key: cord-0777957-f9id76v2 authors: Meyyazhagan, Arun; Pushparaj, Karthika; Balasubramanian, Balamuralikrishnan; Kuchi Bhotla, Haripriya; Pappusamy, Manikantan; Arumugam, Vijaya Anand; Easwaran, Murugesh; Pottail, Lalitha; Mani, Poonkothai; Tsibizova, Valentina; Di Renzo, Gian Carlo title: COVID‐19 in pregnant women and children: Insights on clinical manifestations, complexities, and pathogenesis date: 2021-11-13 journal: Int J Gynaecol Obstet DOI: 10.1002/ijgo.14007 sha: beb44f97a3814f883bcbb801e86b4e4c7b28c6cb doc_id: 777957 cord_uid: f9id76v2 Pregnancy changes the body's immune system to counteract the spectrum of infections, including COVID‐19, which can pose complications. Pregnant women are less likely to contract COVID‐19 infections than the general public. However, pregnant women are at slightly increased risk of becoming severely unwell if they do catch COVID‐19, and congenital conditions in pregnant women may worsen the state of infection and lead to critical stages and even mortality. The possibility of vertical transmission has been reported in only a few cases of COVID‐19; however, it was not noted in cases of SARS and MERS. Vaccination coverage in pregnant women remains a challenge. Children are the next suspected and vulnerable population to acquire infection after the first and second waves. Children are disproportionately infected compared with older populations, but the severity of infection is less compared to adults. This review highlights the complexities of COVID‐19 in pregnant women and the underlying reasons why children tend to be comparatively less severely affected. Ethnicity, nutrition, lifestyle, and therapeutics influence the severity of infection in children. Low expression of angiotensin‐converting enzyme 2 receptors, indigenous virus competence, and maternal immunity is the first‐line defense for children against COVID‐19. Habituating herbal medicines from childhood may help support a robust and defensive immune system to counteract novel antigens and encourage healthy generations. Understanding the span of coronavirus disease (COVID-19) that onset towards the end of 2019 has become an urgent undertaking. [1] [2] [3] [4] The virus causing the disease (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) indiscriminately affected individuals with varying severity, causing the ongoing global pandemic. Research has revealed that the pathogenesis and transmission of COVID-19 are similar to those of severe acute respiratory syndrome (SARS) . Extensive acceptance of COVID-19 vaccines is the crucial step in fighting the pandemic; however, achieving a high percentage of vaccinated populations is challenging. Vaccination campaigns are needed to create awareness to prevent public misconceptions. Social distancing, wearing masks, quarantine measures, and curfews are the suggested ways to break the chain of transmission. East respiratory syndrome (MERS), and other respiratory viruses. No proven reports on vertical transmission (i.e. mother to neonate) were available for SARS and MERS, and most infected pregnant women experienced mild symptoms. In the first wave of COVID-19 clinical findings became more complicated and frequent in pregnant women and were oriented with a spectrum of complications such as severe pneumonia, cardiovascular disease, multiorgan failure, thrombosis, and ventilation requirement. 5 The higher percentage of maternal morbidity and mortality reflected the increasing numbers of neonates testing positive for SARS-CoV-2. The potential capability of SARS-CoV-2 for intrauterine maternal-fetal transmission is concerning. 6 The most crucial, complex, and challenging concern is the effects of viral infection in pregnant women, fetuses, and neonates. The severity of the disease is closely associated with still birth; the pandemic may also indirectly influence the birth weight of neonates due to the poor nutrition and health of mothers exposed to the associated socio-economic crisis. The immune complex differs between a child and an adult, with different stages during childhood, namely newborn, infant, toddler, and preschooler; there should be a notable difference in the expression of children's immune systems to viral infection, environmental exposure, and novel antigens such as SARS and COVID-19. Recent research pointed out the possibility of analogous viruses in the mucosa of respiratory pathways in young children which impede the growth of SARS-CoV-2 through virus-to-virus interactions and competition. 7 The infection is mediated by the angiotensin-converting enzyme 2 (ACE2) receptor, which is lodged abundantly in the lower respiratory passages (lungs and intestine) and is not localized to any immune cells. 5 Several studies have shown that COVID-19 shares the same common receptor as SARS, 7 which provided indicators for drug development by blocking the virus's receptor binding sites for ACE2. The aim of the present review is to highlight the complexities associated with COVID-19 in pregnant women and the precautionary measures needed in neonatal care, and to raise awareness of the susceptibility of children to counteract infection in the forthcoming waves by recognizing mild onset of clinical symptoms. Coronaviruses are a group of nonsegmented, positive-stranded RNA viruses with a genome size of approximately 30 kilobases surrounded by a distinct protein envelope with specific receptors to mediate the infection. Almost all strains of coronaviruses cause diseases in their respective host species (high host specificity) and can infect humans through cross-species transmission. The mechanism of SARS-CoV-2 is similar to the SARS coronavirus, with critical clinical infections and impairment of organs including lungs, heart, liver, and kidney, and a high risk of pneumonia in patients. 