Long COVID‑19 and pregnancy: A systematic review
- Authors:
- Published online on: November 19, 2024 https://doi.org/10.3892/br.2024.1893
- Article Number: 15
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Copyright: © Georgakopoulou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The coronavirus disease 2019 (COVID-19) pandemic has significantly affected global health, with varying impacts on different population groups (1-4). Pregnant women have been identified as a particularly vulnerable subgroup due to physiological changes in the immune and cardiovascular systems, which may influence their response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (5). Recent research has highlighted that not only are pregnant women at a higher risk for severe outcomes during the acute phase of COVID-19, but they may also experience lingering post-acute sequelae of SARS-CoV-2 infection, known as Long COVID-19 syndrome (6,7). This condition, characterized by a range of symptoms persisting beyond four weeks post-infection (8), has raised concerns about its impact on maternal health and pregnancy outcomes.
Long COVID-19 syndrome, also referred to as post-acute sequelae of COVID-19 (PASC), includes a variety of symptoms such as fatigue, cognitive dysfunction, respiratory issues and psychological disturbances (9-12). The prevalence of these symptoms and their intensity appear to vary among pregnant women depending on factors such as the severity of the initial infection, pre-existing health conditions and sociodemographic characteristics (13-15). Studies have reported that pregnant women often experience distinct post-infection symptoms, including dyspnea, fatigue and mood disturbances, which can complicate pregnancy (7,13).
The potential impact of Long COVID-19 on maternal and fetal health is a growing area of research. Early findings indicate that pregnant women with severe COVID-19 are more likely to develop long-term respiratory and neurological symptoms, which could interfere with their ability to perform daily activities and care for their newborns (16). Additionally, the presence of these prolonged symptoms may increase the risk of adverse pregnancy outcomes, such as preterm birth, low birth weight and increased need for intensive care for both the mother and the infant (7,17).
The aim of the present systematic review is to comprehensively evaluate the prevalence, risk factors and clinical outcomes of Long COVID-19 syndrome in pregnant women. By synthesizing findings from multiple studies, the review aims to provide a clearer understanding of the burden and nature of Long COVID-19 in this unique population. The results will inform healthcare providers and policymakers, facilitating the development of targeted interventions and strategies to support maternal health during and after the pandemic.
Materials and methods
The present systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (18) to evaluate the prevalence, risk factors and clinical outcomes of Long-COVID-19 in pregnant women. Studies were included if they reported original data on post-COVID-19 symptoms and outcomes specifically in the context of pregnancy. The review included studies utilizing prospective, retrospective, pilot, longitudinal and cross-sectional designs to ensure comprehensive coverage of the topic. In addition, the present systematic review has been registered in the International Register of Systematic Review Protocols (PROSPERO) under accession number CRD42024600019 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=600019).
Inclusion and exclusion criteria
Studies were included if they met the following criteria: i) reported on pregnant women diagnosed with COVID-19 during pregnancy, ii) provided information on Long COVID-19 or PASC, iii) included a minimum follow-up duration of at least four weeks post-acute infection, and iv) were peer-reviewed articles published in English. Exclusion criteria included review articles, case reports, or studies not focused on Long COVID-19 outcomes. Studies with insufficient data on clinical outcomes or missing critical methodological details were also excluded.
Search strategy
A systematic search was conducted in the PubMed, Scopus and Google Scholar databases, covering literature published between January 2020 and October 2024. Search terms included combinations of ‘COVID-19’, ‘pregnancy’, ‘Long COVID’, ‘post-acute sequelae’, ‘PASC’, ‘pregnant’, ‘SARS-CoV-2’ and ‘maternal outcomes’.
PRISMA process
The PRISMA process is illustrated in Fig. 1. Identification: A total of 1,600 records were identified through systematic searches in PubMed (https://pubmed.ncbi.nlm.nih.gov/), Scopus (https://www.scopus.com/home.uri) and Google Scholar (https://scholar.google.com/). An additional 50 records were identified from reference lists of relevant articles and other databases, resulting in a total of 1,650 records for initial consideration.
Screening: After removing 450 duplicate records, 1,200 unique records were screened based on their titles and abstracts. During this screening phase, 850 records were excluded for not meeting the inclusion criteria. The excluded records comprised review articles, case reports and studies that did not focus on pregnancy or Long COVID-19.
