Abstract
Objectives
To assess perinatal outcomes of COVID-19 infections during pregnancy and the possibility of vertical transmission.
Methods
An analysis was performed using Stata 15.0, and Q-test was used to evaluate the heterogeneity of the included studies.
Results
The most common symptoms were found to be fever (64.78%), cough (59.81%) and shortness of breath or dyspnea (23.86%). Of this 88.73% patients demonstrated typical COVID-19 signs on chest CT or X-ray. Intubation was carried out in 35.87% of patients, and 4.95% of mothers were admitted to the intensive care unit, where the rate of maternal death was <0.01% and that of premature delivery was 25.32%. The rate of the birth weight being <2,500 g was 30.65% and that of Neonatal intensive care unit (NICU) admission was 24.41%. Positive nasopharynx swabs or sputum from newborns was <0.01%.
Conclusions
Pregnant patients with COVID-19 most commonly presented with fever, cough, shortness of breath and dyspnea, most of which possessed imaging manifestations. The risk of intubation and admission to intensive care unit were high. The risk of premature delivery was higher, leading to a high risk of NICU admission and low neonatal birthweight. Vertical transmission of SARS-CoV-2 from mother to child was found to be unlikely.
Introduction
SARS-CoV-2 was first discovered in Wuhan, China in December 2019, eventually causing the coronavirus disease 2019 (COVID-19) pandemic just a few months after it was discovered [1].
SARS-CoV-2 is a novel coronavirus and belongs to the subgenus sarbecovirus of betacornavirus, having about 79% identity with SARS coronavirus [2]. It has been confirmed that SARS-CoV-2 enters cells by binding spike protein (S protein) with receptor angiotensin converting enzyme 2 (ACE2), and modulates host cells through reshaping cellular pathways such as translation, splicing, carbon metabolism, and nucleic acid metabolism [3], [4], [5].
COVID-19 is mainly manifested by fever, fatigue, and dry cough. In the early stage of onset, the number of lymphocytes may decrease and white blood cells may be normal or also decreased. Some patients may have increased liver enzymes and lactate dehydrogenase (LDH) [6]. Additionally, studies have shown that lymphopenia can be predictive of COVID-19 progression.
Although most patients with COVID-19 showed mild symptoms, about 5% of patients developed critical illness with severe pneumonia even multiple organ failure [7]. Studies of these outbreaks have revealed that the overall mortality rate of COVID-19 patients was 2.3% in the Chinese mainland during the epidemic [7]. However, the mortality rate of patients requiring mechanical ventilation in the New York area of the United States reached 24.5% [8], and the mortality rate of ICU patients in Lombardy, Italy was as high as 26% [9].
The global COVID-19 pandemic worsened the outcomes of several patient populations, including the elderly and patients with chronic comorbidities [10]. However, the effects of COVID-19 on pregnant women and their fetus remains unclear. During pregnancy, associated maternal immune changes, increased oxygen consumption and rise of diaphragm are known risk factors of pneumonia [11]. Moreover, upper respiratory tract swelling and restricted lung expansion indicate that pregnant women are vulnerable and susceptible to COVID-19 [12]. As the receptor SARS-CoV-2 enters the cell, ACE2 is upregulated during normal pregnancy [10], which may aggravate the clinical manifestations of pregnant women with COVID-19. Current evidence shows that ACE2 is widely expressed in the ovaries, uterus, vagina, and placenta, hence, the possibility of vertical transmission cannot be ignored [13].
Therefore, this study attempted to investigate the clinical manifestations, laboratory tests, clinical outcomes, and pregnancy outcomes of pregnant women with COVID-19 along with the possibility of vertical transmission in these patients. In June 2020, a similar systematic review was published, however, it did not study the risk of neonatal infection and did not include other indicators such as intubation and ICU admission [14]. Additionally, a later retrospective cohort study comprised 427 pregnant women in UK was published [15].
Objectives
The aim of this study was to assess the perinatal outcomes of COVID-19 infections during pregnancy as well as the possibility of vertical transmission.
