During the early phase of the coronavirus disease 2019 (COVID-19) pandemic, pregnant women faced uncertain maternal and perinatal risks associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [1].

Compared with non-pregnant patients, the severity and susceptibility to infectious diseases during pregnancy is different because of immunological alterations induced by hormonal changes [2]. Estradiol in high concentrations during pregnancy enhances several aspects of innate immunity, whereas, progesterone produced by the placenta suppresses the maternal immune responses [2,3]. As pregnancy advances, the activity of T-cell, natural killer cell, and possibly B-cells decreases through the complex interplay between sex hormones and the immune system, which causes an increase in the severity of some infections in late pregnancy [2,4]. Similarly, with COVID-19, the prevalence of symptomatic and severe infections increases in the later stages of pregnancy [5-7]. Functional residual capacity, end-expiratory volume, and residual volume also decrease steadily due to diaphragmatic splinting and elevation by the gravid uterus. This results in a reduced total lung capacity and an inability to effectively clear pulmonary secretions [8]. Besides these immunological and physiological alterations, increased oxygen consumption and respiratory mucous membrane edema could potentially affect the severity and susceptibility to COVID-19 in pregnant women, increasing hypoxic compromise [9-12].

The optimal management of pregnant women with COVID-19 remains under debate because of concerns regarding its effect on neonates. In a global systematic review, meticulously observed increases in several adverse maternal and neonatal outcomes during the pandemic were noted compared to before it. These adverse outcomes resulted from the pandemic, its effects on the healthcare system and its direct impact on pregnancy. Initial data were not national representative samples, lacked appropriate comparison groups, and could not be adjusted for confounding factors, and thus, the results could be biased. The prevalence of SARS-CoV-2 infection among pregnant women is reportedly 3-20% with a broad spectrum of severity, ranging from asymptomatic to extremely severe cases [13,14].

Herein, we have reviewed the latest information on COVID-19 in pregnant women and adverse maternal and perinatal outcomes. Additionally, we discussed vaccine administration, management, and prenatal counseling regarding COVID-19 during pregnancy.

SARS-CoV-2 infection in pregnant women can lead to a variety of consequences, ranging from asymptomatic cases to critical diseases, which is similar to infections in non-pregnant women [15-18]. The World Health Organization reported that approximately 80% of COVID-19 infections during pregnancy are mild or asymptomatic, 15% are severe and require supplemental oxygen, and 5% are critical, requiring mechanical ventilation [19]. However, other studies suggest that 40-45% of the infected population [20], or even only 20% [21], remain asymptomatic. Lee et al. [22] reported that 13.6% of the infected pregnant population in South Korea was asymptomatic. Preliminary data suggests that infection with the delta variant during pregnancy may be associated with a higher risk of placental dysfunction and fetal compromise than the previous alpha and omicron variants [22,23].

Although most pregnant women with SARS-CoV-2 experience mild disease and recover, 1 in 11 develop a severe or critical disease, 1 in 10 are hospitalized specifically due to a COVID-19 concern, 1 in 30 are admitted to the intensive care unit (ICU) for respiratory concerns, 1 in 60 are mechanically ventilated, and 1 in 80 die, suggesting an increased risk of hospitalization and an elevated case-fatality rate among pregnant women compared to non-pregnant women of a similar age [24]. Shortness of breath reportedly occurs in 18% of patients with COVID-19 [12]. Physiological dyspnea, due to increased maternal oxygen demands from a heightened metabolism, gestational anemia, and fetal oxygen consumption is common in pregnancy and must be distinguished from pathological breathlessness.

Compared to non-pregnant women, pregnant women are three times more likely to be admitted to an ICU, 2.9 times more likely to require invasive ventilation, and 1.7 times more likely to die [25]. A Canadian surveillance study and Norwegian population level analysis also showed that the risk of hospitalization and ICU admission was significantly higher among pregnant women with COVID-19 than among nonpregnant women in the reproductive-age group [26,27].

The pandemic and its effects on the healthcare system could have also caused adverse maternal morbidities. In South Korea, where COVID-19 was controlled relatively well without any lockdowns or medical health system collapse, most pregnant women with COVID-19 were less likely to manifest symptoms and showed less severe disease progression [22].

Older age and underlying medical conditions are associated with an increased risk of moderate-to-severe or critical COVID-19 illness among pregnant women. This information can be used for targeted public health messaging to help pregnant women understand their risk of moderate-to-severe or critical COVID-19 illness [28,29]. The risk factors for severe disease are similar between pregnant and non-pregnant women [18,30], and include obesity, older age, and underlying medical conditions such as chronic lung disease, chronic hypertension, and pre-gestational diabetes.

