Clinical and Obstetric Aspects of Pregnant Women with COVID-19: A Systematic Review

Objective  To analyze the clinical and obstetric aspects of pregnant women with COVID-19. Methods  A systematic literature review in the MEDLINE/PubMed , LILACS , SCIELO, and CNKI databases was performed from March to May 2020, with the descriptors: Pregnancy ; 2019-nCov ; Coronavirus ; SARS-Cov-2 , Covid-19 . Of those chosen were original titles, without language and period restriction and that addressed pregnant women with a clinical and/or laboratory diagnosis of COVID-19. Revisions, editorials, and duplicate titles were excluded. The Newcastle-Ottawa (NOS) and Murad et al. scales were used to assess the quality of the studies. Results  We included 34 articles with 412 pregnant women infected with severe acute respiratory syndrome (SARS-Cov-2), with an average age of 27.5 years of age and 36.0 gestational weeks. The most common symptom was fever (205 [49.7%]), and 89 (21.6%) pregnant women progressed to severe viral pneumonia. Laboratory tests showed an increase in C-reactive protein (154 [37.8%]), and radiological tests showed pneumonia with peripheral ground-glass pattern (172 [51.4%]). Emergency cesarean delivery was indicated for most pregnant women, and the most common gestational complication was premature rupture of ovarian membranes (14 [3.4%;]). We detected 2 (0.5%) neonatal deaths, 2 (0.5%) stillbirths, and 1 (0.2%) maternal death. Conclusion  Pregnant women with COVID-19 presented a clinical picture similar to that of non-infected pregnant women, with few obstetric or neonatal repercussions. There was a greater indication of cesarean deliveries before the disease aggravated, and there was no evidence of vertical transmission of the infection.


Introduction
At the end of December 2019, in Wuhan, capital of the Hubei province, located in China, there was an outbreak by a virus that suddenly worried the authorities, due to their lack of knowledge and the rapid spread of the virus to other countries. The virus, belonging to the coronavirus family, was named severe acute respiratory syndrome (SARS-CoV2), and the illness caused by it was called coronavirus disease 2019 . This virus causes a highly transmissible infectious disease that can entail mild symptoms, such as dry cough, fever, odynophagia, or even severe acute respiratory syndrome. 1,2 Given the accelerated spread of the virus among countries, in March 2020, the World health Organization (WHO) declared a status of pandemic, and the beginning of the need for measures of social distance, with the purpose of avoiding the crowding of people and containing the spread of such infection. Data for the month of June 2020 already highlight more than 10 million confirmed COVID-19 cases worldwide and $ 500 thousand deaths. 3,4 Nevertheless, based on the information referring to the other aforementioned coronaviruses, SARS-CoV and middle east respiratory syndrome coronavirus (MERS-CoV), we noted a higher incidence of abortions, growth restriction, preterm births, and fetal death. In addition, these viruses in pregnant women determined a high number of complications, such as hospitalization in intensive care units (ICU), the need for assisted ventilation, renal failure, and death. 3 These complications are erroneously explained by the understanding of pregnancy as a condition of immunosup-pression, which is a misconception, since pregnancy represents a peculiar immune condition that is modulated, but not suppressed. The correct concept allows caregivers and policy makers to make valid recommendations for the treatment of pregnant women during pandemics. Accordingly, in this COVID-19 pandemic, health care professionals need to understand the spectrum of presentations and outcomes of COVID-19 infection during pregnancy and childbirth. 5 Systematic reviews [5][6][7][8] published recently demonstrated good obstetric results for pregnant women with COVID-19; however, there are still gaps on the influence of infection on the choice of life of delivery, fetal and neonatal repercussions, as well as the possibility of vertical transmission. This study, therefore, aims to contemplate these points still little discussed and strengthen the knowledge about the behavior of the virus during pregnancy and perinatal. Furthermore, it aims to concentrate the best evidence, since most of the published works are case reports/series, in Chinese, which makes it difficult to homogenize information and summarize perinatal results in pregnant women with COVID-19.
Thus, a systematic literature review was performed to analyze the clinical and obstetric aspects of COVID-19 in pregnant women.

