The objective of this review was to identify the most significant studies reporting on COVID-19 during pregnancy and to provide an overview of SARS-CoV-2 infection in pregnant women and perinatal outcomes. Eligibility criteria included all reports, reviews; case series with more than 100 individuals and that reported at least three of the following: maternal characteristics, maternal COVID-19 clinical presentation, pregnancy outcomes, maternal outcomes and/or neonatal/perinatal outcomes. We included eight studies that met the inclusion criteria, representing 10,966 cases distributed in 15 countries around the world until July 20, 2020. The results of our review demonstrate that the maternal characteristics, clinical symptoms, maternal and neonatal outcomes almost 11,000 cases of COVID-19 and pregnancy described in 15 different countries are not worse or different from the general population. We suggest that pregnant women are not more affected by the respiratory complications of COVID-19, when compared to the outcomes described in the general population. We also suggest that the important gestational shift Th1-Th2 immune response, known as a potential contributor to the severity in cases of viral infections during pregnancy, are counter-regulated by the enhanced-pregnancy-induced ACE2-Ang-(1–7) axis. Moreover, the relatively small number of reported cases during pregnancy does not allow us to affirm that COVID-19 is more aggressive during pregnancy. Conversely, we also suggest, that down-regulation of ACE2 receptors induced by SARS-CoV-2 cell entry might have been detrimental in subjects with pre-existing ACE2 deficiency associated with pregnancy. This association might explain the worse perinatal outcomes described in the literature.
Zoonoses are diseases in which transmission from animals to humans can occur , , mostly due to the increase in human population, the expansion of commercial and scientific-technological activities to rural areas and the invasion of wild habitats by humans . It was previously described that 60% of human infectious diseases arise from animal transmission . Zoonoses can represent a real threat to human lives, as seen in previous pandemics with world wide spread, with the potential for high mortality rates , , . Seven different bat-borne viruses have caused world-wide outbreaks since 1994: Hendra in 1994, Nipah in 1998, Marburgh virus in 1998 and 2004, SARS in 2002, MERS in 2012, Ebola in 2014 and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused by the novel Coronavirus 2019, also called COVID-19, in 2019 . Other incidents include the H5/N1 avian influenza outbreak in 2005, H1/N1 influenza “swine-flu” pandemic in 2009, and the West African Ebola outbreak in 2013 and 2016 , .
The first stage of a pandemic caused by zoonotic agents, like SARS-CoV-2, is called spillover, when the virus jumps from wild animals to humans . There are four stages that are required for zoonotic agents to emerge in humans: 1) human contact with the infectious agent; 2) cross-species transmission of the agent; 3) sustained human-to-human transmission and 4) genetic adaptation by the human host , . All these steps occurred when COVID-19 pandemic started in Wuhan, China on late December 2019 , and the possible initial source of the SARS-CoV-2 virus was a species of horseshoe bat found in caves in Yunnan Province , , , . It was also identified that secondary or intermediate hosts in which SARS-CoV-2 lived prior to reaching humans were likely the pangolins . After the sustained human-to-human transmission was identified and the virus was adapted to humans, international outbreaks of COVID-19 were reported in South Korea, Iran, and Italy and the virus then rapidly spread worldwide , , .
As of July 20 2020, the COVID-19 pandemic had caused almost 15 million (14,938,874) people infections worldwide with more than 615,000 deaths (4.1%) in 188 countries (https://coronavirus.jhu.edu/map.html). The total number of people infected so far by SARS-CoV-2 virus represents approximately 0.2% of world population (15 million/7.8 billion). The objective of this review was to identify the most significant studies reporting on COVID-19 during pregnancy and to provide an overview of SARS-CoV-2 infection in pregnant women and perinatal outcomes.
Materials and methods
We conducted a comprehensive literature search using PubMed, EMBASE, Cochrane Library and Google Scholar until July 20, 2020. We used the combination of the following terms: SARS-CoV-2, COVID-19, coronavirus 2019, pregnancy, gestation, maternal, perinatal, fetal, outcomes, vertical transmission, neonatal, mortality and morbidity. Titles and abstracts were reviewed by all authors to evaluate their relevance for our study. Eligibility criteria included all reports, reviews, case series with:
More than 100 individuals and
Reported at least three of the following criteria and/or sub-criteria:
Maternal characteristics (age, BMI, race-ethnicity, comorbidities).
Maternal COVID-19 clinical presentation (symptoms, radiological and laboratory findings);
Pregnancy Outcomes (gestational age at diagnosis, gestational age at delivery, mode of delivery);
Maternal Outcomes (ICU admission, respiratory support, hospitalization, recovered cases, maternal death);
Neonatal/Perinatal Outcomes (live birth, birth weight, gestational age at delivery, apgar, preterm birth, newborn complications, neonatal hospitalization, fetal demise/Stillbirth, SARS-CoV-2-positive tests).
Once we defined the published/accepted articles that met these criteria, we performed a detailed analysis of the papers and we plotted the information on Tables. We added all reported cases to extract as much as possible the absolute and relative values of each analyzed parameter.
