The global impact of non-communicable diseases on macro-economic productivity: a systematic review

Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case–control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries. Electronic supplementary material The online version of this article (doi:10.1007/s10654-015-0026-5) contains supplementary material, which is available to authorized users.


Introduction
Non-communicable diseases (NCDs), such as coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD), cancer, type 2 diabetes and chronic kidney disease (CKD) currently constitute the number one cause of morbidity and mortality worldwide, claiming 36 million lives each year (accounting for 63 % of all adult deaths) [1]. Infectious disease prevention and control, economic growth, improvements in medical and scientific knowledge, and health and social systems development have all contributed to increased life expectancy, improved quality of life and increased likelihood of living to age 60 years and beyond. While these are notable achievements, together with lifestylerelated shifts, these epidemiological and socio-demographic changes also mean that the burden of NCDs will grow [2].
Productivity is a measure of the efficiency of a person, business or country in converting inputs into useful outputs. The productive age span of a person is from adulthood to retirement and ranges from 18 years to around 65 years of age depending on, amongst other things, profession and country. The measurement of productivity greatly relies on the output and the economic or social system context. The focus in this report is macro-economic productivity loss in the productive age range due to NCDs. Key macro-economic measures related to the labor market include: (un-) employment, (loss in) hours worked (including full or part-time work status change), presenteeism (defined as impaired performance while at work), absenteeism, disability adjusted life years (DALYs) and productivity costs/losses. Key macro-economic outcomes are reduction in the able workforce, NCD-related health and welfare expenditure and loss of income earned by the productive workforce. While both the burden of NCDs and the socio-economic contexts vary greatly, the impact of the former on macro-economic outcomes across the global regions remains unclear.
We aimed to systematically identify and summarize the literature investigating the impact of six NCDs (CHD, stroke, COPD cancer, type 2 diabetes and CKD) on macroeconomic productivity and to determine directions for future research.

Search strategy and inclusion criteria
We systematically searched the electronic medical databases (Medline, Embase and Google Scholar) up to November 6th, 2014 (date of last search) to identify relevant articles evaluating the macro-economic consequences of the six selected NCDs, specifically the impact on economic productivity of working age citizens. The complete search strategy is available in ''Appendix 1''. We defined the major NCDs of interest as CHD, stroke, chronic obstructive lung disease (COPD), type 2 diabetes mellitus (DM), cancer (lung, colon, breast and cervical) and chronic kidney disease (CKD). The step-wise inclusion and exclusion procedure is outlined in Fig. 1. Eligible study design included randomized controlled trials (RCTs), cohort, case-control, cross-sectional, systematic reviews, metaanalysis, ecological studies and modeling studies. We included studies that estimated the impact of at least one of the NCDs defined above on at least one of the following measures of macro-economic productivity: DALYs, economic costs related to reduced work productivity, absenteeism, presenteeism, (un) employment, (non-) return to work (RTW) after sickness absence and medical/sick leave. DALY is also considered as essentially it is an economic measure of human productive capacity for the affected individual and when taken together (e.g. all those in a company, society etc.) forms an economic measure also on the group level. Only studies involving adults ([18 years old) were included, without any restriction on language or date.

Study selection
Two independent reviewers screened the titles and abstracts of the initially identified studies to determine if they satisfied the selection criteria. Any disagreements were resolved through discussion and consensus, or by consultation with a third reviewer. In order to ensure that all retrieved full texts (of the selected abstracts) satisfied the inclusion criteria appropriately, they were further assessed by two independent reviewers. We further screened the reference lists of all retrieved studies to retrieve relevant articles. Systematic reviews were not included in the data extraction but a supplementary scan of their reference lists was performed to identify any additional studies.

Data extraction
A data collection form (DCF) was prepared to extract the relevant information from the included full texts, including study design, World Health Organization (WHO) region, participants, NCD-related exposure and macro-economic outcome characteristics. When evaluating economic costs, US dollars (USD) was used as outcome measure. If a study reported costs in another currency, the corresponding exchange rate to USD as reported by the study itself was used. However, if an exchange rate was not provided, we calculated USD applying the conversion rate for the indicated study time-period.

