Women's health from a global economic perspective Zakiyah, Neily
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WOMEN’S HEALTH FROM A GLOBAL ECONOMIC PERSPECTIVE
Neily Zakiyah
ISBN (printed version): 978-94-034-0648-0 ISBN (electronic version): 978-94-034-0647-3
Author : Neily Zakiyah Cover Design : Zahratu Shabrina Lay-out : Neily Zakiyah Printed by : Off Page
The research presented in this thesis was supported by Graduate School of Science (GSS), the Research Institute for Health Research (SHARE), University of Groningen and i+ Solutions, The Netherlands. Printing of this thesis was financially supported by the Research Institute for Health Research (SHARE).
Copyright © Neily Zakiyah, 2018
All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage or retrieval system, without written permission of the author. The copyright of previously published chapters of this thesis remains with the publisher or journal.
WOMEN’S HEALTH FROM A GLOBAL ECONOMIC PERSPECTIVE
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. E. Sterken
and in accordance with the decision by the College of Deans.
This thesis will be defended in public on Monday 25 June 2018 at 09.00 hours
by
Neily Zakiyah
born on 13 October 1986 in Cirebon, Indonesia
Prof. M.J. Postma
Co-supervisor Dr. A.D.I. van Asselt
Assessment Committee Prof. T.I.F.H. Cremers Prof. S. Evers
Prof. L. Garrison
Chapter 1 General introduction 7
Section I: Reproductive Health
Chapter 2 Economic evaluation of family planning
interventions in low and middle income countries; a systematic review
21
Chapter 3
Cost-effectiveness of scaling up modern family planning interventions in low- and middle- income countries: an economic modeling analysis in Indonesia and Uganda
45
Section II: Maternal Health
Chapter 4
Antidepressant use during pregnancy and the risk of developing gestational hypertension: a retrospective cohort study
77 Chapter 5 Pre-eclampsia diagnosis and treatment options:
a review of published economic assessments 99 Chapter 6 Early cost-effectiveness analysis of screening for
pre-eclampsia 123
Chapter 7 General discussion 157
Summary 175
Samenvatting 177
Acknowledgements 181
List of publications 185
CHAPTER 1
General introduction
The concern for maternal and reproductive health is a major part of the reproductive, maternal, newborn, and child health (RMNCH) agenda that has been a global health priority worldwide. Maternal and reproductive health -often also referred to as women’s health- encompasses women’s reproductive years, from adolescence until pregnancy and childbirth. An essential framework in order to improve reproductive and maternal health is the continuum of care approach, which recognizes the need for health services across women’s reproductive life span, including integrated and comprehensive preventive and therapeutic health interventions1.
Women’s reproductive health
Reproductive health is fundamental to the health and wellbeing of individuals, families and communities. Poor reproductive health outcomes for women can affect not only individuals, but also their children, partner and society1. Global population trends show that rapid population growth is problematic to wellbeing in the low and middle income countries (L-MICs), while low fertility is alarming for the future of many high-income countries (HICs)2. Most low-income countries, especially in sub-Saharan Africa, are portrayed by rapid growth of more than 2% per year, while large countries such as India, Indonesia, north Africa and western Latin America are characterized by moderate annual growth of 1-2%2. The implementation of family planning programs as one of the main public health policy options should be considered by countries with rapid population growth as an effort to improve the wellbeing of families and communities in general, and of women in particular1,2.
According to The Millennium Development Goals (MDGs) report in 2015, approximately 12% of women of reproductive age worldwide wanted to delay or avoid childbearing but were not using any method of contraception or had an unmet need for family planning3. This unmet need is most dominantly present in L-MICs where an estimated of 74 million unintended pregnancies occurred in 20124. As the most substantial reductions in the number of unintended pregnancies especially for those that are in increased risk to maternal and perinatal survival can be obtained by increased contraceptive use, the availability of effective interventions to reduce the unmet need especially in this group of countries is imperative5.
Organized family planning was first introduced in the 1950s in L-MICs as a strategy to slow down the rapid population growth. Along the years, it has emerged as an important public health approach to improve both maternal and child health6. However, despite an increase in contraceptive use over the past decades, the World Health Organization (WHO) estimated that approximately 225 million women in L-MICs were still experiencing an unmet need for family planning to either delay or limit childbearing7.
