Avicenna Vol.2013 Issue 1 by Christopher Leonard

ISSN 2220-2749

Examining the links between air quality, climate change and respiratory health in Qatar

Volume 2013 Issue 1

Trends and projections of annual birth volumes in the State of Qatar: 1970â&#x20AC;&#x201C;2025

Pharmaceutical care in the Arabic-speaking Middle East: literature review and country informant feedback

Avicenna A Qatar Foundation Academic Journal Aims and Scope Avicenna is an international, peer-reviewed, open access journal that informs and stimulates scholarly discussion toward improving the delivery of healthcare in the Middle East. Specific topics covered in the journal include: • clinical, operational and translational research and the systems and processes that support its successful integration into the cultural setting(s) epidemiology and population data that drive and inform service planning • • organizational governance, regulation and licensing • performance standards and education • health resource regulation and licensing • facility commissioning, economic evaluations and resource management • health literacy and education. The journal welcomes submitted papers covering original research, clinical and epidemiological studies, reviews and evaluations, guidelines, expert opinion and commentary, case reports and extended reports, that reflect upon the specific challenges that healthcare delivery faces in the Middle East.

ISSN: 2220-2749

Editorial Board Editor-in-chief Prof Lord Ara Darzi, Imperial College, London, UK Managing Editor William Greer - Sidra Medical & Research Centre, Doha, Qatar [also Statistical Editor] Editorial Board James Pelegano - Physician Consultant, Doha, Qatar Michael Fahey - Hamad Medical Corporation, Doha, Qatar Alison Kitson - University of Adelaide, Adelaide, Australia Bruce MacRae - College of North Atlantic – Qatar, Doha, Qatar Ahmed Nadir Mohamed Kheir - Qatar University, Doha, Qatar Alan Pearson - University of Adelaide, Adelaide, Australia Brad Johnson - University of Calgary - Qatar, Doha, Qatar Renee Pyburn - Sidra Medical & Research Centre, Doha, Qatar Deborah Norton-Westwood - Sidra Medical & Research Centre, Doha, Qatar Denis Geary - Toronto Sick Children's Hospital, Toronto, Canada Mohamud A Verjee - Weill Cornell Medical College in Qatar, Doha, Qatar Mohammed Al-Ismaily - Al Nahda Hospital, Muscat, Oman Aiman El-Khatib - Ministry of Health, Cairo, Egypt Yousif Asiri - King Saud University, Riyadh, Saudi Arabia Sabah Abu-Zinadah - Chairperson of the Scientific Board of the Saudi Nursing Council, Saudi Arabia Suzanne Robertson-Malt, Sidra Medical & Research Centre, Doha, Qatar FRONT COVER: Ibn-Sina (Avicenna), b.980 d.1037, was a Persian polymath famous throughout the Golden Age of Islamic science for his treatsies on health and medicine, including The Book of Healing and the Canon of Medicine.

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Editorial

Avicenna – The innovation in healthcare! William Greer* Sidra Medical and Research Center, Doha, Qatar *Email: bgreer@sidra.org

http://dx.doi.org/ 10.5339/avi.2013.10 Submitted: 11 March 2013 Accepted: 30 July 2013 ª 2013 Greer, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