Quality evaluation
To evaluate the quality of the included non-randomized studies, we applied the Newcastle-Ottawa Scale (NOS) [3]. The NOS scale assesses the quality of articles in three domains: selection, comparability and exposure. 'Selection' assesses four items and a maximum of one star can be awarded for each item. 'Comparability' awards a maximum of two stars to the one item within the category. Finally, 'exposure' includes four items for which one star can be awarded. A quality score is made for each study by summing the number of stars awarded, and thus the NOS scale can have maximum of nine stars. We used this scale to assess the quality of case-control and cohort studies. For cross-sectional and descriptive studies, we used an adapted version of NOS scale (''Appendix 2'').

Statistical methods
We aimed to pool the results using a random effects model. If pooled, results would be expressed as pooled relative risks with 95 % confidence intervals. Pooling possibility was conditional on the level of heterogeneity between studies.

General characteristics of the included studies
From 4542 references initially identified, a total of 126 unique studies met the inclusion criteria ( Fig. 1  The global impact of non-communicable diseases on macro-economic productivity: a systematic… 359 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 361 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 363 We found no studies from South East Asia. The majority of the identified studies were observational in design, analyzed prospectively as well as cross-sectional. Two studies reported cross-sectional data from an RCT and six were modeling studies. National or hospital-based disease registries were often used to select patients, which were in some cases linked to national socio-economic databases to extract corresponding employment data. The control group, if used, was often a sample from the general population and sometimes sought within the same environment of the patients (e.g. same company). Many studies focused on the impact of more than one NCD on productivity. Most studies used one measure of productivity. Of all the published studies including cancers, cervical cancer was included in seven studies, breast cancer in 45, colon cancer in 24 and lung cancer in 16. Stroke was included in a total of 31 studies, COPD in 24, DM in 22 and CHD was included in 15 studies. Relevant data on CKD was included in only two of the studies and two of the studies mention NCDs in general.

Measures of productivity
Measures of productivity impact in the available studies included DALYs, absenteeism, presenteeism, labor market (non-) participation, RTW, change in hours worked and medical/sickness leave. Most studies focused on the direct impact on the patient but a minority also examined the impact on caregivers/spouses. Outcomes were quantified using risks, proportions, odds, dollars, years and days. In some studies, time-to-event data was analyzed using Cox proportional-hazards regression. Adjusting for education, age and employment status was most frequently applied, although the measurement of education and employment was not consistently defined, measured or validated. A small minority of studies reported differences in impact according to ethnicity. Pooling of outcomes was not possible due to substantial heterogeneity across and within NCD groups (I 2 [ 70 %).

Impact of cardiovascular disease on productivity
Of all DALYs on a population level in Spain (Table 2a) [6]. CHD-related productivity loss in the USA was estimated to be 8539 USD per person per year (PP/PY), at 10175 USD PP/PY [7] for absenteeism and 2698 USD PP/ PY for indirect work-related loss [8]. Total absenteeismrelated costs in Australia were estimated at 5.69 billion USD, mortality-related costs at 23 million USD and costs related to lower employment at 7.5 billion USD [9]. An estimated 4.7 working days PP/PY were lost in the USA owing to CHD [10]. Also in the USA, the odds of experiencing limited amount of paid work due to illness were significantly higher for those with CHD compared to the control group, with an odds ratio (OR) of 2.91 for women (95 % CI 2.34-3.61) and 2.34 for men (95 % CI 1.84-2.98) [11]. In Denmark workforce participation increased with increasing time from 37 % after 30 days to 65 % after 5 years of diagnosis [12]. In a study conducted in 10 European Union (EU) countries, no difference was found for the risk of non-participation in the labor force between those with and without self-reported CHD with an OR of 0.96 (95 % CI 0.66-1.40).