We included eight studies , , , , , , ,  that met the inclusion criteria as shown in Table 1, representing 10,966 cases. The studies included were: three Systematic Reviews , , , one Systematic Review & Meta-Analysis , 2 Case Series , , one Population-based Epidemiological Report  and one Prospective Cohort Study . The prospective cohort described the perinatal outcomes of COVID-19 and pregnancy in 241 women from New York (USA)  and the North-American population report described main outcomes in 8,207 pregnant women in the USA with COVID-19 . One case series of 617 women from France  and another with 978 Brazilian pregnant individuals  were also included in the analysis. The remaining four studies were systematic reviews of 108 , 136 , 324  and 385  cases of pregnancies with COVID-19. All papers together represented the total of 10,996 women reported with COVID-19 during pregnancy, distributed in 15 countries around the world (Figure 1) until July 20 2020.
|Zaigham & Andersson 2020 (n=108) ||Khoury et al. 2020 (n=241) ||Kayem et al. 2020 (n=617) ||Elshafeey et al. 2020 (n=385) ||Juan et al. 2020 (n=324) ||Matar et al. 2020 (n=136) ||Ellington et al. 2020 (n=8,207) ||Takemoto et al. 2020 (n=978) |
|Journal Published/Date/Reference||Acta Obstet Gynecol Scand 2020; 99:823–829||Obstet & Gynecol||J Gynecol Obstet Hum Reprod||Int J Gynecol Obstet 2020; 150:47–52||Ultrasound Obstet Gynecol 2020;56:15–27||Clin Infect Dis||MMWR Morb Mort Wkly Rep 2020; 69:769–775||Int J Gynecol Obstet|
|Type of Study||Systematic Review||Prospective Cohort||Case Series||Systematic Review||Systematic Review||Systematic Review and Meta-Analysis||Populational Report||Case Series|
|Accepted on||April 6 2020||June 3 2020||May 31 2020||April 23 2020||May 17 2020||June 16 2020||June 26 2020||July 9 2020|
|Number of articles included (Systematic Review)||18||NA||NA||33||24||24||NA||NA|
|Case Series Included (n>10)||4||NA||NA||16||9||5||NA||NA|
|Individual Reports Included (n<10)||14||NA||NA||17||15||19||NA||NA|
|Country (ies) where Pregnancy and COVID19 cases were reported||China, Sweden, USA, Korea, Honduras||USA||France||China, Australia, Honduras, Iran, South Korea, Sweden, Turkey, USA, Italy, Netherland||China, Australia, Iran, Korea, Sweden, Turkey, USA, Italy, Spain, Peru, Canada, France||China, Iran, South Korea, Honduras||USA||Brazil|
One fact that became clear was the overlapping of studies within the systematic reviews. We made a detailed analysis of all systematic reviews and we found that the review that included 385  women overlapped with the previous reports of 108 , 136  and 324  women. Table 2 describes the overlapping details. Initially all reviews together described the total of 953 cases, distributed in 99 papers, mostly from China. After our analysis we identified that 70 articles were overlapping (representing 579 cases) and the actual number of cases was 374 and not 953. Although we used the information the way it was published to compile all the information hereby described, the actual number of reported pregnant women with COVID-19 during pregnancy so far is 10,417 (10,996 cases in total minus 579 overlapping cases).
|Author, year (n)||Zaigham & Andersson 2020 (n=108)||Elshafeey et al. 2020 (n=385)||Juan et al. 2020 (n=324)||Matar et al. 2020 (n=136)||Total (n=953)|
|Number of articles included||18||33||24||24||99|
|Overlapping articles = cases||13 Overlapping with Elshafeey, Juan, Matar = 67 cases||24 Overlapping with Zaigham & Andersson, Juan, Matar = 225 cases||13 Overlapping with Elshafeey, Zaigham & Andersson, Matar = 185 cases||20 Overlapping with Elshafeey, Juan, Zaigham & Andersson = 102 cases||70 Articles = 579 cases|
|Not overlapping articles = cases||5 Articles not overlapping = 41 cases||9 Articles not overlapping = 160 cases||11 Articles not overlapping = 139 cases||4 Articles not overlapping = 34 cases||29 Articles = 374 cases|
When analyzing the maternal characteristics (Table 3) of all pregnant women with COVID-19 described, most patients were in their 30s, with range from 20–49 years. The American population report described that the majority of cases (4,469/8,207; 54.5%) were in the 25–34 years range. Hispanic and Latino ethnicity also represented the majority of cases (1,822/8,428; 36.5%). Known underlying medical conditions were described in 22.8% of the patients (1,905/8,343) with special attention to chronic respiratory diseases (415/2,495; 16.6%), clinical diabetes (391/3,473; 11.3%) and cardiovascular diseases (316/2,856; 11.1%).
