Introduction

Coronavirus disease 19 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2), which is a positive-sense single-strand RNA virus sharing genomic correspondence with other Betacoronaviruses, such as the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV [1]. More specifically, SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2), an enzyme that is highly expressed in lung epithelial cells, proximal renal tubules, the heart, and the brain, and which is the receptor mediating viral entry into the epithelial cells [2, 90]. Consequently, SARS-CoV-2 infection triggers acute host immune responses, inflammatory reactions, and cytokine storm, causing acute lung injury (ALI) and acute respiratory syndrome [2, 91, 92]. The World Health Organization (WHO) declared the COVID-19 outbreak as a pandemic disease in December 2019 after emergence of several unidentified pneumonia cases in Wuhan, China[3].Chinese researchers recognized that the genetic sequence of SARS-CoV-2 was similar to that of SARS-CoV (approximately 79%)[4, 93].

In January 2020, WHO defined this outbreak as a global pandemic disease due to its rapid spread worldwide. As of early April 2022, more than 489 million affected individuals and approximately six million deaths have been documented globally. Patients with COVID-19 present symptoms of dry cough, headache, fatigue, sweating, and fever [5], and laboratory findings include leukocytosis, lymphopenia, high lactate dehydrogenase, and ferritin with a bilateral pulmonary ground-glass appearance on computed chest tomography (CT) scan [6, 94]. Primarily, data regarding the effect of COVID-19 on pregnancy were insufficient due to the limited number of studies performed during the early stages of this pandemic. Consequently, researchers and medical experts faced a significant challenge in managing COVID-19 during pregnancy, even though a significant number of pregnant women with COVID-19 had already been reported [7]. At the commencement of this outbreak, the American College of Obstetricians and Gynecologists guideline was published to safeguard a scientific approach to COVID-19 during pregnancy [8]. Furthermore, the fatality rate of COVID-19 during pregnancy varied according to individual countries because early assessment could overestimate the percentage of case fatalities [9]. In late December 2020, the European Journal of obstetrics, gynecology, and reproductive biology published a review study entitled "Is pregnancy a risk factor for COVID-19" [48], in which Phoswa et al. found that pregnant women were at higher risk of develo** COVID-19 due to lymphopenia and deregulation of inflammatory cytokines with over-expression of ACE2 [48, 95]. Introductory documents had initially suggested that pregnant women were not strictly affected by COVID-19 compared to the general population [48, 49]. The total number of affected pregnant women was low, and it was not found to be associated with matched non-pregnant females. Similarly, different studies confirmed that pregnant women with COVID-19 were at increased risk of severe illness with COVID-19 compared to non-pregnant women [48]. Also, primary data regarding perinatal and intrauterine infection with SARS-CoV-2 were lacking as there was no confirmation or strong evidence pertaining to neonatal infection from infected mothers. The purpose behind this phenomenon was that nearly all infected pregnant women were in their third trimester, in which the effect of SARS-CoV-2 infection was practically unknown [10, 11, 95].

Amidst large body of literature, findings regarding the potential effect of SARS-CoV-2 infection on pregnancy outcomes and vertical and perinatal transmission are diverse. Therefore, the rationale for the review was to investigate existing literature and assess whether COVID-19 could be mild during pregnancy. Thus, the objectives of the present study were to identify COVID-19 outcomes during pregnancy and evaluate the risk of vertical and perinatal transmission during pregnancy. The novelty of this review was the illustration of the high or low risk of SARS-CoV-2 during pregnancy. This review also revealed that the DPP4 and CD137 receptors that are upregulated during pregnancy might increase the risk of vertical transmission (VT), of SARS-CoV-2 during pregnancy. In addition, this review highlighted that gestational diabetes mellitus (DM) might augment the risk of VT of SARS-CoV-2 during pregnancy due to ACE2 upregulation and associated inflammatory changes.

