key: cord-0770731-of9wxts0
authors: Girolamo, Raffaella Di; Khalil, Asma; Rizzo, Giuseppe; Capannolo, Giulia; Buca, Danilo; Liberati, Marco; Acharya, Ganesh; Odibo, Anthony O; D'Antonio, Francesco
title: Systematic review and critical evaluation of quality of clinical practice guidelines on the management of SARS-CoV-2 infection in pregnancy
date: 2022-05-02
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2022.100654
sha: 2b99c77607f7f38c5db86e21a3a1c16368783c1c
doc_id: 770731
cord_uid: of9wxts0

Objective: To systematically identify and critically assess the quality of clinical practice guidelines (CPGs) for the management of SARS-CoV-2 infection in pregnancy.

considered as the gold standard for CPG quality assessment. To define a CPG as of good quality we adopted the cut-off score according to Amer et al.: if the overall guideline score was >60%, CPGs was recommended.

The following clinical points related to the management of pregnant women with SARS-CoV-2 infection were addressed: criteria for maternal hospitalization, recommendations for follow-up fetal growth scan, specific recommendations against invasive procedures, management of labor, timing of delivery, postpartum care and vaccination strategy.

Results: Twenty-eight CPGs were included. All of them recommended hospitalization only for severe disease. Forty-six percent (6/13) of CPGs suggested a fetal growth scan after SARS-COV-2 infection while 23.1% (3/13) did not support this practice. Thromboprophylaxis with low molecular weight heparin (LMWH) was recommended in symptomatic women by 77.1% (7/9) of the CPGS. None of the CPGs recommended to administer corticosteroids only for the presence of SARS-CoV-2 infection in preterm gestation, unless specific obstetric indication exists. Elective induction of labor from 39 weeks of gestation was suggested by 18.1% (2/11) of the CPGs included in the present review, while 45.4% (5/11) did not recommend elective induction unless other obstetric indications co-existed. Twenty-seven percent (3/11) of the CPGs suggested shortening of the second stage of labor and active pushing was supported by 18.1% (2/11) of them. A general agreement was found among the CPGs in not recommending Cesarean Section (CS) only for the presence of maternal infection and recommending vaccine booster at least 6 months after the primary series of vaccination. The AGREE II standardized domain scores for the first overall assessment (OA1) of CPGs had a mean of 50% (SD±21.82%) and 9 CPGs scored more than 60%.

Conclusions: A significant heterogeneity was found in some major aspects of the main aspects of the management of SARS-CoV-2 infection in pregnancy reported by the published CPGs. 

The pandemic caused by severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that was first identified in December 2019, still remains a major public health issue remains to be a major concern. 1 Pregnancy is an independent risk factor for adverse outcomes generally in women with SARS-CoV-2, especially when several morbidities, as diabetes or pre-eclampsia co-exist. 2, 3 The rapid spread of the pandemic and the higher risk of adverse maternal outcome reported in women with SARS-CoV-2 infection underscores the importance of available evidence-based guidelines on the management of this infection in pregnancy. Clinical Practice Guidelines (CPGs) are statements that include recommendations intended to optimize patient care. CPGs should follow a rigorous methodology to provide clinicians with the most-up to date and objective clinical evidence. However, high quality CPGs are methodologically complex to develop, which makes them relatively incompatible with emergency situations. Rapid Guidelines (RGs) are defined as CPGs which are completed in a 1-to 3-months' timeframe and are alternatives to comprehensive CPGs to provide guidance in response to an emergency. 33 Since the beginning of the pandemic a multitude of RGs reporting different aspects of the management of SARS-CoV-2 infection in pregnancy has been released. However, the methodological robustness of such guidelines has yet to be determined. 34 The Appraisal of Guidelines for REsearch and Evaluation tool (AGREE II) is the most widely utilized tool to appraise the quality of CPGs, and it has been considered as the gold standard for CPG quality assessment. 35 The primary aim of this systematic review was to objectively evaluate the quality of the published CPGs on the management of SARS-CoV-2 infection in pregnancy using the AGREE II tool. The secondary aim was to assess and report the agreement or heterogeneity among the CPGs regarding different aspects of clinical management of SARS-CoV-2 infection.