Eligibility: The eligibility assessment included a review of 350 full-text articles. Out of these, 337 articles were excluded based on specific reasons: 150 articles did not focus on Long COVID-19 or PASC, 142 articles lacked sufficient data on pregnancy outcomes, 30 articles had a follow-up duration of <4 weeks post-infection, and 15 articles were excluded because they were not published in English.
Included studies: A total of 13 studies were deemed suitable for narrative synthesis due to the heterogeneity in study designs and outcome measures. These studies provided the most comprehensive data on Long COVID-19 in pregnant and postpartum women, which was crucial for synthesizing meaningful conclusions.
Data extraction and synthesis
Data from each study was extracted independently by two reviewers using a standardized data extraction form. Key variables included study design, sample size, population characteristics, outcome measures and results related to Long COVID-19 symptoms and associated risk factors. Disagreements were resolved through discussion or consultation with a third reviewer.
The extracted information included: i) author, year and type of study; ii) population characteristics (for example, number of participants, demographics and inclusion criteria); iii) measurements (for example, diagnostic tools and questionnaires used to assess post-COVID-19 symptoms); and iv) key findings (for example, prevalence of specific symptoms and identified risk factors).
Quality assessment
The quality of included studies was assessed independently by two reviewers using validated tools. Cohort and case-control studies were evaluated using the Newcastle-Ottawa Scale (19), which assesses selection, comparability and outcome domains. Each study was assigned a score, and the quality was categorized as high (7-9 stars), moderate (4-6 stars), or low (<4 stars).
Data analysis
Due to the heterogeneity of study designs and reported outcomes, a narrative synthesis was used to describe key findings across studies. Where applicable, the prevalence of Long COVID symptoms was summarized, and risk factors were identified. Meta-analyses were not conducted due to significant variability in symptom assessment tools and follow-up durations across studies.
The present systematic review synthesizes evidence on the impact of Long COVID in pregnant women, highlighting prevalent symptoms, risk factors and the need for targeted management strategies.
Results
Study characteristics
The systematic review included 13 studies (6,7,13-15,17,20-26), encompassing a total of 13,729 participants. Studies varied in design, with most employing prospective or cross-sectional approaches. The sample sizes ranged from 33 to 5,397 participants, and studies were conducted across diverse geographical regions, including the United States, Brazil, China, Turkey, Ecuador and Russia. Study populations included pregnant women at various gestational stages and postpartum women. The characteristics of the included studies and the quality assessment are summarized in Table I.
Prevalence of Long COVID-19 in pregnant women
Across the included studies, the prevalence of Long COVID-19 in pregnant women varied widely, ranging from 9.3-93%. The variation in prevalence can be attributed to differences in study design, follow-up duration and the definition of Long COVID-19. Studies such as Metz et al (14), a large multicenter cohort study, reported a lower prevalence of Long COVID-19 at 9.3% when evaluating symptoms at a median follow-up of 10.3 months. By contrast, smaller single-center studies, such as Malgina et al (6), observed a significantly higher prevalence (93%) in pregnant women compared with non-COVID-19 controls (38.4%).
Persistent symptoms
The reported symptoms of Long COVID-19 in pregnant women encompassed a wide spectrum, with fatigue, cognitive dysfunction, respiratory symptoms and psychological disturbances being the most reported. Fatigue was the most frequently observed symptom across studies, with prevalence rates ranging from 54.5% (22) to 76% (7). Cognitive impairment and memory loss were prominent in studies such as Malgina et al (6), affecting nearly 50% of the affected women. Psychological symptoms, including depression and anxiety, were highlighted by both Vetrugno et al (24) and Muñoz-Chápuli et al (15), indicating a significant impact on health-related quality of life (HRQoL).
Some studies also identified unique symptoms or sequelae associated with Long COVID-19 in pregnancy. Gu et al (21) found a high incidence of liver function abnormalities in 40.6% of pregnant women, suggesting a potential organ-specific impact of COVID-19 during pregnancy. Vásconez-González et al (23) noted difficulty concentrating and hair loss as distinctive symptoms among pregnant women, although no significant difference was observed compared with non-pregnant controls. These findings underscore the variability and complexity of Long COVID-19 symptomatology in the maternal population.