Search strategy

We applied different search strategies in various databases, including Embase, Medline, Web of Science, Scopus, and Cochrane Central Register of Control Clinical Trials using specific keywords such as [Pregnancy] AND [COVID-19 OR SARS-CoV-2 OR nCoV-19] OR [Perinatal transmission, VT, Pregnancy complications], [Pregnancy] AND [Hyperinflammation OR Cytokine storm]. In addition, the reference lists of relevant research studies were examined, and we considered articles published in languages other than English because it was our purpose to also include case-reported studies in this mini-review study. Exclusion criteria were as follows: in vitro and experimental studies; ex-vivo studies; and animal studies methods (Fig. 1). According to the PRISMA 2020 checklist [12], this review met the inclusion criteria according to the retrieved reports. To exclude the risk of bias during data collection and interpretation, all included studies were peer-reviewed publications. The mean difference and risk ratios regarding COVID-19 in pregnancy were also evaluated. This review is estimated to tabulate study intervention characteristics and compare them against the planned groups for each synthesis. In addition, heterogeneity among study results was assessed.

Fig. 1
figure 1

Flowchart of the present study

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Pregnancy and COVID-19

Increased female sex hormones during pregnancy induce an immune suppression status which renders pregnant women more susceptible to viral infections. Accordingly, SARS-CoV-2 in pregnant women leads to severe complications with significant mortality rate, due to comorbidities [13, 96]. The Center for Disease Control (CDC) has published distinct guidelines for the effective management of COVID-19 during pregnancy, depending on the previous coronavirus outbreaks during pregnancy. Furthermore, CDC has issued diverse recommendations regarding the pathogenesis, epidemiology, medical sequence, and disease progression of COVID-19 during pregnancy [14, 97]. Though clinical experience in the management of COVID-19 during pregnancy was rather restricted, various complications were reported, including preterm delivery, fetal distress, premature rupture of membrane, and abortion in pregnant women with COVID-19 [15, 81].

It has been reported that most pregnant women are frequently predisposed to the development of respiratory viral infections and severe pneumonia due to physiological immune suppression alterations and pregnancy-induced changes [16]. Previously, approximately 50% of pregnant women with SARS met the prerequisites for admission to intensive care units and mechanical ventilation with a 25% case-fatality rate [17]. Pregnant women during the 2009 swine influenza (H1N1) were at higher risk of hospitalization compared to non-pregnant women [18]. Nonetheless, COVID-19 in pregnant women is not significantly different from that in non-pregnant women; however, COVID-19 pulmonary consolidations and a ground-glass appearance are more evident at both lower lobes on low-dose CT scan imaging [19, 90, 98].

A previous study on 11 patients with COVID-19 pneumonia revealed that the primary symptoms were mild fever and cough. Among these patients, one pregnant woman delivered vaginally, whereas the remaining ten delivered via cesarean section [20]. The minor clinical presentation of COVID-19 during pregnancy might be related to the higher expression of ACE2 [21]. Lai et al. [22] confirmed that advanced expression of ACE2 during pregnancy, mainly in the feto-maternal interface, may increase the risk of COVID-19 severity. However, the renin–angiotensin–aldosterone system (RAAS) is highly activated during pregnancy and plays a possible role in pulmonary vasoconstriction and the progress of ALI. Consequently, a higher expression of ACE2 during pregnancy overwhelms the harmful effect of activated RAAS [23].

The connotation between over-expression of ACE2 and COVID-19 severity is weak since the ACE2 protein is located on the X chromosome, which is more abundant in females. Despite the low expression of ACE2, the COVID-19 fatality rate is higher in males, and the severity of COVID-19 in elderly patients is high [99, 100]. Also, ACE2 has a protective role against ALI in influenza [22]. Therefore, the ultimate link between COVID-19 severity during pregnancy and ACE2 over-expression should be reviewed and appropriately explained. Moreover, pregnancy and fetal delivery did not worsen the clinical outcomes and lung radiological imaging findings of COVID-19. In addition, most pregnant women with COVID-19 presented with mild symptoms and did not require antiviral therapy [24, 101].

