key: cord-0838951-4ki993nt
authors: Mirbeyk, Mona; Saghazadeh, Amene; Rezaei, Nima
title: A systematic review of pregnant women with COVID-19 and their neonates
date: 2021-04-02
journal: Arch Gynecol Obstet
DOI: 10.1007/s00404-021-06049-z
sha: 4b32ecb7524a69985d127d8aeb3198a82ba74de5
doc_id: 838951
cord_uid: 4ki993nt

BACKGROUND: In December 2019, a novel coronavirus disease (COVID-19) emerged in Wuhan, China, with an incredible contagion rate. However, the vertical transmission of COVID-19 is uncertain. OBJECTIVES: This is a systematic review of published studies concerning pregnant women with confirmed COVID-19 and their neonates. SEARCH STRATEGY: We carried out a systematic search in multiple databases, including PubMed, Web of Science, Google Scholar, Scopus, and WHO COVID-19 database using the following keywords: (Coronavirus) OR (novel coronavirus) OR (COVID-19) OR (COVID19) OR (COVID 19) OR (SARS-CoV2) OR (2019-nCoV)) and ((pregnancy) OR (pregnant) OR (vertical transmission) OR (neonate) OR (newborn) OR (placenta) OR (fetus) OR (Fetal)). The search took place in April 2020. SELECTION CRITERIA: Original articles published in English were eligible if they included pregnant patients infected with COVID-19 and their newborns. DATA COLLECTION AND ANALYSES: The outcomes of interest consisted of clinical manifestations of COVID-19 in pregnant patients with COVID-19 and also the effect of COVID-19 on neonatal and pregnancy outcomes. MAIN RESULTS: 37 articles involving 364 pregnant women with COVID-19 and 302 neonates were included. The vast majority of pregnant patients were in their third trimester of pregnancy, and only 45 cases were in the first or second trimester (12.4%). Most mothers described mild to moderate manifestations of COVID-19. Of 364 pregnant women, 25 were asymptomatic at the time of admission. The most common symptoms were fever (62.4%) and cough (45.3%). Two maternal deaths occurred. Some pregnant patients (12.1%) had a negative SARS‐CoV‐2 test but displayed clinical manifestations and abnormalities in computed tomography (CT) scan related to COVID‐19. Twenty‐two (6.0%) pregnant patients developed severe pneumonia. Two maternal deaths occurred from severe pneumonia and multiple organ dysfunction. Studies included a total of 302 neonates from mothers with COVID‐19. Of the studies that provided data on the timing of birth, there were 65 (23.6%) preterm neonates. One baby was born dead from a mother who also died from COVID-19. Of the babies born alive from mothers with COVID‐19, five newborns faced critical conditions, and two later died. A total of 219 neonates underwent nasopharyngeal specimen collection for SARS‐CoV‐2, of which 11 tested positive (5%). Seventeen studies examined samples of the placenta, breast milk, umbilical cord, and amniotic fluid, and all tested negative except one amniotic fluid sample. CONCLUSIONS: A systematic review of published studies confirm that the course of COVID-19 in pregnant women resembles that of other populations. However, there is not sufficient evidence to establish an idea that COVID-19 would not complicate pregnancy.

The World Health Organization (WHO) announced the novel coronavirus disease (COVID-19) as a Pandemic on March 7, 2020, when the number of confirmed cases just exceeded 100,000 [1] . As of April 21, 2020, COVID-19 has reached all over the world, with about 180,000 deaths of a total of more than 2 million confirmed cases. Moreover, it seems there is an underestimation in the mortality rate of this infectious disease. Studies estimate the real mortality rate to be about 6% in China, rising to about 15% in other countries [2] . Therefore, COVID-19 is, in general, a lifethreatening condition.

COVID-19 can affect multiple organs and systems [3] [4] [5] [6] [7] [8] [9] [10] [11] , although it mainly involves the respiratory system, where its involvement can cause a wide range of symptoms from a common cold to severe respiratory distress [12] [13] [14] [15] . In particular, the disease is more severe and deadly in older age groups and people who have pre-existing comorbidity. The immunopathogenesis of the disease is not clear [16] [17] [18] [19] [20] [21] . However, as for other infectious conditions, immune dysregulation might increase the risk of severe illness and death from COVID-19 [21] [22] [23] [24] [25] [26] [27] .

Pregnancy is a particular condition that can have significant effects on the biological systems of a woman's body. Notably, pregnant women acquire changes so that their immune system will be able to tolerate pregnancy. These changes mostly place the maternal immune system under a down-regulated condition. As a result, pregnant women are generally considered vulnerable to infectious diseases.