|Zaigham & Andersson 2020 (n=108)||Khoury et al. 2020 (n=241)||Kayem et al. 2020 (n=617)||Elshafeey et al. 2020 (n=385)||Juan et al. 2020 (n=324)||Matar et al. 2020 (n=136)||Ellington et al. 2020 (n=8,207)||Takemoto et al. 2020 (n=978)||Total (n=2,789; 10,996)|
|Age , years||30.4± 3.6||32 (18–47)||INA||21–42||20–49||21.7 (25–41)||INA||30.5±7.2||NA|
|Age>35 years||INA||INA||194/617 (31.4%)||INA||INA||INA||1,817/8,207 (22.1%)||INA||2,011/8,824 (22.8%)|
|15–24 years||INA||INA||INA||INA||INA||INA||1921/8,207 (23.4%)||INA||1921/8,207 (23.4%)|
|25–34 years||INA||INA||INA||INA||INA||INA||4,469/8,207 (54.4%)||INA||4,469/8,207 (54.4%)|
|35–44 years||INA||INA||INA||INA||INA||INA||1,817/8,207 (22.1%)||INA||1,817/8,207 (22.1%)|
|BMI||INA||30.5 (21–56)||INA||INA||INA||INA||INA||30.5 (21–56)|
|>30||INA||98/178 (55.0%)||139/617 (22.5%)||INA||INA||INA||INA||89/978 (9.1%)||326/1,773 (18.4%)|
|30–39.9||INA||84/178 (47.2%)||INA||INA||INA||INA||INA||INA||84/178 (47.2%)|
|>40||INA||14/178 (7.9%)||INA||INA||INA||INA||INA||INA||14/178 (7.9%)|
|Asian, non-Hispanic||INA||INA||INA||INA||INA||INA||254/8,207 (3.1%)||INA||254/8,207 (3.1%)|
|Black, non-Hispanic||INA||24/221 (10.9%)||INA||INA||INA||INA||1,459/8,207 (22.1%)||INA||1,483/8,428 (17.5%)|
|White, non-Hispanic||INA||67/221 (30.3%)||INA||INA||INA||INA||1,520/8,207 (23.0%)||235/978 (24.0%)||1,822/9,406 (19.4%)|
|Hispanic or Latino||INA||33/221 (14.9%)||INA||INA||INA||INA||3,048/8,207 (46.2%)||INA||3,081/8,428 (36.5%)|
|Multiple or other race||INA||INA||INA||INA||INA||INA||321/8,207 (3.9%)||743/978 (76.0%)||1,064/9,185 (11.6%)|
|Known underlying medical condition||INA||INA||INA||INA||INA||27/136 (19.8%)||1,878/8,207 (22.9%)||INA||1,905/8,343 (22.8%)|
|Asthma||INA||INA||37/617 (6%)||INA||INA||INA||INA||23/978 (2.4%)||60/1,595 (3.76%)|
|Chronic respiratory diseases||INA||INA||6/617 (1%)||INA||INA||INA||409/1,878 (21.8%)||INA||415/2,495 (16.6%)|
|DM 1/2||INA||INA||14/617 (2.3%)||INA||INA||INA||288/1,878 (15.3%)||89/978 (9.1%)||391/3,473 (11.3%)|
|History of preeclampsia||INA||INA||27/617 (4.4%)||INA||INA||INA||INA||INA||27/617 (4.4%)|
|Cardiovascular disease||INA||INA||INA||INA||INA||INA||262/1,878 (14.0%)||54/978 (5.5%)||316/2,856 (11.1%)|
|Chronic hypertension/hypertensive disorders in P||INA||INA||18/617 (2.9%)||INA||11/178 (6.2%)||INA||INA||INA||29/795 (3.64%)|
|Preeclampsia||INA||INA||21/617 (3.4%)||INA||3/178 (1.7%)||INA||INA||INA||24/795 (3.01%)|
|GDM||INA||INA||71/617 (11.5%)||INA||18/220 (8.2%)||INA||INA||INA||89/837 (10.6%)|
|Hypothyroidism||INA||INA||INA||INA||2/234 (0.9%)||INA||INA||INA||2/234 (0.9%)|
|Chronic renal disease||INA||INA||INA||INA||INA||INA||12/1,878 (0.6%)||INA||12/1,878 (0.6%)|
|Chronic liver disease||INA||INA||INA||INA||INA||INA||8/1,878 (0.4%)||INA||8/1,878 (0.4%)|
|Immuno compromised condition||INA||INA||INA||INA||INA||INA||66/1,878 (3.5%)||INA||66/1,878 (3.5%)|
|Neurological/Neurodevelopmental/intellectual D||INA||INA||INA||INA||INA||INA||17/1,878 (0.9%)||INA||17/1,878 (0.9%)|
|Placenta previa/acreta||INA||INA||INA||INA||1/38 (2.6%)||INA||INA||INA||1/38 (2.6%)|
|Smoking in pregnancy||INA||INA||16/617 (2.6%)||INA||INA||INA||INA||INA||16/617 (2.6%)|
NA, not applicable; INA, information not available; DM, diabetes mellitus; GDM, gestational diabetes.