Impact of stroke on productivity
Stroke accounted for 3.5 % of all DALYs reported in Spain (Table 2b) with a rate of 3.8 per 1000 people [4]. Another study from Spain reports a total count of DALYs of 418,052 with a higher number of male than for female (220,005 vs. 198,046) [13]. A study from Kenya reports a rate of 166 DALYs per 100,000 person-years observed [6]. In Western Australia, the average annual stroke-attributable DALY count is an estimated 26,315 for men and 30,918 for women [14]. In Spain, costs after diagnosis increased over time for caregivers but declined for patients (14,732 USD in caregivers compared to 2696 USD among patients after 1 year and 15,621 USD to 1362 USD after 2 years) [15]. Modeled productivity losses in South Korea were higher for a severe stroke among men (537,724 USD) than women (171,157 USD) [16]. A prospective surveillance study from Tanzania report a mean costs of productivity loss to be 213 USD [17]. Inconclusive evidence of the impact of stroke on RTW was reported. Estimates ranged from 26.7 to 75 % in studies reporting RTW in stroke patients after 1 year of the event [18,19]. In Nigeria, 55 % returned to work at a mean of 19.5 months after stroke. A report from the United Kingdom (UK) found that 47 % were unemployed 1 year after stroke [20]. Increased odds to report limited ability for paid work were found among men (3.86) and women (2.26) after stroke [11]. The global impact of non-communicable diseases on macro-economic productivity: a systematic… 367 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 369 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 371 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 373 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 375 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 377 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 379 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 381 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 383 The global impact of non-communicable diseases on macro-economic productivity: a systematic… 385

Impact of cervical cancer on productivity
There are strong regional differences in the percentage of DALYs attributable to cervical cancer (Table 2c) [21,22]. Cervical cancer patients in Argentina reported negative outcomes after 1 year; 45 % of patients reported reduced labor market participation, 28 % experienced work interruption and 5 % changed work [23]. Compared to the general population, the relative risk (RR) for cervical cancer survivors in labor force participation was 0.77 (95 % CI 0.67-0.90), 2-3 years after diagnosis in Finland [24]. In Norway however, no differences were found 5 years from diagnosis with an OR of 0.92 (0.63-1.34) [25].

Impact of breast cancer on productivity
Of all the DALYs attributable to cancers among women, 27.3 % (17,840 per year) in New Zealand (Table 2d) and 13.4 % (6280 per year) in Brazil are attributable to breast cancer [21,22]. Total mortality-related lifetime productivity loss costs in the USA were estimated to be 5.5 billion USD [26]. This was differentially distributed between the two ethnic groups reported, with 71 % (or 3.9 billion USD) of the costs attributable to white women and 24 % (or 1.3 billion) attributable to black women. Differential RTW and sick absence rates are also observed comparing black and white women in the USA; the percentage of white women returning to work three months after diagnosis was 74.2 % compared to 59.6 % of black women; the proportion reporting sick leave was 25.8 % of white women compared to 40.4 % of black women [27]. 1 year after primary surgery in Germany, nearly three times as many cancer survivors had left their job as compared to women in the control group. [28] Various studies suggest higher unemployment among breast cancer survivors, reported by around half after 1 year, 72 % after 2 years [29], 43 % after 6 years and 18 % after 9 years [27,28,[30][31][32]. In contrast, in a study assessing unemployment among the spouses of breast cancer patients, no differences were found [33]. Differences between countries in average time to RTW were also found, from 11.4 months in the Netherlands [34] and 7.4 months in Canada [35] to only 3 months in Sweden [36]. Percentage of RTW after 1 year ranged from 54.3 % in a cross-sectional study from France to 82 % in a prospective study from the USA [37,38].