Methods
This is a systematic literature review developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation. 9 The study protocol and review were not registered with PROSPERO due to the need for urgent information. We sought to answer research

Resumo
Objetivo Analisar os aspectos clínicos e obstétricos de gestantes com COVID- 19 questions: "What are the clinical and obstetric repercussions in pregnant women infected with SARS-Cov-2?" The search strategy was held in the following electronic bibliographic databases: Medical Literature and Retrieval System online (MEDLINE / PubMed); Latin American and Caribbean Literature on Health Sciences (LILACS); Scientific Electronic Library Online (SCIELO); Chinese National Knowledge Infrastructure (CNKI). In addition, we considered secondary research and gray bases in the pertinent literature in other sources, such as Google Scholar and OPENGREY. The reference section of the included studies was manually searched for additional relevant studies.
The search strategy included only key terms, according to a preestablished acronym of PICO (Population/Intervention/-Comparison/Outcome). The search strategy that combines medical subject headings (MeSH) terms and free text words that will be used in MEDLINE (PubMed) and adjusted to other electronic databases, in the following manner: Pregnant Women AND (coronavirus OR coronavirus OR COVID-19 OR 2019-nCoV OR SARS-CoV-2) AND Pregnancy. The strategy details are presented in ►Table 1.
The eligibility criteria included complete original primary studies, available online in the selected databases and published in any languages, with no time frame, that addressed pregnant women with a clinical and/or laboratory diagnosis of COVID-19. All primary designs were considered, including case reports and case series. Given the infancy of the pandemic, urgent need of guidance, and limited higher quality information available on the topic, this was deemed reasonable. The exclusion criteria were literature reviews, editorials, or studies in which it was not possible to identify a relationship with the theme and duplicates in the databases as well as unreported maternal or perinatal results.
In the databases, we defined a peer search with specific descriptors, from March to April 2020. The search for data ended on May 13 th , 2020. The selection was made in pairs, with three authors, who independently selected the titles of the articles and then proceeded to read all abstracts. Those who complied with the study object were read in full. We considered original articles whose theme was related to pregnant women with COVID-19, regardless of the employed diagnostic technique. After selecting the articles, we held consensus meetings to confirm the equality of the selected articles. If there was disagreement, a fourth author was invited to give his/her opinion.
After agreement with the selected studies, we used a form developed by the authors to manually extract the following data: -Variables related to the studies: authorship, year, country, method, population, and sample; -Maternal variables: age, gestational age, signs, and symptoms of the pregnant woman with COVID-19, radiological and laboratory manifestations, gestational repercussions (delivery, obstetric complications), complications and clinical outcomes (respiratory failure, maternal mortality); -Perinatal variables: perinatal complications (fetal distress, low birth weight, prematurity), vertical transmission of COVID-19, perinatal mortality.
The primary outcomes were to identify obstetric repercussions, such as delivery route, gestational complications, severity of SARS-Cov-2 infection, and mortality; the fetal repercussions were complications such as fetal distress, fetal and neonatal mortality, and vertical transmission of COVID-19. The severity was assessed based on pregnant women who developed severe pneumonia or severe acute respiratory syndrome (SARS), requiring oxygen supply.
The quality of the studies was based on checking international guidelines. For case studies, we used the tool proposed by Murad et al. (2018), 10 composed of four domains: selection, verification, causality, and communication. According to the recommendation, we made a general judgment about the methodological quality based on the questions considered more critical in the specific clinical setting. The quality was considered either satisfactory or unsatisfactory, with satisfactory being when at least 1 item from each domain of the instrument was met. We used the Newcastle-Ottawa Scale (NOS) 11 for cohort studies in the cases of observational studies. The NOS uses a star system (0-9) to assess the selected studies in 3 domains: selection (0-4), comparability (0-2), and results (0-3). Higher scores represent better quality. and then, we considered: strong evidence (6-9 points), moderate evidence (4-5 points), and limited evidence (< 4 points).
The studies were presented and synthesized in tables with exposure of the most relevant data, and the treatment of these tables was performed in the Microsoft Office Excel software (Microsoft Corp., Redmond, WA, USA), to determine the percentage of incidence of the variables.

