Biomedical Research and Therapy Biomedical Research and Therapy http://www.bmrat.org/ Biomedical Research and Therapy 10.15419/bmrat.v8i10.701 Impact of COVID-19 on Pregnancy and Maternal Health: An Update Jummaat Fauziah drfauziahjummaat@gmail.com 1 0000-0002-1599-1754 Yahya Esam Bashir essam912013@gmail.com 2 Adnan A.S. 1 A.K. Atty Sofea 3 Management Science University Medical Centre, University Drive, Off Persiaran Olahraga, Section 13, 40100 Shah Alam, Selangor, Malaysia School of Industrial Technology, Universiti Sains Malaysia, Penang 11800, Malaysia Hospital Seberang Jaya, Jalan Tun Hussein, Seberang Jaya, Permatang Pauh, 13700, Penang, Malaysia 8 10 4655 4667 Abstract

The current pandemic caused by the novel coronavirus disease 2019 (COVID-19) is spreading at an accelerated rate globally. Global concerns were raised following its discovery in December 2019, as previous similar diseases. Diseases such as the severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the Middle East respiratory syndrome-related coronavirus (MERS-CoV) are known to lead to adverse outcomes in pregnant women and those in early maternal stages, with significantly higher rates of complication and mortality compared to other groups of individuals. The anatomical, physiological, and immunological changes that occur during pregnancy lead to higher risks associated with respiratory infections for pregnant women, as they can directly affect the well-being of pregnant women and infants. Vertical transmission of COVID-19 from mother to child was a concern, as such transmission could endanger a child. Three mechanisms of vertical transmission have been suggested: intrauterine transmission, placental blood transmission, and intrapartum transmission. This review discusses the impact and pathogenicity of COVID-19 on the well-being of pregnant and early maternal women, both the clinical aspect, health aspects, and diagnostic and therapeutic options. It will also discuss the adverse outcomes among pregnant women and newborn infants who contract the disease and the different mechanisms of vertical transmission from infected mother to child. The diagnostic and therapeutic approaches of COVID-19 that have been recently used have also been highlighted, in addition to the challenges faced by pregnant women who have contracted the virus during the pandemic.

Keywords COVID 19 health care infection maternal pandemic pregnancy vertical transmission Introduction

The novel coronavirus disease 2019 (COVID-19) was first reported in Wuhan city, Hubei province, China, in late December 20191. The causative agent of this novel disease was identified on January 7th 2020, from throat swab samples taken from patients by the Chinese Centre for Disease Control. They subsequently named the disease based on its symptoms, severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)2, 3. After a few months, the World Health Organisation (WHO) named the disease COVID-192. To date, most COVID-19 infected individuals have developed mild symptoms that persist for periods ranging from days to weeks, such as fever, malaise, sore throat, dry cough, and shortness of breath4, 5. The majority of patients have spontaneously recovered without the need for special treatment. However, some patients have developed serious complications, including septic shock, organ failure, severe pneumonia, pulmonary edema, and acute respiratory distress syndrome5, 6, 7. Various global studies have consistently shown that more than 80% of the total number of COVID-19-related deaths have been reported among older age individuals who suffer from other chronic diseases. Only 0.1% of deaths have occurred in individuals under 19 years of age8, 9, 10.

Several physiological and immunological changes occur in a woman’s body during pregnancy. These changes may predispose pregnant women towards significant health complications from respiratory infections, such as an increased risk of miscarriage, preterm birth, or even fetal mortality and morbidity10, 11, 12. Worldwide concerns were raised following the first reported cases of COVID-19, as previous similar diseases such as the severe acute respiratory syndrome-related coronavirus (SARS‐CoV) and the Middle East respiratory syndrome-related coronavirus (MERS‐CoV) were known to lead to adverse outcomes for pregnant women. Namely, pregnant women who contracted these diseases had greater mortality rates than non-pregnant individuals13, 14, 15. On March 11th, 2020, WHO characterized COVID-19 as a global pandemic. This decision was based on the previous coronavirus outbreaks that led to the loss of millions of lives, such as the Spanish flu (H1N1), which resulted in the highest number of deaths (approximately 50 million worldwide) and the Asian flu (H2N2), which resulted in between 1 – 4 million deaths16, 17. Figure 1 presents the recent pandemics caused by coronaviruses worldwide, with the approximate number of deaths caused by each. Few previous studies have classified pregnant women as not significantly immune-compromised18. Various immunological changes have recently been found to occur during pregnancy, which may, therefore, increase the susceptibility of pregnant women to certain intracellular pathogens, such as COVID-1919, 20. This, in turn, may render them more susceptible to infection and increase the risk of them being adversely affected when compared to the non-pregnant individuals.