This review was performed according to a protocol recommended for Systematic Review of Clinical Guidelines. 36 The review protocol was not designed a priori, given the rapid evolution of the pandemic and the speed of the evidence synthesis. PRISMA guidelines were followed 36 and its checklist was provided in the Supplementary Tables (Table S1 ). The literature search was conducted in the MEDLINE (PubMed), Scopus, ISI Web of Science databases to identify all relevant CPGs published before February 15 th , 2022. Combinations of the following keywords and MESH search terms were used: ("management" OR "managing") AND ("SARS-CoV-2" OR "COVID-19" OR "coronavirus") AND ("pregnancy" OR "pregnant" OR "pregnant women" OR "during pregnancy" AND ("antenatal care" OR "prenatal" OR "vaccine" OR "ultrasound" OR "delivery") AND ("guidelines"). No restrictions for geographic location were applied. The reference lists of relevant recommendations and considerations were also hand-searched to complement database search. The search was restricted to guidelines published in English language.

Only CPGs including recommendations on the management of pregnant women with SARS-CoV-2 infection were considered eligible for this systematic review. Two reviewers (RDG, GC) independently evaluated titles and abstracts. Disagreements were resolved by discussion among authors, and if required, with the involvement of a third author (FDA). When more than one version was available, the most updated version was included, considering last versions methodologically as the same as the previous, given that the authors wrote it with the same approach. Any CPGs on the organization of antenatal or postnatal services or information for healthcare professionals in the context of SARS-CoV-2 pandemic were excluded.

The main data extracted for the present review included publication ID (first author, a research consortium, or a professional society), year of publication, country, title, society, scope of the CPG, Date of publication, number of revisions and type of methodology adopted. The outcomes were extracted and reported in an online Google sheet for sharing among all authors.

The assessment of risk of bias and quality assessment of the included CPGs were performed using "The Appraisal of Guidelines for REsearch and Evaluation (AGREE II)" tool. 35 The AGREE II tool comprehends 23 items divided in six quality domains:

Scope and purpose, Stakeholder involvement, Rigour of development, Clarity of presentation, Applicability and Editorial independence.

Each of the 23 items targets various aspects of CPGs quality of the practice guideline. Each item was evaluated on a seven-point scale from 1 (strongly disagree) to 7 (strongly agree).

A final overall assessment includes the rating of the overall quality of the CPG (OA1) and whether the CPG would be recommended for use in practice (OA2).

To begin the Appraisal Process, it is recommended that at least two, and preferably four, appraisers review each clinical guideline to increase the reliability of the assessment. The standardized domain score would be 0% if each appraiser scored 1 for all the items included in this domain (https://www.agreetrust.org/resource-centre/agree-ii). 35 Reaching consensus method to score the items was applied. After reviewing 23 items and the comprehensive judgement of the reviewers, the evaluation of the CPGs was divided into three categories according to the AGREE II score, (recommended, recommended after revision, and not recommended).

Statistical analysis was carried out as descriptive statistic. We calculated frequencies and raw proportions to summarize the main recommendations in managing perinatal care of pregnant women with SARS-CoV-2 infection and their timing for delivery. In addition, we analyzed the guidelines evaluating other issues addressed, such as admission to hospital, vaccination policy etc, and calculated proportions and percentages for each issue.

Moreover, we calculated the quality of CPGs using AGREE II domain scores. Mean ± standard deviation (SD) was used to summarize the scores across all the guidelines per domain. The AGREE II tool does not provide any advice on how to define scores. To define a CPG as of good quality we adopted the cut-off score according to Amer et al. 37 : if the overall guideline score was >60%, CPGs was recommended; if the overall guideline score was 40% to 60%, CPGs was recommended after modification; and if the guideline score was <40%, it was not recommended. The analysis was performed using Excel 16.57 (© 2021 Microsoft Corporation. All rights reserved.) statistical software.

The following outcomes related to the management of pregnant women with SARS-CoV-2 infection were addressed:

Criteria for maternal hospitalization, Recommendations for follow-up growth scan, Specific recommendations against invasive procedures, Use of supportive therapy (antenatal or maternal care), Management of labor, Indication for Cesarean Section (CS), Postpartum care, Indication for vaccine booster.

A total of 20798 articles were identified and screened, 38 were assessed with respect to their eligibility for inclusion and 28 CPGs 5-32 were included in the qualitative analyses, while 19 were included in quantitative analysis (Table 1-2, Figure 1 ). Main recommendations were extracted and reported as syntheses in Table 3 . General characteristics of other studies included in qualitative analyses, also CPGs excluded and the main reasons are summarized in Supplementary Tables (Table S2 -S3). The CPGs included in this systematic review (SR) consisted of Expert opinion, Review of literature, expert panel consensus and were representative of different countries (16 are national, 10 are international, 2 are local). Sixty-point sevenpercent (17/28) were published in 2021, and 7.1% (2/28) had more than 5 revisions.

