Participants

The population of interest is healthy term infants (under 12 months of age) with colic, regurgitation and/or functional constipation.

Studies that include infants who meet the Rome III criteria for the clinical diagnosis of infantile colic, regurgitation and/or constipation will be eligible for inclusion. Ideally, the cost of each of these conditions should be explored separately, but it is anticipated that this may not be possible due to the overlap in these conditions. FGID-related signs and symptoms that do not fulfil the Rome criteria will also generate direct and indirect costs (figure 1). Therefore, studies which include infants with symptoms, including hard stools or straining, vomiting, problematic feeding (eg, spitting) or inconsolable or persistent crying, will be eligible for inclusion, provided that these symptoms are linked to at least a suspicion of FGID in all cases (figure 2). Studies with these symptoms where no statement on the suspected underlying cause is made or where the symptoms could be the result of a non-FGID cause will not be eligible for inclusion (figure 1).

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Figure 1

Defining the population of interest. Infants who present in daily paediatric practice or receive treatment for functional gastrointestinal symptoms may not always fulfil the stringent criteria for a functional gastrointestinal disorder (FGID) as defined by the Rome criteria (dark centre). However, these FGID-related symptoms do still cause direct and indirect costs and need to be considered (light circles).

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Figure 2

Search strategy for Ovid MEDLINE^® in-process and other non-indexed citations and Ovid MEDLINE^® <1946 to present>.

Studies involving exclusively preterm infants or where the majority of the infants are preterm will not be eligible.

In all cases, the definition used by authors for FGIDs and related signs and symptoms will be recorded.

Studies of participants from any country are eligible.

Interventions

Studies reporting on the costs of any intervention or no intervention are eligible for inclusion.

Comparators

A study with any or no comparator will be eligible for inclusion in this SR.

Outcomes

The outcomes of interest are:

• Reported treatments of FGIDs and related signs and symptoms (regardless of their effectiveness), or the specific symptom combinations described in the Population description above, and the frequency and volume of use.

• Costs to third-party payers and/or parents of infants with FGIDs and related signs and symptoms of:

  • prescribed treatments;

  • over the counter or home remedies;

  • visits to orthodox and complementary health professionals and other providers of care;

  • change in infant formula purchases.

• Loss of income for parents/carers from infants with FGIDs and related signs and symptoms, or the specific symptom combinations described in the Population section above, through:

  • inability to return to work;

  • time taken off work;

  • out of pocket costs.

Study types

Studies of the following designs will be eligible for inclusion in the review:

• randomised controlled trials (RCTs);

• non-RCTs;

• COI studies;

• economic evaluations;

• observational studies.

Previously published SRs will not be eligible for inclusion, but their reference lists will be checked to identify any additional relevant studies.

Studies published as abstracts or conference presentations will not be included in the review but will be listed for information and used as clues to full publications.

Any study of a design not listed above will not be eligible for inclusion in the SR. This includes, but is not limited to, case studies and non-SRs. Opinion pieces, letters and editorials will not be eligible for inclusion.

Limits

The searches are limited to English language studies published since 2005 to focus on the most current costs and most recent practice in terms of care of FGIDs and related signs and symptoms.

Identifying relevant studies

The search strategy to identify studies for this review is shown in figure 2. The search excludes publication types that are unlikely to contain research results. Records of publications published prior to 2005 are excluded and only studies in English will be retrieved.

The searches will be conducted in the following databases:

• MEDLINE and MEDLINE in process (via OvidSP);

• PubMed;

• EMBASE (via OvidSP);

• PsycINFO (via OvidSP);

• NEXIS (media database useful for commercial/market reports on over the counter sales of interventions such as gripe water);

• Database of Abstracts of Reviews of Effects (DARE) in the Cochrane Library;

• Health Technology Assessment Database (HTA Database) in the Cochrane Library;

• NHS Economic Evaluation Database (NHS EED) in the Cochrane Library;

• CEA Registry (via https://research.tufts-nemc.org/cear4/);

• Evidence Search (https://www.evidence.nhs.uk/);

• OAISTER (http://www.oclc.org/oaister.en.html);

• RePEc (http://repec.org/).