8 Human populations are at high risk of COVID-19 infection, particularly pregnant women and children owing to the unique state of immune suppression. Furthermore, perinatal infection may lead to fetal distress, premature labor, respiratory complications, thrombocytopenia accompanied by abnormal liver function, and even fatality. 9 The possibility of vertical transmission of SARS-CoV-2 is currently being investigated. 9 In a standard population it is estimated that 81% of those with COVID-19 have mild symptoms, 14% have severe complications, and 5% experience a critical stage of the disease. 10 Pregnant women suffer a similar rate of clinical complications; however, pregnant women with mild infection experience the same outcomes as uninfected pregnant women, while pregnant women with severe and critical disease have much higher risks of perinatal infection, morbidity, and mortality. 11 The higher rate of positive cases is due to the increased percentage of screening; however, most pregnant women undergo testing only if they are only symptomatic, while most asymptomatic cases are often excluded from testing procedures. The degree of disease complexity in pregnant women increases with comorbid conditions such as diabetes, cardiovascular disease, hypertension, transplantation, pregestational diabetes mellitus, age, chronic lung disease, healthcare occupation, and trauma. Risk factors are found to vary across race, maternal age, and body mass index (BMI). 12 Older age and increased BMI were critical factors associated with severe disease in pregnant women in France and Latin America. 13 Plausible reasons for racial variation in the severity of COVID-19 depend upon genetics and lifestyle. 13 Indeed, the presence of asthma has been over-represented in pregnant women with severe disease. 14 Pregnancy-related complexities associated with COVID-19 were commonly reported during the second wave (more so than in the first wave), with comorbidities and secondary infections threatening the affected population. According to a recent study, COVID-19-positive pregnant women have a higher risk of miscarriage, pre-eclampsia, preterm labor, and cesarean delivery. 15 The risk is exponentially higher in the third trimester due to increased BMI, which proportionally increases pneumonia, hypoxia, and coagulation complications. 15 Multiorgan failure is due to the inflammatory action of cytokines leading to a cytokine storm that activates thrombin. 16 A high concentration of D-dimer (>1 μg/ml) is a biomarker for high thrombin levels associated with greater risk of mortality due to sepsis-induced coagulopathy. 17 However, anticoagulant treatment involving heparin has improved prognosis in patients with severe infection. 17 These complications directly induce fetal distress, leading to mechanical support ventilation and ICU monitoring. 18 The long-term effects of COVID-19 on maternal, neonatal, and child health have been considered largely in terms of noncommunicable diseases. Neonates born prematurely have exponential risks of developing metabolic syndrome, type 2 diabetes, hypertension, and stroke compared to those born at full term. 19 Despite the quarantine and checks, the surge in incidence was due to asymptomatic carriers who tested negative at airport screening because symptoms appear virtually immediately after infection. It is significant to understand that children can be asymptomatic but may potentially transmit the virus to others during the preclinical or symptomatic stages. 29 Reports from Italy showed similar results, with 318 (0.5%) con- In general, infants and young children are at high risk and may be admitted to hospital owing to infection in the upper respiratory pathways due to respiratory syncytial virus and influenza virus. The underlying reason is the immature respiratory tract and immune system in this age group. 31 In contrast, COVID-19 had very few pediatric patients worldwide, which has confused clinicians, epidemiologists, and scientists. ACE2 is a type I membrane protein widely expressed in the lungs (type II alveolar epithelial cells and type II pneumocytes), heart, intestine, and kidneys, where it is essentially involved in the maturation of angiotensin II. 33 ACE2 has been proven to be the functional receptor of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and, recently, of SARS-CoV-2. 34 Xu et al. 35 The common symptoms of COVID-19 include cough, throat pain, fever, diarrhea and, notably, pneumonia found prevalent in patients 41 Thus, it was evident that young mice were infected, but they did not develop the disease. They carried the same virus levels as older mice, but they did not fall sick. Figure 4 depicts the low-and high-risk factors associated with infection among children and adults, respectively. The connecting link between age and disease severity in humans is that the effectiveness of the immune system is inversely proportional to age as it induces more senescence in immune cells and thus becomes inactive. The adaptive immune response had a critical role in SARS-CoV-2 infection, as stated by Medzhitov and Janeway. 