Pregnancy and risk of vertical transmission in COVID-19

Low risk of vertical transmission

Viral infections during pregnancy are typically alarming due to likelihood of VT to the fetus. Viral infections during pregnancy are associated with intrauterine growth retardation, preterm birth, abortion, and poor perinatal outcomes [25].It has been proposed that the typical VT pathways include intrauterine transmission (IUT), standard vaginal delivery, and breast milk [25]. IUT requires the least amount of management and control, yet poses the greatest risk to both the mother and the fetus [26].

Karimi-Zarchi et al. [27] did not established any proof that COVID-19 during pregnancy may affect the fetus through IUT due to the negative results obtained by RT-PCR of cord blood, placental blood, amniotic fluid, and vaginal secretions. Nevertheless, neonatal infection has been established and reveals that direct contact between mothers and their neonates is the main route of infection. Al-kuraishy et al. [7] found no evidence for VT of SARS-CoV-2 during pregnancy, a finding that is also supported by the Li et al.’s study [25]. However, VT was confirmed in a single case report study by Dong et al. [28] as a result of positive RT-PCR tests, which nonetheless, did not estimate amniotic, cord, and placental blood. Furthermore, the majority of published studies on VT of SARS-CoV-2 infections during pregnancy based on RT-PCR tests and nasal swabs reveal sensitivities of 63 and 29%, respectively. Subsequently, immunoglobulin (IgG, IgM) appears within two weeks of SARS-CoV2 infection. It is evident that IgG but not IgM crosses the placenta; thus, anti-SARS-CoV-2 IgG in fetal blood does not indicate an intrauterine infection, as described by a recent Chinese study [37]. Also, SARS-CoV-2 viremia is present transiently only in 1% of patients with symptomatic COVID-19 pneumonia, suggesting the low possibility of this virus to be transmitted across the placenta. In addition, pathological studies of placental samples have not shown any histopathological changes associated with SARS-CoV-2 infections [38, 102, 103]. Dissimilar experimental studies exemplify that low expression of placental ACE2 receptors, principally at 6–12 weeks of gestation, limits SARS-CoV-2 transmission from mother to fetus[61]. A systematic sco** review found that higher expression of ACE2 with underlying chronic inflammatory reactions and exaggerated platelet activation in pregnant women with DM might cause placental dysfunction, which may increase the risk of VT SARS-CoV-2 infection during pregnancy [61,62,63,64]. According to a meta-analysis study performed by Yang et al., DM was the most common comorbidity observed during the COVID-19 pandemic [65]. Al-kuraishy et al. illustrated that DM was linked with severe COVID-19 complications due to changes in blood glucose and hyperinflammation, which enhance the pathogenesis of SARS-CoV-2 infection [66, 67]. Notably, diabetes increases the risk of SARS-CoV-2 infection due to T cell function and immune response impairment caused by high advanced glycation end-product diet [65,66,67,68,69]. Likewise, insulin resistance and endothelial dysfunction augment the risk of prothrombotic events, a hallmark of severe COVID-19 [70]. Preexistent DM during pregnancy increases the risk of develo** severe COVID-19 and the requirement for intensive care support [71].

Higher expression of ACE2 and TMPRSS2 in the placenta, concurrent with high rates of pro-inflammatory cytokines during pregnancy with DM, may favor SARS-CoV-2 infection and the dysregulation of the placenta environment with subsequent VT of SARS-CoV-2 infection [61, 111]. Besides, placental hypoxic-ischemic injury induced by high circulating AngII may cause vasoconstriction and disruption of the placental function [72]. Interestingly, SARS-CoV-2 infection during pregnancy may increase the risk of new-onset gestational DM development through injury of pancreatic β-cells [61, 112].

These findings suggest that gestational DM may augment the risk of COVID-19 and VT of SARS-CoV-2 infection during pregnancy.

Management of COVID-19 during pregnancy

The common principles in the management of COVID-19 during pregnancy comprise early diagnosis, isolation, oxygen therapy, experiential antibiotics for secondary bacterial infections, monitoring uterine contraction and fetal distress, and preparation and planning for delivery [42]. Regular monitoring and consultations for the prompt recognition of early and late difficulties and complications, such as preterm delivery and premature rupture of the membrane, should be performed [42, 113].