INNOVATION In July 2013, there were approximately 53,000 articles in PUBMED that mentioned innovation; their content ranged from basic science through clinical research to organizational and performance issues in the provision of healthcare services. It would therefore appear that innovation is a familiar concept in the medical world. However innovation is difficult to define; indeed it could almost be said to be a controversial subject. There are different views about what it is and how to measure it. A common dictionary definition states that innovation is “the introduction of something new”, but it has been pointed out by some that this “newness” should be apart from simply doing the same thing better – rather it should embrace the notion that innovation stems from a “novel” idea. Another, more practical, view would assert that innovation should result in the generation of more (or better) outcomes from considerably less effort. There is also a viewpoint that it is a process whereby different ideas (each novel in their own right) combine to create a change in the way something is done. Clearly, innovation may be a common aspiration in the medical world but it can mean different things to different people. It has also been emphasized that the word “innovation” carries with it the implication of putting a novel idea to some practical use, and it is within this context that the true meaning of Avicenna’s subtitle, “Innovations in Healthcare”, becomes clear. Avicenna’s purpose is to facilitate this process by offering a platform where the different sides of this equation can come together. Potentially transforming ideas can come face-to-face with the everyday world of healthcare in the Arabian Peninsula and the wider Middle East. INNOVATION RESEARCH All innovation in healthcare must be underpinned by appropriate, targeted and successful research efforts to define and quantify the current problems facing the local population(s) and the healthcare community. The inevitable lists of questions that naturally arise from good research studies then need to be addressed and recommendations followed through. However, innovations in healthcare need to go much further. It is not enough to simply address known problems, estimate the magnitude of known population risk factors, and examine the consequences of known procedures, etc. Rather, innovation needs to look beyond what is currently known to peer over the existing healthcare horizons and view healthcare issues and infrastructures (hospitals, primary care systems, available treatments and diagnostic modalities) as they will be, twenty or thirty years from now. Innovations emerge from a vision of how things should be, not simply an understanding of the way things are. Nevertheless, innovation can only emerge through the efforts of contemporary research investigators. Healthcare research in particular must be tuned to the present-day needs of local populations. In this regard, the Arabian Gulf poses unique problems. Qatar has a population which is currently approaching 2 million, and yet 1.7 million are not Qatari. This extremely large expatriate population offers considerable challenges – not just to healthcare providers in relation to the development of appropriate planning strategies – but also for healthcare and medical research studies. The extremely divergent ethnic expatriate populations can have different disease propensities and/or diagnostic thresholds, will speak different native languages and often display wide variation in

Cite this article as: Greer W. Avicenna – The innovation in healthcare!, Avicenna 2013:10 http://dx.doi.org/10.5339/avi.2013.10

Page 2 of 2 Greer. Avicenna 2013:10

nutritional and cultural habits. These issues complicate almost all clinical epidemiological studies, randomized clinical trials, the identification of local risk factors and the conduct of population-based genetic studies. The lack of local data is also a major impediment to the development of healthcare and healthcare research in the Arabian Peninsula – and is therefore also a significant obstacle to healthcare innovation. Avicenna represents a generalized response to this situation by attempting to harness the experience and opinions of local healthcare professionals towards innovating all aspects of healthcare within Qatar. This is reflected in the breadth of the membership of its local Editorial Committee, which encompasses all of Qatar’s major healthcare institutions (including those from Qatar Foundation). On the regional stage, Avicenna particularly encourages high-quality publications from all countries across the Arabic-speaking Middle East, as it attempts to create a bridge between what is often regarded as “local research material” and those articles which are judged to be of more international interest. Avicenna is both an international and a local journal. INNOVATION SUPPORT As we have seen, innovation can be a difficult and complex task. This can be especially true in the Arabian Gulf because the research infrastructure for healthcare is significantly less developed. So – how can Avicenna offer practical help to support “Innovation in Healthcare”? The answer is that we are in the process of creating new peer-reviewed “article types” that extend the content of Avicenna into several new dimensions: Healthcare Perspectives: We now accept articles as a “Perspectives” article type, which is not primarily research-orientated but instead offers some insightful and detailed “perspective” on current healthcare practices in Qatar or other parts of the Arabic-speaking Middle East. Evidence-Based Healthcare: We showcase articles that describe the application of evidencebased principles to local and regional healthcare issues. This includes systematic reviews and evidence summaries targeted to these populations, but also articles that illustrate how the evidence-based approach can best be implemented. Letters: We are now encouraging the more active use of the “Letters” article type in Avicenna as a means of exchanging ideas; letters can function as an academic form of social media – an “Arab springboard” – towards the development of a more integrated and functional professional healthcare body in the Gulf that can transcends within-country issues and explore possible innovative solutions to a variety of healthcare problems. FUTURE AVICENNA INNOVATIONS We will also be shortly introducing the following additional “ innovations” within Avicenna; Healthcare Focus: From January 2014, in addition to its regular “Original Research” articles, every Avicenna issue will also have a “Research Focus” section that will contain a collection of six original research and review articles, all originating from a particular healthcare institution within the Arabian Peninsula. Each issue will focus on a different country and a different institution. Data-Archive: Avicenna will become a valuable archive of local healthcare information and data. We will offer the facility of lodging full datasets within the Avicenna Website. Self-Assessment Tools: Where possible, we will enhance our assessment of the quality of research publications by introducing current evaluation tools. This will eventually involve the authors’ own self-assessments, effectively bringing quality issues right up to the researchers’ front door. This editorial is an academic “call to arms” for all healthcare researchers in Qatar, the wider Arabian Gulf and the Arabic-speaking Middle Eastern nations who want to do more. Avicenna is no longer simply a place to read high-quality articles – it is also becoming a healthcare resource. Its archives of original research coupled with its burgeoning pool of additional material should make it the first point of contact for new healthcare projects in this part of the world. To borrow from a local advertising catch phrase, we can say: “The Avicenna Journal – More Than a Journal”. This is the first issue of the “New Look” Avicenna. In the future, Avicenna will be published on a quarterly basis, with one special issue released each November/December dedicated to a specific healthcare theme. A limited number of hard copies will also be made available.