Methods
Data sources and search strategy
In this systematic review, MEDLINE, PubMed, Web of Science, Cochrane library, China National Knowledge Infrastructure (CNKI), WANFANG DATA, VIP, SinoMed, and Clinical trials.gov were searched for studies or abstracts published between December 1, 2019 and June 10, 2020. Various combinations of the relevant medical subject heading (MeSH) terms, keywords, and word variants for “COVID-19” and “pregnancy” or “newborns” or “vertical transmission” were used. The search and selection language were not restricted so as to include more exhaustive reports.
Eligibility criteria and participants
Eligible studies required satisfying all of the following inclusion criteria: 1) participants must have been pregnant women with COVID-19 infection confirmed by RT-PCR or diagnosed clinically according to typical manifestations; and 2) pregnancy outcomes were reported. All studies that met the inclusion criteria were investigated repeatedly with careful review of different institutions reporting the results in order to avoid the inclusion of patients in more than one report.
Data analysis method
The analysis was performed using Stata 15.0, and Q-test was used to evaluate the heterogeneity of the included studies. If p>0.1 and I2 ≤ 50%, the fixed effect model was used; otherwise, the random effect model was used. The combined efficiency was calculated using double arcsine conversion.
Results
Study selection and characteristics
In total, 959 articles were identified, of which 73 were assessed for eligibility and 36 studies were finally included in the systematic review (Figure 1). The basic characteristics are shown in Table 1.
Systematic review flowchart.
Basic characteristics of the included studies.
| Title | Year | Country | Study design | Cases, n | Mean age, years | Mean gestational age, weeks |
|---|---|---|---|---|---|---|
| Li et al. [16] | 2020 | China | Case report | 1 | 30 | 35 |
| Sun et al.[17] | 2020 | China | Case series | 3 | 29 | 34.5 |
| Xu et al. [18] | 2020 | China | Case series | 28 | 30 | NA (4/28 < 28 weeks) |
| Yan et al. [19] | 2020 | China | Case series | 116 | 30.8 ± 3.8 | NA (10/116 < 28 weeks) |
| Li et al. [20] | 2020 | China | Case report | 1 | 31 | 35 |
| Chen et al. [21] | 2020 | China | Case series | 3 | Range 30–38 | 22 |
| Peng et al. [22] | 2020 | China | Case report | 1 | 25 | 34 |
| Xiong et al. [23] | 2020 | China | Case report | 1 | 25 | 33 |
| Chen et al. [24] | 2020 | China | Case series | 118 | Median 31 | NA (43/118 < 28 weeks) |
| Zhou et al. (In Chinese) [25] | 2020 | China | Case report | 1 | 30 | 37 |
| Taghizadieh et al. [26] | 2020 | Iran | Case series | 1 | 33 | 34 |
| Martinelli et al. [27] | 2020 | Italy | Case report | 1 | 17 | 29 |
| Ferrazzi et al. [28] | 2020 | Italy | Case series | 42 | 32.9 | NA |
| De Socio et al. [29] | 2020 | Italy | Case report | 1 | 33 | 40 |
