Coronavirus disease 2019 (COVID-19) and Pregnancy

1Department of Physiology, Rungta College of Dental Sciences and Research, Bhilai, Chhattisgarh, India. 2Formar Guest Faculty, Department of Physiology, Bijoygarh Jyotish Ray College, Kolkata, West Bengal, India. 3Department of Physiology, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Malaysia. 4Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Malaysia. 5Department of Physiotherapy, Nopany Institute of Health Care Studies, Kolkata, West Bengal, India. 6Department of Obstetrics and Gynecology, KPC Medical College and Hospital, Kolkata, India. *Corresponding Author E-mail: koushik22.2009@rediffmail.com

The appearance of novel coronavirus (CoV) infection that originated in Wuhan, China in December 2019, has emanated in an infestation that has rapidly tumefied to become one of the most noteworthy public health impendences of current century [1][2][3][4] . This novel CoV is termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the disease it produces has been named coronavirus disease-2019 (COVID 19) [5]. It has become a global pandemic as declared by the World Health Organization (WHO) on March 11, 2020 6 . It causes respiratory infection which often leads to major pneumonia and can even turn fatal 7 .
Genetic, virologic, epidemiologic and clinical aspects of SARS-CoV2 are being intervened to recognize its exact mechanism of human transmission and propagation 8 . It has been reported that SARS-Cov-2, alike human pathogenic coronavirus SARS-CoV, binds with angiotensinconverting enzyme-2 (ACE2) receptor located on the target cells in host body. The expression of ACE2 have been shown in epithelial cells of the lung, intestine, kidney, and endothelial cells 9 as well in the placental cells 10 .
The etiopathology of fetal COVID-19 and vertical transmission of SARS-CoV-2 from mother to fetus have sparsely been documented, but mostly remain opaque 9,11 . Since COVID-19 is a prominent public health issue, adequate understanding about pathology of this disease in pregnant women is very essential which will serve to provide better obstetrical management to these patients. Contemporarily, few case histories of the Zika, Ebola and Marburg virus along with the other agents clearly showed the vertical maternal-fetal transmission which can be an intimidation about the health and constancy of an affected mother and fetus 12,13 .

Transmission of SARS-CoV-2
SARS-CoV-2 is believed to be transmitted from bats to human via intermediate animal at the Huanan Seafood Wholesale Market of Wuhan 14,15 . Since then, the virus soon spread all over the globe through human to human transmission. Individuals without symptoms of COVID-19 (asymptomatic or silent carrier) can also be a possible source for the spread of novel Coronavirus. Thus, social isolation is proposed to control this contamination due to communication 16 .
Unlike the other respiratory pathogens (e.g. common flu or rhinovirus), the emerged nascent novel coronavirus can also be transmitted by the dispersion of infected droplets from symptomatic COVID-19 patients 17 . Other possibility is airborne transmission, which can also be elevated by the prolonged exposure in a suffocated or non-airy space 17 . This viral contamination is prominent among the hospital staffs and professionals, and high within the hospitals or nursing homes, as well as via relatives and other nearest contacts 18 .

