Consequences of SARS-CoV-2 Infection in Pregnant Women and Their Infants: A Systematic Review

Coronavirus disease 2019 (COVID-19) is a worldwide health problem, particularly for pregnant women. This review assesses the effects of COVID-19 on pregnant women and their infants. A systematic search was performed of studies published on PubMed, Web of Science, Google Scholar, and Embase from January 2020 to January 2021, without restriction by language. This review included 27 studies (22 from China, one from the United States, one from Honduras, one from Italy, one from Iran, and one from Spain), which cumulatively evaluated 386 pregnant women with clinically confirmed COVID-19 and their 334 newborns. Of the 386 pregnant women, 356 had already delivered their infants, four had medical abortions at the time of research, 28 were still pregnant, and two died from COVID-19 before they were able to give birth. Cesarean sections were performed on 71% of pregnant women with COVID-19 to give birth. Fever and cough were common symptoms among women. Premature rupture of membranes, distress, and preterm birth were pregnancy complications. Low birth weight and a short gestational age were common outcomes for newborns. The common laboratory findings among pregnant women were lymphopenia, leukocytosis, and elevated levels of C-reactive protein. Chest computed tomography revealed abnormal viral lung changes in 73.3% of women. Eleven infants tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There was no evidence of vertical transmission. Most infants were observed to have lymphopenia and thrombocytopenia. The clinical features of pregnant women were found to be similar to those of generally infected patients. There is evidence of adverse pregnancy and neonatal outcomes caused by COVID-19.


Study Strategy and Selection Criteria
The study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7].

Research Question
What are the consequences of SARS-CoV-2 infection in pregnant women and their newborns?

Search Strategy and Data Sources
We included studies published between January 2020 and January 2021 in PubMed, Web of Science, Google Scholar, and Embase, using the following keywords: "COVID-19" or "SARS-CoV-2" or "2019nCoV" or "coronavirus" and "pregnancy" or "pregnant" or "newborn" or "infant" or "child" or "neonatal," without any language restrictions. The papers were processed with EndNote® software (Clarivate, London, UK) to eliminate duplicates. Primary articles that evaluated the characteristics of COVID-19 during pregnancy were selected, and their titles and abstracts were screened for potential eligibility. Then, these studies were classified as relevant or irrelevant. The full texts of the relevant identified studies were read to determine final eligibility.

Inclusion Criteria
We included studies that involved pregnant women with COVID-19 and had data from positive COVID-19 cases performed using real-time reverse transcription polymerase chain reaction (RT-PCR), with the availability of descriptions of clinical characteristics, chest radiograph images, laboratory findings, treatment at admission, and neonatal outcomes.

Exclusion Criteria
Studies that did not have complete findings, studies that did not have access to data, and systematic reviews (to avoid overlapping data) were all excluded.

Data Extraction
We extracted the authors' names, study design, place, sample size, clinical findings for pregnant women, pregnancy outcomes in the event of delivery, and primary limitations.

Outcome of Interest
The clinical features of pregnancy, maternal comorbidities, obstetric difficulties, clinical findings, delivery procedures, medicines given to infected pregnant mothers, mothers' deaths, the chance of vertical transmission of infection, and neonatal outcomes were accessed.

Statistical Analysis
Information on outcomes of interest was gathered and the data were entered into an Excel® spreadsheet (Microsoft Corporation, Redmond, WA) for evaluation. Categorical variables were expressed as numbers and percentages.

Results
In this systematic review, 1,575 studies were recognized in four databases. Of these, 1,084 were excluded due to duplicates. Of the 491 remaining studies, 450 were excluded because they did not evaluate pregnant women with COVID-19. Forty-one abstracts were selected, 14 of which were excluded because they did not meet the inclusion criteria. Finally, 27 studies were eligible for inclusion in the study. The search process was summarized in a flow diagram ( Figure 1).