Impact of Long COVID-19 on maternal and perinatal outcomes
The severity of acute COVID-19 symptoms appears to be a significant predictor of Long COVID-19 development and its impact on pregnancy outcomes. Bruno et al (20) demonstrated that women who contracted SARS-CoV-2 during pregnancy had a lower overall risk of Long COVID-19 (adjusted hazard ratio=0.85), but those who experienced severe symptoms were more likely to develop thromboembolic events and abnormal heart rhythms. Similarly, Yao et al (26) reported that pregnant women with long-term COVID-19 had a significantly higher risk of developing gestational hypertension [odd ratio (OR)=3.344], gestational diabetes (OR=2.301) and fetal intrauterine growth restriction (OR=2.817). No significant differences were observed in the rates of premature rupture of membranes, preterm delivery, or neonatal asphyxia between the long-term COVID-19 and non-COVID-19 groups.
Ghizzoni et al (17) similarly reported a higher rate of adverse pregnancy outcomes, including preterm birth and neonatal complications, in women with persistent symptoms.
In addition to obstetric outcomes, Long COVID-19 also influenced maternal HRQoL. Vetrugno et al (24) used the SF-36 and IES-R scales to assess HRQoL and post-traumatic stress disorder (PTSD) symptoms, revealing that 30% of participants tested positive for PTSD one-year post-infection. Women with underlying comorbidities such as cardiac or pulmonary disease had significantly poorer HRQoL scores, suggesting that pre-existing health conditions may exacerbate the long-term impact of COVID-19.
Risk factors for long COVID in pregnancy
Several studies identified risk factors associated with an increased likelihood of developing Long COVID-19 among pregnant women. Metz et al (14) highlighted that obesity, pre-existing mental health conditions, and severe acute infection were significantly associated with higher odds of Long COVID-19. Similarly, Muñoz-Chápuli et al (15) identified non-vaccination and multiparity as key risk factors. Oliveira et al (13) found that women who experienced severe acute COVID-19 were at a 2.43-fold increased risk of persistent fatigue compared with those with milder symptoms, emphasizing the importance of acute symptom management to potentially mitigate long-term sequelae. Risk factors and outcomes of Long COVID-19 in pregnant women are illustrated in Fig. 2.
Discussion
The present systematic review highlights the significant prevalence and variability of Long COVID-19 in pregnant women, with rates ranging from 9.3-93%. The wide range in prevalence is due to differences in study designs, definitions and timing of symptom assessment. Common symptoms included fatigue, dyspnea, cognitive impairment and psychological issues such as anxiety and depression, emphasizing the need for mental health support. The severity of acute COVID-19 was found to be a key predictor of Long COVID-19, with severe cases linked to prolonged symptoms such as liver dysfunction and thromboembolic events. The clinical impact of Long COVID-19 on pregnancy extends beyond persistent symptoms. It is associated with adverse maternal and perinatal outcomes, such as preterm birth, low birth weight and an increased need for neonatal intensive care. The presence of long-term respiratory and neurological symptoms, such as thromboembolic events, may complicate daily activities and postpartum care, further stressing the need for targeted follow-up and support for pregnant women with Long COVID-19. This highlights the need for comprehensive care models that integrate physical, mental and perinatal health (27). Several studies within the review identified key risk factors for developing Long COVID-19 in pregnancy, such as severe acute infection, obesity and non-vaccination. Additionally, pre-existing mental health conditions were significantly linked to prolonged psychological symptoms including anxiety and depression. The identified risk factors for Long COVID-19 in pregnancy (severe acute infection, obesity, non-vaccination and pre-existing mental health conditions) are not unique to pregnant women but are also well-established risk factors for Long COVID in the general population (28-31). Identifying key risk factors for Long COVID-19 in pregnancy, such as severe acute infection, obesity, non-vaccination and pre-existing mental health conditions, highlights the need for targeted clinical interventions. Pregnant women with these risk factors should receive closer monitoring during and after pregnancy to detect and manage prolonged symptoms early. Emphasizing COVID-19 vaccination is crucial to reducing severe infection and long-term complications, while addressing obesity through lifestyle interventions during pregnancy can help lower the risk of Long COVID-19(32). Additionally, women with pre-existing mental health conditions require tailored postpartum mental health support, and understanding these risk factors enables more efficient resource allocation to prioritize care for high-risk individuals (33).
