COVID-19: Risks to Pregnancy and Immunity between Mother and Fetus

Coronaviruses contains A simple-stranded RNA as a nucleic
material, its whole is ranging from 26 to 32kbs in length and its...


COVID-19
Coronaviruses contains A simple-stranded RNA as a nucleic material, its whole is ranging from 26 to 32kbs in length and its diameter is 65-125 nm ( Figure 1) by [1]. Coronaviruses subgroups are alpha (a), beta (b), gamma (c), and delta (d) coronavirus. Many diseases cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), pulmonary failure and may be fatal as severe acute  SARS-CoV, 2002 in Guangdong, China [2]. Only a decade later, another pathogenic coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV) caused an endemic in Middle Eastern countries [3,4] demonstrated that in December 2019, many diseased conditions with pneumonia appeared in Wuhan city in China and these cases suffered from many symptoms like weakness, dry cough and restlessness with high temperature reached to dyspnea in serious cases besides peripheral pulmonary plaques and interstitial lesions in chest scan.
Liu et al., [5] showed that this virus which appeared in China and distributed to many countries was named severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which has a hereditary resemblance to SARS-CoV

COVID-19 Spreading
WHO announced that MERS coronavirus causes infection to more than 2428 individuals and 838 deaths [6]. MERS-CoV is a beta-coronavirus subgroup and genetically varied from other human-CoV. The epidemic of MERS CoV started with simple flu like symptoms then progressed to all parts of the respiratory system and cause serious pneumonia. Similar to SARS coronavirus, patients diseased with MERS-coronavirus suffer pneumonia, followed by ARDS and kidney defects [7]. The virus was described as a unique coronavirus from the genetic sequence of patients isolates. Initially, [8] was indicated that the source of infection was the fish market or from diseased animals or birds in china. Besides, a survey revealed that the spreading of virus infection occurred from one person to another by direct contact with infected one exposed to sneezing, coughing, respiratory droplets, and these enter the lung through the nasal or oral passage. [9] showed that the communication between mother and semi allogeneic fetus to placental protection of the fetus was due to expression of histocompatibility antigens in fetal tissues and regulation of maternal immunity for providing an immune tolerance environment for the fetus. At the time of placentation, immune cells count rise in uterine tissue 3-5 days after ovulation reached 25%-40% of uterine leukocytes before implantation and considered the highest number at early three months of pregnancy due to their functions in placentation and protection against infection [10]. The uterine killer cells are different from peripheral killer cells in their genetic structure and action. They are revealed a large number of (CD56), but they lack expression of CD16 which present on most peripheral natural killer cells [10]. Peripheral CD56 and CD16+ NK cells were considered killer cells as they interfered with both natural and specific antibody killer, whereas uNK cells are faint cytotoxic and do not attack trophoblast cells in normal conditions [11]. In addition, uNK cells produce a high number of immunomodulatory cytokines, [12] matrix metalloproteinases (MMPs), [13], and angiogenic factor [14]. In a healthy pregnancy, macrophages cells are found in decidua before the presence of trophoblast and play a role in blood supply by producing (MMP-9) that make tissue remodeling and (vascular endothelial growth factor [VEGF]) for angiogenesis [15].

Pregnant Mother Immunity and Infection
Mor et al. [16] said that pregnancy is a period of high risk for infection and her maternal immune system is responsible for defending against infectious microbes because the fetus and placenta responses are restrained Jamieson et al., [17] showed that the main target of the immune system during pregnancy is protecting both mother and fetus from viral and microbial infections. The suppression of pregnant mother cell-mediated immunity turned the Th1 to the Th2 immunity and rise the perceptivity to any disease [18]. However, Zhang et al., [19] showed that certain diseased cases among pregnant patients have bad outcomes ranged from symptoms to death which differ between developed and non-developed countries as in the US or Canada, pregnant women with varicella are better than those diagnosed in underdeveloped countries.
Brown and Derkits, [20] demonstrated that children of infected mothers during pregnancy have significantly higher frequencies of neurological disorders as schizophrenia and autism spectrum disorders. The reason for these disorders is due to activation of the maternal inflammatory immune responses reviewed by [21,22].

Studies in rodents proved by clinical findings confirmed rat models
have disorders from immune system activation [23]. Mandal et al., [24] showed that pregnant mother immunity enhances the brain and the immune system development in the offspring due to secretion of interleukin 1, interleukin6 and interleukin 12. In addition to granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha in the blood of pregnant mothers and secreted in amniotic fluid surrounding the fetus.
Mandal et al., [25] showed that fetuses have a proinflammatory response and high levels of T helper1, T helper17, and cytotoxic T-cell due to stimulation of the immune system of their mothers.
Infection is very dangerous during pregnancy not only on the mother but also on the fetus. Clinical studies showed that during placental infection, concentrations of Interleukin 1, 6, 8, and TNF-α increased and fetal this called fetal inflammatory response syndrome (FIRS) [26]. However, any infection that enters the placenta stimulates a rapid immune response that leads to uterine infection. [27] and this is caused by activation of pattern recognition receptors and high secretion of interleukin 1 (IL1) and TNF-α [28]. The result of the infection affects both mother and fetus as poor pregnancy may lead to fetal deformities, decrease fetal weight and early parturition [29].