FIGURE 1: Study selection
Among the 27 studies, 17 were retrospective, five were case series, four were case reports, and one was a cohort study. Twenty-two studies were carried out in China, one in the United States, one in Honduras, one in Italy, one in Iran, and one in Spain. This study involved 386 pregnant women who had positive results for SARS-CoV-2 using real-time RT-PCR to confirm COVID-19 infection. Most of them were evaluated for clinical characteristics and other complications during pregnancy and postpartum. Of pregnant women investigated, 67% were evaluated using additional laboratory tests, such as complete blood count, kidney and liver function tests, as well as C-reactive protein (CRP) tests. Of the 386 pregnant women with COVID-19, 356 had a successful delivery, four had medical abortions, 28 were still pregnant at the time of research, and two died from COVID-19 before they were able to deliver. The pregnancies produced 360 newborns (352 singletons and four sets of twins). Of the newborns, 71% were delivered by cesarean section due to pregnancy complications (i.e., fetal distress and placental disorders). Cesarean sections were also performed to mitigate the possibility of vertical transmission of SARS-CoV-2 to neonates ( Table 1).    2%), B-lynch suture (1%), obesity (1%), polycystic ovary syndrome (1%), cardiovascular disease (1%), multiple organ dysfunction syndrome (0.2%), hepatitis B (0.2%), and underweight (0.2%) ( Table 2).
Co-infection with other pathogens was observed in four studies. Six pregnant patients tested positive for mycoplasma pneumonia, two for influenza, and one for Legionella pneumophila. Of pregnant women examined with COVID-19, 356 gave birth, producing 360 newborns (352 singletons and four sets of twins). Of these 356 women, 255 (71%) delivered their infants by cesarean section, 97 (27.2%) had natural vaginal deliveries, and four had medical abortions. There was no evidence of vertical transmission; umbilical cord blood, amniotic fluid, breast milk samples, and the placenta were negative using real-time RT-PCR ( Table 2).

3: Treatments given to mothers infected with SARS-CoV-2
The relevant data on babies born to COVID-19-positive mothers are included in Table 4. Of the articles included in the review, 24 studies reported on 334 newborns. The weight of newborns ranged from 910 to 4,750 g. Forty-two (12.5%) newborn babies had a birth weight of less than 2,500 g. Sixty-four (19.1%) were small for gestational age (SGA). Ten (2.9%) newborns had an abnormal APGAR (appearance, pulse, grimace, activity, and respiration) score. Fifty-two babies (15.5%) were admitted to the neonatal intensive care unit (NICU); six of them died (2.3%). Throat swabs using real-time RT-PCR were used to test 301 neonates for infection with SARS-CoV-2. Of these 301 babies, 11 tested positive for SARS-CoV-2 between six and 36 hours after birth. Ten of the positive infants were delivered by cesarean section and one was delivered vaginally. None of them developed severe complications ( Table 4).  Laboratory findings and chest CT scans were used to test 35 neonates, which revealed that five (15.6%) had leukocytosis, three (9.3%) had leukopenia, and 75.8% were within the normal range. Thirty-five newborns were tested for lymphocyte count; 15 (42.8%) had lymphopenia and 20 (57.1%) had a normal lymphocyte count. Platelet count assessments were performed on 24 neonates; four (16.6%) had thrombocytopenia, and the rest were within the normal range. Finally, 76 neonates underwent chest CT scans; 17 (22.3%) showed abnormalities, the most prevalent of which were opacity of "ground glass," patchy "shadows," and consolidations ( Table 4).