In regard to maternal COVID-19 clinical presentation, Table 4 describes the wide range of symptoms and radiological and laboratory findings in this cohort of patients during pregnancy. Most of the described pregnant women enrolled in the studies manifested symptoms (7,169/7,576; 94.6%), but with mild presentation (921/1,243; 74.1%). The symptoms that were more frequently described during pregnancy were: cough (51.8%), fever (40%) and myalgia (43%), although more than 1/3 of cases manifested a variety of other symptoms, with a special significance to loss of taste/smell in almost 20% of cases (759/4,091; 18.4%). The most common and frequent radiological sign described was patchy shadowing/ground glass opacity (88%) and laboratory results revealed reduced leukocytes (80%), elevated CRP (27%) and elevated D-dimer (22%).
|Zaigham & Anderson 2020 (n=108)||Khonry et al. 2020 (n=241)||Kavem et al. 2020 (n=617)||Elshafeev et al. 2020 (n=385)||Juan et al. 2020 (n=324)||Matar et al. 2020 (n=136)||Ellington et al. 2020 (n=8.207)||Takemoto et al. 2020 (n=978)||Total (n=2,789; 10.996)|
|Maternal COVID-19 clinical presentation|
|Asymptomatic||INA||102/241 (42.3%)||120/617 (19.5%)||29/385 (7.5%)||INA||INA||156/5,355 (2.9%)||INA||407/6,598 (6.2%)|
|Symptomatic||INA||139/241 (57.7%)||497/617 (80.5%)||356/385 (92.5%)||INA||INA||5,199/5,355 (97.1%)||978/978 (100%)||7,169/7,576 (94.6%)|
|Mild||INA||64/241 (26.5%)||489/617 (79.2%)||368/385 (95.6%)||INA||INA||INA||INA||921/1,243 (74.1%)|
|Severe||INA||63/241 (26.1%)||93/617 (15.1%)||14/385 (3.6%)||INA||INA||INA||INA||170/1,243 03.7%)|
|Critical||INA||12/241 (5.0%)||35/617 (5.7%)||3/385 (0.8%)||INA||INA||INA||INA||50/1,243 (4.0%)|
|Maternal COVID-19 symptoms|
|Fever||63/92 (68%)||46/139 (33.0%)||285/617 (46.2%)||259/385 (67.3%)||138/295 (46.8%)||69 136 (51%)||1,190/3,474 (343%)||INA||2,050/5,138 (39.994)|
|Cough||37/108 (34%)||54/139 (38.8%)||384/617 (62.2%)||253/385 (65.7%)||101/295 (34.2%)||39 136 (29%)||1,799/3,474 (51.8%)||INA||2,667/5,154 (51.7594)|
|Loss of taste/smell||INA||INA||172/617 (27.9%)||INA||INA||INA||587.3,474 (16.9%)||INA||759/4,091 (18–494)|
|Malaise||14/108 (13%)||INA||INA||INA||0 (0%)||INA||INA||INA||14/108 (1394)|
|Dyspnea||13/108 (12%)||19/139 (13.6%)||165/617 (26.7%)||28/385 (7.3%)||39/295 (13.2%)||7/136 (5.1%)||1,045/3,474 (30.1%)||INA||1,303/5,154 (25.394)|
|Myalgia||11 108 (7%)||INA||INA||24/385 (6.2%)||27/295 (92%)||10/136 (7.35%)||1,323/3,474 (38.1%)||INA||1,861/4,290 (43.494)|
|Sore throat||8/108 (7%)||INA||INA||27/385 (7.0%)||10/295 (3.4%)||5/136 (3.7%)||942/3,474 (27.1%)||INA||984/4,290 (22.9494)|
|Headache||INA||INA||INA||INA||INA||INA||1,409/3,474 (40.6%)||INA||1,409/3,474 (40.694)|
|Nausea/Vomitting||INA||INA||INA||INA||INA||INA||682/3,474 (19.6%)||INA||682/3,474 (19.694)|
|Diarrhea||7/108 (6%)||INA||54617 (8.8%)||28/385 (7.3%)||11/295 (3 7%)||7/136 (5.1%)||497/3,474 (14.394)||INA||597/5,154 (11.6%)|
|Fatigue||INA||INA||INA||27/385 (7.0%)||28/295 (9.5%)||INA||INA||INA||55/680 (8.1%)|
|Chills||INA||INA||INA||21/385 (5.5%)||INA||INA||989/3,474 (28.594)||INA||989/3,474 (28.594)|
|Runny nose||INA||INA||INA||INA||INA||INA||326/3,474 (9.4%)||INA||326/3,474 (9.494)|
|Other||INA||INA||INA||<5%||INA||INA||1,190/3,474 (343%)||INA||1,190/3,474 (34.394)|
|Symptoms during Post-Partum||INA||INA||INA||19 385 (4.9%)||INA||INA||INA||224 978 (22.9%)||243/1,363 (4.994)|
|Radiological and laboratory findings|
|Patchy shadowing ground glass opacity||INA||INA||INA||102/125 (81.6%)||183/190 (96.3%)||111/136 (81.6%)||INA||INA||396/451 (87.894)|
|No Radiological findings||INA||INA||INA||4/125 (3.2%)||7/190 (3.7%)||INA||INA||INA||11/315 (3 .4994)|
|Leukocytes (reduced)||INA||INA||INA||INA||146/182 (80.2%)||INA||INA||INA||146/182 (80294)|
|Lymphocyte (reduced)||INA||INA||INA||54/385 (14.0%)||85/197 (45.7%)||INA||INA||INA||139/582 (23.894)|
|CRP (elevated)||INA||INA||INA||72/385 (18.7%)||90/197 (45.7%)||INA||INA||INA||162/592 (27.49.)|
|AST, ALT (elevated)||INA||INA||INA||43/385 (11.2%)||5/42 (11.9%)||INA||INA||INA||48/427 (11.294)|
|Platelet (reduced)||INA||INA||INA||4/385 (1.0%)||INA||INA||INA||INA||4/385 (1.094)|
|D-dimer (elevated)||INA||INA||INA||86/385 (22.3%)||INA||INA||INA||INA||86/385 (22.394)|
NA, not applicable; INA, information not available; CRP, C-reactive protein; AST, aspartate aminostransferase; ALT, alanine aminotransferase.