Provision of effective contraceptive methods in a family planning program is essential to improve reproductive health outcomes. It has also proven to be associated with improved overall health and economic outcomes5,8,9. In recent years, MDGs and SDGs (Sustainable Development Goals) have considered family planning as one of the prominent drivers of progress towards their targets in ensuring universal access to sexual and reproductive health3,10.
Within the reproductive health section, we focused on the interventions to improve reproductive health in L-MICs as the current situation in these countries indicates that implementation of family planning programs to reduce the unmet need for contraception should be a priority as one of their main global health policy options.
Maternal health
Maternal health is vital for sustainable development, as approximately 210 million women become pregnant worldwide, annually11. The success of management and intervention with regards to maternal health is usually expressed as the rate of maternal morbidity and mortality. Although maternal mortality has decreased by roughly 43% in last 15 years, the goal of reducing maternal mortality by 75% by 2015 as stated in MDGs point 5, was not met in many countries3,8. Due to increased number of women who survive childbirth, a shifting trend is observed from avoidable deaths towards a progressively diverse range of maternal morbidities12. This includes the contribution of non-communicable diseases, such as an increasing incidence of hypertension, heart disease, diabetes mellitus, and other chronic conditions, as well as those related to mental health11, reflecting great transitions in demographic, epidemiological, socioeconomic and environmental aspects11,12.
Within this thesis’ maternal health section, we highlighted one of the maternal morbidities which is also one of the leading causes of maternal mortality, i.e., gestational hypertension and pre-eclampsia.
Gestational hypertension and preeclampsia
Gestational hypertension is one of non-communicable diseases that can be prevented to a certain extent and also managed. The cause of gestational hypertension is still unclear, however some predisposing factors such as genetics, environment and other conditions for instance diabetes mellitus, kidney disease, anxiety and depression may be associated with an increased risk of developing this condition13,14.
One of the most prevalent types of gestational hypertension is pre-eclampsia.
Pre-eclampsia affects approximately 3-5% of pregnancies and typically involves the presentation of high blood pressure (systolic higher than 140
mm Hg or diastolic higher than 90 mm Hg) after 20 weeks of gestation combined with proteinuria. Recent diagnostic criteria suggested by the International Society for the Study of Hypertension in Pregnancy (ISSHP) further defined that pre-eclampsia could also be characterized by newly diagnosed hypertension in combination with other maternal organ dysfunction e.g. renal insufficiency, uteroplacental dysfunction, impaired liver function, or neurological and hematological complications, without any proteinuria15,16.
If left untreated, pregnant women with pre-eclampsia face a risk of severe complications such as eclampsia, pulmonary edema, and kidney failure that can be life-threatening for both the mother and her offspring 17. Pre- eclampsia is also associated with fetal growth restriction and a high rate of preterm birth. Therefore, the clinical importance of pre-eclampsia follows from its relation with maternal and neonatal morbidity and mortality15. Prediction, prevention and treatment of pre-eclampsia
Although effective early prediction for pre-eclampsia remains to be introduced into clinical practice, a certain distinction between those in low and high risk is possible. Specific strong risk factors for developing gestational hypertension or pre-eclampsia are associated with the presentation of comorbidities such as chronic kidney disease, hypertension, diabetes (type 1 or type 2), and autoimmune disorders, including systemic lupus erythematosus or antiphospholipid syndrome18,19. A history of pre- eclampsia or gestational hypertension is also considered to be a strong risk factor18. Besides, there are also several moderate risk factors for developing this condition, i.e. first pregnancy, pregnancy interval more than 10 years, body-mass index more than 35 kg/m2, age over 40 years old, family history of pre-eclampsia, and multiple pregnancy18. However, the clinical risk prediction is considered modest as it predicts less than 30% of women who develop pre-eclampsia20.