<bold id="s-0dd3c74c5e8a">A time-line of global death caused by different coronavirus pandemics, as of September 2021</bold>. https://doi.org/10.6084/m9.figshare.16909204.v1

Numerous research papers have been published regarding the clinical manifestation, characteristics, and symptoms of COVID-19, as well as on therapeutic clinical trials21, 22, 23, 24. Systematic reviews examining its effect on women who are pregnant or in early maternal stags also have been published25, 26. However, most have been limited in the number of patients able to be examined due to the recency of the pandemic. Della Gatta et al.14 reviewed the clinical outcomes reported in six studies that involved 51 pregnant women infected with COVID-19. Karimi-Zarchi et al.27 examined the risk of COVID-19 being vertically transmitted from infected mothers to fetuses using published data in articles and official websites up till March 2020. Other reviews have further discussed the possibility of COVID-19 vertical transfer with controversial results27, 28, 29, 30, 31. The current review discusses the impact of COVID-19 on pregnant individuals, specifically in relation to its clinical manifestation and adverse maternal and fetal outcomes compared to non-pregnant individuals. Recent studies examining the mechanisms of vertical transmission of COVID-19 from infected mothers to newborns and/or fetuses have been used, in addition to the studies examining the placental pathology of infected mothers. Diagnostic approaches for COVID-19 and the therapeutic options that have been used are also highlighted, as well as the challenges pregnant women have faced during this pandemic.

<bold id="s-a7e24a2b88ba">Clinical characteristics of pregnant women infected with COVID-19</bold>

All genders and ages are susceptible to COVID-19 infection, including pregnant women and newborns32. The clinical manifestation of COVID-19 among pregnant women has been characterized by mild and sometimes severe upper respiratory tract symptoms, such as dry cough and chest tightness, as well as other, less commonly observed symptoms such as high fever, fatigue, dyspnea, diarrhea, and headache33, 34. Typically, severe upper respiratory tract infections are confirmed using chest computed tomography (CT images). China’s case-control study revealed that 94% of pregnant women with confirmed COVID‐19 infections had severe infections35. However, another study reported that most pregnant women with COVID-19 were asymptomatic upon admission to hospital, and none experienced any severe respiratory failure during their hospital stay36. This suggests that different stages of pregnancy and different immune responses in each case may affect the presenting symptoms of COVID-19 in pregnant women. A study by Yang et al.37 found that COVID-19 positive cases did not show any expectoration, dyspnea, or myalgia. However, CT images of their pulmonary systems resembled COVID‐19 pneumonia. Furthermore, pleural effusion was significantly higher among COVID-19 positive cases in pregnant women compared to non‐pregnant women. Figure 2 presents a summary of the symptoms and potential complications that can occur in COVID-19-infected pregnant women.

<bold id="s-e5bbd35450dc">Summary of COVID-19 symptoms and complications during pregnancy</bold>. The virus can affect both mother and unborn child, causing serious adverse outcomes. https://doi.org/10.6084/m9.figshare.16909207.v1

<bold id="s-85981dfe50a8">Adverse outcomes of COVID‐19 among pregnant women</bold>

