Economic burden of adverse perinatal outcomes from births to age 5 years in high-income settings: a protocol for a systematic review

Introduction

Adverse perinatal outcomes include both perinatal morbidity (including preterm birth (gestational age less than 37 weeks), small for gestational age (SGA) and congenital anomalies) and mortality (stillbirth and neonatal death).1 Adverse perinatal outcomes result in tremendous negative outcomes for newborns with a significant lifelong health implication, impacting families, societies and the health system more generally, resulting in a major global economic, health and societal burden.2–8

Globally, 13.9 stillbirths per 1000 total births,9 10 18 neonatal deaths per 1000 live births11 and approximately 11% of preterm birth rates have been reported every year,12 with an increasing rate of preterm birth over time.13 The magnitude of adverse perinatal outcomes also varies across socioeconomic groups14 15 and other obstetric factors such as twin pregnancy,16 and it remains a significant public health problem and a challenge for the health system. The magnitude of stillbirth ranges from 2.63 per 1000 total births in western European countries to 23.03 per 1000 total births in the west and central African countries. While neonatal deaths also range from 1.27 per 1000 live births in Finland to 39.63 per 1000 live births in South Sudan,17 preterm births range from approximately 5% in northern Europe to over 15% in Asia and sub-Saharan African countries. While perinatal morbidity and mortality disproportionally occur in low-income and middle-income countries, rates are still significant in high-income countries.

Evidence suggests that perinatal morbidity will have implications for early childhood health and development outcomes and later in life.18–20 For example, in the short term, infants born preterm and SGA are at an increased risk of prolonged hospitalisations and acute respiratory disorders immediately after birth. In the medium and long term, babies born preterm are at an increasing risk of mortality during childhood period,21 feeding challenges,22 adverse early childhood outcomes,23–27 long-term lung function abnormalities28–30 and disabilities.19

Adverse perinatal outcomes not only impose a significant health burden but also have negative impacts on education, psychosocial well-being of families and caregivers, and financial expenditures.19 31 32 It has been reported to place a considerable burden on the national health system due to the high healthcare resources they require.12 33 34 A substantial economic impact of adverse perinatal outcomes on families and societies were reported.35 36 Few studies reported the direct healthcare cost, intangible economic cost and macroeconomic cost associated with adverse perinatal outcomes. For example, a review of the economic burden of preterm birth in Organisation for Economic Co-operation and Development (OECD) countries reported that the initial hospitalisation costs varied between US$576 972 per infant born at 24 weeks’ gestation and US$930 per infant born at term (USD, 2015 prices).37 The average hospital cost for 533 stillbirths in south-eastern Michigan, USA, was US$7495 (±US$7015) which was abstracted from 10-year hospital charts.38 Similarly, a study in Canada showed that the cost of care among late preterm (34+0 to 36+6 weeks)39 40 infants is estimated to be double that of term infants because morbidity among late preterm remains higher than morbidity among term infants,41 which intern increases the cost of care.

Studies have explored the costs of hospitalisations for prenatal morbidity after the first year of life and have indicated an inverse relationship between neonatal and postdischarge costs with birth weight and gestational age.42–44 For example, a 2019 study in Northern California45 and a 2016 study in Germany,46 showed that a 1-week decrease in gestational age is significantly associated with more healthcare utilisation and higher hospitalisation cost for very preterm infants (≤32 weeks) compared with term infants.

Even though adverse perinatal outcomes are lower in high-income countries,17 the healthcare interventions and technologies investing in managing them can be overly embellished. Furthermore, the disparities of perinatal morbidity and mortality across different population groups are significant which leads to a considerable financial burden to vulnerable individual/families. However, this burden has been receiving less attention and overlooked in the healthcare system of high-income countries and comprehensive evidence is scarce. Therefore, our aim is to systematically and comprehensively identify and synthesise evidence that quantifies the economic burden of adverse perinatal outcomes from birth to age 5 years in high-income countries. By estimating the economic burden, policy-makers can better understand the costs of inaction and the potential benefits of investing in preventive measures and early interventions to improve perinatal health and cost savings at later years. As the healthcare landscape is dynamic, with constant changes in regulations, reimbursement models, technology and patient demographics, the use of recent cost data can reflect the current healthcare environment. Given that costs change considerably over time, due to a range of factors including inflation and differences in market conditions, we believed that data earlier than 2010 was increasingly unreliable in estimating current patterns. Thus, we will limit our review to studies from 2010 onwards.

Methods

A systematic review of empirical evidence on the economic burden of adverse perinatal outcomes in high-income settings will be conducted. The findings of this review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.47

Search and search strategy

In this systematic review, the Patient/Population-Intervention/Exposures-Comparison-Outcomes-Type of study-Context approach is used to address the research in question.48 The population will include all births until the age of 5 years. Exposures will be individuals who experienced at least one of the adverse outcomes at births. The comparator will be those births without adverse perinatal outcomes. In this review, the outcomes will include the cost of at least one of the following perinatal outcomes: stillbirth, neonatal death, preterm birth, SGA, low birth weight and congenital anomalies.

Databases—EconLit, MEDLINE(Ovid), CINAHL (EBSCO), Embase (Ovid), Global Health and PubMed will be used to search all peer-reviewed articles. Additionally, Google Scholar and snowballing of the references list of included papers will be considered to search for additional literatures. Our search terms will include broadly three concepts: (1) costs such as cost of illness analysis, economic aspects of health and economic burden, (2) adverse perinatal outcomes such as stillbirths, fetal death, preterm birth, SGA, congenital anomalies and (3) settings such as developed countries, high-income countries, OECD countries, Scandinavian countries, Nordic countries which will be built using a variant of subject headings and keywords according to the searching databases by linking through ‘AND’ and ‘OR’ Boolean operator terms as appropriate49 (table 1).