| Lee et al. [30] | 2020 | Korea | Case report | 1 | 35 | 37 |
| Alzamora et al. [31] | 2020 | Peru | Case report | 1 | 41 | 33 |
| Dória et al. [32] | 2020 | Portugal | Case series | 12 | 31.9 | 37.5 |
| Lyra et al. [33] | 2020 | Portugal | Case report | 1 | 35 | 39 |
| Díaz et al. (In Spanish) [34] | 2020 | Spain | Case report | 1 | 41 | 38 |
| Pereira et al. [35] | 2020 | Spain | Case series | 60 | NA | NA (10\60 < 28 weeks) |
| González et al. (In Spanish) [36] | 2020 | Spain | Case report | 1 | 44 | 29 |
| Martínez-Perez et al. [37] | 2020 | Spain | Case series | 82 | NA | NA |
| Baud et al. [38] | 2020 | Switzerland | Case report | 1 | 28 | 19 |
| Kalafat et al. [39] | 2020 | Turkey | Case report | 1 | 32 | 35 |
| London et al. [40] | 2020 | US | Case series | 68 | 30.2 | NA (3/68 < 28 weeks) |
| Pierce-Williams et al. [41] | 2020 | US | Case series | 64 | 33.2 ± 5.8 | 29.9 ± 5.8 |
| Lokken et al. [42] | 2020 | US | Case series | 46 | 29 | Median (range) 27.0 (21.0–33.9) |
| Mehta et al. [43] | 2020 | US | Case report | 1 | 39 | 27 |
| Silverstein et al. [44] | 2020 | US | Case series | 2 | 25.5 | 35 |
| Iqbal et al. [45] | 2020 | US | Case report | 1 | 34 | 39 |
| Schnettler et al. [46] | 2020 | US | Case report | 1 | 39 | 31 |
| Kelly et al. [47] | 2020 | US | Case report | 1 | NA | 33 |
| Juusela et al. [48] | 2020 | US | Case series | 2 | 35.5 | 36 |
| Hantoushzadeh et al. [49] | 2020 | US | Case series | 9 | NA | 31 |
| Knight et al. [15] | 2020 | UK | Case series | 427 | NA | Median (range) 34 [29], [30], [31], [32], [33], [34], [35], [36], [37], [38] |
| Cooke et al. [50] | 2020 | UK | Case series | 2 | 38.5 | 28 |
NA, not available.
Gestational age at onset of symptoms and main clinical manifestations
Among the enrolled patients, the rate of pregnancy <28 gestational weeks was 2.71% (95% CI 0.00–10.59%), while that of 28–36+6 weeks was 39.59% (95% CI 22.80–57.29%) and that of ≥37 weeks was 30.22% (95% CI 10.98–52.45%).
The most common symptoms were fever (64.78% ,95% CI 49.45–79.12%), cough (59.81%, 95% CI 45.07–73.95%), shortness of breath or dyspnea (23.86%, 95% CI 9.83–40.33%). Other symptoms included sore throat (0.84%, 95% CI 0.00–7.25%), chest pain (1.31%, 95% CI 0.00–7.51%), rigors (0.59%, 95% CI 0.00–13.13%), myalgia or arthralgia (0.09%, 95% CI 0.00–1.36%), and diarrhea (<0.01%).
Additionally, 88.73% of the enrolled patients demonstrated typical COVID-19 signs on chest CT or X-ray (95% CI 66.3–100.00%). In respect of laboratory examinations, 89.84% of patients had normal or decreased leukocytes (95% CI 70.21–99.99%), while 49.43% had decreased lymphocytes (95% CI 28.88–70.06%), 37.82% had increased LDH (95% CI 11.43–67.37%), and 20.74% had increased ALT or AST (95% CI 0.73–51.08%) (Table 2).
Gestational age at onset of symptoms and main clinical manifestations.
