Coronavirus Disease 19 (COVID-19), also known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is caused by a novel coronavirus that belongs to the Coronaviridae family    . COVID-19 has transmitted rapidly across the globe after being first erupted in Wuhan, China during the late December of 2019; it was shortly declared as a worldwide pandemic on the March 11th of 2020 by the World Health Organization (WHO), calling attention to the immensity of the viral outbreak    . Up till September 25th 2021, there is an accumulated 230 million cases worldwide, resulting in deaths of over 4.7 million . Meanwhile, COVID-19 is estimated to affect 13.9 per 1000 deliveries in pregnant women .
While such viral outbreaks are not new in this recent two decades with the emergence of the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) in the years 2002 and 2012, respectively, COVID-19 has spread faster and caused higher mortality than that of SARS, and MERS combined, which is approximately 10,000 deaths   . Looking back in history, the pregnant population has been seriously affected by various adverse pregnancy events following the outbreaks of SARS and MERS. Also, the severity of a respiratory infection is likely to be increased for a pregnant woman due to ineffective airway clearance secondary to anatomical and physiological changes during pregnancy . Considering that the COVID-19 virus is from the same human coronavirus family as the previous SARS-CoV-1 and MERS-CoV outbreaks, there are emerging worries that the pregnant population who are infected with COVID-19 will have potential similar adverse outcomes as the previous two outbreaks   . This review paper aims to appraise the currently available evidence through a systematic approach to identify the factors influencing the maternal obstetrics outcomes of COVID-19 infected pregnant women. The review findings will contribute to developing a comprehensive maternal care modality and appropriate preventive strategies for COVID-19 related pregnancy complications.
2.1. Search Strategy
We conducted this systematic review in the databases including PubMed, Embase, Scopus and Web of Science. The primary reviewers’ institution subscribes these four electronic databases; hence, it was convenient to get access to full-text resources. The search was performed from January 1st 2020 to June 20th 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to identify relevant articles on COVID-19 infected pregnancies and maternal outcomes. We searched all databases using keywords and MeSH terms related to COVID-19 disease (Table 1), pregnant women and maternal outcomes. We used search string across all databases, which included [(“Covid” OR “SARS-CoV-2” OR “Covid-19” OR “Coronavirus disease 2019” OR “2019-nCoV”) AND (“Pregnancy” OR “Pregnant” OR “Pregnant woman”) AND (“Maternal outcomes” OR “Pregnancy outcomes” OR “Obstetrics outcomes”)]. To refine the search results further, we also applied a filter including “only articles in English language and females with age ranging from 19 to 44 years as the research population”.
2.2. Selection Criteria
1) Inclusion criteria: Following inclusion criteria were considered before including any study in this review:
・ Study types: Cohort studies, randomized controlled trials, database analysis;
・ Study sample size: More than 150 COVID-19 infected pregnant women;
・ Reported outcomes of COVID-19 infected pregnancies;
・ If the full text is available;
・ English language.
2) Exclusion criteria: Following criteria were considered before excluding
Table 1. Keywords and subject headings according to PECO concept.
any study from this review:
・ Study types: Review articles, case reports, case series, protocol papers, cross-sectional studies;
・ Study sample size: Less than 150 COVID-19 infected pregnant women;
・ Occurring of COVID-19 infection before the pregnant period;
・ If the specific outcomes of pregnancy are not mentioned;
・ If the language is not in English;
・ Incomplete trials or duplicate publications of the same study that yield similar results.
We aimed to screen the articles published from January 1st 2020 onwards. Initially, we identified 2389 articles from the four databases: Pubmed (448 articles), Embase (867 articles), Scopus (768 articles), and Web of Science (306 articles). Thereafter, we exported all articles to the citation manager Endnote and identified the duplicates using the EndNote software before removing them. Two reviewers simultaneously screened all the potential articles by title and abstract based on the inclusion and exclusion criteria. Lastly, we selected 13 articles (Figure 1) after full-text screening and included those for data extraction under this review. Out of 13 articles, the majority articles were available in PubMed (Table 2).
2.4. Data Extraction
Two primary reviewers (JT and JK1) used a standardized form, which included: study design, sample size, main study findings and conclusion, to extract all the potential data independently from 13 finally selected articles. Thereafter, they compared their individual data and reached a consensus before including the data for analysis by NVivo software. They invited the 3rd reviewer, either SSSH or NKJ2, when they could not resolve any discrepancies.