COVID-19 infection has been associated with maternal hypercoagulability and pyrexia (cytokine storm), which can lead to increased infarction, placental intervillous thrombosis, and maternal hypoxia38, 39. However, evidence regarding fetal morbidity and mortality due to COVID-19 infection is still limited. Still, maternal changes secondary to COVID-19-infected pregnant women may lead to hypoxia and fetal heart rate changes38. In two recent studies by Zhu et al.40 and Chen et al.41, it was found that in eighteen middle-aged pregnant women infected with COVID-19, all had at least one or more common clinical symptoms, such as a dry cough, fever, sore throat, chest pain, or diarrhea. A significant variation in newborn birth weight was observed in these mothers, with weights ranging from 1520 g to 3820 g. The authors reported that more than half of the pregnant women in the studies had preterm deliveries, which is a higher rate than seen in non-infected pregnant women. They also reported other obstetrical complications in these women, such as preeclampsia, irregular contractions, premature rupture of membrane, and stillbirth, indicating early pregnancy intervention. Anatomical changes during pregnancy, such as diaphragm elevation, increased thoracic cage transverse diameter, decreased maternal tolerance to hypoxia, put pregnant women at a higher risk from respiratory infections42. Baud et al.43 observed contractive abdominal pain and fever among pregnant women suffering from COVID-19. Fetal distress has also been reported in pregnant women; however, it remains unclear whether it is caused by the COVID-19 infection or pneumonia14. A study from Iran reported that, out of nine COVID‐19 infected pregnant women who were displaying initial symptoms of pneumonia, seven women died following a few days of hospitalization. Of the two who survived, one of them was critically sick and ventilator-dependent, while the other was successfully cured after prolonged hospitalization44. Table 1 summarizes the maternal outcomes of COVID-19-infected pregnant women and their neonates observed in various studies.

<bold id="s-76adb216078d">Maternal and fetal effects of COVID‐19 reported in various studies</bold>

Study

Location

Number of patients

Maternal effects

Fetal effects

Blitz et al.45

USA

462 pregnant women

Preterm births, elevated inflammatory markers, tachycardia, lymphopenia, and hypoxia

Preterm babies and COVID-19 positive babies

Yan et al.46

China

116 pregnant women

Increase in spontaneous preterm birth.

Severe neonatal asphyxia and neonatal death

Sayeed et al.47

Bangladesh

68 pregnant women

Dyspnea, myalgia, and increased rate of abortion

Preterm babies, neonatal pneumonia, hyperbilirubinemia, and fetal death

Elshafeey et al.48

Global

385 pregnant women

Mechanical ventilation dependency, increases in abortion and maternal mortality

Neonatal death, preterm birth, intrauterine fetal distress, and COVID-19 positive babies

Savasi et al.49

Italy

77 pregnant women

Increased pregestational body mass indexes and abnormal respiratory and heart rates

COVID-19 infection in the early postpartum period

Smith et al.50

Global

92 pregnant women

Preterm births, fetal distress, and fetal intensive care and ventilation requirement

Signs of vertical transmission, low birth weight, and requirement for NICU admission

Capobianco et al.51

China

13 research studies

ICU admission and preterm infants pooled proportion

Pneumonia, infected infants pooled proportion, and respiratory distress syndrome

Zaigham & Andersson52

Global

108 pregnant women

Lymphocytopenia, elevated CRP, and ICU admission

Intrauterine death and intrauterine growth restriction

Diriba et al.53

Global

879 pregnant women

Preterm birth, miscarriage, preeclampsia, and fetal growth restriction

Neonatal asphyxia, apgar score, ICU admission, and perinatal death
<bold id="s-2b7a61a31508">Fetal outcomes in COVID‐19 infections </bold>

The first reported newborn infant delivered by a COVID-19 positive mother was on February 5th 2020. This was announced by the official Xinhua news agency. The infant had no fever or cough and stable vital signs but had observable shortness of breath, unusual chest radiographs, and abnormalities in liver function54, 55. Dashraath et al.56 observed numerous adverse neonatal outcomes from COVID-19 positive mothers, including fetal distress (43%), preterm birth (39%), intrauterine growth restriction (10%), perinatal death (7%), and miscarriage (2%). These outcomes were mainly dependent on the stage and complications during the pregnancy; increased effects of COVID-19 on pregnant women led to more adverse fetal outcomes. In their systematic review, Yang et al.25 reported that other COVID-19-related adverse fetal and neonatal outcomes had been observed, including fetal distress, stillbirth, neonatal death, and neonatal asphyxia. In a different study, the prognosis of infected infants was reported to be good, although preterm births with significantly low birth weights were observed, and many newborns suffered intrauterine fetal distress and respiratory distress syndromes. Some newborns were immediately admitted to neonatal intensive care units as they had neonatal pneumonia, which requires neonatal mechanical ventilation48. The placenta has been reported to execute and orchestrate the pathways of fetal growth. Some studies have revealed the ability of COVID-19 to induce placental gross pathological alterations57. Vascular abnormalities that occur in the placentas of infected mothers included fetal vascular malformations and malperfusion in 50% of pregnancies58, 59. Chen et al.33 reported an increased incidence of spontaneous and induced abortions among infected mothers, suggesting the potential risks of abortion, premature gestational loss, and congenital defects in neonates in infected mothers.