Pathophysiology of SARS-CoV-2 infection
The nascent emerged novel SARS-CoV-2 virus has embraced structures with nucleocapsid whose genetic material consists of a single-stranded RNA that is positive (or sense) strand which encodes mRNA (messenger RNA) and protein 19 . The genomic and viral structure with the disease-causing mechanisms of SARS-CoV-2 should be contemplated 19 . The viral single stranded positive sense RNA (~30 kb) has a 52 cap structure and 32 poly A tail. The viral RNA serves as template for translation of polyprotein 1a/1ab (pp1a/pp1ab) and these polyproteins encode nonstructural proteins (nsps) forming the replication transcription complex (RTC) 20 . The RTC synthesizes subgenomic RNAs (sgRNAs) 21 with common 52 leader and 32 terminal sequences, located between open reading frames (ORFs). The sgRNAs are used to produce the subgenomic mRNAs 22 . Minimum of six ORFs can be observed in the CoV genome. Except the ORF1a and ORF1b, the other open reading frames encodes for various structural proteins (like spike protein, proteins of membrane envelope, nucleocapsid and accessory protein chains) 22 . Various CoVs represent significantly specially structured accessory proteins which are been enormously translated by the specific sub-genomic RNAs 23 .
The functions of structural and nonstructural proteins are intricately related to the pathophysiology and virulence mechanism of CoVs. It is been explained that nsps can directly hinder the innate immunity response of the infected individual 24 . Structural proteins are not only crucial for the envelope, but also may promote the virus assembly and their release. Nevertheless, maximum of these subsequent observations has not been elaborated yet such in those of nsp-2 and -11 25 . The spikes on viral surface are made up of homotrimers of S-proteins also known as spike glycoproteins, composed of S1 and S2 subunits 26 . Of note, in SARS-CoV-2, the S2 subunit contains a fusion peptide, a transmembrane domain, whereas cytoplasmic domain is highly conserved 19 . Thus, it could be a target for antiviral (anti-S2) compounds. Though SARS-CoV-2 shares 79.0% nucleotide identity to SARS-CoV 27 , many structural features are different to some extent, for example, the spike receptor binding domain has only 40% amino acid identity with other SARS-CoV, ORF-3b and ORF-8 encoded proteins are not identical with SARS-CoV 28 . Following the comparison of the gene sequences between SARS-CoV-2 with that of SARS-CoV, Angelette et al. have reported that the transmembrane helical segments encoded nsp2 and nsp3 in ORF-1ab which denotes that, the position of 723 has glycine residue in place of serine and 1010 position is engaged by proline instead of the isoleucine 29 . The SARS-CoV-2 gene sequences were published by the researchers in several International Gene Banks for instance Gen Bank, helped researchers to find the evolutionary tree of the CoV-2 virus and to specify the strains which differed due to mutations. Few recent studies have mentioned about 'spike mutation' which had already emerged in late November 2019, is being multiplicated in a jumping manner among the human beings 30,31 . It is suggested that mutation is the key for potential disease relapse.
Due to the shortage of extensive clinical data it is not feasible to produce concrete information about the symptoms and clinical manifestations of CoV-2. However, it is quite evident that the viral infection leads to the path of exaggerated immune reaction in an infected individual. This leads to 'cytokine storm' causing massive tissue damage. Interleukin-6 (IL-6) is one of major cytokines contributing significantly to elicit an uncontrolled immune response in COVID-19 patients. It is produced by the activated leucocytes primarily at the site of inflammation. IL-6 contributes to host defense through the stimulation of acute phase protein responses, induces the differentiation of B-lymphocytes, capable of crossing the blood brain barrier and initiates the synthesis of other inflammatory mediators, such as prostaglandins in hypothalamus which is one of the major factors that attribute to elevated body temperature 32 . Thus, induction of high levels of IL-6 release along with other cytokines like interferon gamma (IFNã) leads to pathogenicity related with systemic inflammatory responses. This results in a feedback circuit to induce surge of various pro-inflammatory cytokines and may cause cytokine release syndrome (CRS) 33 . CRS is been characterized by fever and multiple organ dysfunction connected with chimeric antigen receptor (CAR)-T-cell therapy, therapeutic antibodies and haploidentical allogenic transplantation 34 .