All the CPGs included in the SR did not recommend maternal hospitalization only for SARS-CoV-2 infection and there was general agreement that admission to hospital should be restricted to those women with severe infection. Fifty-percent of the included guidelines specifically stated the criteria for maternal admission, including respiratory distress, respiratory rate (RR) > 22/min, O2 saturation < 95% or rapid deterioration in respiratory status.

Forty-six-point one-percent (6/13) of CPGs suggested a fetal growth scan after SARS-COV-2 infection generally two weeks after the infection, 23%

(3/13) did not support this practice while the remaining 46.1% (6/13) did not address this point. Thirty-eight-point four-percent (5/13) of the CPGs included in the present review suggests monthly maternal assessment after the infection. The large majority of CPGs (80%, 4/5) did not report any contraindication in case the patient should undergo invasive procedures, while one suggested delaying chorionic villus sampling and opting for amniocentesis.

Thromboprophylaxis with low molecular weight heparin (LMWH) was recommended in symptomatic women in 77.7% (7/9) of CPGs. None of the CPGs recommended to administer corticosteroid only for the presence of SARS-CoV-2 infection in preterm gestation, unless specific obstetric indication co-exists, since that corticosteroid therapy is specifically for fetal lung maturity. Management of labor in women with SARS-CoV-2 infection was addressed by 11 CPGs. Elective induction of labor at 39 weeks of gestation was recommended by 18.1% (2/11) of the CPGs, while 45.4% (5/11) did not recommend election induction unless other obstetric indications co-exist with maternal infection. Oxygen support was suggested by 75% of CPGs (9/12), and continuous fetal electronic monitoring by 58.3 % (7/12). Twenty-seven-point two-percent (3/11) of the CPGs recommended shortening of the second stage of labor, mainly with iatrogenic rupture of the membranes or oxytocin infusion, and active pushing was supported by 18.1% (2/11) of them. A general agreement was recorded among the CPGs in not recommending cesarean section only for the presence of maternal infection, although 77.7% (7/9) of the guidelines suggested to considered it in case of severe maternal SARS-CoV-2 infection with worsening of maternal conditions. The need for postpartum thromboprophylaxis with LMWH was mentioned only in one of all CPGs included, as well as the needing to send placenta to histopathology for examination. Finally, a general agreement was found in recommending vaccine series at least 6 months after the primary vaccine (Table 4 ) and 88.9% (8/9) of the included CPG did not report any specific restriction as regard as the gestational age at vaccination.

The AGREE II domains are summarized in Table 2 . The average AGREE II standardized score for each domain is reported below (mean ± SD).

High quality of CPGs reached cut-off > 60% and it was represented in green ( Table 2) . A medium quality (with 40%-59% cut-off) was reported in yellow and a low grade of CPGs was showed in red.

Only one CPG 11 reported the use of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

The AGREE II standardized domain scores for the first overall assessment (OA1) had a mean of Fifty-percent (SD±21.0%). Nine CPGs scored more than 60% 10,11,13,15,25,27-30 and revealed a consensus agreement between the reviewers on recommending the use of these CPGs.

The findings of this systematic review of CPGs showed that a significant heterogeneity and disagreement were assessed in several aspects of clinical management of SARS-COV-2 infection in pregnancy as reported by the published CPGs. There was a general agreement in the criteria for maternal hospitalization, mode of delivery, and recommendation for vaccine booster. Conversely, a large heterogeneity was addressed in several other management aspects, including type and frequency of maternal assessment after the infection, ultrasound scans, timing of delivery and type of fetal monitoring during labor.

This is, to the best of our knowledge, the first systematic review of CPGs on SARS-CoV-2 infection in pregnancy using a recognized tool for judging medical guidelines (AGREE-II tool). Other strengths included the thorough literature search and assessment of the multitude of management aspects of pregnant women with SARS-CoV-2 infection. The main weakness of the present review relies on the methodological quality of some of included CPGs as highlighted by the low-grade score in the AGREE-II tool.

Of note, the methods for development of the guidelines were not reported for the majority of included CPGs, making assessment of Domain 3 with AGREE-II challenging, thus limiting an objective evaluation of the included CPGs. It has been suggested that that Domains 3 and 5 (applicability), in addition to domain 6 (editorial independence) may have the strongest influence on the results of the 2 overall assessments a given CPGs. These guidelines were developed as an acute response in a period of crisis, thus partially explaining the lack of detailed methodological description for some of the included guidelines. However, a positive sign of improvement in the CPG development methodology was the application of GRADE in some of the more recent CPGs, which underlines the improvement in their quality and trustworthiness.