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Research article

Correlates of early motherhood in slum areas of Rajshahi City, Bangladesh Md. Mahfuzur Rahman*, Md. Abdul Goni, Md. Rizvi Akhter Department of Population Science and HRD, University of Rajshahi, Rajshahi, Bangladesh *Email: mahfuz_pops@yahoo.com; mahfuz.ru.pops@gmail.com

ABSTRACT Background: Teenage pregnancy comprises 24.2 percent of the total pregnancies of Bangladesh,

which is a great threat to the overall health of the country. In Bangladesh, a large number of young women migrate to urban areas for work and most of them live in slum areas. This study aims at shedding light on the factors that contribute to the incidence of pregnancy among the women before reaching the age 18 in slum areas. Methods: This study is based on primary data, and a total of 522 samples were sorted out from the total 609 interviewed ever married women. These 609 respondents were interviewed using purposive sampling technique. Both bivariate and multivariate analytical techniques have been applied to analyze the data. Results: Result shows that as much as about 83.7 percent respondents were found to be married before reaching age 18, and 79 percent conceived before age 18. Incidence of early conception decreases with the increase in the education of respondents and in the education of their husbands. Respondentsâ&#x20AC;&#x201D;with higher family income, and who have ever used family planning are less likely to experience early conception compared to their counterparts. Conclusions: The situation indicates that the overall health of the community is at stake. For the traction of the situation, priority should be given to enhance education and income level of slum people, especially women. Family planning programmes should be strengthened and improved with a special focus to the coverage of the slum areas. Keywords: motherhood, conception, early marriage, health

http://dx.doi.org/ 10.5339/avi.2013.6 Submitted: 4 June 2013 Accepted: 4 July 2013 ÂŞ 2013 Rahman, Goni, Akhter, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Rahman MM, Goni MA, Akhter MR. Correlates of early motherhood in slum areas of Rajshahi City, Bangladesh, Avicenna 2013:6 http://dx.doi.org/10.5339/avi.2013.6