Whereas its transmission mainly occurs through humanto-human contact, the novel coronavirus has shown its potential to transmit via multiple transmission routes [28] and affect both children and adults [13, 29] . It, however, remained unclear whether or not this potentially fatal virus can vertically be transmitted and what are the possible effects of the disease on the pregnancy outcomes.

The present systematic review was developed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [14] . Before the study begins, the authors developed the study protocol that is available on request.

We carried out a systematic search in multiple databases, including PubMed, Web of Science, Google Scholar, Scopus, and WHO COVID-19 database using the following keywords: (Coronavirus) OR (novel coronavirus) OR (COVID-19) OR (COVID19) OR (COVID 19) OR (SARS-CoV2) OR (2019-nCoV)) and ((pregnancy) OR (pregnant) OR (vertical transmission) OR (neonate) OR (newborn) OR (placenta) OR (fetus) OR (Fetal)). The search took place in April 2020 (Fig. 1 ).

We sought studies that investigated the potential effect of COVID-19 on pregnancy and neonatal health. Original articles published in English were eligible if they included pregnant patients infected with COVID-19 and their newborns. The outcomes of interest consisted of clinical manifestations of COVID-19 in pregnant patients with COVID-19 and also, the effect of COVID-19 on neonatal and pregnancy outcomes.

The systematic search yielded a total of 1068 search results, of which 785 discrete records remained for screening after removing duplicates. During title and abstract screening, we selected 48 articles for detailed review. In the detailed review process, we excluded thirteen articles with the following reasons for exclusion: seven articles not provided data on pregnant patients or neonatal outcomes [28, [30] [31] [32] [33] [34] [35] , three studies lacked data on neonates or vertical transmission [36] [37] [38] , one study reported a 17-day neonate who had exposure to parents complaining of fever and cough [39] , one study was not original research [40] , and the full-text was not available for one article [41] .

Also, we carried out an additional search through reviewing reference lists of 35 included articles from systematic search and related review articles and found two additional articles [42, 43] . Finally, a total number of 37 studies, including case reports and case series, were eligible to be included in this systematic review . Tables 1, 2, 3 provide an overview of the characteristics of the included studies. Below is a narrative synthesis of studies that included pregnant women with confirmed COVID-19 and their neonates.

Of 37 studies, two provided no data on clinical symptoms of pregnant patients [43, 44] . A total of 364 pregnant women was, thus, included in the data synthesis of clinical manifestations of COVID-19 in pregnant women.

Of 364 pregnant women, 25 were asymptomatic at the time of admission. The most common symptoms were fever (62.4%) and cough (45.3%) . The other common symptoms Neonatal throat and anal swab nucleic acid testing 5th min Apgar score: 9

No case of death was reported We considered GA < 37 weeks as preterm delivery *One complicated with pre-eclampsia, one with history of 2 stillbirth, one with history of 2 previous c-sections and irregular contractures, and one with premature rupture of membranes **One neonate in which first symptom was increased heart rate developed refractory shock and gastric bleeding which lead to death, another neonate with shortness of breath and moaning and later with DIC that cured ***SARS-CoV-2 IgG level: 140.32 AU/mL and IgM level: 45.83 AU/mL 2 h after birth and also 16 days after birth repeated test revealed IgG level of 69.94 AU/mL and IgM level of 11.75 AU/ mL ****The specimens collected from three neonates whom delivered by cesarean section *****The study claimed that no COVID-19 infection was represented in neonates but did not clarified by which method -clinical or nucleic acid testing-******Specimens collected from three neonates and positive sample was collected 36 h after birth *******Except one of infected neonates with confirmed COVID-19 infection born with need of resuscitation and Apgar score of 3, 4, 5 in 1, 5 and 10 min ********The total number of neonates were 57 and 20 neonates tested for COVID-19 but study did not clarify how many neonates belong to the case group *********2 neonates had elevated serum IgM levels ϕNasopharyngeal swab was taken from 8 neonates ϕϕApgar score was measured for 66 neonates included myalgia, diarrhea, dyspnea, headache, and chest tightness. There were two women with specific presentations: one with Cholecystitis [50] and another with oil intolerance [67] . For nearly all pregnant women, the diagnosis was made based on a combination of clinical symptoms, nucleic acid testing for the novel coronavirus, and computed tomography (CT). As for the general population, some pregnant patients (n = 44) had a negative SARS-CoV-2 test but displayed clinical manifestations and abnormalities in CT scan related to COVID-19 [50, 53, 55] .

Twenty-two (6.0%) pregnant patients developed severe pneumonia. Among them, 10 cases (2.8%) required mechanical ventilation and therefore were admitted to the intensive care unit (ICU) [42, 44, 53, 58, 60, 63, 65, 73, 74] . Two of these ten patients died from severe pneumonia and multiple organ dysfunction [65, 73] .