Impact of cancer on productivity
In New Zealand, of all the DALYs attributable to cancers, 12.9 % (8431 per year) among women and 13.5 % (8316 per year) among men are attributable to colon cancer (Table 2e) [22]. In Brazil, these proportions are 9.3 % among women and 7.5 % among men [21]. In Spain, 2.1 % of DALY's overall are attributable to colon cancer [4]. In Iran the total burden of colorectal cancer in 2008 was 52,534 DALYs and higher for men than for women [39]. In the USA, annual productivity losses were calculated to be 20.9 billion USD [40], while costs due to absenteeism after 1 year of diagnosis was 4245 USD per patient compared to the general population [41]. Although the DALY and dollar costs of colon cancer are undoubtedly large, the evidence for micro-level labor market indicators including risk and proportions of RTW, sickness absence and employment following diagnosis and treatment is however inconclusive [25,[42][43][44][45][46][47][48][49] [43,46]. Average time to re-enter the labor market was 484 days for full-time work and 377 for parttime work in the Netherlands [50]. The odds of re-entry into the labor market were significantly lower for lung cancer than the general population [24,25,51].
Impact of COPD on productivity COPD patients have a higher chance of working fewer hours, of absenteeism and of poorer work performance (presenteeism) (Table 2g). [11,52,53]. A COPD patient loses around 8.5 workdays per year due to disease [10,54]. Between 39 and 50 % of people stopped working due to the onset of COPD in the Netherlands [55,56]. COPDrelated productivity losses cost the US economy around 88 million USD or around 482,966 working days per year [57]. Modeled annual costs of COPD, estimated at 1.47 billion USD [58], are higher in Japan than the USA. The productivity loss costs PP/PY were somewhat comparable between Germany, Sweden and the Netherlands (566, 749 and938 USD respectively) [57,59,60], but differed fourfold to estimated costs in Denmark (2816-3819 USD) [61,62] and more than tenfold to what was estimated (9815 USD) in the USA [63]. In the USA, 8.5 work days are lost PP/PY on average [10], while COPD patients take an estimated 8.6 days of sickness absence in the Netherlands during a 2 year follow-up period [54]. Also in the Netherlands, 39 % of COPD patients left the labor force due to disease onset [55].

Impact of chronic kidney disease on productivity
Only two studies (Table 2 h) examined the impact of CKD on productivity. One found that renal dysfunction was independently associated with labor force non-participation, with an odds ratio of 7.94 (95 % confidence interval, 1.60-39.43) [64]. The second study, evaluating labor market participation in CKD patients specifically after dialysis or transplantation, found that 35 % of these CKD patients were unemployed [65].

Impact of diabetes mellitus on productivity
In Spain, nearly 2 % of all mortality-related DALYs are attributable to DM [4]. In South Africa, 162,877 DALYs annually are attributable to DM (Table 2i) [4,66]. A study from Kenya reports a rate of 364 DALYs per 100,000 observed person-years [6]. An estimated 7.2 days are lost PP/PY due to DM in the USA [10] and DM patients have an increased risk of absenteeism, presenteeism and inability to work [4,10,11,52,64,[67][68][69]. Productivity days lost per year due to diabetes ranged from 3.6 to 7.3 [10,70]. In the USA, proportion of productivity loss was large due to premature mortality (49 %) and presenteeism (44 %) compared to absenteeisim (4 %) and total productivity related costs were estimated to be 1,962,314 USD [71]. The odds of non-participation of the labor force for diabetes patients compared to the general population were slightly higher with borderline significance in the EU, an OR of 1.38 (95 % CI 0.99-1.93) [69].

Discussion
This systematic review identified 126 studies investigating the impact of NCDs on productivity. Most studies (96 %) were from the Western world (North America, Europe or Asia Pacific), with limited evidence available from Brazil, South Africa, Kenya, Tanzania, Iran, Japan, South Korea and Argentina. Macro-economic productivity losses were measured in percentage and absolute numbers of DALYs and annual productivity loss costs (in USD). Studies also estimated productivity losses using labor market indicators including unemployment, RTW, absenteeism, presenteeism, sickness absence and loss in working hours. There is a clear scarcity in literature concerning the effect of CKD on productivity, with only two studies both reporting a substantial impact on productivity [64,65].