Page 2 of 5 Rahman et al. Avicenna 2013:6

INTRODUCTION Early motherhood has emerged as an issue of increasing concern to the policy planners due to its adverse health effect. Early motherhood is the state of becoming mother at a younger age of reproductive span, and in this study conceiving before age 18 has been defined as early motherhood. In Britain, teenage pregnancy has been labeled alongside cardiovascular disease, cancer and mental health as a major public health problem.1 The health hazard of early pregnancy (pregnancy before age 18) and childbirth are well documented which are: increased risk of premature labour, complications during delivery, low birth-weight, and a higher chance that the newborn will not survive.2 The axiomatic fact that early pregnancy has colossal adverse impact on overall health of a country has drawn the attention of researchers. In Bangladesh female adolescents (aged 10 –19 years) constitute about one fourth (25.1%) of the total female population and they comprise about 40 percent of the total female population of reproductive age (10–49 years).3 The average age at first marriage of females in Bangladesh was only 14.8 years during the later part of 1990s,4 and since then the age of marriage has started to increase gradually. States legal provision on minimum age at first marriage in Bangladesh is 18 years for female and at present the average age at first marriage for female is 18.7 years.5 Early marriage provides a long reproductive span that leads to high fertility. Early marriage leads to early pregnancy, and teenage pregnancy comprises 24.2 percent of the total pregnancies of Bangladesh.6 Annually, 13 million children are born to women under age 20 worldwide and more than 90 percent of them are born in developing countries. Complications of pregnancy and childbirth are the leading cause of mortality among women between the ages of 15 and 19 in such areas.7 Early marriage is associated with a number of health problems for girls. Early sexual activity leads to early pregnancy at a time when she is not biologically mature to properly maintain the fetus in the uterus. As such, a pregnant woman in her teens runs a high risk of abortion. Adolescent pregnancy has been defined predominantly within the research field and among social agencies as a social problem. Early pregnancy results into poor maternal health, high maternal mortality, low birth weight, defective birth and increased child mortality.8 To improve the average health of female population, it is very important to contain early pregnancy by finding out the factors contributing to the phenomenon. Few researchers have explored the reasons of early motherhood. Greater rates of teenage childbearing have been associated with different socio-economic factors. Underlying factors have included: reduced sexual abstinence and contraception use amongst adolescents, fewer employment and educational aspirations,9 as well as an acceptance of teenage childbearing as a ‘normal’ pattern of behaviour within this context.10 Adolescents may lack knowledge of, or access to, conventional methods of preventing pregnancy, as they may be too timid to seek such information.11 Hobcraft and Kiernan12 have cited that childhood poverty reinforces the effects of age at first birth; they have also enumerated following as the effects of early motherhood: being a lone parent, lacking telephone, likely to live in social housing, lack of qualifications, extramarital birth, cigarette smoking, and high malaise scores. In spite of a number of studies worldwide, there is dearth of research on early motherhood in Bangladesh and the scarcity of information on the causes of early pregnancy at local level is acute. In Bangladesh, a large number of young women migrate from rural areas to urban areas for work. Most of them live in slum areas. This study aims at shedding light on the factors that contribute to the incident of pregnancy among the women before reaching the age of 18 at slum areas. METHODS AND MATERIALS This study is based on a total of 18 slums of 3 wards (ward is the smallest administrative unit next to sub-district) of Rajshahi City, Bangladesh. The selected wards were ward no. 15, 17 and 30, which contain most of the slums of the City Corporation. The slums where the data were collected from were Dorikhorbona, Ambagan and Sopura from ward no. 15; Uttar Nawdapara, Raypara, Nawdapara (South), Shekpara, Namapara, Baganpara, Chakpara, and Varalipara from ward no. 17; and Mirzapur, Mirzapur West, Mohonpur, Mashkata Dighi, Budhpara West, Budhpara East and Notun Budhpara from ward no. 30. A total of 609 ever-married women were interviewed using purposive sampling technique. The study unit of this article was an ever-married woman who had ever experienced pregnancy till the date of this survey. Among the 609 ever-married women, 87 respondents did not experience any pregnancy till the date of this survey and were removed from the analysis. A total of 522 samples were used in this analysis. The respondents were interviewed directly through a structured questionnaire in October, 2011. Out of 522 respondents, as much as 83.7 percent of the respondents were found to be