Results
From the total of 267 identified articles, 102 were eliminated because they were duplicated in the databases. One hundred and sixty-five titles and abstracts were read, and, of these, 56 manuscripts were chosen to be read in full. After eliminating those that did not meet the object of the study, 34 studies were selected for analysis, according to the flowchart (►Fig. 1).
As for the method, most studies were 1 or multiple case reports (23; 67.6%) and observational (11; 32,4%), with clinical and epidemiological characterization of pregnant women with COVID-19. The quality of the studies is displayed in ►supplementary tables S1 and S2. In ►supplementary table S1, we represented the quality of the studies of one or multiple cases, according to the tool of Murad et al. (2018), 10 in which we observed a satisfactory quality in all studies. ►Table 2 shows the quality of the studies, according to the NOS scale. Quality scores ranged from 6 to 9 points, which denotes studies with strong evidence (Supplementary tables S1 and S2).

Description of the Study Findings
To compose the systematic review, we included 34 articles, all published in 2020, mainly produced in China (61.7%; 21) available in the PubMed/MEDLINE databases (►Table 2).
Altogether, 412 infected pregnant women, with an average age of 27.5 years and who were mostly in the 3 rd trimester of pregnancy, with an average of 36.0 gestational weeks, were assessed in the studies. All pregnant women were diagnosed with COVID-19 through the reverse transcription polymerase chain reaction (RT-PCR) method.

Discussion
Coronaviruses are a large class of viruses, among which the newly discovered SARS-Cov-2 is the 7 th coronavirus currently known due to its capacity of infecting human beings. The disease caused by it, COVID-19, has become a challenging threat to public health worldwide; and when it comes to pregnant women, data on the outcomes of the disease are still limited. 12 We analyzed 34 studies involving 412 infected pregnant women. These papers were all from the current year, and there was a predominance of Chinese productions, probably because it was the region initially most affected by the disease and that, for this reason, gathered early evidence about the affected patients. The findings mainly highlighted young women who were in the third trimester of pregnancy. This is a relevant fact, since the results of the present study cannot be extrapolated to pregnant women with virus infection in the first or second trimester of pregnancy. 13,14 Pregnant women presented a clinical course similar to non-pregnant adult women. 12,[14][15][16][17][18][19][20][21][22][23][24][25][26] The current data on COVID-19 infection suggests that pregnant women experience similar or even lower rates of serious illness compared with non-pregnant women; however, additional data are needed, and it is crucial to determine the peculiar factors in pregnant women who predict a more severe course of this disease, with to the goal of guiding the clinical management, as well as the ideal time of delivery. 26 The most frequent signs and symptoms were fever, dyspnea, cough, and fatigue, respectively. 8- 10 We should underline that asymptomatic pregnant women were detected in the predelivery period and that they presented symptoms such as fever after delivery. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] A total of 89 pregnant women evolved with severe viral pneumonia and/or SARS, and 24 required invasive ventilatory support. 17,26,[28][29][30][31][32][33][34][35][36][37][38][39][40][41] We noted clinical pictures of multiple organ dysfunction and reversed cardiorespiratory arrest; 26 however, there was only one report of maternal death related to COVID-19. 35 The data indicate that 95% of the Abbreviations: CRP, C-reactive protein; GA, gestational age; GW, gestational week; LBW, low birth weight; NB, newborn; NR, not reported; PROM, premature rupture of ovarian membranes; RT-PCR, reverse transcription polymerase chain reaction; SARS, severe acute respiratory syndrome.