In the past few years, several maternal biomarkers including serum concentration of maternal placental growth factor, maternal-related plasma proteins, and soluble fms-like tyrosine kinase-1, have been assessed as potential markers to predict pre-eclampsia21–24. However, these tests have not been evaluated thoroughly in intervention studies across populations and were considered as having a too modest predictive value to be introduced in clinical practice. The combination of clinical factors, aforementioned biomarkers and uterine artery Doppler ultrasound at 20 weeks of gestation has a potential to improve the accuracy, although these multivariable prediction models have been suggested to provide modest prediction as well25. Another promising prediction method includes a metabolomics or proteomics approach to predict pre-eclampsia in pregnant women as early as
15 weeks of gestation26. However, before introducing these models to clinical practice, they need to be validated in population studies15.
Several interventions have been suggested to prevent the onset of pre- eclampsia i.e. diet-related approaches such as garlic consumption and advice to reduce salt, physical activity, vitamins, antioxidants, marine/fish oils, nitrates, and various anticoagulant and antiplatelet medications such as heparin and low-dose aspirin. Few of these interventions showed benefit in preliminary studies; yet the only intervention that has been shown to reduce the risk of pre-eclampsia in rigorous randomized trials is low-dose aspirin only27. Several meta-analyses showed the moderate benefit of low-dose aspirin in the prevention of pre-eclampsia, with reported relative risks (RR) around 0.76, 95% CI 0.49-0.97 27,28 for high-risk women and approximately 0.88, 95% CI 0.49-0.97 27 and 0.90, 95% CI 0.84-0.97 29 for women with moderate risk factors. Calcium supplementation is also recommended for pregnant women with low dietary calcium intake as it reduces the risk for developing pre-eclampsia (RR 0.36, 95% CI 0.20-0.65)30. Although WHO states the recommendation on high dose calcium supplementation (1.5-2 g daily) for women with low dietary calcium intake starting from their second trimester, further robust assessment needs to be done in order to strengthen the evidence of the effectiveness of this intervention31.
Clinical management of women diagnosed with pre-eclampsia includes increased monitoring, antihypertensive drugs for severe hypertension, magnesium sulphate for convulsions and eclampsia prevention, and most importantly, induced delivery. Despite substantial efforts concerning research and development on potential novel therapies for pre-eclampsia, delivery of the fetus remains the most important and most effective treatment for pre- eclampsia15,32. Thus, optimal timing of delivery is really crucial and should be based on benefit and risk assessment in both mother and offspring on either continuing or ending the pregnancy15.
Health economic evaluation
Health economic evaluations are increasingly common nowadays in public health and medical care research, as they can provide comprehensive insights for both effective and efficient healthcare for decision makers33. Due to an increasing amount of potential interventions to improve reproductive, maternal and women’s health in contrast to the scarce resources (in terms of people, time, facilities, equipment, and knowledge), it is necessary to have a full assessment on how to efficiently allocate these resources. Such assessments can be implemented within the setting of a randomized controlled trial or other health-related research, or can be undertaken through decision analytic modelling approaches.
Three main types of economic evaluations are cost minimization analysis (CMA), cost-effectiveness analysis (CEA) and cost-utility analysis (CUA). In CMA, the interventions are compared based on their costs and benefits valued in monetary terms. This type of economic evaluation is deemed as the simplest form of economic evaluation study. Due to its simplicity, CMA only applies to interventions that have been proven equal or are expected to be equivalent in their effectiveness. In contrast, CEA and CUA are the types of economic evaluations that value the effectiveness or consequences of interventions in terms of clinical event and/or health outcome measure. In CEA, natural effects or physical unit such as life-years gained are used to measure the effectiveness of health interventions. In reproductive, maternal and women’s health, the outcome measure can be in the form of costs per pregnancy-related case averted (e.g. unintended pregnancy averted, maternal death averted, or pre-eclampsia case averted)33.
Furthermore, CUA is another type of economic evaluations that uses utility weights as outcome measure, commonly expressed in terms of quality adjusted life year (QALY) or disability adjusted life year (DALY). This means that it is possible to assess the quality of life-years gained, not only the number of years gained. Therefore, CUA is often considered as a more comprehensive analysis than CEA33 . In CEA and CUA, an incremental cost- effectiveness ratio (ICER) is used as a summary measure expressing the economic value of an intervention compared to its comparator. The ICER is defined by dividing the difference in cost between interventions by the difference in their effect33.