COVID-19 and pregnancy: Current scenario and previous experience
The outbreak of COVID-19 has put the public health sector and medical infrastructure in a state of urgency to provide care to the patients as well as to adapt to fast evolving treatment regime 35 . During the previous outbreaks of SARS and MERS, clinicians took time to treat or invent vaccine for pregnant women to cover the fetal safety 36 . A constraining reason is important to remove the pregnant women from consideration, possibly in this hefty contagious hazard 37 The mediations for the mother and fetus during the treatment of pregnancy, the merits should be carefully administered as well as the possible risks. Following the close observation of COVID-19 cases during the treatment which are fully set up is mandatory to ensure and report the proper information on the status of pregnancy with the inclusion of maternal and fetus outcome. In a case control study, between pregnant and nonpregnant women with SARS CoV, it has been reported that the pregnant women did not show any unusual clinical symptoms 38 . Ramifications and unpropitious situations including the staying duration in hospital, kidney failure, septicemia and disseminated intravascular coagulopathy (DIC) in conceived women were statistically and considerably expanded 39,40 . Need of ventilation had increased death rate among the pregnant women as compared with non-pregnant women has been reported 38 . Moreover, some studies also reported the same that, the pregnant women were observed more frequently with ventilation and hemodialysis as treatment tool because of renal failure, and positive cerebrospinal fluid for SARS-CoV 41, 42 without any reporting case of stillbirth from the affected pregnant women. The mothers were seen with exaltation for their recovery and the neonates were also reported as negative for SARS-CoV RNA test 43 . According to Maxwell et al., out of seven pregnant mothers who were admitted with SARS-CoV in designated SARS unit, two of them were passed away and four mothers were recommended for intensive care unit (ICU) supervision and ventilation. Two vitiated pregnant women had come out from that unpropitious condition but had neonates with intrauterine growth restriction (IUGR) without clinical evidence of SARS-CoV infection among the live newborns 44 . According to Ng et al., placental pathological examination among seven infected pregnant women inferred that two of them who were recovering from SARS-CoV during the early gestational period, the placentas were found to be normal. Besides that, elaboration of expanded sub-chorionic and intervillous fibrin were reported in three women may be due to impaired maternal to placental blood flow 45 .

COVID-19 and pregnancy complications: Susceptibility and severity
In lieu of current researches and evidences, it can be suggested that during COVID-19 pandemic, men are more susceptible to the infection than women 3, 46-49 . According to the studies, regarding SARS or MERS, a concrete inference cannot be drawn about the tendency of infestation among the conceived women. So far, this novel coronavirus is not at all gender bias, the above-mentioned information about the infestation of COVID-19 on the basis of gender difference is based only on some following subsequent situations like susceptibility, subjection and detection of contamination. No references or studies has given the proven data about the expansion of infestation of COVID-19 among these would be mothers. According to the preceding studies, related to SARS and MERS, a quite abnormal clinical observation had been noticed in conceived women that may lead from severity to death without any foregoing symptoms (Table 1) 9, 37, 50-62 . Agitation or high temperature with acute respiratory tract distress observed among 80% of the hospitalized patients 3 . Few clinical observations were suggested by Chen et al. 9 , about few pregnant women whose symptoms has somewhat similarities with nonpregnant adult women also in some aspect. Out of nine pregnant women subsequent observations are being followed: (a) high temperature in seven of them, (b) respiratory distress in four, (c) three of them were suffering from myalgia, (d) pain or irritation in the throat with some sorts of discomfort in each of the two women, (e) reduced lymphocyte count or lymphocytopenia was observed among five of them, (f) each of them had pneumonia but by god's grace no death reports has been confirmed yet. Everybody was placed for surgical or c-section delivery, followed by, the observed Apgar scores were 9-10 at 5 minutes and 8-9 at one minute.
According to a study conducted by Zhu et al 54 , another series of nine pregnant women along with 10 infants into which one set of twins were observed following symptoms: out of nine pregnant women prior 1 to 6 days of delivery, four of them were confirmed, two cases were observed at the day of parturition exactly and three cases were confirmed after delivery. No differences administered in the perspective of COVID-19 symptoms when compared with infected and non-infected individuals. Few more complications observed within those nine pregnant patients, such as six of them was observed with development of intrauterine fetal distress, seven of them had to be considered with C-Section or surgical delivery, and out of those ten infants, six were found with premature delivery. So far, these information and reports has been concerned, confirm or exact conclusion about the severity among pregnant women in the perseverance related with COVID-19, is still under scrutiny.
Besides the other physiological changes, the pregnant women undergo cardio-respiratory and immunological changes leads to become more susceptible for the development of severe health issues after infection with any respiratory virus. It has been observed that, 1% of pregnant women infected with influenza-A subtype H1N1 virus, but 5% of all H1N1 related deaths were also accounted for them 63 .
Moreover, SARS CoV and MERS CoV both are responsible for onset of such multiple complications during pregnancy provoking urgent use of endotracheal intubation and intensive care unit (ICU), even causing renal failure and death 45,64 . But surprisingly, COVID-19 causes less severe infection than SARS CoV and MERS CoV to the pregnant women. The study described earlier conducted by Chen et al 9 , observed only fever and coughing as primary signs of laboratory confirmed COVID 19 women with positive third trimester of pregnancy. Symptoms like muscular pain, sore throat, diarrhea and shortness of breath were also included later. Within those nine affected pregnant COVID-19 patients, most of them were reported with abnormally lesser count of lymphocytes with higher C reactive protein, besides the presence of multiple patchy ground glass shadows in the lungs observed on chest CT scan. Due to COVID-19 infection, 22.22% of nine affected patients were observed with fetal distress and separately 22.22% of nine affected patients were again were found with premature rupture of feto-placental membrane although all nine patients were staying alive without developing the severe COVID-19 pneumonia. Lei et al., 65 also conducted a study among nine pregnant women (pregnancy of mid trimester onwards or during the postpartum period) with confirm COVID- 19 showing similar report as previous study but only one woman was kept under the ICU care and ventilation for the sudden appearance of acute respiratory distress syndrome, as the viral infection was diagnosed two days after the delivery. Both the studies also described that the clinical characteristics of COVID 19 pneumonia are similar for both the group of patients pregnant and non-pregnant 2, 66 . Thus, the healthcare professionals who are pregnant, have to aware and must use personal protective equipment (PPE) and follow the infection control guidelines prior exposure to the patients with COVID-19. Simultaneously, prevention and control practices against the infection are also important part to protect all the healthcare professionals in clinical settings 67 .