42 The stimulation of pro-inflammatory mediators prompted both Th1 ICMR-Guidance for Management of Pregnant Women in COVID-19 Pandemic Vertical transmission of coronavirus disease 2019: severe acute respiratory syndrome coronavirus 2 RNA on the fetal side of the placenta in pregnancies with coronavirus disease 2019-positive mothers and neonates at birth Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis Clinical characteristics of children with COVID-19 Severe coronavirus infections in pregnancy: a systematic review Placental pathology of covid-19 with and without fetal and neonatal infection: trophoblast necrosis and chronic histiocytic intervillositis as risk factors for transplacental transmission of SARS-CoV-2 Virus-virus interactions impact the population dynamics of influenza and the common cold Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention Epidemiology of coronavirus disease 2019 in pregnancy: risk factors and associations with adverse maternal and neonatal outcomes Risk factors for severe and critical Covid-19 in pregnant women in a single center in Brazil Covid-19 in pregnant women: general data from a French National Survey Clinical characteristics of 46 pregnant women with a severe acute respiratory syndrome coronavirus 2 infection in Washington State Coronavirus disease 2019 in pregnancy: consider thromboembolic disorders and thromboprophylaxis COVID-19 cytokine storm: the interplay between inflammation and coagulation COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation Clinical manifestation and maternal complications and neonatal outcomes in pregnant women with COVID-19: a comprehensive evidence synthesis and meta-analysis Viewpoint Building resilient societies after COVID-19: the case for investing in maternal, neonatal, and child health Delivery in pregnant women infected with SARS-CoV-2: a fast review Could children born to mothers with COVID-19 be more prone to non-communicable diseases? Integrated analyses of singlecell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells SARS-CoV-2 infection and glucose homeostasis in pregnancy. What about antenatal corticosteroids? Diab Metab Syndr ions-for-obste tricgynec ologi c-care 26. International Federation Gynecology and Obstetrics. COVID-19 vaccination for pregnant and breastfeeding women Centers for Disease Control and Prevention. COVID data tracker CDC COVID-19 Response Team. Coronavirus disease 2019 in children -United States Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy Will children reveal their secret? The coronavirus dilemma Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology COVID-19) Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2 Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor A pneumonia outbreak associated with a new coronavirus of probable bat origin Will children reveal their secret? The coronavirus dilemma Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges A mouse-adapted SARScoronavirus causes disease and mortality in BALB/c mice Complete protection against severe acute respiratory syndrome coronavirus-mediated lethal respiratory disease in aged mice by immunization with a mouse-adapted virus lacking E protein Innate immunity: impact on the adaptive immune response Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic SARS-CoV-2 infection in children: transmission dynamics and clinical characteristics COVID-19 in children: a review and parallels to other hyperinflammatory syndromes NKG2A is a NK cell exhaustion checkpoint for HCV persistence Immunomodulating effect of influenza vaccination in the elderly differing in health status A small jab -a big effect: nonspecific immunomodulation by vaccines Functional exhaustion of antiviral lymphocytes in COVID-19 patients T cell-mediated immune response to respiratory coronaviruses Expanding roles for CD4 + T cells in immunity to viruses Children with coronavirus disease 2019: a review of demographic, clinical, laboratory, and imaging features in pediatric patients Maternal immune responses and obstetrical outcomes of pregnant women with COVID-19 and possible health risks of offspring Kerala plans on using Ayurveda to mitigate COVID-19 spread Ayurveda and COVID-19: where psychoneuroimmunology and the meaning response meet Time to realise the true potential of Ayurveda against COVID-19 Immunity against COVID-19: potential role of Ayush Kwath Immunomodulatory potential of Tinospora cordifolia and CpG ODN (TLR21 agonist) against the very virulent, infectious bursal disease virus in SPF chicks Ayurveda's holistic lifestyle approach for the management of coronavirus disease (COVID-19): possible role of Tulsi Ayurveda practitioners consensus to develop strategies for prevention and treatment of corona virus disease (COVID-19) Preparing an obstetric unit in the heart of the epidemic strike of COVID-19: quick reorganization tips COVID-19 in pregnant women and children: Insights on clinical manifestations, complexities, and pathogenesis The authors have no conflicts of interest.