The rapid spread of the pandemic has made the availability of objective evidence-based guidelines on the management of SARS-CoV-2 infection in pregnancy critical. Pregnancy represents an independent risk factor for severe SARS-CoV-2 infection and infected women are at higher risk of adverse maternal outcome, including mechanical ventilation, admission to intensive care unit and even death compared to non-pregnant infected women. [38] [39] [40] Several risk factors have been associated with an increased risk of symptomatic infection, including obesity, hypertension, underlying respiratory disorder and Black or Asian race. [41] [42] In view of such association, all pregnant women with SARS-CoV-2 infection should be closely monitored for development of symptoms and signs of severe COVID-19 disease. Importantly, some of the clinical manifestations of COVID-19 overlap with symptoms of normal pregnancy (i.e, fatigue, shortness of breath, nasal congestion, nausea/vomiting), which should be considered during the evaluation of afebrile symptomatic women. Despite that, 75% of women will experience an asymptomatic infection, not requiring hospitalization. 43 In the present review, a general agreement was on the criteria for maternal hospital admission in those with SARS-CoV-2 infection, all the included CPGs recommending hospitalization only for severe disease. Moreover, although pregnant women still show hesitancy towards COVID-19 vaccine [44] [45] [46] , CPGs already declared the safety and efficacy of available mRNA vaccines against SARS-CoV-2 infection, and the usefulness of the booster dose also in reducing the rate of complications during pregnancy (Table 3- 4) . The association between COVID-19 variants and maternal or perinatal outcomes represent another peculiar issue as the risk of adverse outcome may vary according to the virus variants, thus affecting the recommendation provided by CPGs. Most of the reported data on the association between SARS-CoV-2 infection and maternal outcomes come from the early stages on the pandemic when wildtype SARS-CoV-2 predominated. A recent study carried out through the UK Obstetric Surveillance System, including over 4000 pregnant women reported that alpha and delta variants have been associated with more severe disease in pregnancy than the wildtype 47 . After adjustment for potential confounding factors, both alpha and delta were independently associated with admission to intensive. Conversely, the no difference was found in the risk of perinatal outcomes, mainly evidence stillbirth, between wildtype and alpha or delta variants. The influence of Omicron variant in affecting maternal and perinatal outcomes is more difficult to assess as most studies women. 49 A recent meta-analysis of observational studies reported 62% higher odds of developing preeclampsia among infected patients.

Furthermore, preeclampsia with severe features, eclampsia, HELLP syndrome and preterm birth are also reported to be increased in pregnant women with SARS-CoV-2 infection, while the association with preterm birth is less established. Likewise, the risk of stillbirth evidence is now emerging and is also increased in pregnant women with SARS-CoV-2 infection. A recent report from the United States including 1.2 milion births reported that the risk of stillbirth was 1.26% in infected women with compared to 0.64% in those without infection. The risk of stillbirth increased when other co-morbidities including chronic hypertension, multiple gestation, cardiac disease, placental abruption, acute respiratory distress syndrome or mechanical ventilation co-exist and was mainly due to the Delta variant of the virus. 50 In the present review, there was no general agreement on the need for increased maternal and fetal surveillance after the infection, with nearly half of the CPGs suggesting an increased fetal surveillance starting from 15 days following maternal infection. (Table 3- It is collective authors' opinion that, despite the coverage offered by the COVID-19 vaccines, women with SARS-CoV-2 infection should be strictly followed up to detect early signs of severe infection. Risk stratification is crucial when assessing these mothers as some peculiar medical conditions, manly pre-eclampsia and diabetes, represent additional independent risk factors for the development of severe infection. In this scenario, women with such additional risk factors should undergo a closer follow-up. A growth scan within a month from the infection is advisable in view of the association between SARS-CoV-2 infection and placental related disorders, mainly fetal growth restriction. Last, timing at IOL should be carefully evaluated. Although, it is not clinical practice from all the authors' institution to offer elective IOL at 39 weeks in women with a current or prior SARS-CoV-2 infection, a closer follow-up to these women is commonly considered in view of the association between infection and placental related disorders, in order to identify those pregnancies at higher risk of adverse perinatal outcome, who may benefit from elective IOL.