| Types | n (studies) | Event | Total | Proportion, % | 95% CI, % | Heterogeneity | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| χ2 | I2 | Variance | p-Value | |||||||
| Gestational age at onset of symptoms | <28 weeks | 30 | 148 | 807 | 2.71 | 0.00–10.59 | 57.79 | 48.82 | 0.05 | 0.00 |
| 28–36+6 weeks | 27 | 224 | 595 | 39.59 | 22.80–57.29 | 46.04 | 43.52 | 0.07 | <0.01 | |
| ≥37 weeks | 27 | 237 | 593 | 30.22 | 10.98–52.45 | 77.90 | 66.62 | 0.18 | <0.01 | |
| Peripartum | 31 | 35 | 845 | <0.01 | 0.00–0.00 | 46.61 | 35.63 | 0.03 | 0.03 | |
| Symptom types | Fever | 32 | 568 | 954 | 64.78 | 49.45–79.12 | 135.66 | 77.15 | 0.14 | <0.01 |
| Cough | 30 | 506 | 952 | 59.81 | 45.07–73.95 | 118.60 | 75.55 | 0.12 | <0.01 | |
| Shortness of breath or dyspnea | 30 | 241 | 885 | 23.86 | 9.83–40.33 | 143.41 | 79.78 | 0.17 | <0.01 | |
| Sore throat | 23 | 69 | 624 | 0.84 | 0.00–7.25 | 29.93 | 26.51 | 0.02 | 0.12 | |
| Diarrhea | 26 | 37 | 787 | <0.01 | 0.00–0.00 | 17.26 | <0.01 | <0.01 | 0.87 | |
| Chest pain | 21 | 23 | 253 | 1.31 | 0.00–7.51 | 12.69 | <0.01 | <0.01 | 0.89 | |
| Rigors | 21 | 4 | 38 | 0.59 | 0.00–13.13 | 13.38 | <0.01 | <0.01 | 0.86 | |
| Myalgia or arthralgia | 26 | 83 | 678 | 0.09 | 0.00–1.36 | 33.09 | 24.45 | 0.02 | 0.13 | |
| Chest X-rays or CT | Typical signs of COVID-19 | 31 | 420 | 896 | 88.73 | 66.3–100.00 | 403.90 | 92.57 | 0.56 | <0.01 |
| Laboratory tests | Normal or decreased WBC | 19 | 212 | 252 | 89.84 | 70.21–99.99 | 54.49 | 66.97 | 0.19 | <0.01 |
| Decreased lymphocytes | 20 | 137 | 383 | 49.43 | 28.88–70.06 | 85.19 | 77.70 | 0.21 | <0.01 | |
| Increased LDH | 14 | 26 | 147 | 37.82 | 11.43–67.37 | 39.72 | 67.27 | 0.26 | <0.01 | |
| Increased Alt or Ast | 8 | 14 | 71 | 20.74 | 0.73–51.08 | 12.89 | 45.69 | 0.13 | 0.07 | |
n (studies): number of studies included; Event: the number of occurrences; Total: Total sample size. Interpretation of results: Taking the “<28 weeks” as an example, 37 studies were included, with 157 occurrences in a total sample size of 828. For p < 0.1, the random effect model was adopted, and the combined effect amount was 4.87% (95% CI: 0.13–13.74%), indicating that the incidence of gestational age < 28 weeks at the time of symptom onset was 4.87%.
Complications, maternal outcomes, and mode of delivery
Among the enrolled patients, gestational hypertension or preeclampsia occurred in <0.01%, and premature rupture of membranes occurred in 4.03% (95% CI 0.16–11.22%) (Table 3).
Complications, maternal outcomes, and mode of delivery.
| Types | n (studies) | Event | Total | Proportion, % | 95% CI, % | Heterogeneity | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| χ2 | I2 | Variance | p-Value | |||||||
| Complications | Gestational hypertension or preeclampsia | 27 | 24 | 381 | <0.01 | 0.00–0.00 | 11.36 | <0.01 | <0.01 | 0.99 |
| Premature rupture of membranes | 27 | 32 | 176 | 4.03 | 0.16–11.22 | 22.14 | <0.01 | <0.01 | 0.68 | |
| Main outcome measures | Intubation | 26 | 36 | 221 | 35.87 | 10.29–65.04 | 93.74 | 73.33 | 0.44 | <0.01 |
| ICU | 31 | 81 | 895 | 4.95 | 0.01–15.15 | 94.53 | 68.26 | 0.10 | <0.01 | |
| Death | 33 | 13 | 1005 | <0.01 | 0.00–0.00 | 53.19 | 39.84 | 0.03 | 0.01 | |
| Pregnancy outcomes | Full term delivery | 35 | 543 | 743 | 68.53 | 55.87–80.29 | 91.75 | 62.94 | 0.09 | <0.01 |
| Premature delivery | 35 | 188 | 743 | 25.32 | 14.19–37.74 | 93.66 | 63.70 | 0.09 | <0.01 | |
| Spontaneous abortion or artificial abortion | 35 | 20 | 743 | <0.01 | 0.00–0.00 | 43.40 | 21.67 | 0.01 | 0.13 | |
| Stillbirth | 34 | 8 | 663 | <0.01 | 0.00–0.00 | 33.22 | 0.66 | 0.04 | 0.46 | |
| Mode of delivery | Caesarean delivery for SARS-CoV-2 | 29 | 135 | 586 | 28.59 | 13.11–46.14 | 82.57 | 66.09 | 0.12 | <0.01 |
| Caesarean delivery for other indications | 29 | 254 | 586 | 34.63 | 22.69–47.28 | 44.63 | 37.26 | 0.04 | 0.02 | |
| Vaginal delivery | 35 | 283 | 733 | 26.83 | 13.04–42.45 | 149.77 | 77.30 | 0.19 | <0.01 | |
Intubation was carried out in 35.87% (95% CI 10.29–65.04%) of patients (Figure 2), and 4.95% (95% CI 0.01–15.15%) were admitted to the intensive care unit (ICU) (Figure 3), where the rate of maternal death was <0.01%.