The search strategy (figure 2) will be adapted suitably to perform efficiently in these databases.

The following conferences will be searched via Embase or via conference websites for the past 3 years, to identify recently completed research and to provide contact details, so that the authors can be contacted for full text:

• ISPOR;

• European Society for Paediatric Gastroenterology, Hepatology and Nutrition;

• North American Society for Pediatric Gastroenterology, Hepatology and Nutrition;

• American Academy of Pediatrics National Conference;

• World Congress of Pediatric Gastroenterology, Hepatology and Nutrition.

The reference lists of any included studies and SRs will be checked to identify any studies that may have been missed by the database searches.

Details of all search strategies and search results will be provided in the SR report. The search and record selection process will be presented in a PRISMA flow diagram (http://www.prisma-statement.org/statement.htm).

Incidence/prevalence data would be required to perform a de novo calculation: these values will be sought from the published literature using a pragmatic focused epidemiology search in MEDLINE (figure 3). This strategy will be combined with specific country terms depending on the exemplar country.

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Figure 3

Pragmatic focused epidemiology search in MEDLINE.

Study selection

The results of the searches will be loaded into an EndNote library and deduplicated. Following the removal of obviously irrelevant records by a single experienced information specialist, studies will be added to Covidence software.(The Alfred Hospital, Monash University, National ICT Australia, et al. Covidence. Secondary Covidence [reviewing software]. https://www.covidence.org.)

Study selection will be undertaken by two reviewers independently, based first on information in the titles and abstracts (when available). Disagreements will be resolved by discussion or involvement of a third reviewer. Studies that are not excluded based on title and abstract screening will be retrieved as full-text documents. Records excluded based on an assessment of the full text will be recorded in an excluded studies table with a reason for exclusion.

Data extraction

Double independent reviewer data extraction will be undertaken into an Excel spreadsheet. Any disagreement between the two reviewers will be resolved by discussion and, if necessary, by a third reviewer.

The following data will be extracted from all eligible included publications:

• bibliographic data;

• publication type;

• country;

• patient population (number, age, gender, ethnicity);

• definition of FGID and, if applicable, the definition of the symptoms related to FGID.

Topic specific information will also be extracted (table 2).

Quality assessment

Double independent reviewer quality assessment will be undertaken. Any disagreement between the two reviewers will be resolved by discussion and, if necessary, a third reviewer will be involved to adjudicate. The quality of COI studies will be assessed using the following questions:

• Was the type of COI method clearly described?

• Was the quality of the data used described?

• Were the data sources and dates reported clearly?

• Were data gaps described?

• Were data extrapolations reasonable?

• Were reasonable methods employed to avoid double counting?

• Were the calculations of cost clearly described?

• Were the methods used to handle uncertainty appropriate?

• Have the researchers offered assessments of the limitations of the study approach?

The quality of other studies will be assessed using instruments listed in table 3.

Data synthesis

Studies identified for the SR and the extracted data will be summarised in tables.

Results will be presented by geographical region and/or country and by specific FGID conditions. A distinction will be made in the tables to highlight interventions that are reported in the literature to be common or accepted practice and those that have been trialled.

An overview of treatments in use and costs incurred will be provided, with any geographical or other differences highlighted. An assessment of how the totals for cost differ across countries and the elements that contribute to the differences—such as the difference in costs for treatments or the different ways healthcare is provided between countries—will be undertaken as far as the detail in the identified literature allows. If applicable, gaps and limitations of this approach will be highlighted and discussed in detail.

If data permit, one exemplar of what the COI would be in total across all cost areas considered for a developed country will be produced (de novo calculation) using data from the review where possible. Following data synthesis, a recommendation will be made regarding which country should be chosen, based on the completeness of evidence from the literature for making a COI calculation, and the accessibility of unpublished data to fill any gaps.

All costs identified will be adjusted for inflation and converted to 2015 US$.