With respect to pregnancy and maternal outcomes, Table 5 shows that the gestational age at diagnosis had a wide range of 6–41 weeks, with almost half of cases diagnosed from 32–36 weeks (23%) and after 37 weeks and post-partum (22.3%). This information was only available in the French report . The systematic review including 385 patients  described that 72% of cases were diagnosed with COVID-19 with GA>24 weeks. At the time of all publications, approximately 62% (1,119/1,811) of patients had delivered, therefore this information was not available in the American population report , nor in the Brazilian case series . Out of the patients delivered, the gestational age at delivery ranged from 28–41 w, with cesarian deliveries representing 68% (761/1,119) and vaginal births 31.2% (349/1,119). Cesarian indicated exclusively for severe COVID-19 infection was found in 28% of cases (149/531).
|Zaigham & Anderson 2020 (n=108)||Khoury et al. 2020 (n=617)||Kayem et al. 2020 (n=617)||Elshafeey et al. 2020 (n=385)||Juan et al. 2020 (n=324)||Matar et al. 2020 (n=136)||Ellington et al. 2020 (n=8,207)||Takemoto et al. 2020 (n=978)||Total (2,789; 10,996)|
|Gestational age at diagnosis||36||INA||INA||6–41||5–41||35.1 (30–40)||INA||NA|
|14–21 weeks||INA||INA||INA||INA||INA||INA||INA||INA||105/617 (17.0%)|
|22–31 weeks||MA||INA||INA||INA||INA||INA||INA||INA||238/617 (38 6%)|
|32–36 weeks||INA||INA||INA||INA||INA||INA||INA||INA||142/617 (23.0%)|
|>37 weeks/post partum||INA||INA||INA||INA||INA||INA||INA||224/978 (229%)||356/1,595 (213%)|
|Diagnosis <24 weeks||INA||INA||INA||109/385 (28%)||INA||INA||INA||INA||109/385 (28%)|
|Diagnosis >24 weeks||INA||INA||INA||276/385 (72%)||INA||INA||INA||INA||276/385 (72%)|
|Nulliparous||INA||52/201 (25.9%)||INA||INA||INA||INA||INA||INA||52/201 (25.9%)|
|Parous||INA||149/201 (74.1%)||INA||INA||INA||INA||INA||INA||149/201 (74.1%)|
|Deliver at time of publication||86/108 (79.6%)||241/241 (100%)||181/617 (29.3%)||252/385 (65.5)||223/324 (68.8%)||136/136 (100%)||INA||INA||1,119/1,811 (61.8%)|
|Gastational Age at Delivery, weeks||INA||39 (24.7–41.6)||INA||30–41||28–41||36.2 (30–40)||INA||INA||INA|
|Cesarian||79/86 (92%)||100/241 (415%)||132/181 (73%)||175/252 (69.4%)||171/223 (76.7%)||104/136 (76.3%)||INA||INA||761/1,119 (68%)|
|Cesarian for COVID (severe/crictical)||INA||44/241 (18.3%)||45/181 (25%)||INA||60/109 (55.0%)||INA||INA||INA||149/531 (28.0%)|
|Spontaneous vaginal delivery||7/86 (92%)||136/241 (56.4%)||49/181 (27%)||77/252 (30.6%)||48/223 (21.5%)||32/136 (23.5%)||INA||INA||349/1,119 (31.2%)|
|Operative delivery||INA||5/241 (2.1%)||INA||INA||INA||INA||INA||INA||5/241 (2.1%)|
|Indication for cesarian|
|Nonreassuring fetal heart/fetal distress||INA||23/100 (23%)||INA||INA||INA||6/114 (5.3%)||INA||INA||29/214 (13.6%)|
|Failed induction of labor||INA||11/100 (11%)||INA||INA||INA||INA||INA||INA||11/100 (11%)|
|Worsening respiratory distress||INA||10/100 (10%)||INA||INA||INA||INA||INA||INA||10/100 (10%}|
|Active phase arrest||INA||5/100 (5%)||INA||INA||INA||INA||INA||INA||5/100 (5%)|
|Arrest descent||INA||5/100 (5%)||INA||INA||INA||INA||INA||INA||5/100 (5%)|
|Malpresentation||INA||5/100 (5%)||INA||INA||INA||INA||INA||INA||5/100 (5%)|
|Repeat||INA||31/100 (31%)||INA||INA||INA||INA||INA||INA||31/100 (31%)|
|other||INA||10/100 (10%)||INA||INA||INA||INA||INA||INA||10/100 (10%)|
|Gestational age at Diagnosis||37||INA||INA||6–42||5–42||35.1 (30–40)||INA||NA|
|14–21 weeks||INA||INA||105/617 (17.01%)||INA||INA||INA||INA||INA||105/617 (17.0%)|
|22–31 weeks||INA||INA||238/617 (38.6%)||INA||INA||INA||INA||INA||238/617 (38.6%)|
|32–36 weeks||INA||INA||142/617 (23.0%)||INA||INA||INA||INA||INA||142/671 (23.0%)|
|>37 weeks/Post-partum||INA||INA||132/617 (21.4%)||INA||INA||INA||INA||224/978 (22.9%)||356/1,595 (22.3%)|
|Diagnosis <24 weeks||INA||INA||INA||109/385 (28%)||INA||INA||INA||INA||109/385 (28%)|
|Diagnosis >24 weeks||INA||INA||INA||276/385 (72%)||INA||INA||INA||INA||276/385 (72%)|
|Nulliparous||INA||52/201 (25.9%)||INA||INA||INA||INA||INA||INA||52/201 (25.9%)|
|Parous||INA||149/201 (74.1%)||INA||INA||INA||INA||INA||INA||149/201 (74.1%)|
NA, not applicable; INA, information not available.