Most studies, except one, have reported that COVID-19 infection during pregnancy is associated with a higher rate of preterm birth [27,31-34]. National data in the United Kingdom and United States (US) registries of pregnancies with COVID-19 suggest that pregnant women should be counseled that SARS-CoV-2 infection increases the risk of preterm delivery [35]. Fever, hypoxemia, and severe respiratory disease increases the risk of preterm labor and premature rupture of membranes. Initial data showed that >90% of hospitalized mothers with COVID-19 had pneumonia, and preterm birth was the most common adverse pregnancy outcome. Additionally, infection-induced hypoxemia was poorly tolerated by the fetus and frequently stimulated preterm labor after midpregnancy [33]. Overall, preterm birth rates were higher in pregnant women with COVID-19 than in those without COVID-19 in the US (7.2% vs. 5.8% in Jering et al. [36], 12.9% vs. 10.1% in a national rate [37,38], and 14.8% vs. 10.2% in Katz et al. [39]; respectively).

A limitation of several studies was that they did not distinguish between spontaneous and iatrogenic preterm births. Although this hypothesis is unproven, several third-trimester cases were delivered by planned cesarean sections because of a bias catalyzed by the belief that management of severe maternal respiratory disease would improve after delivery. Whether preterm birth is associated only with severe or critical SARS-CoV-2 infection remains controversial. Some studies have asserted that an increase in preterm births appears to be limited to women with severe or critical diseases [24,40,41]; underlying comorbidities also likely play a role.

Another study found an increased risk of preterm birth among all pregnant women with COVID-19 compared to those without COVID-19 [32]. The fact that higher maternal stress is associated with preterm birth should be considered in situations where the maternity service may change during the pandemic [42]. According to Chmielewska, the overall incidence of preterm births before 37 weeks of gestation did not significantly change in pandemic (relative risk [RR], 0.94; 95% confidence interval [CI], 0.87-1.02); however, the incidence of preterm births were lower in high-income countries (RR, 0.91; 95% CI, 0.84-0.99), where spontaneous preterm births are already low, which indicated that preterm birth during the pandemic was associated with healthcare system collapse [43]. There is an urgent need to prioritize safe, accessible, and equitable maternity care within the strategic response to the pandemic and in future health crises.

COVID-19 infection is also associated with a higher rate of cesarean delivery [33,44,45]. A large cohort study in the US reported that the overall rates of cesarean delivery were generally similar or modestly higher in pregnant women with COVID-19 than in those without COVID-19 [38]. This elevated risk was primarily due to an increase in medically indicated preterm cesarean deliveries; only symptomatic patients with SARS-CoV-2 required cesarean deliveries because of lower utilization of labor analgesia [39].

During the early pandemic period in South Korea, it was difficult to secure the transfer of infected mothers from the delivery room to the operating room when an emergency cesarean section was required. Additionally, there were concerns about transmitting the infections to medical staff and newborns. Therefore, most mothers underwent cesarean section with a shorter delivery time, which seemed to reduce the possibility of medical staff being infected. Given accumulating evidence regarding infection route, it is necessary to discuss the appropriate delivery mode for pregnant women with COVID-19.

Pregnant women with SARS-CoV-2 infection reportedly have higher rates of preeclampsia [35,46], although this was not observed in a Canadian national research using Canadian COVID-19 in pregnancy surveillance-preg [27]. Further, among pregnant women, severe COVID-19 is associated with preeclampsia, gestational diabetes, and low birth weight compared to mild COVID-19 in review article on the early phase of pandemic [32].

The therapeutic management of pregnant women with COVID-19 should be the same as that of non-pregnant patients, except for molupiravir. The use of molnupiravir is not recommended in pregnant women unless there are no other options and the need for therapy is clearly indicated. The therapeutic management of pregnant women with COVID-19 based on disease severity is summarized in Table 1 [61].

As mentioned previously, even though the incidence of severe maternal complications of COVID-19 infection is low in pregnant women, it has been reported to be higher than in non-pregnant women of the same age, as reflected by factors such as ICU admission and the need for mechanical ventilation. In this way, the SARS-CoV-2 infection in pregnant women appears to be more severe, and so pregnant women were included early in the COVID-19 vaccination target.

Breastfeeding does not influence vaccination timing [71]. Vaccination-induced maternal SARS-CoV-2 antibodies pass into the breast milk and appear to offer passive protection to infants [72,73].

COVID-19 mRNA vaccines generate robust immune responses in the plasma and milk of lactating women without any reported severe adverse events [28]. Vaccines lower the risk of infection and severe disease and improved treatments for COVID-19 lower the risk of progression; thus, indications for delivery are reduced, which in turn reduce prematurity [41]. An adjusted hazard ratio of 0.22 (95% CI 0.11-0.43) for SARS-CoV-2 infection with BNT162b2 vaccination versus non-vaccination was reported in a large registry of 15,060 pregnant women in Israel [74]. Vaccination decreases the risk of progression to severe or critical COVID-19 and the need for hospital and ICU admissions in pregnant women [75,76].