Forest plots of pooled prevalence of intubation.
Forest plots of pooled prevalence of ICU admission.
The rate of full-term delivery was 68.53% (95% CI 55.87–80.29%), while that of premature delivery was 25.32% (95% CI 14.19–37.74%) (Figure 4) and that of abortion or stillbirth was <0.01%. In addition, 28.59% patients had caesarean section for SARS-CoV-2 (95% CI 13.11–46.14%), 34.63% patients had caesarean section for other indications (95% CI 22.69–47.28%), and 26.83% patients had vaginal delivery (95% CI 13.04–42.45%).
Forest plots of pooled prevalence of premature delivery.
Neonatal outcomes and samples PCR results
As shown in Table 4, among neonates born to mothers with COVID-19, the rate of the 1 min Apgar score being ≤7 was 18.76% (95% CI 0.32–48.46%), while that of the 5 min Apgar score being ≤7 was 0.65% (95% CI 0.00–12.30%). In addition, the rate of birth weight being <2,500 g was 30.65% (95% CI 9.84–54.98%) (Figure 5), and asphyxia occurred in <0.01%.
Neonatal outcomes and samples PCR results.
| Types | n (studies) | Event | Total | Proportio, % | 95% CI, % | Heterogeneity | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| χ2 | I2 | Variance | p-Value | |||||||
| Neonatal outcomes | 1 min Apgar score ≤7 | 21 | 12 | 160 | 18.76 | 0.32–48.46 | 69.96 | 71.41 | 0.46 | <0.01 |
| 5 min Apgar score ≤7 | 22 | 9 | 202 | 0.65 | 0.00–12.30 | 43.76 | 52.02 | 0.15 | 0.00 | |
| Birth weight <2,500 g | 15 | 12 | 33 | 30.65 | 9.84–54.98 | 14.39 | 2.72 | 0.01 | 0.42 | |
| Asphyxia | 22 | 4 | 223 | <0.01 | 0.00–0.00 | 23.95 | 12.32 | 0.02 | 0.30 | |
| Intubation | 18 | 7 | 54 | 11.13 | 0.00–39.99 | 33.59 | 49.40 | 0.32 | <0.01 | |
| NICU | 26 | 108 | 341 | 24.41 | 7.44–45.09 | 104.62 | 76.10 | 0.27 | <0.01 | |
| Neonatal death | 32 | 5 | 599 | 0.00 | 0.00–0.00 | 21.16 | <0.01 | <0.01 | 0.91 | |
| Samples test positive for SARS-CoV-2 | Nasopharynx swabs or sputum from newborns | 30 | 21a | 559 | <0.01 | 0.00–0.00 | 32.42 | 10.54 | 0.01 | 0.30 |
| Cord blood | 7 | 0 | 16 | 0.00 | 0.00–6.40 | 1.11 | <0.01 | <0.01 | 1.00 | |
| Amniotic fluid | 8 | 0 | 17 | 0.00 | 0.00–6.34 | 1.21 | <0.01 | <0.01 | 1.00 | |
| Placenta | 8 | 1 | 13 | 0.04 | 0.00–23.87 | 4.73 | <0.01 | <0.01 | 0.69 | |
| Cervical or vaginal secretions | 3 | 0 | 3 | 0.00 | 0.00–61.92 | <0.01 | <0.01 | <0.01 | <0.01 | |
| Breast milk | 6 | 0 | 10 | 0.00 | 0.00–20.72 | 0.22 | <0.01 | <0.01 | 1.00 | |
aSix of the 21 newborns tested positive for SARS-CoV-2 RNA within the first 12 h after birth, two of which were from unassisted vaginal births and four were born by caesarean. No viral analyses were performed on umbilical cord blood, placenta, or vaginal secretions.