Table 1

Sample searching strategy for MEDLINE (Ovid)

Inclusion and exclusion criteria

All primary studies published in English in peer-reviewed journals that report on the economic burden of at least one of the adverse perinatal outcomes in high-income countries from 2010 will be included in the review. High-income countries will include those countries with a gross national income per capita of US$13 205 and more based on the World Bank definition of 2023 and will include a total of 81 countries.50 Studies may report costs associated with both perinatal and maternal morbidity and mortality, but we will extract the costs associated with the perinatal outcomes (when possible). Interventional, experimental, and qualitative studies, reports, and systematic reviews will be excluded from the review. Conference papers and editorials will be excluded from the review.

Study selection

All retrieved articles will be first exported to EndNote V.20 to remove duplicates and then export to Rayyan (a systematic review management software package) for screening. In the second stage, two independent reviewers apart from the principal investigator will screen the studies based on the title and abstract. In the third stage, a review of the full text of these relevant records will independently be assessed based on the inclusion and exclusion criteria. The detailed inclusion and exclusion criteria are summarised in table 2. Additional relevant studies from the included articles will be assessed and included (citation snowballing) in the final review. Any disagreement during screening phases will be handled based on consensus and through discussion with one of the senior research team (GAT). Finally, the study selection process will be presented using the PRISMA flow diagram.47

Table 2

Study inclusion and exclusion criteria

Outcome

The main outcome of our review is the economic burden associated with adverse perinatal outcomes, quantified by the costs incurred due to the presence of at least one adverse perinatal outcome. These costs encompass hospitalisation expenses, outpatient health services costs, individual (out-of-pocket) payment, the indirect costs to the family/guardian due to the adverse perinatal outcomes and societal costs. Generally, the costs will include all direct (both medical and non-medical), indirect, and societal costs, measurable from the perspectives of individual/families, the healthcare system and society at large.

Data extraction and analysis

A consistent Excel spreadsheet will be developed to extract data from the included studies. The abstracted data will include: (1) study characteristics such as first author, year of publication, country/setting, year of study (data collection) and publication, WHO region (WHO geographical region), type of study, study design (cohort, case–control and cross sectional); (2) study population (neonate, infant, children under 5 years), (3) participants characteristics (sample size, mean/median age, birth weight and gestational age at birth), (4) clinical characteristics such as maternal comorbidity, type of adverse perinatal outcome(s), (5) outcomes of the study such as cost measure (health system, societal, individual/household), total cost, disaggregation cost (medical, non-medical, indirect and societal), (6) other characteristics such as measurements of association (if any), associated variables with β coefficient or adjusted risk ratio with their CI; (7) cost in common currency (USD). Cost will be adjusted for inflation using the Consumer Pricing Index for each specific country for the current value using the original currency. To allow comparison, all cost values will be converted and reported into US dollar using a purchasing power party.

Once we convert the cost into a common currency, we will pool the overall costs of adverse perinatal outcomes. We will also present a narrative and tabular summary of the cost for each cost category and outcome will be presented separately (box 1). Furthermore, subgroup analysis based on the type of adverse perinatal outcomes over the different cost category will be conducted for a better description of the burden.

Box 1

Data abstraction sheet to describe the study in the final review.

Data elements

Author(s), year

Year of study

Country

Study design (prospective cohort, retrospective cohort, case–control and cross-sectional)

Study population/participant (perinatal, neonate, infant, children under 5 years)

Study population/participants’ details (mean/median age, proportion by gender at birth)

Sample size

Outcome

Methods of analysis

Cost perspective (health system, societal, individual/household)

Key findings (cost in local currency)

Cost category (medical, non-medical, indirect and societal)

Exchange rate to USD (using purchasing power parity)

Final total cost in USD

Risk of bias and quality of evidence assessment

The critical appraisal checklist for Consolidated Health Economics Evaluation Reporting Standards 202251 and cost of illness studies adapted from other studies will be used to assess the quality of each study.52–55 Accordingly, we will use a total of 17 criteria adopted from a critical appraisal of cost-of-illness (COI) studies to apprise the quality of each study.55 These appraisal criteria can improve the comprehensiveness, transparency and consistency of COI studies, to address heterogeneity, and to enable better comparability of methodological approaches across international studies. Finally, we will report the overall score of each study out of 17 points. All eligible studies will be included in the final analysis irrespective of their appraisal score. Subsequently, we will explain the different quality scores in our discussion and a great care will be taken in the recommendation as the strength of recommendations depends on the level of quality of evidence.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Ethics and dissemination

This systematic review will not involve human participants and requires no ethical approval. The review will be published in a peer-reviewed journal. The findings will be presented at national and international scientific conferences and will be used by other relevant organisations and stakeholders for decision-making.

Study period and amendments of review

Our review will be conducted until the end of February 2024. Important protocol amendments will be documented in the systematic review’s PROSPERO record (registration number CRD42023400215) and the updated part of the protocol will be published together with the full systematic review.

Discussion

This will be the first systematic review to comprehensively identify the recent economic burden of all adverse perinatal outcomes and evaluate the quality of evidence generated from each included study using the quality assessment checklist for COI studies.

The variation in costs can depend on factors such as the type of medical condition, healthcare facility, severity of illness and length of stay. Thus, we will identify the drivers of cost of adverse perinatal outcomes, and we firmly believe this will be transferable to other settings. Finally, we anticipate the possible limitation of language bias, as we will include only studies published in the English language.

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