Prenatal and neonatal complications of COVID‐19: A systematic review

The outbreak of coronavirus disease 2019 (COVID‐19) over the past year has affected public health worldwide. During pregnancy, the maternal immune system and inflammatory responses are widely suppressed. Pregnancy‐related immune system suppression could make the mother vulnerable to infectious diseases like SARS‐COV‐2. However, current data suggest little to no possibility of COVID‐19 transmission in pregnant women to the fetus during pregnancy or childbirth. This systematic review focused on the possible complications of COVID‐19 infection in the fetus and newborn babies including the possibility and evidence of vertical transmission by reviewing articles published during the first year of the COVID‐19 pandemic.

Conclusion: It appeared that most pregnant COVID patients were mildly ill, and there is currently no convincing evidence to support the vertical transmission of COVID-19 disease. Therefore, neonates do not represent any additional risk for adverse outcomes neither during the prenatal period nor after birth. year has affected public health worldwide and led to many deaths. 1,2 As of January 8, 2021, a total of 86 436 449 clinically confirmed COVID-19 positive and 1 884 341 death reported globally. 3 Mothers and newborns are at-risk populations and need special attention. 4 During pregnancy, the maternal immune system and inflammatory responses are widely suppressed, and the fetus in the womb without the mother's immune system attacking. 5 Pregnancy-related immune system suppression could make the mother vulnerable to infectious diseases and increases the risk of being infected, including coronavirus-related diseases. 6,7 Studies exploring the indirect adverse events of COVID-19 on the population have reported that pregnant women are at greater potential risk. [8][9][10] Maternal death, stillbirth, ruptured ectopic pregnancy, and maternal depression have had significant increase during the pandemic, 11 albeit the symptoms and severity of COVID-19 are as mild in most pregnant women as in the general population. [12][13][14][15] Moreover, the findings of a study showed asymptomatic infection in one-third of pregnant women. 16 The most common symptoms reported in COVID-19-positive pregnant women are fever, shortness of breath, diarrhea, and cough. In some severe cases, mechanical ventilation was performed [17][18][19][20][21][22] and maternal deaths were reported. [23][24][25] In a systematic review of the effects of COVID-19 on perinatal and maternal outcomes, the findings of studies from highincome countries (HICs) and low-income and middle-income countries (LMICs) showed a significant heterogeneity in the incidence of pregnancy complications; meaning that the adverse outcomes were much higher in LMICs. It also found that lack of immediate healthcare response in LMICs was responsible for heterogeneity of most of the outcomes rather than the stringent lockdown measures. The COVID-19 pandemic has manifested several lacunae in healthcare systems around the world, widening the gap between HICs and LMICs. 11 There are still many challenges related to SARS-CoV-2 infection in newborns and approaching the respiratory involvement in the case of infection. 26 However, the possibility of COVID-19 transmission from pregnant women to the fetus during pregnancy or childbirth is still unknown. 27,28 The consequences of pregnancy-related diseases could be detrimental to both mother and fetus. 29,30 Although most studies considered the vertical transmission unlikely, 31-37 a recent case report of a newborn with a positive early test indicated the possibility of vertical transfer in the uterus. 38 Additionally, four births with COVID-19 have been reported in recent studies. 24

| Design
We conducted a systematic search using keywords on PubMed, Embase, and Scopus databases. The identified records were screened by title/abstract to meet the inclusion criteria. Following this step, the full text of the included studies were evaluated based on the parameters mentioned in Section 2.2.Two researchers then extracted the data of the retrieved articles for drafting this systematic review.

| Search strategy
We utilized the following search strategy using the approach men-  nonpregnant patients. 83 The results from the present review indicate that one-third of pregnant women who tested positive for COVID-19 were asymptomatic that is approximately similar to the general population. [12][13][14][15] In the present review, women were often in their second and According to findings, cough and fever were the most common symptoms in mothers. 45,46 Other relatively common symptoms included dyspnea, diarrhea, and cardiac symptoms such as tachycardia. 24,51,57 However, fever and respiratory tract symptoms such as cough and dyspnea were the most common symptoms in neonates. 66,67 But one of the most important and noticeable findings were cardiovascular problems, particularly tachycardia and hypotension. 23,63,66 Neonatal pulmonary changes in chest CT scans were mostly unilateral or bilateral ground-glass opacities. The most common laboratory findings were the increase of C-reactive protein and decrease of lymphocytes (lymphocytopenia). Although less than half of neonatal patients had comorbidities (12%), fetal distress was the most common.
Five neonatal death occurred along with the mother. However, other neonatal deaths did not involve maternal death (n = 8). Pneumonia was also one of the most common neonatal complications of COVID-19 disease reported in other reviews. 44,46 This study comes with limitations. Some of the included studies lacked information related to the severity of the complications in the neonates. Some also did not report the final status of the newborns and whether they were cured or not, or had short-or long-term sequels. Also it will be useful if the studies mention the long-term outcomes of the patients and the impact of the disease and its possible complications in longer periods. On the other hand, there were also some limitations related to the data about the mothers in a portion of the studies, for example, the starting date of COVID-19 and the duration of the disease. We also did not perform a statistical analysis.
Neverthless, this study provided some important information related to perinatal and neonatal complications of COVID-19 and future welldesigned meta-analyses can increase our awareness of this disease more.

| CONCLUSION
Evidence suggests that vertical transmission in the uterus is responsible for COVID-19 in neonates that makes neonatal infection through the umbilical cord unlikely. [31][32][33][34][35][36][37]43 In addition, parental infection is less severe due to the suppression of immune system during pregnancy.
Neonates do not present any additional risk for COVID-19 complications during the prenatal period. However, further epidemiological studies are recommended to explore the possibility of mother-to-child T A B L E 2 (Continued)

FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest regarding the publication of this manuscript.

AUTHOR CONTRIBUTION
The conception and design of the study: Esmaeil Mehraeen and

AVAILABILITY OF DATA AND MATERIAL
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.

CONSENT TO PUBLICATION
Not applicable.