COVID-19 and pregnancy: Measures, diagnostic testing and vaccination
The indications and manifestations of COVID-19 like respiratory distress, cough and high body temperature 55 , should not be neglected, thus, must be diagnosed in a proper way not only in normal adults but also in pregnant individuals. Before taking the pregnant women inside the delivery unit or prenatal care unit the diagnosis procedure is to be presented usually. An individual with the symptoms has appointment, should be instructed all the does and don'ts and if prior the next call the patients feeling any severity, should immediately be provided with proper face musk by health personnel and must be isolated from the gathering.
The patient should be isolated in an isolation room to prevent from the crosscontamination from one room to the other rooms. This isolation room includes a ventilation system that releases a 'negative pressure' (a pressure lower than the surrounding pressure). The patient should be kept inside the isolation room till the proper testing of the appropriate prototypes are not been received. Simultaneously, notifications must be sent to the infection control departments governed by the local or state or national health departments in a serious content. The urgent samples required are the swab of upper and lower respiratory tract specimens and plasma, but stool and urine testing can be done later.
Till date COVID-19 vaccine is not been invented yet. Different organizations that also refer the "National Institute of Health" with their efficient warriors are doing their best jobs to discover, depending on that SARS-CoV-2 virus genetic sequence published online on 28 th April 2020 68 . Scientists and researchers may correlate research outcomes with that of invention related to SARS and MERS vaccines 69 . The real-life saver saints those who have sacrificed their valuable life for the nation as well as whole world and are trying to reach the unknown fact where they can relief the mankind from this unknown deadly disease.

Management of COVID-19 during pregnancy
The COVID-19 outbreak is really a crucial time for each and every human being, but it is a more challenging time for the conceived women who need special care and close observations. A maximum level of equipment and facilities are recommended which must incorporate a close observation and prior detection of an emergency situation and proper monitoring of the worst clinical conditions for example premature delivery or still birth is most important. Other clinical complications like respiratory abnormality detected in mother, can be cause of irregular heart rate pattern in fetus. Not only those previous studies related with SARS and MERS has explained that in extreme conditions when uncontrollable respiratory troubles occur in the patient, sometimes artificial ventilation might not enough tackle that situation. Extracorporeal membrane oxygenation (ECMO) is the one and only way out at that crucial moment to be managed by the trained experts only 70 . Some event of relief is gained by the affected mother after delivery or not, it is still not known but before taking any steps related to delivery, should be consulted with the professional who is in the supervision 71 .
Research works are on their own way but still no medications against COVID-19 has been invented and stamped by the US food and drug weeks' gestation due to poorly a rapid decline in tidal volumes and controlled type 2 diabetes mellitus minimal end-tidal carbon dioxide were and intrahepatic cholestasis of noted. Auscultation revealed wheezes pregnancy followed by reported with minimal air movement. Severe SARS-CoV-2 positive.
bronchospasm was suspected and medically Patient 2: 33-year-old and was managed and followed by SARS-CoV-2 admitted for induction of labor at 37 testing appears positive. Did not mention weeks' gestation due to worsening the status of newborn. chronic hypertension with medical • For patient 2: approximately 25 hours history of mild-intermittent asthma after delivery, and 60 hours after presentation and type 2 diabetes mellitus.
to Labor and Delivery, the patient developed a cough that progressed to respiratory distress. Vital signs included temperature of 39.4oC (102.9oF), tachycardia (pulse 130s beats/minute) and 88% oxygen saturation on room air, and she was dyspneic and diaphoretic. There was no description for newborn.