The range of costs (and effects) included in the economic evaluation study depends upon the perspective taken, which could be that of the healthcare payer perspective (e.g national health insurance, government) or society. The healthcare payer perspective takes into account direct medical costs such as medication cost, cost of healthcare personnel, and hospitalization cost which are type of costs that are directly paid by -for instance- health insurance or government. The societal perspective considers not only direct medical costs, but also indirect costs (e.g productivity losses).
Thesis objectives
As the continuum of care in women’s health is very broad, this thesis covers a small part of this topic. This thesis is arranged into two sections; family planning in the reproductive health section (I) and gestational hypertension and pre-eclampsia in the maternal health section (II), with the following main aims:
1. To perform the economic evaluation of scaling up family planning interventions in L-MICs.
2. To evaluate both the epidemiological and economic impact of screening, diagnosis and treatment of gestational hypertension and pre-eclampsia.
Thesis outline
Section I: Reproductive health
In many L-MICs, the provision of any modern family planning method is relatively low despite the increasing demand for contraceptive use, indicating the unmet need of family planning. Chapter 2 systematically summarizes the existing economic evaluations of strategies to improve family planning interventions in L-MIC, followed by a decision analytic study in Chapter 3 that assesses the long-term cost-effectiveness of scaling up family planning interventions in L-MICs with varying levels of unmet need, with Indonesia and Uganda as reference cases.
Section II: Maternal health
In Chapter 4, one of the predisposing factors that may be associated with the risk of developing gestational hypertension, i.e. depression and exposure to antidepressants, is described. Chapter 5 provides a comprehensive insight into the current evidence on both the clinical and economic impact of screening, diagnosis and treatment options for preeclampsia. In Chapter 6, an early cost-effectiveness analysis using decision analytic modeling was developed to evaluate costs and health effects of a new screening test for pre- eclampsia in four European countries i.e. United Kingdom, the Netherlands, Ireland and Sweden. This analysis is used to guide the implementation of a novel screening technology for pre-eclampsia that is currently being developed. Chapter 7 summarizes and discusses the overall results of this thesis, including main findings, implementations and recommendations for future research.
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2013;381(9878):1642-1652. doi:10.1016/S0140-6736(12)62204-1.
9. Canning D, Schultz TP. The economic consequences of reproductive health and family planning. Lancet. 2012;380(9837):165-171. doi:10.1016/S0140-6736(12)60827-7.
10. UN. Transforming our world: the 2030 Agenda for Sustainable
Development.https://sustainabledevelopment.un.org/post2015/transformingourworl d. Published 2015.
11. Graham W, Woodd S, Byass P, et al. Diversity and divergence: the dynamic burden of poor maternal health. Lancet. 2016;388(10056):2164-2175.
12. McDougall L, Campbell ONR, Graham WI. Maternal health: an executive summary for the Lancet series. Lancet. 2016;388.
13. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet (London, England).
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14. Roberts JM, Lain KY. Recent Insights into the pathogenesis of pre-eclampsia. Placenta.
2002;23(5):359-372. doi:10.1053/plac.2002.0819.
15. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, De Groot CJM, Hofmeyr GJ.
Pre-eclampsia. Lancet. 2016;387(10022):999-1011.
16. Tranquilli AL, Dekker G, Magee L, et al. The classification, diagnosis and
management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens. 2014;4(2):97-104.
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17. Souza JP, Gülmezoglu AM, Vogel J, et al. Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet. 2013;381(9879):1747-1755.
18. National Institute for Clinical Excellence (NICE). Hypertension in pregnancy.
https://www.nice.org.uk/guidance/qs35. Published 2013.
19. Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Chappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ.
2014;348:g2301. doi:10.1136/bmj.g2301 [doi].
20. North RA, McCowan LM, Dekker GA, et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort.
BMJ. 2011;342:d1875. doi:10.1136/bmj.d1875 [doi].
21. Gonen R, Shahar R, Grimpel YI, et al. Placental protein 13 as an early marker for pre- eclampsia: a prospective longitudinal study. BJOG An Int J Obstet Gynaecol.
2008;115(12):1465-1472.
22. Chappell LC, Duckworth S, Seed PT, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study.
Circulation. 2013;128(19):2121-2131. doi:10.1161/CIRCULATIONAHA.113.003215 [doi].
23. Romero R, Kusanovic JP, Than NG, et al. First-trimester maternal serum PP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol. 2008;199(2):122. e1-122. e11.