2.5. Quality Assessment
We assessed the quality of each study using the Newcastle-Ottawa Scale (NOS) (Table 3), which is a tool to assess the quality of both cohort and case-control studies included in a systematic review. We selected this NOS tool as most of our included studies were cohort studies, either prospective or retrospective. The NOS tool has three parameters: selection = 4, comparability = 2 and outcome = 3; based on that we conducted the quality assessment of all 13 studies. Two primary reviewers conducted the quality assessment independently and invited the third reviewer to resolve any disagreement.
We identified 7030 pregnant women with COVID-19 positive status from the
Figure 1. PRISMA chart used for the selection of articles.
cohort studies conducted in different parts of the world, including the USA, UK, Europe like Spain, South America like Peru, Chili and Middle-east countries like Kuwait and Saudi-Arabia  - . The COVID-19 positive status was confirmed among most of the pregnant women (90% and above) by laboratory SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) assay, SARS-CoV-2 antibody testing, or radiological findings. In the INTERCOVID Multinational Cohort Study, a small proportion (7.1%) of pregnant women was clinically diagnosed with COVID-19 without laboratory confirmation . The main study findings and conclusion are summarized in Table 4.
Table 2. Selected articles and their source.
3.1. Socio-Demographic Status
The maternal age ranged from 18 to 49 years  -    . With regards to the median age, the range was from 28 to 32 years    . Seven studies included the ethnic backgrounds of the patients       . Non-Hispanic whites or Hispanics made up the majority (up to 64.2%) of the research population       . Other ethnicities included were non-Hispanic Blacks, Asians, and others       . Low socioeconomic status, defined as having no educational background, no employment history or being unemployed for more than two years, was found to be 33.3% among the COVID-19 positive pregnant women in one study .
3.2. Pregnancy Characteristics
The percentage of nulliparous women ranged from 19.5% to 53%      , while up to 80.5% of women were multiparous   . In one study, multiparity was associated with higher rates of moderate and severe COVID-19 as compared to nulliparous pregnant women who were infected with the virus (87.5% vs. 12.5%; 62.5% vs. 37.5%) . Most of the pregnancy was a singleton, and only 1.1% to 2.5% were of multiple pregnancies       .
3.3. Pre-Existing Comorbidities
Obesity, defined as body mass index (BMI) more than 30 kg/m2, was the most common pre-gestational comorbidities identified, with the highest prevalence of 55.1%   -   . Pregnant women who were overweight or obese
Table 3. Risk of bias assessment of the selected articles.
were more likely to be hospitalized due to symptomatic COVID-19 and are at risk of higher maternal morbidity and mortality  . In the group of patients admitted for critical-severe COVID-19, there was a higher proportion of women with a BMI of 30 kg/m2 or more (58.4%) . Pre-pregnancy asthma had affected up to 8.3% of women        . Chronic lung disease was only found in 0.2% to 0.4% of COVID-19 infected pregnant women   . While most of the infected pregnant women were non-smokers, up to 14.2% of them had a smoking history       .
We also found that 1.2% to 4.6% of pregnant women had chronic hypertension       . When compared to non-hospitalized pregnant women with COVID-19 disease, it was found that those with obesity,
Table 4. List of selected articles which are included in review with the main findings and conclusion.
asthma, and hypertension were more likely to be hospitalized due to COVID-19 symptoms or concerns (21.1% vs. 6.3%, p = 0.01; 20.8% vs. 6.9%, p = 0.02; 20.8% vs. 2.8%, p < 0.001) . The prevalence of cardiovascular diseases before pregnancy (excluding hypertension) was found to be low (0.3% to 2%)    .
Pre-gestational type 2 diabetes mellitus was also uncommon among the infected pregnant women (0.5% to 5.4%)        . However, in the study by Metz et al., critical or severe COVID-19 diseases were more likely to develop in pregnant women with pre-existing asthma, chronic obstructive pulmonary disease, chronic hypertension, and diabetes .
Other comorbidities such as thyroid dysfunctions, liver and renal diseases, haematological diseases, autoimmune diseases, and psychological disorders were infrequently reported       .
The median gestational age at maternal diagnosis of COVID-19 ranged from 29 to 38 weeks   . Half or more (51.3% to 56.3%) of the SARS-CoV-2 diagnoses were confirmed during the third trimester  . The rates of asymptomatic and symptomatic pregnant women showed a huge variability among the studies, ranging from 22.9% to 88.6% and 11.4% to 88.6% for both categories, respectively  - . The commonly reported symptoms were fever, cough, sore throat and shortness of breath        . It was found that pregnant women presenting with any duration of fever and dyspnoea were more likely to develop severe maternal complications (RR: 2.56; 95% CI: 1.92 - 3.40) .