The vast majority of patients were in their third trimester of pregnancy, and only 45 cases were in the first or second trimester ( [53] . There were three cases of spontaneous abortions, two ectopic pregnancy, and four induced abortions. Pregnant women seeking induced abortion were most afraid of COVID-19 and its potential effects on pregnancy outcomes [53] .

Thirty-seven studies included a total of 302 neonates from mothers with COVID-19. Two studies have not indicated the timing of birth [43, 57] . Of the studies that provided data, there were 210 full-term and 65 preterm neonates.

Karami et al. reported the death of a mother from COVID-19 and also her fetus [65] . The dead baby was born with an Apgar score of 0, did not respond to resuscitation, and was not considered for COVID-19 diagnostic tests. Of the babies born alive from mothers with COVID-19, five newborns faced critical conditions. One of them presented with a fast heart rate developed gastric bleeding and refractory shock later and died. The second complicated case was a premature newborn born from a mother, who had a diagnosis of severe COVID-19 pneumonia [50] . This neonate showed shortness of breath at presentation and developed disseminated intravascular coagulation (DIC). This case could be cured. The third neonate died due to the multiple organ dysfunction syndrome and could not survive [58] . The nasopharyngeal samples of these three babies were all negative for SARS-CoV-2 RNA detection. The fourth one suffered from pneumonia and needed intubation at birth. Sixteen hours after birth, the neonate tested positive for SARS-CoV-2 RNA with throat swab nucleic acid testing [74] . This neonate was later extubated and discharged without any complications. The fifth one was a premature baby with the gestational age of 31 weeks and 2 days. This neonate had an Apgar score of 3, 4, and 4 at the first, fifth, and tenth minute after delivery and required resuscitation [66] . This neonate was later confirmed as a definite case of COVID-19 and developed DIC. Vital signs were successfully stabilized on the day of 14. This neonate had close contact with the mother after delivery.

Except for the babies mentioned above, most babies born alive had a 5-min Apgar score of 8 and 9 (Table 2) . A total of 219 neonates underwent nasopharyngeal specimen collection for SARS-CoV-2 nucleic acid testing. Of them, 11 tested positive, and two of which were described above. A study by Wang S et al. reported a neonate with a positive throat specimen for COVID-19 [48] . This neonate had early close contact with COVID-19 positive mother, and the specimen was collected 36 h after birth, while the placental and cord blood specimens taken at birth were negative. Yu N et al. collected nasopharyngeal swab from three neonates, of which one was positive for COVID-19 [56] . This specimen was collected 36 h after birth, and that no nucleic acid testing was performed for the placenta, cord blood, or other pregnancy products.

In a cohort study of 33 neonates, there were two neonates with a positive test [66] . Both neonates survived. None of the placenta, cord blood, and other pregnancy products were tested for COVID-19 in this study. Zamanian et al. reported another newborn with a positive test who had fever without any further complications. By the end of the study, the neonate was healthy and stable [73] . Also, the other four COVID-19 positive neonates did not develop any complications and survived [46] . Seventeen studies reported the collection of the amniotic fluid, cord blood, placenta, and breast milk samples, and all tested negative except one amniotic fluid sample. Zamanyan et al. reported a pregnant woman with COVID-19 infection and her positive newborn. Nucleic acid testing was done on the cord blood and amniotic fluid samples [73] . Whereas no viral RNA was detected in the cord blood, the amniotic fluid was positive for viral RNA.

In a case-control study by Zhang et al., there was no difference between 16 pregnant women with COVID-19 and 45 pregnant women without COVID-19 in terms of pregnancy complications, including eclampsia, fetal distress, and premature rupture of membrane (Table 3 ) [44] .

This systematic review included 386 pregnant women with COVID-19. There were 257 cesarean sections and 42 vaginal delivery. This relatively higher rate of cesarean sections would reflect the existence of indications for a cesarean section as well as the role of fear of vertical transmission. Most women represented common symptoms, and two deaths occurred (death rate of 0.5%). While COVID-19 has, to date, caused a total number of 163,097 deaths out of 2.4 million confirmed cases, corresponding to the mortality rate of about 7% [77] . Therefore, compared to the general population, pregnant women have not shown a more aggressive form of COVID-19.

Among the total number of 302 neonates from mothers with COVID-19, there were nasopharyngeal specimens collected from 219 neonates, of which 11 tested positives for SARS-CoV-2. One study reported a positive SARS-CoV-2 for amniotic fluid samples [73] . Interestingly, two studies reported high IgM levels in neonates who tested negative for SARS-CoV2 [43, 69] . Because there is no possibility of IgM transfer through the placenta, this laboratory data can be suggestive of vertical transmission of COVID-19. More studies are required to investigate the potential of COVID-19 to be transmitted via the vaginal route and the possible association between maternal infection with COVID-19 and long-term child health.