24. Baumann MU, Bersinger NA, Mohaupt MG, Raio L, Gerber S, Surbek D V. First- trimester serum levels of soluble endoglin and soluble fms-like tyrosine kinase-1 as first-trimester markers for late-onset preeclampsia. Am J Obstet Gynecol.
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25. Kenny LC, Black MA, Poston L, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertens (Dallas, Tex 1979). 2014;64(3):644-652. doi:10.1161/HYPERTENSIONAHA.114.03578 [doi].
26. Kenny LC, Broadhurst DI, Dunn W, et al. Robust early pregnancy prediction of later preeclampsia using metabolomic biomarkers. Hypertens (Dallas, Tex 1979).
2010;56(4):741-749. doi:10.1161/HYPERTENSIONAHA.110.157297 [doi].
27. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG.
Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the US Preventive Services Task ForceAspirin for Prevention of Morbidity and Mortality From Preeclampsia. Ann Intern Med.
2014;160(10):695-703.
28. Werner EF, Hauspurg AK, Rouse DJ. A Cost-Benefit Analysis of Low-Dose Aspirin Prophylaxis for the Prevention of Preeclampsia in the United States. Obstet Gynecol.
2015;126(6):1242-1250. doi:10.1097/AOG.0000000000001115 [doi].
29. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet.
2007;369(9575):1791-1798.
30. Hofmeyr GJ, Lawrie TA, Atallah ÁN, Duley L, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2014;6(6).
31. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG An Int J Obstet Gynaecol. 2007;114(8):933-943.
32. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of
Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1131. doi:10.1097/01.AOG.0000437382.03963.88 [doi].
33. Drummond MF, Sculpher MJ, Torrance GW, J. OB, Stoddart GL. Methods for the Economic Evaluation of Health Care Programmes. Oxford University Press; 2005.
http://econpapers.repec.org/RePEc:oxp:obooks:9780198529453.
SECTION I
REPRODUCTIVE HEALTH
CHAPTER 2
Economic evaluation of family planning interventions in low and middle income countries; a systematic review
Zakiyah N, van Asselt A.D.I, Roijmans F, Postma M.J
Zakiyah N, van Asselt ADI, Roijmans F, Postma MJ. Economic evaluation of family planning interventions in low and middle income countries; a
systematic review. PLoS One. 2016
ABSTRACT
Background: A significant number of women in low and middle income countries (L-MICs) who need any family planning, experience a lack in access to modern effective methods. This study was conducted to review potential cost-effectiveness of scaling up family planning interventions in these regions from the published literatures and assess their implication for policy and future research.
Study design: A systematic review was performed in several electronic databases i.e Medline (Pubmed), Embase, Popline, The National Bureau of Economic Research (NBER), EBSCOHost, and The Cochrane Library.
Articles reporting full economic evaluations of strategies to improve family planning interventions in one or more L-MICs, published between 1995 until 2015 were eligible for inclusion. Data was synthesized and analyzed using a narrative approach and the reporting quality of the included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
Results: From 920 references screened, 9 studies were eligible for inclusion.
Six references assessed cost-effectiveness of improving family planning interventions in one or more L-MICs, while the rest assessed costs and consequences of integrating family planning and HIV services, concerning sub-Saharan Africa. Assembled evidence suggested that improving family planning interventions is cost-effective in a variety of L-MICs as measured against accepted international cost-effectiveness benchmarks. In areas with high HIV prevalence, integrating family planning and HIV services can be efficient and cost-effective; however the evidence is only supported by a very limited number of studies. The major drivers of cost-effectiveness were cost of increasing coverage, effectiveness of the interventions and country-specific factors.
Conclusion: Improving family planning interventions in low and middle income countries appears to be cost-effective. Additional economic evaluation studies with improved reporting quality are necessary to generate further evidence on costs, cost-effectiveness, and affordability, and to support increased funding and investments in family planning programs.
INTRODUCTION
Family planning allows people to attain their desired number of children, which is achieved through the use of effective contraceptive methods1. However, despite the decrease of unmet need for family planning globally for the last two decades2, a significant number of women in low and middle income countries (L-MICs) who need any family planning methods to delay or cease fertility, still experience a lack in access to modern effective methods1,2. Ensuring access to family planning services is one of the crucial strategies to ensure the health and well-being of women, as a woman’s abilities to limit, plan and manage her pregnancies have a direct impact on her health outcomes as well as on the outcomes of pregnancies1.