Most symptomatic pregnant mothers experienced mild to moderate COVID-19 disease, only requiring oxygen supplementation through nasal cannula or face mask, or none at all       . Severe COVID-19 disease occurred in 3.2% to 26.1%, while only 1.7% to 4% of pregnant women developed critical COVID-19 disease  - . Among the severe and critical COVID-19 group, maternal hypoxia and acute respiratory failure were reported up to 61% and 67%, respectively .
Mechanical ventilation was required in 2.1% to 16.7% of the symptomatic pregnant population    . Lymphopenia, elevated liver enzymes (ALT, AST), elevated CRP and procalcitonin, and chest imaging abnormalities consistent with COVID-19 pneumonia were the frequently encountered investigation findings    - . Mothers of positive COVID-19 were commonly treated with antibiotics, antivirals, low molecular weight heparin (LMWH) and corticosteroids    .
We found that 1.4% to 4.6% of the pregnant mothers experienced a pregnancy loss before 24 weeks of gestation     , and 19.4% of pregnancy loss occurred in mothers who were infected in the first-trimester . In terms of hypertensive disorders during pregnancy, which includes gestational hypertension, pre-eclampsia, eclampsia and Haemolysis, Elevated Liver enzyme and Low Platelet Syndrome (HELLP), the incidence rate was from 1.3% to 40.4%          . The risk of developing pre-eclampsia or eclampsia was increased for pregnant women infected with COVID-19 disease (RR: 1.76, 95% CI: 1.27 - 2.43), even for the asymptomatic mothers (RR: 1.63, 95% CI: 1.01 - 2.63) . It was also found that 89.5% of new-onset gestational hypertensive disorders were detected at or after the diagnosis of COVID-19 infection . Pregnant women with gestational diabetes ranged from 5.24% to 11.0%      .
In general, 1.1% to 11.1% of women were admitted to the intensive care unit (ICU)  - . Pregnant women diagnosed with COVID-19 infection had a higher tendency for ICU admission as compared with non-infected mothers (RR: 5.04, 95% CI: 3.13 - 8.10) . Among the COVID-19 positive pregnant women, those who were symptomatic, especially with a severe form of the disease, were at a higher risk of ICU admission   . Maternal deaths were uncommon, with mortality rates of no more than 1.6%. However, despite a wide range of confidence intervals, it was worth noting that pregnant women with COVID-19 were at a 22 times higher risk of dying (RR: 22.3; 95% CI: 2.88 - 172) .
The prevalence of preterm birth among pregnant women diagnosed with COVID-19 ranged from 9.7% to 26.6% (Table 5)  - . Comparing symptomatic COVID-19 positive mothers to those without the infection, there was a 10-fold increased risk of preterm births in the infected women (OR: 11.43, 95% CI: 5.07 - 25.75) . However, the rates of preterm births were similar among the asymptomatic maternal COVID-19 infection and non-infected pregnant women . Medically indicated or iatrogenic preterm labour was more likely to occur in COVID-19 positive mothers (RR: 1.97, 95% CI: 1.56 - 2.51) . Up to 83% of the iatrogenic preterm births were indicated due to COVID-19 symptoms
Table 5. The rates of preterm birth among COVID-19 positive mothers across different studies and their characteristics.
*All figures were given in percentage; *NA: Not available.
or pneumonia   . Among them, up to 63.6% of the cases were from mothers with severe or critical COVID-19 disease  . In another study, more than half of the women with severe COVID-19 delivered preterm, all of them being iatrogenic .
On the other hand, non-COVID-related indications for preterm deliveries that were commonly reported in the COVID-19 positive pregnant women were as follows: hypertensive disorders of pregnancy (7% - 33%), stillbirth (16%), preterm prelabour rupture of membranes (PPROM) (13%), spontaneous rupture of membranes (20.0%), small for gestational age (SGA) (15.5%), and foetal distress (13.2%)     .