<bold id="s-8eaa8f73a23a">Mechanisms of vascular damage of COVID-19 among pregnant women </bold>

The COVID-19 nucleocapsid proteins contain a highly complex RNA. However, as is typical of coronaviruses, the nucleocapsid is surrounded by a membrane containing three proteins: spike protein, small membrane protein E, and membrane protein M60. When the virus attaches to the respiratory tract, cell entry occurs via two pathways. One pathway is the direct plasma membrane route, which involves the transmembrane serine protease 2 and is used by most viruses61. The other pathway is through viral spike proteins, which tightly attach to the ACE2 receptor (angiotensin-converting enzyme 2) and release the viral genome into the host cell. The viral genome is translated inside the host cell, replicating and producing more RNA genomes and viral proteins, and consequently, continuing the life cycle of the virus62. Narang et al.63 reported that the ACE2 enzyme plays an essential role in the conversion of many angiotensin compounds, including the conversion of angiotensin I to angiotensin-(1-9) and angiotensin II to angiotensin-(1-7), which causes antithrombotic, vasodilatory, and anti-inflammatory effects64. During pregnancy, a women’s hormonal profile changes, increasing the levels of renin-angiotensin-aldosterone system compounds, including ACE2.7. These changes put pregnant women at a greater risk of contracting and suffering adverse outcomes from COVID-1965. Systemic vasodilatory responses are maintained in pregnant women to balance their blood pressure. This occurs through the conversion of angiotensin II, resulting in increased levels of angiotensin-(1-7)66. Garovic et al.67 reported that 3.5% of all pregnancies suffer from the pregnancy-specific hypertensive disorder, preeclampsia. Preeclampsia is characterized by multisystem involvement due to the loss of angiotensin regulation leading to imbalanced blood pressure. COVID-19 has been reported to downregulate the ACE2 receptor after it binds to it68. This downregulation potentiates renin-angiotensin-aldosterone system abnormalities if the infection occurs during the pregnancy, and leads to an increase in the conversion of angiotensin II relative to the decreased angiotensin-(1-7) levels that are present in preeclampsia69. Coagulation abnormalities and endothelial cell dysfunction are two other common mechanisms shared between COVID-19 and preeclampsia, both of which cause vascular damage. Endothelial cells are known to express ACE2 receptors. Infection with COVID-19 during pregnancy may significantly mimic and/or initiate microvascular dysfunction of endothelial cells by causing endotheliitis. Endotheliitis has been reported to cause systemic inflammation and microcirculatory dysfunction. Some studies have reported that the induction of endothelial cell injury via an immune cell-mediated response is characterized by the resulting vasoconstriction and ischemia69, 70, 71. Cattaneo et al.72 reported that COVID-19 patients recorded high rates of stroke, deep vein thrombosis, and pulmonary embolism due to a pro-coagulopathic state. Pregnant women with COVID-19 can be particularly prothrombotic due to coagulation abnormalities resulting from hormonal alteration, which may potentiate a hypercoagulable state63. Thus, pregnant women are significantly susceptible compared to non-pregnant women for invasive infection with COVID-19.

<bold id="s-14e7c69734b5">The immune responses to COVID-19 in pregnancy </bold>

Since the outbreak of COVID‐19, numerous infections have been reported among pregnant women73. It is known that during pregnancy, the female immune, respiratory, circulatory, secretory, reproductive, and endocrine systems undergo significant physiological changes, making them more sensitive to viral infections such as COVID-1955, 74, 75. During pregnancy, the immune system faces significant challenges regarding establishing and maintaining tolerance to the growing allogeneic fetus while concurrently responding to potential generated cancers and/or microbial infections20, 76. COVID‐19 infected mothers have been confirmed to be at a higher risk of developing more severe respiratory complications27. Many studies have confirmed the ability of COVID-19 to alter immune responses, particularly at the pregnancy and maternal-fetal interface, which directly affects the well-being of pregnant women and infants77, 78, 79.