Forest plots of pooled prevalence of low birthweight.
Intubation was carried out in 11.13% (95% CI 0.00–39.99%) of newborns, and 24.41% (95% CI 7.44–45.09%) were admitted to the neonatal intensive care unit (Figure 6), where the rate of neonatal death was <0.01%.
Forest plots of pooled prevalence of NICU admission.
The rate of placenta positive to SARS-CoV-2 was 0.04% (one positive in 14 samples), and positive nasopharynx swabs or sputum from newborns occurred in <0.01%. The rate of cord blood, amniotic fluid, cervical or vaginal secretions and breast milk positive to SARS-CoV-2 was 0.
Discussion
SARS-CoV-2, due to its strong infectivity and pathogenicity [51], is one of the most serious epidemics in the 21st century. The disease process involves the respiratory system; however, studies have confirmed that it may also involve organ systems such as the cardiovascular system. During the epidemic, pregnant women suffering from COVID-19 have garnered increased attention from clinicians due to their special immune and physiological conditions. In this regard, many unsolved mysteries exist in their clinical characteristics and outcomes. Through the systematic review of 36 articles comprised 1,103 patients, a comprehensive perspective in understanding the clinical characteristics and disease outcomes of pregnant women with COVID-19 was provided. Here, a larger number of studies than similar articles that were previously published as well as nine articles with patient numbers exceeding 40 were included. Accordingly, a more detailed analysis of the indicators was presented in this study, making this analysis the most comprehensive and credible report available. In particular, the conclusions show that pregnant patients have a high rate of ICU admission and intubation, suggesting that the prognosis of the condition is still very grim.
Clinical manifestations
This study illustrated that the most common symptoms in pregnant women with COVID-19 were fever (64.78%), cough (59.81%), shortness of breath or dyspnea (23.86%), which was consistent with the clinical presentations of the general population as well as earlier systematic reviews [52], [53], [54], [55]. Studies have shown that SARS-CoV-2 can be detected in the upper respiratory tract with a high viral load [56]. As a result, patients can present with upper respiratory tract symptoms [57], most of whom have cough and positive nasopharyngeal and throat swabs. During pregnancy, some women may suffer from temporary dyspnea, especially in the third trimester, and they are more likely to have symptoms such as shortness of breath and tachycardia. In late pregnancy, the enlarged uterus lifts the diaphragm upward, causing the chest to become smaller, affecting cardiopulmonary activity. Therefore, clinicians should pay attention to complaints of dyspnea in pregnant women with COVID-19 in order to exclude physiological conditions and cardiac diseases. Other symptoms included sore throat (0.84%), chest pain (1.31%), chills (0.59%), myalgia or arthralgia (0.09%), and diarrhea (<0.01%). Evidently, such symptoms may not serve as the main clinical manifestations of pregnant women. However, when atypical symptoms manifest as initial symptoms, clinicians should be concerned and not ignore the possibility of COVID-19.