Unmet need for family planning is associated with a considerable amount of disability-adjusted life years and also one third of maternity-related disease burden3–5. It is estimated that by improving family planning interventions, the risk of maternal death can be decreased as much as 40% 3,6. This risk can be reduced by preventing high-risk pregnancies in for instance, women of high parities, as well as by preventing pregnancies in those who would otherwise be exposed to unsafe abortion6. Additionally, unmet need is especially high among adolescents, migrants, urban slum dwellers, refugees, women in the postpartum period and women with HIV7,8.
Family planning is one of the important drivers of progress towards target of Millennium Development Goal (MDG) no 5, i.e. to improve maternal health9,10. Reducing the unmet need for family planning is included in the continuum of care in reproductive, maternal, newborn and child health (RMNCH), which is one of the pillars in MDG 5. Despite the recommendation, access to any of these interventions is still insufficient in many L-MICs11.
In order to prioritize among many competing global health needs in these resource-constrained regions, evaluation to identify not only effective but also cost-effective strategies needs to be addressed. As a matter of fact, economic evaluation studies to assess both costs and effectiveness of global health interventions are increasingly considered in the decision making process in L-MICs12. Some studies have already been published aiming to summarize the evidence on the effectiveness as well as cost effectiveness of approaches to improve maternal and infant health care13–15. However, the synthesis of evidence on cost effective strategies in early interventions, such as family planning, remains limited.
The aim of this study is to conduct a systematic review of published economic evaluation studies, providing a synthesis of evidence on costs, consequences and cost-effectiveness of strategies to improve family planning interventions in L-MICs and assess their implication for policy and future
research. Increased investments in family planning are needed especially in L- MICs where unmet need is still high2,16,17. Additionally, the term “unmet need for family planning” in this study refers to the proportion of women who do not want to become pregnant, but are not using any contraceptive method7. Information on the economic value to assess the strategies can contribute to the design of evidence-based, feasible and sustainable policies12,18.
METHODS Literature search
The literature search followed the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)19. Medline (Pubmed), Embase, Popline, The National Bureau of Economic Research (NBER), EBSCOHost, and The Cochrane Library databases were reviewed. In addition, we also searched the homepages of a number of major international organizations which covered research in family planning such as the World Health Organization (WHO), the Guttmacher Institute, the World Bank, United Nations Population Fund (UNFPA), USAID and the Population Council. The combination of terms “AND” and “OR” as well as (MeSH) and text words were used to narrow the search. The key search strategies applied in the databases included several terms related to the following three concepts: 1) family planning, 2) costs or economic evaluation, and 3) L-MICs in accordance with The World Bank (including low income, lower-middle income, and upper-middle income economies)20. Appendix S1 summarizes the search terms used in the electronic databases.
Study selection and inclusion criteria
The initial search results from electronic databases were exported to a reference manager package, i.e. Refworks, and checked for duplicates.
Afterwards, preliminary screening based on title and abstract, followed by a full-text review of the selected articles was performed by two reviewers (NZ and ADIvA) using the following inclusion criteria:
• Type of studies - Economic evaluation assessing strategies to improve family planning interventions in L-MICs settings (based on The World Bank classification of income groups)20. The studies can be in the form of cost-analysis (CA), cost-effectiveness analysis (CEA), cost-utility analysis (CUA), and cost-benefit analysis (CBA)21.
• Interventions - All strategies associated with improved family planning interventions (by means of the holistic approach of the program), including interventions to specific population groups with high unmet need such as adolescents, refugees, women in the postpartum period and women with HIV.
• Participants - Women in the reproductive age
• Time limits -The article search was limited to the period between January 1995 until April 2015.
The articles that were selected from the international organization websites were screened in the same manner. Any disagreements and differences on the study selection were discussed. Economic evaluation studies assessing specific methods of contraceptives, studies exceeding the pre-specified time limits, and conference proceedings were excluded.