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married before reaching age 18, and 79 percent experienced pregnancy under age 18. About 40.9 percent respondents were with no education, and 31 percent were used to living in a joint family. A joint family is a family that possesses more than one family that eats and lives in a single household. Occupations of the majority (74.1 percent) of the respondents were housewives and only about 63.7 percent respondents ever used family planning methods. If a respondent conceived before reaching age 18, then the incident was considered early conception. The correlates considered in the study were respondent’s education, respondent’s husband’s education, family type, family income (monthly), family expenditure (monthly), respondent’s occupation, and ever used family planning method. Family income and family expenditure have been measured in Bangladeshi currency, Bangladeshi Taka (BDT). Respondent’s occupation has been divided into four categories; housewives, services, domestic worker and others. Respondents who were engaged in structured jobs in different organizations were considered as service holders; while those who were working as maids or servants were considered as domestic workers. Both bivariate and multivariate analyses were used to study the phenomenon. To study the odds of the events occurring, the binary logistic regression13 technique was applied, and all the analyses were performed using computer software SPSS 16. RESULTS To study the early conception, both, bivariate and multivariate analyses were used. To dissect the differentials in early motherhood descriptive statistical technique was applied, and to identify important contribution of predictors on early motherhood, logistic regression analysis was applied. The results of the analyses have been presented in the following sections. DIFFERENTIALS IN EARLY MOTHERHOOD Table 1 shows that the incidence of early conception decreases with the increase of respondents’ and husbands’ levels of education. The highest proportion of the respondents (84.1%), conceived before age 18, was found to be with no education. Early conception was observed to be higher among those

Table 1. Distribution of conceptions by age among different background characteristics. Respondents by age at first conception ,18 years Characteristics

Respondent’s education No education Primary Secondary and higher Husband’s education No education Primary Secondary and higher Family type Nuclear Joint Family income (monthly) , BDT 3500 BDT 3500þ Family expenditure (monthly) , BDT 3000 BDT 3000þ Respondent’s occupation Housewives Services Domestic worker Others Ever used family planning method Yes No Total BDT ¼ Bangladeshi Taka.

$18 years

No.

132 167 113

84.1 78.3 74.2

25 46 39

15.9 21.7 25.8

85 144 183

81.8 79.2 77.5

19 38 53

18.2 20.8 22.5

125 287

77.2 79.8

37 73

22.8 20.2

274 138

79.4 78

71 39

20.6 22

248 165

79.8 78.2

63 46

20.2 21.8

305 18 68 21

78.9 84 83.2 65.8

82 3 14 11

21.1 16 16.8 34.2

139 273 412

73.3 82.2 78.9

51 59 110

26.7 17.8 21.1

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who used to live in joint family than those of a nuclear family. More respondents of income group less than BDT 3500 (79.4%) and expenditure group less than BDT 3000 (79.8%) were observed to conceive before age 18 than that of those who had higher income and expenditure respectively. Highest percentage of the respondents (84.0%), who experienced early conception, were service holders, followed by domestic workers (83.2%), housewives (78.9%) and others (65.8%). Those who ever used family planning methods (26.7%) conceived at higher ages (18 and over) than that of those who never used family planning method (17.8%). LOGISTIC REGRESSION ANALYSIS In logistic regression analysis, a variable is considered significantly associated if its p-value is below 0.10. Such a high p value, instead of the usual 0.05, is chosen in order not to miss any possible variables having associations with dependent variables. Results (Table 2) show that the respondents with primary, and secondary and higher education and the respondents whose husbands had primary, and secondary and higher education were less likely to conceive before age 18 than that of their counterparts. Table 2. Logistic regression estimates of relative odds of early conception. Attributes

Respondent’s education No education (RC) Primary Secondary and higher Husband’s education No education (RC) Primary Secondary and higher Family type Nuclear (RC) Joint Family income (monthly) , BDT 3500 (RC) BDT 3500þ Family expenditure (monthly) , BDT 3000 (RC) BDT 3000þ Respondent’s occupation Housewives (RC) Services Domestic worker Others Ever used family planning method Yes (RC) No

Coefficient (b)

SE (b)