Retrospective
One A 30-year-old pregnant woman at • She had 2-days history of dry cough without case Study 35 weeks' gestation; she had been fever, chills, or shortness of breath before [53] confirmed positive for SARS-CoV-2 attending the hospital. infection at her local hospital on • On the delivery day, although the woman's the basis of a sputum sample. sputum was positive, serum, urine, feces, amniotic fluid, umbilical cord blood and placenta, and breast milk samples were negative.
• She delivered a healthy infant, suggesting that mother-to-child transmission is unlikely for this virus Retrospective Nine All subjects were pregnant, and • All nine patients had a caesarean section case analysis all were found as COVID-19 in their third trimester. [9] positive • Seven patients presented with a fever and other symptoms.
• Fetal distress was monitored in two cases.
• Three patients had increased aminotransferase concentrations.
• None of the patients developed severe COVID-19 pneumonia or died till the study was processed for the publication.
• Nine livebirths were recorded without any report of neonatal asphyxia. • All nine livebirths had a 1-min Apgar score of 8-9 and a 5-min Apgar score of 9-10.
• Amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from six patients were tested for SARS-CoV-2, and all samples tested negative for the virus.

Retrospective
Nine Pregnant women and their 10 • For the pregnant women, clinical symptoms analysis neonates including twins. were noted before delivery among 4 cases, [54] Initially all nine pregnant women on the day of delivery among 2 cases, and were COVID-19 positive after delivery among rest of the 3 cases.
• Among 10 newborns, 4 were full-term infants and 6 were born premature besides that, 8 singletons and 2 twins were observed.
• Some symptoms were observed in the neonates like shortness of breath, fever, thrombocytopenia, accompanied by abnormal liver function, rapid heart rate, vomiting, and pneumothorax.
• Till the date of publication of this study, 5 neonates were reported as cured and discharged, 1 has died, and 4 neonates remain in hospital with stable condition although these nine neonates reported negative result for their Pharyngeal swab specimens.

Retrospective 13
Chinese patients with SARS-CoV-2 • All the patients cooperated for analysis admitted to hospitals all were successful delivery [55] pregnant with age between 22-35 • 10 C-section delivery, 6 years with 25th to 38th weeks of premature delivery were reported gestation period.
• One case of severe neonatal asphyxia resulted in neonatal death. Furthermore, 86 of the 100 neonates tested for SARS-CoV-2 had negative results; of these, paired amniotic fluid and cord blood samples from 10 neonates used to test for SARS-CoV-2 had negative results. Clinical Five Pregnant women confirmed • All pregnant women did not have an analysis COVID-19. Gestational weeks antepartum fever but developed a low-grade [58] ranged from 38th weeks to fever (37.5?-38.5?) within 24 hours 41st weeks after delivery.
• All patients had normal liver and renal function; two patients had elevated plasma levels of the myocardial enzyme.
• Unusual chest imaging manifestations, featured with ground-grass opacity, were frequently observed in bilateral (three cases) or unilateral lobe (two cases) by computed tomography (CT) scan.
• All labors smoothly processed, the Apgar scores were 10 points 1 and 5 minutes after delivery, no complications were observed in the newborn.
• No newborns showed the signs of perinatal COVID-19 infection, umbilical cord blood and amniotic fluid were not applied for virus detection due to the lack of reagent. No complications of placenta infarction and chorionic amniotic inflammation were reported. All patients were advised to stop breastfeeding and empirically given oseltamivir and azithromycin for treatment.