Interestingly, the cytokine profiles in non-pregnant COVID-19 infected women have been extrapolated to account for the different severities of the disease in affected pregnancies. Preferential activation of Th1 immunity has been observed among pregnant women infected with COVID-19. This activation has been found to lead to a marked increase in the production of pro-inflammatory cytokines (IFNγ, IL-6, IL-1β and IL-12) for more than 14 days following the onset of disease, which, in turn, causes extensive lung damage34. The activation of Th1 and Th2 cells during COVID-19 infection leads to a significant increase in IL-6 levels and the Th1 response. This activation is associated with an increased mortality risk, particularly among pregnant women34. The natural immune response to the placenta and its tropism increase pregnant womens’ susceptibility to COVID-19 and other certain infectious diseases80. Decreased numbers and activity of natural killer cells (NK) and T lymphocytes in the late stage of gestation have been reported to affect the clearance rate of the viruses, favoring the onset of viral infection55. Tsafaras et al.81 reported that dysregulation of many immune factors, such as the complement cascade and several cytokines, as a result of viral infection may have deleterious consequences to fetuses and newborns, particularly in relation to brain development and function. More importantly, immature immune systems put fetuses and newborns at a high risk of developing infections after birth82.

<bold id="s-0d78084b2838">Vertical transmission of COVID‐19 from mother-to-child </bold>

The transmission method of COVID-19 from mother to fetus has not yet been well-established83. The possibility of vertical transmission has always been of great concern to obstetricians and neonatologists. Karimi et al.27 collected data from published research articles and hospitals’ official websites at the beginning of the pandemic and found that no COVID-19 infection had been detected in neonates or placentas. The authors reported two deaths of mothers after delivery from COVID-19-related respiratory complications. However, recent studies have reported three potential mechanisms of vertical transmission of the virus from mother to fetus, namely intrauterine transmission84, placental blood transmission85, and intrapartum transmission86. Komine-Aizawa et al.87 suggested four mechanisms for COVID-19 to cross the placental barrier, namely passaging from the maternal circulation to extravillous trophoblasts (placental cells) passaging through maternal immune cells, direct infection of syncytiotrophoblasts, and ascending infection through the maternal vaginal tract. Intrauterine transmission occurs during pregnancy at any time88. Multiple findings suggest the possibility of intrauterine vertical transmission of COVID-19. Some studies have reported positive real-time PCR (RT-PCR) testing for COVID-19 of a neonate directly after birth, the elevation of specific immunoglobulins (Ig M), and the early onset of symptoms in neonates89, 90. However, other studies have revealed the opposite. Elósegui et al.91 found no evidence to suggest the possibility of COVID-19 passage from mother to amniotic fluid. The same conclusion has been drawn in many other studies92, 93, 94. Intrapartum transmission or transmission of COVID-19 from mother to baby during or directly after delivery have been reported to occur, despite initial negative test results, due to the incubation period of the virus being 14 days95. Intrapartum or early postnatal infection have also been reported to possibly occur through direct exposure of the newborn to COVID-19 infected maternal blood or other secretions96. Placental blood transmission of COVID-19 may occur at different stages of pregnancy, which will result in different impacts depending on the developmental stage of the fetus97. In a recent study by Schwartz et al.89, it was suggested that the diagnosis of intrauterine transplacental COVID-19 among infected mother-neonate dyads should be based on the identification of COVID-19 in fetal-derived cells, using advanced techniques such as in situ hybridization, nucleic acid-based technique, or immunohistochemistry. The authors demonstrated that COVID-19 was able to enter the placenta and pass to the fetus prior to delivery. These findings confirm placental viral infection in different neonates.

<bold id="s-2e46d786d02c">Placental pathology in COVID-19-infected mothers </bold>

The RNA of COVID-19 has been proven to transfer through placental tissues, leading to adverse effects for developing fetuses98. Numerous studies have confirmed the potential transmission of COVID-19 through the placenta. In a study by Yang et al.99, evidence of COVID-19 infection was found in nine out of 83 neonates. Zaigham et al.52 reviewed 18 research articles and found one neonatal death and one intrauterine fetal demise that resulted from placental pathology. Vascular malperfusion has been reported to be the most common placental pathology among COVID-19-positive mothers. Mulvey et al.100 investigated the placentas of five COVID-19 infected mothers who delivered at term and reported that all showed fetal vascular malperfusion and multiple thromboses. The evidence of thrombosis in all five mothers was seen in larger vessels in the fetal circulation. The presence of the spike protein and RNA of COVID-19 within the placentas of infected mothers was rare, indicating that COVID-19 did not directly infect the placentas, and thus the observed effects of thrombosis were a result of the systemic effects of the virus100. Maternal and fetal tissues are known to be separated by syncytiotrophoblast layers, which act as a physical barrier against the vertical transmission of many pathogens, including viruses. However, Baergen et al.58 reported nine cases of fetal vascular malperfusion among 20 cases of COVID-19 infected mothers.