Data extraction
Study characteristics, methodology, study design (including country/setting, perspective, model type, time horizon and discount rates), parameters and results were extracted from full text articles. When several interventions were assessed, only outcomes measured in regard to family planning were extracted. Thresholds based on per capita gross domestic product (GDP) were used for considering cost-effectiveness. When any necessary information was not available in the main text, supplementary data were observed. The funding of a study was directly obtained from acknowledgements or other sources of funding. Extracted information was summarized in Table 1 and 2.
Main findings and data synthesis
The incremental cost-effectiveness ratios (ICERs) and other outcome measures were adjusted to 2014 USD by using inflation rates from the World Bank annual Consumer Price Index and purchasing power parities (PPPs) for comparability. In data synthesis, a narrative approach was used to analyze the findings due to diversity in interventions, comparators, methods and study populations. The outcome measures and results from included studies were presented in Table 2.
Quality of reporting
The quality of reporting of all included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement22. With the intention of obtaining overall reporting quality assessments, studies were assigned 1 point per item if the requirement from the checklist was fulfilled, 0.5 each when partially fulfilled and 0 point when no or insufficient information was reported. Even though the CHEERS checklist is not designed as scoring instrument, the application of a scoring method for CHEERS checklist has been used and published elsewhere15,23. Twenty-four checklist items were divided into six main categories (title and abstract, introduction, methods, results, discussion, and other). These items were subsequently calculated as a percentage score with the underlying
assumption that all criteria were weighted equally and criteria which were not applicable were excluded from the estimation. Studies with a score higher than 75% were categorized as good, studies in the range 50-74% were categorized moderate and studies with scores lower than 50% were categorized as low. Even though in this way studies will be assigned a quality of reporting score, this score is not a measure for the quality of the study.
The mere fact that some items were not reported on does not imply that study quality is low. Therefore, applying the CHEERS checklist was mainly performed to provide additional information and not to generate a weighting factor for study importance.
RESULTS
Figure 1 shows the flow diagram for the identification of studies. The initial database search identified 920 published studies, of which 53 were excluded as duplicates. The additional search on the homepages of international organizations discovered an extra 12 articles which appeared relevant to the topic. The 879 studies thus identified were screened by title and abstract.
Based on this screening 865 studies were excluded, mainly because they analyzed a different topic, for instance issues in pregnancy and abortion, concerned non-economic evaluation studies, were not done in L-MICs, or published before the year 1995. The full texts of 14 studies were retrieved for further screening and 6 of these were excluded. One extra relevant study24 was identified from the included reference during the full text screening, resulting in final inclusion of 9 studies24-32.
Figure 1. PRISMA flow diagram depicting the process of the study selection
Overview of included studies
The characteristics of included studies are presented in Table 1. From the included studies, six articles assessed the cost-effectiveness of improving family planning interventions in Mexico25, India26, Afghanistan27, Nigeria28, Uganda29 and Pacific islands30, of which four were evaluating family planning as one of several interventions to reduce maternal mortality25-28. The remaining three studies assessed strategies to reduce the unmet meet of family planning for HIV-infected women by means of providing integrated family planning and HIV services in multiple countries in Africa24,31,32. There were six single-country studies and three multi-country studies. Almost all country-specific studies focused on improving family planning interventions in the general population, while most multi-country studies were in African countries and examined the topic of integrating family planning and HIV services. Moreover, the studies were mainly funded by the private sector/ foundations.
Descriptive information about methodological characteristics and results is presented in Table 2. The healthcare provider perspective was used on most included studies, either mentioned explicitly or not. From all nine studies, six used an economic model (decision tree or Markov), two studies used demographic data and the other one used data from a cluster-randomized trial to perform the evaluation. None of the studies concerning the cost- effectiveness of integrated HIV service and family planning used GDP per capita as a benchmark to consider the cost-effectiveness of the interventions.
Most other studies however, used GDP per capita as a benchmark, to assess the willingness to pay threshold for their analysis. While most of the studies considered a lifetime time horizon for the analysis, the studies in HIV- positive women considered a relatively short (1 year) time horizon for their analysis. Despite the fact that many studies applied a lifetime time horizon, only very few mentioned or reported the discount rates for both cost and health outcome26,29,30. Detailed information about categories of included costs was provided in Table 3.