Population 427
Pregnant women admitted to • Most pregnant women admitted to hospital based cohort hospital with confirmed with SARS-CoV-2 infection were in the late study [59] SARS-CoV-2 infection second or third trimester. between 1 March 2020 and • 281 (69%) were overweight or 14 April 2020 obese, 175 (41%) were aged 35 or over, and 145 (34%) had pre-existing comorbidities. 266 (62%) women gave birth or had a pregnancy loss; 196 (73%) gave birth at term. Forty-one (10%) women admitted to hospital needed respiratory support, and five (1%) women died. Twelve (5%) of 265 infants tested positive for SARS-CoV-2 RNA, six of them within the first 12 hours after birth.
• Almost 60% of women gave birth by caesarean section; most caesarean births were for indications other than maternal compromise due to SARS-CoV-2 infection. One in 20 of the babies of mothers admitted to hospital subsequently had a positive test for SARS-CoV-2; half had infection diagnosed on samples taken at less than 12 hours after birth. Clinical 617 Pregnant women • Ninety-three women (15.1%) had required analysis [60] with COVID-19 oxygen therapy and 35 others (5.7%) had a critical form of COVID-19.
• The severity of the disease was associated with age older than 35 years and obesity, as well as preexisting diabetes, previous preeclampsia, and gestational hypertension or preeclampsia.
• Among the women who gave birth, rates of preterm birth in women with non-severe, oxygen-requiring, and critical COVID- 19 [62] weeks of 33+6 to 40+5 weeks, were and none of the patients developed severe admitted to hospital with confirmed COVID-19 symptoms or died. SARS-CoV-2 • Two patients underwent vaginal delivery, two patients underwent intrapartum cesarean section, and the remaining six patients underwent elective cesarean section. They delivered including 9 singletons and 1 twin newborn.
• All eleven live births had a 1-min Apgar score of 8-9 and a 5-min Apgar score of 10.
• Four newborns were premature, two of them had a birthweight lower than 2500 g • After 14 days, eleven newborns were recorded no neonatal death or neonatal asphyxia was observed, and no one presented with fever, cough, or diarrhea. administration 69 . Regarding previous researchers related to the invention of medicine applied on animal models of MERS has been examined for the sake of SARS-CoV-2 70 Pneumonia developed as a foremost sign and symptom in COVID-19 patients were not advised to take corticosteroidbased medicines until and unless the accessory symptoms are not being prominent. The main reason to avoid this corticosteroid was confirmed by previous researchers related to MERS which unworthy as it can proceed to detain MERS-CoV approval 72 . Any conclusion regarding the lung maturation of fetus by applying corticosteroids must be taken under the advice of the in-charged professionals or neonatologists in addition with the infectious disease specialists. These information are subjected to be improvised time to time on the basis of further data on pregnant women available in relation with COVID-19.