Vaginal birth accounted for 41.7% to 64.2% of all deliveries       . The overall caesarean section rates among the COVID-19 positive cohort ranged from 22.4% to 54.2%  - . We observed a trend of Caesarean section for COVID-19 positive mothers who were symptomatic or experiencing severe forms of the disease      . Vousden et al. showed a statistically significant increased risk of caesarean section delivery, as high as 1.5 -times, among pregnant women with symptomatic COVID-19 compared to those who were asymptomatic (OR = 1.51, 95% CI = 1.11 - 2.06) . Severe and critical COVID-19 further increased the risk of caesarean section (RR: 1.62, 95% CI: 1.1 - 2.3, p = 0.01; RR: 2.8, 95% CI: 2.0 - 3.8, p < 0.001) . Elective and maternal requests for caesarean delivery were as high as 44.3%, while other indications included hypertensive disorder of pregnancy, malpresentation, foetal distress, placental abnormalities and failed induction of labour      .
The incidence of perinatal losses (stillbirth and foetal death) remained low, accounting for 0.6% to 8.4% of deliveries  -  . Up to 12.9% of neonates born to mothers with COVID-19 were tested positive for the disease    - . Nearly half of the newborns were found to have IgG antibodies alone without any presentation of infection during the neonatal period .
Obesity has always been a huge concern for women in the reproductive age range, and it is as common as affecting one-third of the pregnant women population in the West  . Maternal obesity plays a role in disrupting maternal metabolism and predisposes pregnant women to a higher risk of gestational diabetes and pre-eclampsia, which can lead to adverse pregnancy outcomes such as preterm birth and perinatal mortality . In our review, a BMI of more than 30 kg/m2 was the most common pre-gestational comorbidities in the COVID-19 positive women. It was found that a higher proportion of pregnant women with severe COVID-19 disease were obese. A comparison with other studies identified a similar link between obesity and severe COVID-19 presentation among pregnant mothers   .
There was a variability in the percentage of asymptomatic COVID-19 pregnant women in our systematic review. In part, the high proportion of COVID-19 pregnancies that were asymptomatic can be attributed to the universal screening of all pregnant women who were admitted to the hospital for deliveries . We also observed that half or more (51.3% to 56.3%) of the COVID-19 diagnoses were made during the third trimester, which can be explained by the practice of conducting testing near term . This situation has contributed to a higher proportion of women being tested positive in the 3rd trimester rather than in earlier stages of pregnancy, especially if they were asymptomatic.
Most symptomatic COVID-19 pregnancies in our study reported mild-to-moderate symptoms. This finding was consistent with the World Health Organization (WHO) report, which stated that pregnant women are not more vulnerable to a severe illness course . Albeit the similar vulnerability between pregnant women and those of a similar reproductive age in terms of COVID-19 severity, the same cannot apply if the pregnancy is complicated with pulmonary comorbidities [aOR 4.3, 95% CI: 1.9 - 9.5], hypertensive disorders [aOR 2.7, 95% CI: 1.0 - 7.0] and diabetes [aOR2.2, 95% CI: 1.1 - 4.5] .
In this review, we did not identify any mention of the mutated SARS-CoV-2 strains and their impact on the COVID-19 severity in pregnant patients. However, a recent publication mentioned a potentially increased risk of developing severe COVID-19 if the mothers were infected with the delta variant, compared to the alpha variant .
Preterm birth can lead to higher neonatal and infant mortality rates, especially at lower gestational ages . Babies born prematurely face issues like the requirement of intensive care services after birth, the need for ongoing health and developmental support, a higher risk of long-term neurological impairment and developmental delay, and increased mortality rates  . We found that preterm birth was not more common (9.7% to 26.6%) for pregnant women with COVID-19 positive status per se, a finding supported by various other studies as well as global preterm birth rate estimations   .
However, pregnancies with symptomatic or severe COVID-19 symptoms had a higher likelihood of preterm birth, mainly iatrogenic . Delahoy et al. reported preterm birth rates for symptomatic and asymptomatic pregnant women with COVID-19 infection at 23.1% and 8%, respectively . The dilemma to deliver prematurely stems from the need to balance between the benefit of improved maternal disease outcome and the risk of neonatal morbidity and mortality . Still, it was inconclusive whether or not the delivery of infants showed significant improvement to the mothers’ respiratory functions   .
We reported that not more than half of the COVID-19 positive pregnant women underwent caesarean section. To date, no clear evidence has been found to support the indication of caesarean section for active COVID-19 infection   . Nonetheless, systematic reviews by Capobianco et al., Di Toro et al. and De Melo et al. have reported high rates of caesarean sections   . There are concerns on vertical transmission as vaginal delivery increases the risk of cross-infection, and caesarean sections are performed to minimize maternal exertion during labour and improve maternal respiratory function as per local guidelines or recommendations  .