Similarly, Shanes et al.101 examined 16 placentas of COVID-19 infected mothers and reported that in the 15 third-trimester placentas, fetal vascular malperfusion and maternal vascular malperfusion were observed in 12 of them. In contrast, some studies examining other newly emergent viral diseases, such as the Zika virus, have found a lack of placental pathology except for some cases that report chorionic villous stromal macrophages hyperplasia (Hofbauer cells)102, 103. Focusing on placental features can significantly contribute to understanding the impacts of COVID-19 infection on maternal and fetus well-being. Due to the limited number of studies and patients, it is important to further investigate the histology, immunohistochemistry, and molecular genetics of the placenta of COVID-19 infected women who are in the later stages of pregnancy.

<bold id="s-f21888324e53">Diagnostics and therapeutic options for COVID-19 in pregnancy</bold>

The COVID-19 pandemic spread globally at a rapid pace, causing a necessary and rapid adjustment in the fields of gynecology and obstetrics. RT-PCR has been described as the best diagnostic approach for detecting COVID-19 infection104. However, this technique is highly affected by the quality of the sampling process, where low-quality samples may not give accurate results19. Ali et al.105 used RT-PCR for scanning 11 asymptomatic pregnant women from China, who all tested negative for COVID-19. The authors also performed a CT scan and serum antigen-antibody (IgM and IgG) titers, revealing typical abnormalities related to COVID-19, indicating that infection lesions and ground-glass opacity had resulted from viral pneumonia. The authors also observed elevation in IgM and IgG antibody levels in the serum of patients that were determined to be pregnant following the CT scan, which is another indication of COVID-19 infection. This suggests that both CT imaging and serum antigen-antibody profiles are accurate markers for COVID-19 diagnosis, particularly in asymptomatic pregnant women. Consistency comparisons between CT and RT-PCR have been carried out. Ai et al.106, who reported similar results, suggested the requirement for longer RT-tests for COVID-19 detection. Zhang et al.107 suggested using serum antigen-antibody (IgM and IgG) for COVID-19 detection as a more accurate approach that is not limited by low-quality sampling like RT-PCR. Donders et al.108 suggested that the threshold for frequent testing of pregnant women with COVID-19 symptoms should be lowered to provide more regular follow-ups for both fetal and maternal complications. Clinical assessment determines and decides the requirement for hospitalization in pregnant patients while awaiting the test results. Numerous drugs have been used for COVID-19 treatment in both pregnant and non-pregnant patients. Table 2 summarizes some of the most commonly used drugs.

<bold id="s-86570cba4df6">Therapeutic drugs used for COVID-19 treatment in infected pregnant and postpartum women</bold>

Drug

Mechanism of action

Effect and safety during pregnancy

Referenc

Hydroxy-chloroquine

Reduces inflammatory response and interferes with the synthesis of ACE2 receptor

Considered safe during pregnancy, as it reduces temperature, promotes pneumonia recovery and cough remission, and improves nasopharyngeal viral clearance

109, 110

Remdesivir

Inhibition of viral replication

Shortens the recovery time in pregnant and postpartum women with severe complications

111, 112, 113

Corticoids, such as dexamethasone

Anti-inflammatory actions

Safe during pregnancy, reduces mortality and promotes faster recovery from severe COVID-19 pneumonia

114, 115

Lopinavir and Ritonavir

3-chymotrypsin-like protease inhibitor

Significantly reduces COVID-19 mortality rates, even among HIV+ women

116, 117

<bold id="s-793e7db590b2">Challenges facing pregnant women during the COVID-19 pandemic </bold>