Care of infants born to mothers with COVID-19
According to the previous studies related to SARS and MERS no cases had been found related to infection in neonates after delivery. In contrary, according to recent published media report, a chance of maternal to fetal transmission in a 30hours neonate was found which was supposed due to intrauterine contamination with COVID-19 after detection 73 . The studies flashed by Chen et al 9 and Zhu et al 54 , out of 18 women (19 neonates) were contaminated during the gestational period (probably 3 rd trimester) with SARS-CoV-2, but not laboratory detection of contamination from mother to baby during the period immediately before or after the birth. Trial of amniotic fluid, blood from umbilical cord and samples from infant's throat became negative for SARS-CoV-2, analyzed on six patients confirmed by the study of Chen et al 9 , Zhu et al 54 , suggested that other than the intrauterine transmission, other possibilities could be there after analyzing the complications based on the following symptoms: (a) abnormally breathing in six of them, (b) dyspnea or cyanosis among three of them, (c) intestinal bleeding in two of them, and (d) death of one among them due to multi-organ failure. However, throat swab testing of all infants was found to be negative for SARS-CoV-2.
So, it is not clear that whether SARS-CoV-2 is been communicated from mother to baby or not. Besides that, it can be stated that, the infestation of an infant with COVID-19 can be a contamination either in uterus or during the period around the birth (perinatally) is not confirmed because of the insufficient information till now. An early discussed study, conducted by Chen et al 9 , imposes a close observation regarding newborn death and fetal death or any kind of neonatal respiratory discomfort has not been confirmed caused by COVID-19 yet amidst three months pregnant mothers if also they had experienced C-section delivery. Besides those, among the nine pregnant patients, four women were observed with premature delivery but those were not subjected to COVID 19 infection; although the study calculated an Apgar scoree" 9 at 5 min for all the newborns. The study also observed the negative result for COVID-19 tested in amniotic fluid sample, umbilical cord blood sample collected from six pregnant women and throat swab samples from the six neonates which may confirm the not only the absence of vertical transmission from the COVID-19 positive patients to the newborn during the late pregnancy via the intrauterine environment but also via the breastfeeding as virus free colostrum of was detected from the COVID 19 infected women. But, as the transmission of virus happens through close contact, thus firstly the newborns were allowed to be separated from the affected mothers, at least for 14 days as incubation period of the virus, to confirm the effect of virus appearance among the newborns and mothers were allowed for the breastfeeding until they were tested negative. It has been stated earlier that all nine COVID-19 positive women attained Cesarean delivery, although the time interval between symptomatic diagnosis of the viral infection and Cesarean delivery was found to be lesser which rising a question for any risk of vertical transmission if mentioned interval will be greater. However another study by Shek et al. demonstrated that there is no relation of SARS CoV with inheritance i.e. this infection is not inherited 74 although currently no evidences were found regarding pregnancy linked with any unfortunate incidences like miscarriage, restricted fetal growth, spontaneous preterm birth and congenital anomalies during the COVID-19 pneumonia infection also. In early human placenta (first trimester), a mass level of ACE2 expression had been found in four main cell types, such as decidual stromal cells, decidual perivascular cells in deciduas and villous cytotrophoblast, and syncytiotrophoblast in placenta; on the contrary, the expression of ACE2 has been observed with very low level in extravillous trophoblast at first trimester and found to be elevated at the 24 th week of gestational period as per the recent study 10,75 . From the above studies, it might be inferred that due to high levels of ACE2 expression in placental cells, these cells are highly susceptible in SARS-CoV-2 infection. The possible rout of transmission from mother fetus is the mother-fetus interface which is known as syncytiotrophoblast which is the ectoenvelope of the placental villi creating the straight way to the maternal blood flow 10,76 . So, it is still unknown that, whether from mother to fetus transmission of this deadly COVID-19 infection is possible or not. For this reason, isolation of the infected mothers from their respective infants, as suggested at the time of H1N1, is really a judicious decision 77 .
The transmission of SARS-CoV-2 through mother's breastmilk is not been confirmed yet from a mother who has already recovered from COVID-19; although, on the same perspective, another study was conducted by collecting the breastmilk specimen from a mother with her recovery period of 130 days after the manifestation of infestation, which showed the presence of antibody against SARS-CoV in that breastmilk 41 . On the contrary, an infected mother at her 7 th week of gestation showed the absence of antibody at 12 th and 30 th day after delivery 78 . Randomly, six pregnant mothers were tasted for the presence of COVID-19 in breastmilk but all test reports were appeared to be negative in a study conducted by Chen et al 9 ; thus all those mothers were motivated for breastfeeding. No data or information has been confirmed yet about the duration of isolation and will be marked by close observation on the basis of future cases among the neonatologists and the persons of infection control board. On the basis of the proven data will concise the confusion about this deadly, incourigeous COVID-19 infection in pregnant mothers.

COnCluSIOn
At present, data are limited pertaining to the impact of COVID-19 upon the pregnant women based on which pregnancy-specific care can be recommended. However, experiences gained from previous pandemics owing to SARS, MERS, and other respiratory infections, risks associated with pregnant COVID-29 patients can be presumed. It is essential to include the records of COVID-19 mediated changes (if any) on gestation and/or the maternal and fetal outcomes, in the recorded database of COVID-19. As the pandemic COVID-19 reaches every 'nook and corner' of the communities across the globe, it is necessary to be more attentive for prevention of further spreading by providing some rapid implementations of management measures for outbreak control. Standard rigorous team-based actions are to be taken to care, manage as well as to improve any case of acute respiratory tract infection to any pregnant woman infected with COVID-19.