Maternal ICU admission was described in 3.7% of cases, with respiratory support necessary in 5.25% of cases. Maternal hospitalization occurred in 35% of cases and 84% of pregnant women recovered from COVID-19 (1,340/1,595). Maternal death was described in 1.13% of cases (144/10,987) with special attention to the Brazilian report  that described an alarming rate of 12.7% (124/978).
Lastly, Table 6 demonstrates the Neonatal outcomes. Live birth was present in 98% of reports, with 78% term deliveries. Preterm Birth <37 weeks was seen in 21% of cases. The majority of cases had no newborn complications, although admission to NICU was reported in almost 20% of cases. Fetal demise/stillbirth rates were 1.7% (19/11,130), neonatal death described in 0.8% (9/1,137) and SARS-COV2-Negative tests were found in 98.4% of neonates (1,098/1,116). Of note is that the neonatal information was not retrieved from all studies and some of them had no information on babies’ outcomes.
|Zaigham & Andersson 2020 (n= 108)||Khoury et al. 2020 (n=241)||Kayem et al. 2020 (n=617)||Elshafeey et al. 2020 (n=385)||Juan et al. 2020 (n=324)||Matar et al. 2020 (n=126)||Ellington et al. 2020 (n=8,207)||Takemoto et al. 2020 (n=978)||Total (n=1,811; 10,018)|
|Live Birth, g||86/87 (99%)||245/247 (99.2%)||174/181 (96.1%)||251/256 (98%)||INA||91/94 (96.8%)||INA||INA||847/865 (98%)|
|Birth weight||INA||3,135 g (640–4,700 g)||INA||1,520–4,050g||INA||3,127 g (1,500–3,400 g)||INA||INA||NA|
|Low birth weight (<2,500 g)||INA||INA||INA||20/256 (7.8%)||8/103 (7.8%)||INA||INA||INA||28/259 (11%)|
|Gestational age at delivery, weeks||INA||39 (247–41.6)||INA||30–41||28–41||36.2 (30–40)||INA||INA||NA|
|Apgar 5 min||INA||9 (0–9)||INA||INA||7 (7–10)||9 (0–9)||INA||INA||NA|
|Twins||INA||6/241 (2.5%)||INA||4/252 (1.6%)||INA||INA||INA||INA||10/493 (2.0%)|
|Term||INA||198/241 (82.5%)||126/181 (69.6%)||217/256 (84.7%)||INA||63/94 (67.0%)||INA||INA||604/772 (78.2%)|
|Preterm birth < 37 weeks||INA||34/233 (14.6%)||55/181 (30.3%)||39/256 (15.2%)||INA||31/94 (33.0%)||INA||INA||159/764 (21%)|
|Preterm birth < 34 weeks||INA||10/233 (4.3%)||26/181 (14.3%)||20/256 (7.8%)||INA||INA||INA||INA||56/670 (8.35%)|
|Fetal loss 14–21 weeks||INA||INA||5/181 (2.8%)||INA||INA||INA||INA||INA||5/181 (2.8%)|
|Preterm birth 22–31 weeks||INA||INA||21/181 (11.6%)||INA||INA||INA||INA||INA||21/181 (11.6%)|
|Preterm birth 32–36 weeks||INA||INA||29/181 (16%)||INA||INA||INA||INA||INA||29/181 (16%)|
|Overall preterm birth 22–36 weeks||INA||INA||50/181 (27.6%)||INA||INA||INA||INA||INA||50/181 (27.6%)|
|Male||INA||119/247 (48.2%)||INA||INA||INA||INA||INA||INA||119/247 (48.2%)|
|Female||INA||128/247 (51.8%)||INA||INA||INA||INA||INA||INA||128/247 (51.8%)|
|Resuscitation at Delivery||INA||70/233 (30%)||INA||INA||INA||INA||INA||INA||70/233 (30%)|
|Respiratory distress syndrome||INA||14/241 (5.8%)||INA||12/256 (4.7%)||2/79 (2.5%)||INA||INA||INA||28/576 (4.86%)|
|Complications prematurity/preterm birth||INA||21/241 (8.7%)||INA||6/256 (2.4%)||INA||INA||INA||INA||27/497 (5.43%)|
|Sepsis||INA||1/241 (0.4%)||INA||INA||INA||INA||INA||INA||1/241 (0.4%)|
|Congenital anomaly||INA||8/241 (3.3%)||INA||INA||INA||INA||INA||INA||8/241 (3.3%)|
|None||INA||191/241 (79.3%)||INA||INA||INA||INA||INA||INA||191/241 (79.3%)|
|Other||INA||14/241 (5.8%)||INA||INA||INA||INA||INA||INA||14/241 (5.8%)|
|Admission neonatal intensive care unit||INA||61/237 (25.7%)||37/190 (19.5%)||8/256 (3.1%)||49/173 (28.3%)||28/136 (20.6%)||INA||INA||183/992 (18.45%)|
|<2 days||INA||153/245 (62.4%)||INA||INA||INA||INA||INA||INA||153/245 (62.4%)|
|3–7 days||INA||65/245 (26.5%)||INA||INA||INA||INA||INA||INA||65/245 (26.5%)|
|>7 days||INA||29/245 (11.8%)||INA||INA||INA||INA||INA||INA||29/245 (11.8%)|
|Neonatal death||1/87 (1%)||0/247 (0%)||1/190 (0.5%)||3/256 (1.2%)||1/221 (0.5%)||3/136 (2.2%)||INA||INA||9/1,137 (0.8%)|
