This protocol was previously registered in PROSPERO International Prospective Register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42019124342.
This systematic review protocol will be conducted and reported in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis protocols (PRISMA-P) 2015 statement (12) (13). An additional file shows this in more detail (see Additional file 1).
Eligibility criteria are defined as followed owing to the PICOS definitions (Population – Interventions – Comparators – Outcomes – Studies):
Type of populations
We will include three categories of patients: (i) pregnant women infected by CMV (maternal infection); (ii) fetuses infected by CMV (fetal infection); (iii) neonates and young children under 6 years old congenitally infected with CMV. We will exclude studies conducted in patients with immunosuppression factors (e.g. autoimmune disease, immunosuppressive treatment, HIV infection) or in general population (non-pregnant women and adult men). We will also exclude studies focusing only on maternal CMV infection in pregnant women without mentioning fetal or child outcome.
Type of interventions
We will include studies relating to biological, clinical, radiological, therapeutic interventions to diagnose, predict and treat congenital CMV infection in the three populations of interest described above.
We will not include interventions and measures to prevent maternal CMV infections (such as hygiene-based behavioral interventions or hypothetical vaccine), interventions to improve knowledge of CMV infection pathophysiology and interventions that are no longer available in current practice, particularly concerning biologic assays.
Presence of a comparator group is not relevant for this systematic review. Therefore, this review will be excluded studies comparing congenital CMV infection with other congenital infections or other pathologies.
Type of outcome measures
Outcomes that will allow characterize the following items related to congenital CMV infection should be available:
- Pregnancy outcome and termination of pregnancy;
- Mortality and morbidity;
- Economic costs and quality of life;
- Guidelines and current practice of management;
- Treatments efficacy;
- Prenatal and at birth clinical signs;
- Prognosis of congenital CMV infection;
- Adverse effects of different interventions;
- Adverse effects of treatments (short, medium and long term);
- Acceptability of congenital CMV infection management.
Type of studies
We will include all study designs (randomized controlled trials, controlled trials, observational studies, prospective and retrospective cohort studies, guidelines…), except review articles, letters, case reports and case series of less than or equal to 10 patients, with no restriction on the study duration, study period or date of publication.
We will perform electronically searches on the following databases: MEDLINE, EMBASE, the Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science until September 6th, 2019. Relevant medical subject heading (MeSH) terms and key words relating to “Cytomegalovirus infection”, “congenital” will be used as restricting criteria. Grey literature with non-published studies (thesis, congress abstracts) will also be analyzed. Studies will be restricted to English and French languages. In Figure 1, we present our search strategy developed for MEDLINE, then translated for other databases. All references will be registered in Zotero (Version 5.0.60) and duplicates will be removed.
In a first step, two teams of reviewers (CPD and CVF / CPD and OP) will independently screen titles and abstracts to identify relevant studies meeting the pre-specified PICOS inclusion criteria. In a second step, the same reviewers will examine the full text of the selected studies according to the inclusion and exclusion criteria. We will solve discrepancies after discussion with the three reviewers. A flowchart diagram will be generated to document the study selection process (14) and the inter-observer agreement between reviewers will be calculated using kappa coefficient (15). A kappa coefficient higher than 0.6 will indicate an acceptable agreement between reviewers.
Data extraction will include information on the population, interventions, outcomes and study designs. Data will be extracted by CPD using a structured Excel sheet and another reviewer (CVF or OP) will quality check. This will be conducted on twenty percent of articles and discrepancies will be solved through discussion with a third team member when necessary.
Data will be extracted for the following:
- Study characteristics: design of study, sample size
- Participants: age, demographic characteristics
- Interventions: method of diagnosis of CMV, imaging, amniocentesis, neonatal screening, therapeutic, follow up
- frequency of interventions
- circumstances of diagnosis (clinical sign, systematic screening, …)
- pregnancy outcome
- sensitivity/specificity of diagnosis tools
- clinical symptoms, prognosis
- quality of life
- side effects
- adherence of pregnant women to interventions
If necessary, in case of missing data, we will contact the authors for complementary information.
Assessment of risk of bias in included studies
The risk of bias will be assessed by the ROBINS-I tool: "Risk Of Bias In Non-randomized Studies – of Interventions assessment tool" (16). We will analyze seven domains of bias:
- Selection of participants into the study;
- Classification of interventions;
- Deviations from intended interventions;
- Missing data;
- Measurement of outcomes;
- Selection of reported results.
Using this ROBINS-I tool, we will classify each of the seven bias domains according to a risk of bias judgment. Included studies will be classified according to the overall risk of bias: Low / Moderate / Serious / Critical risk of bias.
We will provide a systematic narrative synthesis of the findings from the included studies, structured around the type of intervention, study design, intervention content and outcome of interest. The different interventions will be reported according to the following items: sensitivity analysis, specificity, frequency and evaluation of the outcomes measured regarding management of congenital CMV infection. Subgroups will be established based on the following three circumstances of congenital CMV diagnosis: maternal CMV infection discovered during pregnancy, presence of ultrasound abnormalities and congenital infection diagnosed at birth The impact of including studies assessed as high risk of bias will be considered in a sensitivity analysis.