When cesarean birth or other operative procedure is advised it should be done after wearing PPE⁷⁷.

7. Fetal monitoring and procedures:

a. Continuous electronic fetal monitoring is recommended for all symptomatic patients⁷⁸.

b. COVID-19 is not a contraindication to rupture of fetal membranes, application of a fetal scalp electrode, or insertion of intrauterine pressure catheter⁷⁸.

8. Management of the second stage:

a. Pushing should not be delayed since this involves repeated forceful exhalation and loss of feces which can increase the risk of virus transmission⁷⁸.

b. Patients who are positive for COVID-19 should wear a mask but if they are uncomfortable during exertion, they can remove it⁷⁸.

c. Delayed umbilical cord clamping in patients is highly unlikely to increase the risk of vertical transmission⁷⁸.

9. Management of the third stage:

a. Patients who develop postpartum hemorrhage can be managed according to standard protocols⁷⁸.

b. Mothers with COVID-19 can safely practice skin-to-skin contact and breastfeed in the birthing room if they wear a surgical mask and use proper hand hygiene⁷⁸.

c. No consensus regarding whether maternal COVID-19 is an indication for placental examination by a pathologist⁷⁸.

10. Medications in Obstetric COVID-19:

a. Indomethacin: this popular NSAID is thought to worsen the course of COVID-19 since the NSAID increases the expression of ACE2⁷⁹. However, this has not been established, and several agencies, including WHO and FDA, have suggested that use of NSAID should not be restricted. Nifedipine may be explored as an option in the case of tocolysis⁷³.

b. Betamethasone/Dexamethasone use should be limited after 34 weeks of gestation as there is an increased risk of COVID-19 related mortality associated with the use of steroids^72,79.

c. Magnesium sulfate: may be used as indicated in patients with mild to moderate respiratory symptoms and in those with delivery before 32 weeks of gestation or preeclampsia⁸⁰.

d. Recommendations on medication may change upon update to data⁷².

11. Intrapartum care of COVID-19 positive patients:

Prioritize delivery of term COVID-19 positive patients with mild symptoms. To prevent transmission, a section of the ward should be selected for COVID-19 positive patients⁷². Postpartum care includes the expedited discharge of patients with normal vaginal delivery, patients discharged on day 1, and cesarean deliveries discharged on day 2. Telehealth should be used for consultation including wound healing, mastitis, and any additional routine concerns the family may have⁷². No evidence of transmission of COVID-19 via breast milk, hence, CDC recommends breast milk to infants especially due to the presence of protective antibodies⁸¹.

12. Rooming-in for mother and baby:

Newborns should not be separated from their mother, regardless of COVID-19 status unless in the case of severe maternal or newborn illness⁸².

10. Conclusion

COVID-19 pandemic hit almost all aspects of people’s lives, its effect on pregnancy is also of serious concern. Pregnant women who are infected with COVID-19 are more prone to have an acute illness and it can result in several pregnancy complications like preterm labor and stillbirth. A rare number of newborns have been identified as COVID-19 positive although it is not certain when they got infected with the virus: prior to, during, or following birth. There have been little to no symptoms, and they recovered shortly after. The vaccines are proved to be effective against COVID-19 infection preventing both the mother and the child from getting seriously ill. A vaccinated mother can transfer antibodies to the baby against COVID-19 through breastfeeding, therefore, breastfeeding is recommended. For a safer and healthier pregnancy and childbirth, the recommended guidelines should be properly followed. Researchers are still investigating the additional effects of COVID-19 infection on pregnancy; we hope new findings will help us give more protection to the mother and child against this abysmal virus.