|Fetal demise/stillbirth||1/87 (1%)||2/247 (0.8%)||7/181 (3.9%)||2/256 (0.8%)||4/223 (1.79%)||3/136 (2.2%)||INA||INA||19/1,130 (1.7%)|
|SARS-COV-2-positive||1/75 (1%)||6/236 (2.5%)||2/190 (1.1%)||6/256 (2.4%)||1/223 (0.5%)||2/136 (1.47%)||INA||INA||18/1,116 (1.6%)|
|SARS-COV-2-negative||74/75 (99%)||230/236 (97.5%)||188/190 (98.9%)||250/256 (97.6%)||222/223 (99.5%)||134/136 (98.5%)||INA||INA||1,098/1,116 (98.4%)|
NA, not applicable; INA, information not available.
It is not possible to identify with complete accuracy how many pregnant women have been affected within the total number of people infected by this new virus. The total number of pregnancies can be calculated with the sum of all live births, abortions, and miscarriages  in a determined region in a given time. In 2012, the total numbers of pregnancies described were 213.4 million, out of a global population of approximately 7.1 billion people, which represents 3% of pregnant women out of total world population . If we extrapolate this information, the hypothetical number of pregnant women expected in our current world population of 7.8 billion would be 234 million (3%), with the hypothetical rate of 19.5 million pregnant women per month. Our review found almost 11,000 pregnant women with COVID-19 infection reported, which represents 0.07% of total infections until July 20, 2020 (11,000/15,000,000). The hypothetical number of total pregnancies expected in the world by the end of July (136.5 million), demonstrates that the real number of infected pregnant women by SARS-COV-2 is undoubtedly much higher than the cases hereby described. We relied exclusively on data that had been published by the time this article was written, therefore we presented the most updated number of infected pregnant women described in the literature. Due to the low numbers during pregnancy described so far, one can conclude that we cannot make clinical final decisions or definitive patient counseling based on the available information.
Overall, COVID-19 infection during pregnancy does not seem to be worse than in the general population. The report from Centers for Disease Control and Prevention (CDC) compared 8,207 cases of COVID-19 in pregnant women with 83,205 cases in non-pregnant women . Although the report shows a higher number of hospitalizations among the pregnant group (31.5 vs. 5.8%), the ICU admission during pregnancy was slightly higher (1.5 vs. 0.9%) and the needing of mechanical ventilation was not higher during pregnancy (0.5%) compared to non-pregnant women (0.3%). Moreover, the death rate during pregnancy was low and not different compared to non-pregnant women (0.2% in both groups) .
Special attention should be given to the maternal mortality rate described in the Brazilian series , at 12.7% of cases (124/978). The report identified more comorbidities among the pregnant women that have died (cardiovascular disease 16.3%; diabetes 33.8%; obesity 21.3%; asthma 9.3%) compared to the pregnant group that had recovered (cardiovascular disease 6.7%; diabetes 20.8%; obesity 10.3%; asthma 5.9%). ICU admission was higher (72.3 vs. 17.5%) as well as invasive respiratory support (64 vs. 4.4%) in the group of women that died compared to those that had recovered from COVID-19 in Brazil . When we put together all known underlying medical conditions found in all the pregnancies included in this review, the overall rate of comorbidities described was 22.8% (1,905/8,343) with special attention to chronic respiratory diseases (415/2,495; 16.6%), clinical diabetes (391/3,473; 11.3%) and cardiovascular diseases (316/2,856; 11.1%). These numbers are similar to the Brazilian study on its own, thus demonstrating that other external factors might be involved in justifying the higher rate of maternal mortality observed in that country. The overall maternal mortality rate found among the pregnant women included in this review was 1.13% (144/10,987).