Nearly all mothers were healthy women without underlying severe diseases such as diabetes mellitus, cardiovascular disease, and autoimmune diseases. Therefore, further research is necessary to evaluate whether or not ethnicity/ race, maternal comorbidities, and pregnancy stage would influence the course of COVID-19 in pregnancy and how this, in turn, would affect delivery complications.

Finally, one crucial issue which remained unresolved is the psychosocial effects of the COVID-19 outbreak on mental health during pregnancy. Pregnant women frequently report psychosocial stress, depression, and panic disorder. In particular, there is a direct correlation between the level of antenatal psychosocial stress and the risk of poor pregnancy outcomes in the manner that the higher the antenatal psychosocial stress, the greater the risk of poor pregnancy outcomes. Therefore, pregnancy might be complicated during the COVID-19 outbreak, even if women do not get infected by the virus.

In this study, from 386 parturient women with COVID-19, 257 out of 299 patients gave birth by cesarean section, which means the cesarean section rate among these patients was about to 86%, which is very high. In a national cohort study reported by Knight et al., the cesarean rate in pregnant women with COVID-19 in the United Kingdom was about 59% [78] . In Germany, the CRONOS register website established to gather comprehensive data on mothers with COVID-19 who give birth around this country reports cesarean rate as about 37.5% by the last of January 2021 [79] . These national reports come from two highly developed countries equipped with the best available strategies to control the COVID-19 and related stress. It may positively impact pregnant women's psychological status when choosing delivery method. Another possible reason for the difference in results is the method of data gathering. This study is a systematic review including studies pertinent to different countries. At the time of systematic search by the last of April 2020, many studies reporting pregnant women with COVID-19 were case reports, case series, or studies with a low sample size. Still, the two mentioned studied were at a grander scale, which may effectuate the result. On the other hand, in our study, there is no patient from England or Germany, and most of the patients are from China. Although the CRONOS register is a large-scale registry, it lacks clinically important details, such as signs, symptoms, and history, about every individual registered in this program.

Since December 2019, COVID-19 has been a resident of the world. Early efforts ranged from the development of diagnostic assays [80] [81] [82] [83] and specific therapeutics [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] to optimizing health monitoring [103, 104] . Despite this effort, in addition to our knowledge and experience from the recent outbreaks [105] , it mainly relied on non-pharmacological interventions to control the pandemic, e.g., quarantine and social isolation [106, 107] . Such a condition triggers stress [108] . The stress was, in particular, of high level at the time when the outbreak was initiated. Growing knowledge about different aspects of the disease, namely about the origin and pathogenesis of disease varying dependent on the immunogenetic background and the presence of comorbidities [4, [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] , could protect against the stress and related damage, which is potentially critical in pregnant women and their neonates. Our review included studies conducted in the first six months of the pandemic when there was a high degree of stress and fear. This explains why the cesarean rate we calculated is relatively high, and also one can simply predict its reduction over time.

A major limitation is the lack of data in developing countries. Perinatal care is a crucial issue in less developed countries, while pregnant women in these countries may not have feasible access to health care facilities. Besides, insufficient perinatal care leads to a high rate of perinatal adverse events [122] while worsening during the pandemic. It is, therefore, important to gather enough data on pregnant women and their neonates in these countries. However, when this study was carried out, the data on less developed countries were too scarce, which may be because of lack of diagnostic facilities in these countries, insufficient referring, or reporting system. So further investigations are necessary to discover the impact of COVID-19 on perinatal events in developing countries.

The present systematic review suggests that clinical features and prognosis of pregnant women with COVID-19 may not be worse than the general population as well as some previous studies [121] . Still, this result should not lead to pregnant women ignore their suspect signs and symptoms to present themselves to medical care centers. It is crucial to provide optimum health care for pregnant women during the COVID-19 pandemic and follow their health status, especially respiratory signs and symptoms. The current evidence suggests that clinical features, diagnosis, and prognosis of COVID-19 in pregnant women are not different from those of the disease reported in society. Despite the high rate of contagion of COVID-19, vertical transmission of the novel coronavirus may remain a missing piece of the puzzle due to a lack of sufficient evidence. International collaboration remains a fundamental component of any future attempt to solve the puzzle [123] [124] [125] [126] [127] .

Author contributions MM: Conceptualized the study, conducted database search, search results screening, detailed review, and prepared the initial draft. AS: Prepared the final draft. NR: Supervised the project and critically appraised the manuscript. All authors have read and approved the manuscript.

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The authors declare that they have co conflicts of interest.