Diversity in the macroeconomic measures and outcomes
There were considerable global differences in the NCDattributable DALY burden, especially the differential impact of each NCD comparing high-income countries (HIC) and low-and middle-income countries (LMIC). Lung and colon cancer account for nearly 30 % of all cancer-attributable DALYs in men in New Zealand whereas in Brazil, lung cancer alone accounts for nearly 25 %. Among women in HIC, breast cancer seems to impose a large productivity burden whereas cervical cancer impacts more dramatically in LMIC [4,21,22]. Although DALYs are a reliable measure and capture both years of life lost and years spent in ill-health, we found inconsistent application in the identified studies; some estimated proportions within specific disease groups or of the overall DALY burden in a country; others estimated absolute DALY numbers.
Diversity in the macro-economic impact of the cardiopulmonary diseases Absolute costs (measured in USD) were estimated for COPD, CHD, and stroke events [7,9,15,57,58,71]. These studies mainly came from HIC, although two studies, one from Kenya and one from Tanzania, were also retrieved. In Australia, absenteeism and lower employment due to CHD cost 13.2 billion USD annually, as well as an additional 23 million USD in mortality-related costs [9]. Evidence suggests that COPD costs around 88 million USD or nearly 500,000 working days per year in the US compared to 1.47 billion (modeled) in Japan. While annual COPD-related productivity costs were comparable in Germany, Sweden and the Netherlands (between 566 and 938 USD), costs differed fourfold (2816-3819 USD) in Denmark, tenfold (9815 USD) in the USA [57,[59][60][61][62][63]. In the USA, nearly half of the annual 1.96 m USD productivity losses due to DM are attributable to mortality, with 44 % attributable to presenteeism and just 4 % to absenteeism In South Korea, modeled productivity losses for a stroke were 68 % higher among men compared to women [16]. Around half of all stroke survivors in unemployed after 1 year [20]. In Tanzania, productivity losses after 6 months following stroke were 213 USD on average although these losses were most acutely experienced by those in higher skill roles [17]. Interestingly, indirect productivity losses were higher among caregivers than stroke patients themselves and costs increased for caregivers but declined for patients after 1 and 2 years following a stroke in Spain. COPD patients experience reduced working hours, unemployment, absenteeism and presenteeism [10,11,[52][53][54][55][56]. DM patients also have an increased risk of reduced labor market participation [10,11,52,64]. By contrast, other than for absenteeism [10] the evidence for the risk of reduced labor market participation due to CVD is inconclusive. In Kenya, 68/100,000 person year observed are attributable to CVD compared to 166/100,000 for stroke and 364/100,000 for DM [6]. Although evidence is limited, the higher productivity impact associated with diseases with a large morbidity was perhaps to be expected; chronic diseases such as COPD and DM affect people during their productive years and cannot really be 'cured', only managed. The extent to which employers or societies support and enable NCD populations to remain members of the productive workforce will also differentially distribute the impact. The extent to which secondary or tertiary prevention is possible will also affect productivity estimates, specifically so for labor market indicators such as RTW, change in work status or unemployment.

Diversity in the macroeconomic impact of cancer
Lung cancer survival is associated with reduced labor market participation through sickness absence, extended RTW [36,50] and unemployment [25,43,46]. Total mortality-related lifetime productivity loss due to breast cancer were an estimated 5.5 billion USD in the USA [26] and annual productivity losses due to colon cancer costs the US economy 20.9 billion USD [40].We found inconclusive evidence of risk of reduced labor market participation (RTW, sickness absence and unemployment) following colon cancer diagnosis and treatment [25,[42][43][44][45][46]48]. The evidence for breast cancer-related labor market drop-out shows higher unemployment among survivors 1, 2, 6 and 9 years after diagnosis [29][30][31][32]. Evidence from the USA also suggests ethnicity-patterned differences in sick leave and unemployment [27]. Along with possible socio-economic differences associated with these outcomes [72], pathophysiological differences may also play a role. African-American women have lower incidence of breast cancer but higher mortality and are also diagnosed in later stages and with more aggressive types of tumors [73]. However, we are cautious in over interpretation of this finding as few studies included ethnicity. Geographic differences in average months to RTW were observed from 11.4 in the Netherlands [34] to 7.4 in Canada [35] to just three months in Sweden [36]. Although evidence is limited, the higher productivity impact associated with diseases with a large morbidity was perhaps to be expected; chronic diseases such as COPD and DM affect people during their productive years and cannot really be 'cured', only managed. It is surprising that half of all productivity losses in the USA attributable to DM are due to mortality rather than absenteeism and presenteeism. The extent to which employers or societies support and enable NCD populations to remain members of the productive workforce will also differentially distribute the impact both within societies but also comparing more affluent to less affluent countries. The extent to which secondary or tertiary prevention is possible will also affect productivity estimates, specifically so for labor market indicators such as RTW, change in work status or unemployment.