The present study also showed that 88.73% of pregnant women demonstrated typical COVID-19 signs on chest CT or X-ray (95% CI 66.3–100.00%), which was consistent with previous studies showing that more than 90% of symptomatic patients will develop chest CT evidence of viral pneumonia within 3–5 days of onset [58]. This may reflect viral replication in the lower respiratory tract, accompanied by infection and inflammation of lung cells [59]. In view of laboratory examinations, this study showed that 89.84% of pregnant patients had normal or decreased white blood cells, 49.43% had decreased lymphocytes, and 37.82% had elevated LDH. Though slightly different, one study showed that symptoms of lymphopenia (64.5%), elevated LDH (28.3%), and leukopenia (29.4%) were common in COVID-19 patients [55], while another study showed that about half of patients infected with COVID-19 presented with leukopenia and lymphopenia [60].
In addition, this study demonstrated that 20.74% of pregnant women had elevated ALT or AST levels. Recent studies in the non-pregnant population have shown that the incidence of liver involvement ranged from 14.8 to 53% [61]. Liver injury in mild COVID-19 cases was usually transient and did not require special treatment [62]. However, clinicians must consider all potential causes of liver injury and further investigate if liver biochemistry deteriorates.
Clinical outcomes and pregnancy outcomes
This study demonstrated that the rate of ICU admission and intubation was high in pregnant women suffering from COVID-19. In particular, the intubation rate reached 35.87%, which was far higher than the 19% of severe and critical patients reported in a large-scale retrospective case study in China [7] as well as the 20.2% rate of mechanical ventilation reported in a US study [8]. Due to global awareness of maternal and infant concerns as well as the maximum amount of medical resources given to pregnant patients, the number of maternal deaths reported in the literature only accounts for 0.05–0.41% of all deaths [63]. Similarly, this study illustrated a maternal mortality rate of less than 0.01%, though this result does not signify that the clinical course of pregnant women was milder than that of the general population. The high ICU and intubation rates of the pregnant patients indicated that their clinical manifestations remained severe and that COVID-19 still posed a serious threat to maternal and infant safety worldwide. This finding was different from previous studies that have suggested that the clinical manifestations of pregnant women were not more severe. However, this study’s conclusion was derived from a large number of studies with large sample sizes and excluded all duplicate cases, providing credible evidence that is consistent with recent findings of multicenter case-control studies [64].
A high rate of cesarean section and preterm delivery in pregnant women with COVID-19 was also evident in this study. Preterm delivery resulted in a correspondingly low Apgar score, high rates of intubation and Neonatal intensive care unit (NICU) admission in newborns. The rate of preterm birth in this study was 25.32%, while that in NICU was 24.41%, which was similar to the 22.3% of preterm births in other studies and 38.3% of newborns requiring NICU admission [65]. Pregnant women with COVID-19 may experience critical conditions such as dyspnea, respiratory failure, and multiple organ dysfunction, which may lead to the inability to continue the pregnancy as well as an increased rate of preterm delivery. Preterm birth is a risk factor for more than 50% of neonatal deaths, and the incidence of adverse outcomes increase with decreasing gestational age [66]. Therefore, lower Apgar score and higher intubation as well as NICU rate in neonates are associated with COVID-19, and more with premature delivery. Whether there is an inevitable and direct link between COVID-19 and neonatal prognosis needs to be further investigated in more cases. In addition, studies have shown that increased Apgar scores between 5 and 10 min are associated with reduced neonatal mortality [67]. Our study also showed that the rate of neonatal Apgar score <7 at 5 min was 0.65%, and the mortality rate was correspondingly lower (<0.01%).