women who need intubation will do so 20 days after the onset of symptoms. 26 We can notice that most respiratory symptoms found in the studies were mild; however, pregnant women with comorbidities, such as preeclampsia, can have worse outcomes, since pneumonia can aggravate pulmonary edema and reduce oxygen saturation. 11,28 This is because pregnant women have a higher oxygen consumption, with an increase of 10 to 20%, changes in hormonal levels and decreased lung volumes, caused by an increase in the size of the uterus during pregnancy, as well as edema of the respiratory tract mucosa, which can cause a faster clinical deterioration and make pregnant women more susceptible to respiratory pathogens and severe pneumonia, because they are in a state of adaptive immunity. 13,14,42 Nevertheless, we should consider the high number of asymptomatic pregnant women in all studies and/or with atypical symptoms, which emphasizes the need to improve the investigation of COVID-19 upon admission, as well as the strengthening of infection control measures. 15,21,43,44 Among the most common laboratory changes, we found increased CRP, lymphopenia, and leukopenia. It is recommended that, in addition to the RT-PCR test as the gold standard for the diagnosis of COVID-19-related pneumonia, laboratory tests and a comprehensive assessment of the medical history of the patient, epidemiological exposure and symptoms are accomplished. 14 The radiological findings, mainly by chest CT, demonstrated pulmonary opacities with peripheral ground-glass pattern with bilateral pulmonary involvement, suggestive of viral pneumonia. In most cases, the tomographic images obtained before and after delivery did not show signs of aggravated pneumonia, indicating that pregnancy and childbirth do not seem to aggravate the course of the tomographic characteristics. 45 Given the difficulty and delay in RT-PCR tests, lowdose chest CT, or even the use of chest ultrasound, 23 may be an effective method to screen for COVID-19-related pneumonia in pregnant women in the third trimester. 15 In critical areas, radiological findings consistent with COVID-19 infection may emerge before the results of RT-PCR. 23 Regarding the gestational repercussions, we noted a greater indication of emergency cesarean deliveries for infected pregnant women, many of these involving preterm infants. It is important to emphasize that the uncertainty about the risk of vertical transmission through vaginal delivery or early delivery before the disease aggravation were the main reasons for the recommendation of cesarean sections. 14 In these cases of emergency cesarean sections, maternal clinic should be assessed, giving preference to spinal anesthesia, to reduce the impact on the respiratory circulation of the mother and her baby. If the infected pregnant woman is critical, general anesthesia is recommended for tracheal intubation. 16,37 Management of expectant support of the pregnant woman is reasonable for most 42 ; however, for women over 34 gestational weeks and with associated risk factors, cesarean delivery can be indicated early before the onset of the critical illness. 26 As for the event of severe maternal infection, delivery should be postponed until pulmonary stability is achieved, unless the pregnancy has reached its term. 31 A study demonstrated that pregnant women with COVID-19 presented a higher factor indicating cesarean delivery due to muscle fatigue and uterine contraction (1.3 AE 0.6) than the control group without infection [(0.5 AE 0.7)] (p-value ¼ 0.001). Pregnant women with COVID-19 are in an infected and hypoxic state with greater inflammatory factors, increased uterine contractility and a higher risk of postpartum hemorrhage. The indication of termination of pregnancy depends on the status of the illness, but terminating it early may improve maternal lung function. 26 The studies were not in agreement regarding the relationship between COVID-19 and preterm births. A retrospective study of data analysis of 116 pregnant women did not find association among the gestational infection by SARS-Cov-2, the increase in premature births, and the risk of abortion. 21 Nevertheless, other studies corroborate that there is a higher incidence of premature births in confirmed cases of COVID-19, when compared with non-infected pregnant women, 15,42 and that the need for the accomplishment of this procedure is greater in women with critical infection, to whom the indication is given, mainly, by maternal status, and not fetal. 26,28 The most common gestational complication was the PROM 15,17 ; however, in the studies, it was not possible to clarify the direct relationship between this complication and the SARS-Cov-2 infection. Nevertheless, it is known that inflammatory reactions caused by infection by the virus can impair the development and the function of the placenta, especially in blood vessels, resulting in adverse outcomes in pregnancy. 19 Regarding fetal manifestations, deliveries resulting in two stillborn 8,14 and two neonatal deaths 21,30 were detected, as well as cases of respiratory distress, 28 fetal distress, 15,17,20,32,37 with fetal bradycardia 16,19,20 and LBW. 14,19 Severe SARS-Cov-2 infection can change the fetal intrauterine environment, and the inflammatory storm caused by the infection triggers a systemic immune response that can also attack fetal organs. 30 Despite this frequency of complications, most studies have shown that NBs from infected mothers do not present significant differences in the main indicators of neonatal complications when compared with NBs from non-infected mothers. 