COVID-19 is a highly contagious disease that can be rapidly spread from symptomatic and asymptomatic patients118, 119. It has been confirmed that this disease has the ability to cause serious health impacts in both pregnant women and their newborn fetuses. WHO recommends frequent COVID-19 testing during pregnancy via RT‐PCR testing120. A high proportion of COVID-19 infections worldwide have been caused by asymptomatic patients13. Thus, implementing strict infection control measures as well as conducting universal screening of all pregnant women is critical for early diagnosis and the prevention of any further risk to both mothers and neonates. The Royal College of Obstetricians & Gynaecologists and the American College of Obstetricians & Gynecologists both recommend that pregnant women in all stages of pregnancy should take preventive measures, as they are considered to be at high risk of developing complications compared to other populations. Both colleges recommend wearing masks, washing hands with effective disinfectant, strictly maintaining social distancing, and undergoing frequent COVID‐19 testing in order to prevent transmission of the disease118, 121. It is still uncertain whether COVID-19 can be transmitted via breast milk. However, Groß et al.122 examined milk from two COVID-19 infected nursing mothers and detected COVID-19 in one mother’s breast milk, and suggested that the COVID-19 loads in that mother’s breast milk may have been noticeably higher than detected. The same authors detected COVID-19 RNA in the breast milk of one of the infected mothers, who displayed mild COVID-19 symptoms. The newborn was confirmed to be positive for COVID-19 newborn following breastfeeding, despite health precautions, such as wearing a mask and nipple and surrounding area sanitization, being followed. This suggests that there is a high potential for COVID-19 to be transmitted during breastfeeding122. In a different study, Lackey et al.123 reviewed 13 studies examining the potential detection of COVID-19 in breast milk. They revealed that the COVID-19 specific IgG and the virus itself could be detected in milk, suggesting both are required for fetal immunity to COVID-19 to develop. Recovered mothers may volunteer to breastfeed other newborns to provide protection against this pandemic. The benefits of immunized breastfeeding may outweigh the potential risk of transmitting the viral RNA.

<bold id="s-08e4a75d933c">Conclusion </bold>

The present review investigated the impact of the COVID-19 pandemic on pregnancy, maternal and fetal health. Throughout this pandemic, pregnant women have had to ensure they follow the guidelines set out by organizations such as WHO, the Royal College of Obstetricians & Gynaecologists and the American College of Obstetricians & Gynecologists. Additionally, they have had to undergo frequent COVID‐19 testing to prevent any possible transmission of the disease. As a global pandemic, COVID-19 continues to expand and spontaneously mutate and develop. Therefore, there will be a continuous need for additional information on the impact of COVID-19 on pregnant women, early-stage maternal women, and newborn infants. Many studies have confirmed the symptomatic, clinical, and physical pathogenicity of COVID-19. However, more genetic-based studies should be done to determine whether COVID-19 has a genetic or epigenetic impact on pregnant women that may affect future generations. The need to safeguard the growing fetus during prenatal, labor, and delivery adds to the challenges that face obstetricians and gynecologists in managing this disease. Despite the ability of SARS-CoV-2 to vertically transmit from infected mother to child and its presence in the breast milk of infected women, special precautions are always required to minimize the cross-infection of surrounding people, such as relatives, friends, and healthcare providers.

<bold id="s-941b054aa5e4">Abbreviations</bold>

ACE2: Angiotensin-converting enzyme 2

COVID-19: Coronavirus disease 2019

CT images: Computed Tomography images

H1N1: influenza A virus subtype H1N1 “Spanish flu”

H2N2: Influenza A virus subtype H2N2 "Asian flu"

Ig G: Immunoglobulins G

Ig M: Immunoglobulins M

IL: Interleukin

MERS‐CoV: Middle East Respiratory Syndrome–related Coronavirus

NK: Natural killer cells

RNA: Ribonucleic acid

RT-PCR: Reverse transcription polymerase chain reaction

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2

Th1: Type 1 T helper

Th2: Type 2 T helper

WHO: World Health Organization

<bold id="s-d95895e3ea55">Acknowledgments </bold>

The authors would like to thank the collaboration between Management Science University Medical Centre, Universiti Sains Malaysia, Penang, Malaysia and Hospital Seberang Jaya that made this work possible.

<bold id="s-19f578c2efa9">Author’s contributions</bold>

All authors contributed equally to this work. All authors read and approved the final manuscript.

<bold id="s-0ed52691c5cd">Funding</bold>

None.

<bold id="s-dd6eefd0af07">Availability of data and materials</bold>

Not applicable.

<bold id="s-ddbae3e2d708">Ethics approval and consent to participate</bold>

Not applicable.

<bold id="s-537012a767c5">Consent for publication</bold>

Not applicable.

<bold id="s-fde007002752">Competing interests</bold>

The authors declare that they have no competing interests.

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