Early in the epidemic, clinicians knew little regarding COVID-19 and thought that vaginal delivery may increase the risk of neonatal infection. Additionally, COVID-19 may cause medical emergencies in mothers and the fetus (28.59% of pregnant women underwent cesarean section in this study due to serious conditions related to COVID-19), hence, more patients delivered by cesarean section. However, recent studies have shown that neonatal COVID-19 infection is uncommon when the baby is born vaginally, breastfed or staying with the mother. Among vaginally delivered infants, 8/292 (2.7%) tested positive for SARS-CoV-2, compared to 20/374 (5.3%) of caesarean-delivered infants [68]. Similarly, this study also showed an extremely low rate of neonatal infection (<0.01%) even if the vaginal delivery rate was above 20%. Hence, clinicians should decide the mode of delivery according to obstetric indications as well as the conditions of patients in order to avoid unindicated cesarean section due to viral infection.
The possibility of vertical transmission
Vertical transmission of SARS-CoV-2 has been a common concern for virologists and obstetricians. This study demonstrated that positive nasopharynx swabs or sputum from newborns was <0.01%, and the rate of cord blood, amniotic fluid, cervical or vaginal secretions and breast milk positive to SARS-CoV-2 was zero. Nasopharyngeal swabs or sputum were positive in 21 of 559 newborns, six of whom tested positive for SARS-CoV-2 RNA within the first 12 h after birth. However, no evidence showed that the newborns tested positive at birth. Hence, the positive results were highly likely to be attributed to respiratory and contact transmission.
The corresponding results also indicated the rate of placenta being positive to SARS-CoV-2 was 0.04% (one positive in 14 samples). However, studies have shown that two receptors involved in cytoplasmic entry of SARS-CoV-2, ACE-2, and TMPRSS2, lack placental co-expression, which may make it relatively insensitive to transplacental infection [69]. Moreover, previous studies have shown that the placenta acts as a positive barrier that controls infection and protects the fetus. Even with high viral titers in the placenta and decidua, no virus was detected in the fetus [70].
Rare vertical transmission of SARS-CoV-2 virus occurred during the COVID-19 pandemic, which was similar to other coronaviruses and respiratory RNA viruses. Vertical transmission of SARS-CoV-2 virus rarely took place during the COVID-19 pandemic, similar to other coronaviruses and respiratory RNA viruses. Hence, it would be considered rare if vertical transmission of SARS-CoV-2 occurred [71].
The conclusions of the present study seem optimistic, however, the time from infection to delivery was short and may not have allowed sufficient time for replication for transplacental transmission [72]. Additionally, studies have shown that ACE2 is highly expressed in maternal-fetal interface cells, including stromal cells and perivascular cells of the decidua as well as cytotrophoblasts and syncytiotrophoblasts in the placenta [73]. In terms of the plethora of SARS-CoV-2 receptors in specific cell types of maternal-fetal interface, the possibility of vertical transmission still cannot be excluded. Meanwhile, given the limited data in the early months, there is currently insufficient data regarding the rates of potential risk of vertical transmission in pregnancy.
Study significance
The findings of this study may be helpful for clinicians to better understand and screen pregnant patients with COVID-19. Moreover, the outcomes may provide patients with a perspective on whether to continue their pregnancy and select the appropriate delivery mode. Furthermore, isolation and protection of newborns during the care process may be undertaken.
Limitations
Due to the limitation of the eligibility criteria, errors may exist in the incidence of gestational age at the time of symptom onset and abortion rate. Infections in the first and second trimesters of pregnancy and their pregnancy outcomes have rarely been reported, making it difficult to obtain the corresponding information and conclusions pertaining to the outcomes of the corresponding population. In addition, certain studies included in this article were case reports and retrospective non-randomized designs, which may have a higher risk of publication bias.
Conclusions
In this timely review, we have concluded the following: (1) pregnant patients with COVID-19 most commonly present with fever, cough, shortness of breath and dyspnea, most of which have imaging manifestations and normal or decreased white blood cells. Nearly half of the patients have lymphopenia and some have elevated LDH or liver enzymes; (2) Among the pregnant patients, the risk of intubation and admission to intensive care unit are high; (3) the risk of premature delivery was high, leading to high risk of admission to NICU and low birthweight of neonates; the rate of cesarean section is also high; and (4) vertical transmission of SARS-CoV-2 from mother to child is less likely.
Research funding: None.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
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