COVID-19 and Pregnancy
The physiological changes and stress which occurred during pregnancy cause changes in immune, cardiovascular, and respiratory systems [30]. [31] showed that viral infections that affect the respiratory system during pregnancy may lead to birth defects as low birth weight and preterm birth. Viruses can get congenitally transmitted to the fetus such as Ebola, Cytomegalovirus, Zika, and Rubella, most of these viruses enter the fetus through the hematogenous route in which the virus circulating in the mother's bloodstream reaches and enters the placenta through the chorionic villous tree and reached fetal blood vessels. [32] Clinical data of the SARS epidemic showed that from 12 SARS-COV infected pregnant women, 2 had intrauterine growth problems in the 2nd and 3rd trimester and 3 died during pregnancy [33]. [34] showed that during the MERS-CoV epidemic, 91% of 11 pregnant infected females had problems in pregnancy outcomes such as premature delivery, maternal and perinatal death and there was not one case to suggest the intrauterine transmission of the MERS virus. [35] showed that clinical symptoms of patients infected with SARS and MERS ranged from no symptoms to severe disease and death and 80% of COVID-19 patients in hospitals having cough and fever. [36] showed that the COVID-19 pandemic is spreading around the world and Pregnant women most likely to be affected and most clinical findings of covid-19 pregnant patients are delivered early and by cesarean section. [35] showed that symptoms at the onset of COVID-19 infection were reported for 35 pregnant women (69%), and the symptoms were similar to those described in nonpregnant patients (Table 1).
Fever was presented in 17 pregnant women (48%) in addition to 16 women (46%) who suffered from dry cough and this symptom may be alone or with another symptom. Other 8 infected patients had fever only in the postpartum period with 23%. Other symptoms included fatigue (three cases), myalgia (three cases), sore throat (five cases), dyspnea (four cases), diarrhea (two cases), malaise (two cases), and two cases of cholecystitis. There was a case of hypertension during pregnancy at 27 weeks of pregnancy and a case of preeclampsia at 31 weeks of pregnancy and in these two cases, symptoms appeared after COVID-19 diagnosis [35].  and no cases of abortion or fetal asphyxia or death. However, [37] showed that in Wuhan Children's Hospital 33 newly born baby born to mothers with COVID-19 by caesarian section due to maternal pneumonia and stress, four out of 33 showed breath problems and nasopharyngeal and anal swabs of the other three neonates tested positive SARS-CoV-2 on days 2 and 4 but negative on days 6-7 of their lives. All these COVID-19 neonates had fever and pneumonia and they were treated with antibiotics and proper ventilation. SARS CoV-2 source in the neonates may be from mother to the neonates during pregnancy. World Health Organization (WHO) has reported that women of the same reproductive age have no diversity in symptoms between nonpregnancy state and pregnancy state [38].

Pregnancy Outcomes in COVID-19 Infected Females in
However, [39] demonstrated that physiological changes that occurred to pregnant women altered the immune response and so their response to covid-19 resemble their response to other viral infections. [40] showed that there are no maternal risks, such as covid-19 infection after parturition and early parturition.
In contrast, [41] reported that both mother and fetus suffered from problems as early parturition, breathing problem, and fetal death. Additionally, [42] showed one case with maternal death and one case with intrauterine fetal death at the last three months of pregnancy infected with COVID-19 in Iran. [43] showed nine pregnant women infected with severe COVID-19 at the end of the gestation period. Seven out of nine women died, one out of 9 women still sick and ventilator-dependent and only one case out of nine women recovered after a long time of treatment. Moreover, [44] announced a clinical finding of abortion in the half of gestation period in a woman positive COVID-19, but the clinical finding of samples obtained from amniotic fluid, cord blood, genital swabs, and breast milk, and the neonatal throat swabs showed negative for COVID-19 [45]. In contrast, [46] have reported a study that  [39] mentioned that a small number of clinical cases which determined the relationship between infected mother with SARS-CoV-2 and their newborn and the rate of intrauterine vertical

COVID-19 and Fetus
transmission. [5] demonstrated that more research will be needed for the determination of vertical transmission and Fetal outcomes and problems from infected mothers with COVID-19 and its effect on fetal breath and time of parturition. [40] reported that a clinical study of 7 pregnant mothers positive for SARS COV2 and after their caesarian sections, the newborn babies were suspected for COVID-19 and so they tested, and one baby was recognized suffering from respiratory problems and tested positive for COVID-19. The baby symptoms were regularly managed with specific treatment till complete recovery [41,47] reported a clinical finding of two babies suffering from lymphopenia and mild pneumonia, with no other symptoms, and they were born from an infected mother with COVID-19. [48] supported the previous data with a case of a suspected newly born baby from an infected mother that have no symptoms, but a clinical blood test showed lymphopenia with confused liver function tests. Liu et al., [5,42]