Odds ratio

– 20.230 20.651

– 0.230 0.267

1.000 0.583*** 0.817***

– 20.265 20.101

– 0.2760 0.222

1.000 0.357* 0.726**

– 0.149

– 0.212

1.000 1.161*

– 20.065

– 0.209

1.000 0.937**

– 20.126

– 0.201

1.000 0.882*

– 0.667 1.004 20.943

– 0.361 0.644 0.438

1.000 1.949* 2.730** 0.567*

– 0.521

– 0.202

1.000 1.684***

BDT ¼ Bangladeshi Taka, RC ¼ Reference Category, * ¼ p , 0.10, ** ¼ p , 0.05, *** ¼ p , 0.01.

Respondents with monthly family incomes of BDT 3500 and higher were 6 percent less likely to conceive before age 18 than those with incomes bellow BDT 3500. Those who lived in joint families and have family expenditures of BDT 3000 and higher were 1.16 times more likely and 0.88 times less likely, respectively, to experience early conception. Service holders and domestic workers were 1.95 and 2.73 times more likely to conceive before age 18 than their counterpart, respectively. Family planning was found highly significant in influencing early conception, in which those who never used family planning methods were 1.68 times more likely to conceive earlier. DISCUSSION Given the well-documented fact that early marriage is positively correlated with early pregnancy and despite the adverse effect of early pregnancy on maternal and child health, the vast majority of the slum girls of the study area experienced early marriage and early pregnancy. Our study findings point to the important role of education and family income. Similarly, Nasrin and Rahman14 found in their study that respondents’ and their husbands’ education and families’ monthly income are the most influential factors in determining the likelihood of early conception and they influence early conception

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negatively. Education is likely to enhance autonomy of a person so that she/he develops greater confidence and capabilities to make decision regarding the important events of their life.15,16 Better economic standards enable mothers to have greater health choices.17 Expenditure of a family largely depends on the income of that family, therefore, as found in the study, expenditure is expected to have a similar impact on early motherhood as income. Findings of this study also deem types of family (viz. joint and nuclear) and use of family planning method as very important predictors of early motherhood. In joint families, bringing a child up is relatively easier than in nuclear family, which might have contributed to such higher incidence of early conception in the group. Bongaarts and Potter18 have established that contraceptive use is the main proximate factor to bar fertility. The fact is that, after entering sexual union in absence of physical barrier, the only way to preclude conception is the use of a family planning method. CONCLUSIONS Our objective in this article was to shed light on the factors influencing the early conception among slum women. The majority of the women were found married and to have conceived before reaching age 18, which poses prodigious threat to the overall health of the community, mainly mother and child. In this study, education, income, and ever use of family planning method were found to influence early conception negatively. It has been noticed from this study that the scale of slum women marrying and conceiving before age 18 outruns that of the national level, which plays vital role to bring down the national health and development indicators. It is of paramount imperative for the Bangladesh government to develop a plan to contain the incidence of early pregnancy in slum areas. To mediate the situation, priority should be given to enhance education and income levels of slum people, especially women. The government should reinforce and enforce the legal age of marriage in Bangladesh. Family planning programmes should be strengthened and improved with a special focus to the coverage and counseling in the slum areas. REFERENCES [1] Dickson R, Fullerton D, Eastwood A, Sheldon T, Sharp F, Information Staff of CRD. Preventing and reducing the adverse effect of unintended teenage pregnancy. Effective Health Care Bull. 1997;3:1–12. [2] Senderowitz J. Adolescent Health: Reassessing the Passage to Adulthood. World Bank Discussion Paper no. 272. Washington, DC 1995. [3] Bangladesh Demographic and Health Survey. National Institute of Population Research and Tanning (NIPORT). Mitra and Associates, Dhaka, Bangladesh and Macro International Inc., Calverton, MD, USA; 2004. [4] Bangladesh Demographic and Health Survey. National Institute of Population Research and Tanning (NIPORT). Mitra and Associates, Dhaka, Bangladesh and Macro International Inc., Calverton, MD, USA; 1997. [5] Bangladesh Bureau of Statistics. Statistical Pocket Book of Bangladesh. Statistics Division, Ministry of Planning, Government of the Peoples’ Republic of Bangladesh, Dhaka; 2009. [6] Banerjee B, Pandey G, Dutt D, Sengupta B, Mondal M, Deb S. Teenage pregnancy: a socially inflicted health hazard. Indian J Community Med. 2009;34(3):227–231. [7] Mayor S. Pregnancy and childbirth are leading causes of death in teenage girls in developing countries. BMJ. 2004;328(7449):1152. [8] Mehra S, Agrawal D. Adolescent health determinants for pregnancy and child health outcomes among the urban poor. Indian Pediatr. 2004;41(2):137 –145. [9] Islam MM. Adolescent childbearing in Bangladesh. Asia-Pac Popul J. 1999;14(3):77–87. [10] Kamal SMM. Adolescent Motherhood in Bangladesh. XXVI IUSSP International Population Conference, Session-49; 27 September –02 October, Marrakech, Morocco, 2009. [11] Slater J. Britain: sex education under fire. UNESCO Courier. 2000;53(7/8):17. [12] Hobcraft J, Kiernan K. Childhood Poverty, Early Motherhood and Adult Social Exclusion. London: Centre for Analysis of Social Exclusion, London School of Economics; July, 1999:p.28. [13] Cox DR. Regression and life tables. J Royal Stat Soc. 1972;34:187–220. [14] Nasrin SO, Rahman KMM. Factors affecting early marriage and early conception of women: a case of slum areas in Rajshahi city, Bangladesh. Int J Sociol Anthropol. 2012;4(2):54 –62. [15] Caldwell JC. Maternal education as factor in child mortality. World Health Forum. 1981;2:75–78. [16] Raghupathy S. Education and the use of maternal health care in Thailand. Soc Sci Med. 1996;43:459 –471. [17] Rahman MM, Alam R, Roy TK, Goni A. Mothers’ health seeking behavior at Rajshahi district. Pak J Soc Sci. 2008;5(6):612–619. [18] Bongaarts J, Potter RG. Fertility, Biology, and Behavior: An Analysis of the Proximate Determinants. New York: Academic Press; 1983.