Over the course of the pandemic, it has been clear that public health measures like lockdowns impacted positively on reducing the rates of COVID-19 virus transmission . The French study included in this review had shown a higher rate of comorbidities during pregnancy, although the maternal mortality rate was 0.2% (1/617), suggesting that non-therapeutic and social distancing measures can reduce the rate of complications in specific populations .
The perinatal outcomes in all cases analyzed in this study were reassuring as live birth was present in 98% of reports, with majority (78%) resulting in term deliveries, with no newborn complications, and NICU admission of 20%. Fetal Demise/Stillbirth rates were low at 1.7% (19/11,130) and neonatal death described in 0.8% (9/1,137) of cases. No vertical transmission was identified in 98.4% of neonates (1,098/1,116). It is important to note that only 62% (1,119/1,811) of patients had delivered at the time of publications. Therefore, the perinatal outcomes found so far may be different once all affected pregnant women have delivered. Also, of note is that not all reports included in this review had neonatal/perinatal outcomes described.
Although many previous reports of COVID-19 during pregnancy had suggested that the pregnancy can impact negatively on the clinical course of infection , , , potentially bringing more maternal and perinatal complications , , the data compiled in this review might tell the opposite. It was clear from previous virus outbreaks during pregnancy, especially the 2009 H1N1 , , ,  and also SARS , ,  and MERS , ,  that pregnancy was detrimental in defining perinatal/neonatal and maternal outcomes, when comparing pregnant to non-pregnant population.
The response to viral infections during pregnancy relies mostly on the immunological changes that occur before and during gestation, in order to accommodate the developing fetus, so that the fetal tissues are not rejected by the maternal immune system . These changes are characterized mostly by elevation of humoral immune responses and suppression of cell-mediated immunity, referred to as the T-helper lymphocyte type 1-type 2 (Th1-Th2) shift . Pregnancy-induced alterations in immune cells and their cytokines, disparity between maternal-fetal glycosylation of IgG, and immunoregulatory pathways have important roles in the immunomodulation during pregnancy, which might explain clinical improvements of severe COVID-19 infected pregnant women after delivery , . During influenza infection in pregnant mice, it has been observed that there are significant changes in hormonal synthesis and regulation of progesterone, PGE2, COX2, and PGF2α expression, ultimately leading to inflammatory responses that can trigger preterm-labor and adverse fetal outcomes .
In order to allow the SARS-CoV-2 virus entrance into the human cell, the role of the immune system and the renin-angiotensin system (RAS) is particularly important . To promote a successful entry, it is necessary to have an efficient binding of the spike (S) viral envelope protruding protein that gives the ‘corona’ like appearance, to the cellular angiotensin converting enzyme 2 (ACE2) receptors , . ACE2 receptors are also responsible for a series of chemical events that ultimately converts angiotensin I or II (Ang I or Ang II) to angiotensin1-7 [Ang-(1–7) ] . The discovery of ACE2 receptors and its effect on Ang-(1–7) added a new branch to the complexity of the RAS as a counter-regulatory system of the activity of the vasoconstrictor component (ACE-AngII-AT1 axis), amplifying the vasodilator component (ACE2-Ang-(1–7) axis) , , , resulting in vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin-nitric oxide (NO) system , .
Some conditions are known to be associated with some degree of ACE2 deficiency like older age, diabetes, cardiovascular disease and hypertension , which also represents the group of comorbidities more likely to be infected and develop more severe complications with COVID-19 infection . On the other hand, it was also demonstrated that during pregnancy the expression of Ang-(1–7) is enhanced , thus shifting the RAS to the ACE2-Ang-(1–7) axis rather to the ACE-AngII-AT1 axis. The final effects of the ACE2-Ang-(1–7) axis are increased vasodilation, reduced fibrosis, reduced inflammation, reduced thrombosis and reduced pulmonary damage , , . In theory, in a setting of reduced ACE2 receptors in consequence of SARS-CoV-2 viral invasion, the unbalanced regulation between the ACE-AngII-AT1 axis and the ACE2-Ang-(1–7) axis would contribute to enhance the progression of vasoconstriction, increased fibrosis, inflammatory and thrombotic processes .
The results of our review demonstrate that the maternal characteristics, clinical symptoms, maternal and neonatal outcomes of 10,996 cases of COVID-19 and pregnancy described in 15 different countries are not worse or different from the general population. We suggest that, differently from what was previously published , pregnant women are not more affected by the respiratory complications of COVID-19, compared with non-pregnant available data. We also suggest that the important gestational shift Th1-Th2 immune response , known as a potential contributor to the severity in cases of viral infections during pregnancy , are counter-regulated by the enhanced-pregnancy-induced ACE2-Ang-(1–7) axis . Moreover, the relatively small number of reported cases during pregnancy does not allow us to affirm that COVID-19 is more aggressive during pregnancy. Conversely, we also suggest, that down-regulation of ACE2 receptors induced by SARS-CoV-2 cell entry might have been detrimental in subjects with pre-existing ACE2 deficiency associated with pregnancy. This association might explain the worse perinatal outcomes described in the literature , , , .
Research funding: None declared.
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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