The management of pregnant women with Long COVID-19 should largely mirror that of non-pregnant individuals, with a focus on self-management and medical care. Self-management includes daily pulse oximetry, optimizing general health through adequate sleep, nutrition, smoking cessation and reducing alcohol and caffeine intake. A gradual increase in exercise should be encouraged, as tolerated, alongside setting realistic goals. Medical management involves treating symptoms, managing pre-existing conditions, prescribing antibiotics for secondary infections, and referring patients to specialists such as mental health professionals and pulmonary rehabilitation programs. Social and financial support should also be prioritized (34).
Pregnancy introduces additional complexities to the management of Long COVID-19. Women with severe symptoms should seek pre-conception counseling to optimize their health before pregnancy. The impact of pregnancy on Long COVID-19 remains uncertain, though symptoms such as fatigue and breathlessness may worsen, particularly in the third trimester. During pregnancy, symptom tracking via a diary can help identify new or worsening symptoms, which should not be automatically attributed to Long COVID-19 without thorough evaluation. Regular fetal growth monitoring is recommended for women with severe symptoms. The approach to labor and delivery should be individualized, especially for those with significant fatigue or cardiovascular and respiratory symptoms, reserving caesarean sections for obstetric indications (35).
The present systematic review is, to the best of our knowledge, the first to provide insights from Long COVID-19 syndrome in pregnant women. However, the present systematic review has several limitations that should be considered when interpreting the findings. First, there was significant heterogeneity in study designs, sample sizes, follow-up durations and definitions of Long COVID, which limited the ability to synthesize results quantitatively and may have contributed to the observed variability in prevalence estimates. Numerous included studies relied on self-reported data, which is subject to recall bias and may not accurately capture the true burden of symptoms, particularly for psychological and cognitive outcomes. Additionally, the lack of standardized diagnostic criteria for Long COVID in pregnant populations further complicates the comparison of results across studies. Most studies were conducted in single centers or specific regions, limiting the generalizability of findings to broader, more diverse populations. Finally, the exclusion of non-English language studies and potential publication bias may have resulted in the omission of relevant data, particularly from regions with a high burden of COVID-19, such as Latin America and Asia, potentially skewing the overall D of Long COVID's impact on pregnancy.
Future studies should aim to address these limitations by adopting longitudinal study designs with larger sample sizes and standardized symptom assessment tools. Research should also focus on the long-term impact of Long COVID on both maternal and fetal health, with particular attention to the role of vaccination in mitigating the severity and duration of symptoms. Furthermore, exploring geographically diverse populations could provide a more comprehensive understanding of Long COVID's impact on global maternal health.
The present systematic review highlights the significant burden and complexity of Long COVID in pregnant women. The findings suggest that the prevalence and severity of Long COVID-19 are influenced by multiple factors, including the severity of the acute infection, pre-existing conditions and vaccination status. The wide range in prevalence estimates across studies reflects the need for standardized definitions and diagnostic criteria for Long COVID-19 in this population. Pregnant women with severe or moderate COVID-19 appear to be at the highest risk for persistent symptoms, which may impact not only maternal health but also perinatal outcomes such as preterm birth and neonatal complications. Psychological symptoms, such as anxiety and depression, were prominent in several studies, emphasizing the importance of comprehensive post-infection care that includes mental health support. Despite the valuable insights provided, the review's findings are limited by the heterogeneity of study designs and reliance on self-reported data. Future research should focus on longitudinal studies with larger sample sizes and diverse populations to provide a clearer understanding of the long-term impact of COVID-19 during pregnancy and inform evidence-based guidelines for managing Long COVID in this vulnerable population.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
AS and VEG conceptualized the study. AS, CT, VEG and DAS made a substantial contribution to data interpretation and analysis and wrote and prepared the draft of the manuscript. AS and VEG analyzed the data and provided critical revisions. All authors contributed to manuscript revision, read and approved the final version of the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The other authors declare that they have no competing interests.
Use of artificial intelligence tools
During the preparation of this work, artificial intelligence tools were used to improve the readability and language of the manuscript, and subsequently, the authors revised and edited the content produced by the artificial intelligence tools as necessary, taking full responsibility for the ultimate content of the present manuscript.
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