Discussion
Across the study, 386 pregnant women with COVID-19 were evaluated. Of these, almost all were in their third trimester (91%), which explains the birth and inclusion of 334 newborns in this review. Due to PROM and fetal distress, most women underwent cesarean sections to avoid vertical transmission and reduce adverse perinatal and neonatal outcomes [9,35]. Elective cesarean sections were also administered to minimize the respiratory distress of mothers [6,9]. In this study, most pregnant women were asymptomatic. Symptomatic pregnant women developed mild to moderate symptoms, most commonly fever, nonproductive cough, and postpartum fever, consistent with the results of a previous study [35]. In our study, pregnancies in the early gestational stages were discharged without severe complications. However, due to a lack of data on their perinatal outcomes, it was not possible to interpret neonatal outcomes when the infection is acquired early in pregnancy.
A total of 26% of women had chronic diseases; the top five identified comorbidities were diabetes mellitus, hypertensive disorders, thyroid disease, placental disorders, and anemia. Among the obstetric complications were PROM, fetal distress, preterm labor, acute cholecystitis, placenta previa, and vaginal bleeding in the third trimester, which are consistent with previous studies [35]. The presence of comorbidities increased the risk of poor outcomes and maternal death. Therefore, a proper patient classification must be performed carefully, documenting their medical history. This will help identify which pregnant patients are at high risk for poor outcomes related to COVID-19 [12].
The most significant laboratory findings among pregnant women were lymphocytopenia, leukocytosis, and elevated liver enzymes. Consolidation lesions and patchy ground glass shadows were the most prevalent abnormalities identified on chest CT scans. Pre-or postpartum maternal death due to infection is an area of concern. Seven mothers with COVID-19 were reported to have died in Iran [31]. Three, two, and two of the deaths were related to advanced maternal age, comorbidities, and acute RDS, respectively; two occurred during the second and third trimesters. This suggests that advanced maternal age and comorbidities with COVID-19 could increase the mortality rate in pregnant patients with COVID-19 [31]. However, more data from other countries on pregnant with COVID-19 are needed to confirm maternal mortality from COVID-19.
Pregnant women received the standard treatment used to lessen the severity of their infection. Ninety-four women received individual antibiotics or antibiotics in combination with steroids, mainly methylprednisolone, to prevent bacterial superinfection. A total of 128 patients received oxygen support through a nasal cannula. Antiviral therapies commonly administered to infected pregnant women, such as oseltamivir, ribavirin, interferon, ganciclovir, arbidol, and lopinavir, were also administered. Other studies have suggested the use of hydroxychloroquine during pregnancy [36]. In the current study, traditional Chinese medicine was used in two cases in China. Another patient with multiple organ system dysfunctions was treated with ECOM. It is important to note that physicians must exercise caution when prescribing any antiviral therapy to infected pregnant women.
Of the 334 newborns examined, 42 were born with low birth weight and 64 were preterm. Of all cases that presented evidence of pneumonia following a CT scan, 15 had lymphocytopenia. Commonly encountered neonatal complications, such as skin rash, edema, gastric bleeding, stillbirth, and neonatal death, were not found to be significantly related to SARS-CoV-2 infection. Six newborns found negative for SARS-CoV-2 died. These data demonstrate that maternal COVID-19 had significant adverse effects on newborns. As such, extra attention and care must be paid to newborns of mothers infected with COVID-19, in accordance with a previous study [13].
Eleven of the 290 neonates observed in the current review were clinically healthy and did not experience any complications; however, most of them had lymphopenia and thrombocytopenia. Three had evidence of pneumonia. Although three of the studies included in the review did not identify SARS-CoV-2 in the placenta, cord blood, amniotic fluid, or breast milk samples, it was not possible to determine whether transmission occurred vertically or through direct contact. Therefore, more studies are warranted in this regard.

Limitations and strengths
The first limitation was that most pregnant women were in the third trimester of their pregnancy. Therefore, any interpretations of maternal and neonatal outcomes for infections that were acquired early in pregnancy require further validation. The second limitation was that most of the studies were conducted in China, so the findings cannot be generalized to other populations. The strengths and findings of this review can be used to inform healthcare providers of the clinical and radiological characteristics, laboratory findings, and recommended treatment of pregnant women with COVID-19, as well as the neonatal outcomes of mothers with COVID-19.

Conclusions
The clinical features of pregnant women with COVID-19 were similar to those of general COVID-19 patients. There was no evidence of intrauterine transmission of SARS-CoV-2 in the third trimester, as SARS-CoV-2 was not detected in the placenta, cord blood, amniotic fluid, or breast milk samples. The risks of adverse pregnancy and neonatal outcomes in mothers with COVID-19 were demonstrated. There was evidence of complications such as premature membrane rupture, fetal distress, and preterm delivery. Small size for gestational age, low birth weight, lymphopenia, and thrombocytopenia were common adverse neonatal outcomes. The primary laboratory findings among pregnant women were lymphopenia, leukocytosis, and elevated CRP concentrations. Additional research is necessary to evaluate the long-term impact of COVID-19 on pregnancy and newborn outcomes.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.