Comparison with the previous work
Findings of this systematic review generally concur with and further extend the previous reviews. This study is a comprehensive systematic review tackling work-related burden of six major NCDs using a global perspective and without language limitation. Two reviewers included and assessed the studies and references of the included studies were tracked for any missing evidence. These approaches ensured that we included most of the relevant articles in our review. Similar to previous reviews, we found that, due to a great amount of variation in the studies included, comparability and pooling the studies were not possible. Most of the previous reviews were performed non-systematically and previous systematic reviews have included studies only in English. Previous studies were mainly focused on the impact of cancers [74][75][76][77][78] on work-related outcomes (mainly RTW) and often included a mix of cancers without specifying the type of cancer. Van Muijen and colleagues [78] reviewed only cohort studies of cancer-related work outcomes and were focused on English language. Steiner and colleagues [76] reviewed English publications published up until 2003, Breton and colleagues were focused only on diabetes and Krisch and colleagues focused on COPD in Germany [79].

Strengths and limitations of the current work
In this systematic review we evaluated the literature concerning the impact on productivity of six top NCDs. These six were selected based on their dominance in the global burden of disease and together make a huge contribution to mortality and morbidity worldwide. Several important issues are out of scope for this work but do merit future research. First, we did not look into the underlying mechanisms of what forces people with NCDs in and out of the labor force, specifically in terms of co-morbidities (certain NCDs cluster in the same populations) and financial/social means available at an individual and collective level. How these mechanisms interact will also be different according to the level of economic and social development. For example, children in LMIC are more likely to be forced into the labor market due to the onset of NCDs in parents compared to children in HIC and the productive output of this child cannot replace the loss due to drop out by the parents. These related topics should be addressed separately to better understand how to modify and target these outcomes more specifically. Second, we observed wide heterogeneity in all domains within the studies The global impact of non-communicable diseases on macro-economic productivity: a systematic… 389 selected, including study design, methods and sources used to measure productivity, adjustment for confounders and analyses. Third, no identified studies quantified the differential productivity impact by national economic development and labor market structure across countries. How these inter-country macro-economic differences might mitigate or magnify productivity losses associated with NCDs is worth further exploration. Fourth, we identified a crucial gap of relevant information from LMICs-limiting the relevance of our review most acutely in these settings. This lack of evidence could reflect differences in disease burden, in research capacity, in welfare systems and in epidemiological surveillance. The burden of NCDs is growing rapidly in LMIC; countries that often lack capacity in these key areas of support, prevention and knowledge generation. Further evaluation, therefore, of the macro-economic impact in the LMIC countries is urgently needed. Also, many NCDs affect people cumulatively over time; people may suffer DM, may experience absenteeism/ presenteeism as a result, may reduce work as DM worsens and may finally drop out of the workforce due a stroke or CHD, which is related to the DM. Given NCDs are shifting more and more into chronic conditions, as our understanding of treatment and natural history improve, it would be of great interest to investigate the effects over the life course rather than using short time horizons such as a year. This is no mean feat, but could be crucial for developing a better understanding of the economic impact of NCDs on a regional, national and international level. Also out of scope for this review but of interest for future work are the productivity-related impact of behavioural risk factors that contribute to the development of NCDs.

Conclusions
In summary, available studies indicate that the six main NCDs generate a large impact on macro-economic productivity in the WHO regions. However, this evidence is heterogeneous, of varying quality and not evenly geographically distributed. Data from LMI countries in economic and epidemiological transition are virtually absent. Further work to reliably quantify the absolute global impact of NCDs on macro-economic productivity and DALYs is urgently required.