In a study including 122 pregnant women (gestational age, 35-41 weeks), COVID-19 mRNA vaccines induced a transplacental antibody transfer detectable in cord blood as early as 16 days after the first dose [77].

No safety concerns were detected in the vaccine safety monitoring systems for people who received an mRNA COVID-19 vaccine late in pregnancy or for their babies [78-82]. An mRNA COVID-19 vaccine did not increase the risk of miscarriage in pregnant women who received the vaccine just before or during early pregnancy (<20 weeks) [78-80,83]. Administration of the mRNA COVID-19 vaccine during pregnancy was not associated with an increased risk of complications, including preterm birth, stillbirth, bacterial infection of the placenta, and excessive maternal blood loss after birth [80,83,84]. Furthermore, administration of COVID-19 vaccine before and during the first trimester was not associated with an increased risk of detectable birth defects [84].

Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical for reducing the impact of COVID-19 on stillbirths [68].

An mRNA vaccine (e.g., Pfizer/BioNTech, Moderna) or a recombinant protein subunit adjuvant-vaccine (e.g., Novavax) is preferred over a vector-based vaccine (e.g., Janssen/Johnson & Johnson) for administration. All three COVID-19 vaccines currently available can be administered to pregnant or lactating women, with no preference for the vaccine type. Although the safety data in pregnancy are rapidly accumulating and no concerns have been detected, additional information about birth outcomes, particularly among women vaccinated earlier in pregnancy, is needed [14].

We recommend that unvaccinated women planning for pregnancy, pregnant or recently pregnant women obtain the full vaccination course at the earliest, regardless of the gestational age or breastfeeding status. Booster injections are advised when they are eligible for it. A bivalent mRNA COVID-19 vaccine is recommended for the booster [85].

Primary vaccine administration earlier rather than later in gestation provides the most maternal benefit; it reduces the maternal risk of COVID-19-related hospitalization, death, and pregnancy complications. Although fetal and newborn antibody levels appear to be higher with primary vaccination later in pregnancy [86], this potential benefit does not out-weigh the overall pregnancy (maternal, fetal, and newborn) benefits of early vaccination, or account for the effects of booster doses when eligible [87].

COVID-19 vaccines may be administered at the same time as other vaccines, such as influenza and Tdap, which are routinely administered in pregnancy. An interval between vaccinations is unnecessary, and anti-D immunoglobin does not interfere with the immune response to vaccines. Thus, the timing of administration for prevention of alloimmunization is based on standard clinical protocols.

The collapse of the healthcare system in the early days of the COVID-19 pandemic led to avoidable deaths in both mothers and babies. However, based on current evidence, healthcare providers can counsel pregnant women that SARS-CoV-2 infection does not increase the incidence of severe adverse maternal and perinatal outcomes and that vertical transmission is rare. Additionally, they should recommend COVID-19 vaccination to women planning for pregnancy and even in those who are already pregnant.

The clinical management of pregnant women with COVID-19 is similar to that of non-pregnant women, and effective treatments should not be withheld [61]. Antiviral therapy, dexamethasone, and prophylactic anticoagulation are recommended for SARS-CoV-2 infection management [60].

In the early days of the COVID-19 pandemic, the management of pregnant women was often delayed until the PCR result came out or due to the risk of close contact, even in those without symptoms. Out of concern for the spread of infection, cesarean sections were performed instead of vaginal birth since infection could have led to an increase in maternal and neonatal morbidities. Additionally, the neonate was quarantined if the maternal PCR test was positive, despite infectivity decreasing 10 days after symptom onset. It is necessary to ease the strict measures of infection control in the field of obstetrics. Most of all, we should prepare novel protocols reflecting the latest trends for obstetric and neonatal practice for more efficient management of pregnant women with COVID-19.

Patients with SARS-CoV-2 infection who deliver by cesarean section face a higher risk of complications, such as infection, bleeding, and thromboembolic evens, than those who deliver vaginally [88,89]. If pregnant women in labor have a positive PCR test for COVID-19, the presence or absence of maternal SARS-CoV-2 symptoms should be identified to stratify the risk. Vaginal delivery can be attempted in asymptomatic women with low infectivity. Further research is needed to determine if potential barriers are needed at the time of delivery.

Safety data about vaccination in pregnancy is rapidly accumulating, with more women being vaccinated and no safety concerns have been detected despite the large number of pregnant women being vaccinated. Globally, the recommended COVID-19 vaccine, and numerous other vaccines, have been proven to be safe and effective in preventing COVID-19 in pregnant women [72,78,90,91].

Most experts believe that the SARS-CoV-2 infection is likely to become endemic [92]. Thus, data on the effects of SARS-CoV-2 infection during pregnancy are being constantly collected. It is also necessary to apply the lessons learned from this pandemic to improve our preparations and responses to new infections that may occur in the future. Policymakers and healthcare leaders should determine effective and robust strategies for preserving safe maternal care, even during ongoing global emergencies.