A higher risk of caesarean births was reported for symptomatic pregnant women, a finding also supported by Vouga M et al. . Furthermore, the risk of foetal distress may be increased during labour when the mother is symptomatic for COVID-19    . Possibly, the higher risk for foetal distress and potential maternal compromise led to higher rates of caesarean deliveries in symptomatic mothers, but a clear link between maternal COVID-19 severity and caesarean section was yet to be established. This finding implicated the value of a COVID-19 positive mother to deliver in an obstetrical unit where immediate access to emergency services can be provided if needed .
Pregnancies that were complicated with severe COVID-19 were at a higher risk of developing pre-eclampsia. Similar findings have been reported in a systematic review by Ghayda et al. . It can be explained by the overexpression of proinflammatory cytokines (IL-6, TNF-alpha, IFN-gamma, etc.) during severe COVID-19, whose levels were also significantly raised in the preeclamptic placentas . However, the coronavirus-provoked inflammatory cascade, better known as the “cytokine storm”, was not found to influence the levels of specific pre-eclampsia-related angiogenic and anti-angiogenic markers like P1GF and sFLT-1 . Nonetheless, placental inflammation serves as the linkage between COVID-19 and adverse foetal outcomes . Another theory mentioned the downregulation of ACE2 as SARS-CoV-2 binds to it when entering host cells. With the lower level of ACE2, there is an increased plasmatic concentration of angiotensin II , whose primary function is to raise blood pressure through vasoconstriction .
While ICU admission rates remained low, both COVID-19 infections and their severity are associated with a higher risk of ICU admission. Consistent trends were observed by Huntley et al. and Elsaddig et al., which found that more pregnant women who were positive for COVID-19 required ICU admission compared to their non-infected counterparts  . That being said, there is a possibility of a lower threshold for initiating treatment in pregnancies instead of more serious diseases  .
The most commonly encountered laboratory findings of COVID-19 infection in our reviewed studies include lymphopenia, elevated liver enzymes (ALT, AST), increased CRP, and procalcitonin, which can be useful as parameters to predict ICU admission . We reported a small percentage of perinatal losses from our studies. Despite the low stillbirth rates, a positive COVID-19 diagnosis increases the risk for stillbirth by almost two-fold   . Studies examining the placental histopathology of COVID-19 infected mothers have found an increased frequency of vascular malperfusion and villitis, suggesting a plausible mechanism to explain the higher risk of stillbirth for COVID-19 mothers   .
Despite the inclining rates of COVID-19 infection globally, most pregnant women expressed mild to moderate symptoms when infected with SARS-CoV-2. However, maternal pregestational comorbidity, in particular, an increased BMI, was shown to be associated with severe COVID-19 disease. Women with symptomatic COVID-19 had an increased risk for preterm birth compared to asymptomatic women, but the risk was not nearly as high as those with a severe or critical form of the COVID-19 disease. Another significant outcome was C-section, in which its incidence rate increased significantly, especially in the severe COVID-19 group. Other maternal outcomes, including maternal death, intrauterine death and infection, hypertensive disorders in pregnancy, stillbirth and post-partum haemorrhage, had lower incidence rates.
This review was consistent with previous studies on the increased pre-eclampsia, preterm birth, and caesarean delivery rates in COVID-19 positive pregnant women. This paper mainly contributes to identifying a potential link between COVID-19 severity and iatrogenic deliveries, including caesarean section, while establishing that COVID-19 itself may not be the chief offender in adverse maternal outcomes if the mother is asymptomatic or experiencing only mild COVID-19 symptoms.
This study has some limitations. We acknowledge that most of our study data are from a White or Middle-Eastern background, and thus, it may not be applicable to the Asian, south-east Asian, or Black communities. We also could not conduct a meta-analysis on the available data, which meant that we could not have pooled evidence to draw the conclusions on the summary estimate of the effect. While an effort was made to keep this review as updated as possible, it was understood that more research has to be done to maintain the validity of information as the COVID-19 situation keeps evolving and more papers emerge in the field. In addition, further studies are needed to evaluate the maternal management modality to induce a better prognosis among COVID-19 infected pregnant women in the future.
The authors would like to express their appreciation to the Monash University Library for providing permission to utilize the extensive resources, especially to get access to full-text articles and software (Endnote and Nvivo) for this systematic review.
List of Abbreviation
1JT: Jiexi Teoh; JK: Junwen Khong.
2SSSH: Sharifah Shahirah Syed Hashim; NKJ: Nowrozy Kamar Jahan.
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