Corticosteroids must be avoided during pregnancy because they delay clearance of SARS-CoV-2 and may increase the risk of secondary bacterial infections [43]. Nevertheless, corticosteroid use for induction of fetal lung maturity should be contingent on guidelines and medical consultations [43].

At present, there are no FDA-approved antiviral medications during pregnancy, though broad-spectrum antiviral drugs against MERS are used against SARS-CoV-2 [44]. However, during the pandemic, the proper use of non-licensed medications during pregnancy should adhere to the Monitored Use of Unregistered Interventions (MEURI). Both chloroquine and remdesivir are effective and safe in managing COVID-19 during pregnancy. However, chloroquine has a large volume of distribution, thus a large dose is required during pregnancy [45]. Chloroquine and remdesivir reduce radiological opacities and accelerate clinical and serological resolutions in COVID-19 pregnant women [46]. Chloroquine is safe during pregnancy and is recommended for use as malaria prophylaxis [73]. A small amount of chloroquine can pass through lactating women’s breast milk, which does not cause any serious adverse effects on the neonates [74]. However, an experimental study showed that chloroquine could cross the placenta and accumulate in the fetal eyes, and remained for up to five months after clearance from the body [75]. Similarly, a very high dose of ≥ 250 mg/kg of chloroquine during pregnancy was found to increase the risk of develo** anophthalmia and microphthalmia in rats [75,76,77]. According to the current literature, the effectiveness of chloroquine and hydroxychloroquine is of limited value in COVID-19 [78, 79].

In contrast, remdesivir is a prodrug that needs to be activated by host intracellular enzymes and converted to an active drug that inhibits viral RNA polymerase. It was originally developed to treat Marburg and Ebola virus infections before being repurposed to treat SARS-CoV-2 infections [80,81,82]. The most common adverse effects of remdesivir involve elevated liver enzymes, nausea, sweating, and hypotension, and remdesivir metabolism is affected by enzyme inducers or inhibitors [83]. It has also been shown that hydroxychloroquine and chloroquine reduce the antiviral activity of remdesivir by inhibiting its metabolic activation [84]. Remdesivir induces minor side effects during pregnancy that are well tolerated in most cases. Remdesivir increases the recovery of pregnant women with COVID-19 [85]. A cohort study involving 95 pregnant women with COVID-19, of which 39 women were treated by remdesivir, revealed no severe or allergic adverse effects [86].

Furthermore, antiviral drugs, such as ritonavir and lopinavir, are effective against SARS-CoV-2 in COVID-19 pregnant women. However, a large population-based study did not confirm their safety. Contrariwise, favipiravir, arbidol, ribavirin, and baricitinib cause teratogenic effects on the fetus and are thus contraindicated during pregnancy [47, 87, 88].

The present study has several limitations, including a paucity of clinical studies that focus on COVID-19 infection in different trimesters of pregnancy, and the risk of VT was mainly speculative. However, this review produced evidence that VT of SARS-CoV-2 during pregnancy is rare yet possible, and the clinical course of COVID-19 during pregnancy was not different from that followed by non-pregnant women. The novelty of this review was that it confirmed the high or low risk of SARS-CoV-2 during pregnancy. This review also revealed that the DPP4 and CD137 receptors, which are upregulated during pregnancy, might increase the risk of VT of SARS-CoV-2 during pregnancy. In addition, this review highlighted that gestational DM might augment the risk of VT of SARS-CoV-2 during pregnancy due to upregulation of ACE2 and associated inflammatory changes.

Conclusion

The clinical presentation and management of COVID-19 during pregnancy are nearly identical to the ones in non-pregnant women. VT of SARS-CoV-2 infection during pregnancy is associated with a great deal of controversy and conflict. However, there is still no robust clinical evidence of VT. Only chloroquine and remdesivir are evaluated as adequate for managing COVID-19 during pregnancy. Large-prospective clinical studies are required to evaluate SARS-CoV-2 transmission during pregnancy and determine the true effects of current antiviral agents on pregnancy outcomes.