15 We did not find occurrence of vertical transmission of COVID-19. 19,25,33,38,39,44 Tests with an oropharynx sample from 2 NBs were positive with 36 hours and 48 hours after birth, 13,26 and 2 other NBs were positive two weeks later. 38 Surveys investigating SARS-CoV-2 in maternal serum, placenta, umbilical cord, amniotic fluid, vaginal swabs, and breast milk were negative in the nucleic acid test in all studies that cited them, which precludes vertical intrauterine transmission. Premature neonates may be at particular risk of perinatal COVID-19 infection, since the active transfer of protective maternal immunoglobulins does not reach its peak before 28 to 30 weeks of life, besides the immature integrity of the skin of NBs, which may be a risk factor for perinatal transmission. 28 With regard to breastfeeding, as it is a recent infection, there is currently insufficient evidence to support the presence of SARS-CoV-2 in breast milk; however, breastfeeding by infected mothers, in part of the studies, is not recommended, according to the experience related to SARS. 20,25,27 Nevertheless, an Italian consensus eases this indication by admitting that COVID-19-positive mothers with mild or asymptomatic symptoms can breastfeed while wearing a surgical mask. 22 And those infected and symptomatic should be separated from their NBs, but they can perform weaning to provide their children with breast milk. 34 Four systematic reviews currently published on COVID-19 and pregnant women 5-8 were composed of 9, 6, 24, and 33 studies, the majority of which were case series. Until the moment of completing this search in databases, this systematic review is the one that addressed the largest number of studies and the largest sample of pregnant women infected with SARS-Cov-2.
The present systematic review demonstrated a low maternal mortality rate, as well as a reduced incidence of complications, such as SARS, concluding that COVID-19positive pregnant women have fewer symptoms than the general population and that this infection is not associated with poor perinatal results. [5][6][7][8] One concern, however, was related to the high rate of premature delivery by cesarean section in these women. 6 This review considers the results of the aforementioned research when concluding that the maternal, fetal, and neonatal outcomes in COVID-19 were, in most studies, positive. And it brings new knowledge to the fact that pregnant women can remain asymptomatic or when they have symptoms, fever is their main one, accompanied by the elevated serum CRP and that cesarean delivery is a recurrent outcome in this type of infection. The absence of vertical transmission was reinforced; however, neonatal COVID-19 infection was demonstrated, which serves to reinforce the need for infection control measures at the time of delivery.
Nevertheless, we should underline that the average age of 27.5 years of women in this study reveals that, as in the general epidemiological panorama of the disease, young people are less prone to COVID-19 complications and this factor may be responsible for the reduced number of negative outcomes, which can, consequently, undermine a possible protective factor provided by pregnancy.
We should also underline that the findings of this systematic review predominantly bring characteristics of eastern, Chinese, and North American women, which prevents further generalization of the data, due to phenotypic, cultural, and structural differences in health services. Accordingly, more studies are needed to assess the profile of pregnant women from other countries with a high incidence of the disease, such as Brazil, with a view to comparing the findings.
The present review has limitations, because, as a result of the COVID-19 pandemic, new studies are published daily, and it listed works until May 13 th , 2020. Moreover, the analyzed studies, since they are mostly with case study methods, add up to a small sample of pregnant women and, in addition, despite presenting satisfactory quality, according to the assessment tools, they consist of studies with low evidence. Nevertheless, we believe that the tendency toward the manifestation of symptoms in pregnant women infected with SARS-CoV-2 does not differ much from what was exposed in the results.
Furthermore, the findings of the current study characterized women in the third trimester of pregnancy, and it is not possible to generalize such considerations to pregnant women in the first and second trimesters. Therefore, there is a need for studies that focus on this viral infection in earlier gestational periods.

Conclusion
The course of infection in pregnant women with SARS-Cov-2 is similar to the one in non-infected pregnant women. We did not find occurrence of vertical transmission of COVID-19. The main symptom presented by pregnant women with COVID-19 was fever; however, most of the patients were asymptomatic. The most common laboratory change was the increase in CRP, and the radiological findings were peripheral pulmonary opacities with ground-glass pattern. There was a greater indication of emergency cesarean deliveries for infected pregnant women, many of these involving preterm infants; however, studies have not shown consensus on the risk of prematurity associated with COVID-19. The main fetal manifestations were fetal distress, with reduced fetal heart rate, but not directly related to SARS-Cov-2. Mortality consisted of two stillborn, two neonatal deaths, and one maternal death.