A significant heterogeneity was found in some of the main aspects of the clinical management of SARS-CoV-2 infection in pregnancy as suggested by the published CPGs, especially regarding follow-up after the infection and timing of delivery. The findings from this systematic review highlight the need for developing shared guidelines supported, endorsed and promoted by national and international professional societies in order to make management of SARS-CoV-2 infection in pregnant women more homogenous among the different countries. Table 1 . General characteristics of the CPGs included in the quantitative analyses of systematic review.

Year 

Vaccine booster X X X X X Table S1 . PRISMA 2009 Check-list. Table S2 . General characteristics of other CPGs included in qualitative analyses. 

of Obstetricians and Gynaecologists of Canada (SOGC)

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG); International Federation of Gynacology and Obstetrics (FIGO)

Quebec Maternal-Fetal Medicine group (QMFMG); Government of India (GOI); National Institute for Research in Reproductive Health

North American Fetal Therapy Network (NAFTN); International Society of Infectious Diseases in Obstetrics and Gynecology (ISIDOG)

Italian Society of Gynaecology and Obstetrics/ Association of Italian Hospital Gynaecologists and Obstetricians (SIGO/AOGOI)

Yes (Y); Yes with modifications (YWM)

Cesarean section (CS); low molecular weight heparin (LMWH)

Canadian Association of Perinatal and Women's Health Nurses (CAPWH); Federation of Obstetric and Gynaecological Societies of India (FOGSI)

The Society of Obstetricians and Gynaecologists of Canada (SOGC)

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG)

Quebec Maternal-Fetal Medicine group (QMFMG); Government of India (GOI); National Institute for Research in Reproductive Health

North American Fetal Therapy Network (NAFTN)

Italian Society of Gynaecology and Obstetrics/ Association of Italian Hospital Gynaecologists and Obstetricians (SIGO/AOGOI)

COVID-19: Virology, biology and novel laboratory diagnosis

Working Group on COVID-19. Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection

Counseling in maternal-fetal medicine: SARS-CoV-2 infection in pregnancy

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19

Perinatal-Neonatal Management of COVID-19 Infection -Guidelines of the Federation of Obstetric and Gynaecological Societies of India (FOGSI), National Neonatology Forum of India (NNF), and Indian Academy of Pediatrics (IAP). Indian Pediatr

Fetal interventions in the setting of the coronavirus disease 2019 pandemic: statement from the North American Fetal Therapy Network

EBCOG position statement on COVID-19 vaccination for pregnant and breastfeeding women

ISIDOG Consensus Guidelines on COVID-19 Vaccination for Women before, during and after Pregnancy

ISUOG Interim Guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium: information for healthcare professionals -an update

ISUOG Consensus Statement on rationalization of early-pregnancy care and provision of ultrasonography in context of SARS-CoV-2

Development of rapid guidelines: 1. Systematic survey of current practices and methods

A Guide to Writing a Qualitative Systematic Review Protocol to Enhance Evidence-Based Practice in Nursing and Health Care

Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

International alliance and AGREE-ment of 71 clinical practice guidelines on the management of critical care patients with COVID-19: a living systematic review

Proposal for radiologic diagnosis and follow-up of COVID-19 in pregnant women

Perinatal mortality and morbidity of SARS-COV-2 infection during pregnancy in European countries: Findings from an international study

An update on COVID-19 and pregnancy

Differential occupational risk for COVID-19 and other infection exposure according to race and ethnicity

Risk factors for severe and critically ill COVID-19 patients: A review

Differences in pregnancy and perinatal outcomes among symptomatic versus asymptomatic COVID-19-infected pregnant women: a systematic review and meta-analysis

Pregnant women perspectives on SARS-COV-2 vaccine: Condensation: Most of Italian pregnant women would not agree to get the SARS-COV-2 vaccine, irrespective of having features of high risk themselves, or being high-risk pregnancies

Women perception of SARS-CoV-2 vaccination during pregnancy and subsequent maternal anxiety: a prospective observational study

Worldwide beliefs among pregnant women on SARS-CoV-2 vaccine: a systematic review

Severity of maternal infection and perinatal outcomes during periods of SARS-CoV-2 wildtype, alpha, and delta variant dominance in the UK: prospective cohort study

Clinical severity of SARS-CoV-2 infection among vaccinated and unvaccinated pregnancies during the Omicron wave

Placental histopathology after SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis

Risk for Stillbirth Among Women with and Without COVID-19 at Delivery Hospitalization -United States

Labor Induction versus Expectant Management in Low-Risk Nulliparous Women

Labor and delivery guidance for COVID-19