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Research article

Trends and projections of annual birth volumes in the State of Qatar: 1970 –2025 William Greer* Sidra Medical and Research Center, Qatar Foundation, P.O. Box 26999, Doha, Qatar *Email: bgreer@sidra.org

http://dx.doi.org/ 10.5339/avi.2013.3

ABSTRACT Background: The ethnic profile of Qatar is a combination of its indigenous peoples (Qataris) and non-resident foreigners (non-Qataris). Its population has increased dramatically during the last 30 years to around 1.9 m (although only 15% are Qataris) leading to an increase in the number of local births. A recent unexpected surge in births has lead to a need to re-evaluate the trends in birth numbers and develop more reliable predictions for both near- (2015) and far-term (2025) annual numbers of births to support the many healthcare planning initiatives which are currently underway. Methods: There is considerable information already available in Qatar which can facilitate such a study. This paper collates these various data, charts and investigates their visible trends and develops a simple mathematical model which projects the annual number of births which might reasonably be expected to emerge later in this decade and beyond. Results: The Qatari sub-population has maintained a reliable linear increase in birth numbers since data first began to be collected. The births among the non-GCC and Asian sub-populations are the primary cause of the recent nonlinear increase which can be well-described in the near-term by a simple quadratic curve. Far-term projections require a non-linear mathematical model which combines the regular linear increase among the Qataris with an exponentially decreasing demand for “in-Qatar” births from the non-Qataris. The trend for multiple births in Qatar (i.e. the annual number of live-born twins, triplets etc.) has shown significant increases during the last 20 years but may be reaching a plateau. Among Qataris the numbers have been higher but – at least for triplets and higher-order births – this gap has decreased in the last few years. It appears that the increase in multiple births has been associated with the current expansion of IVF programs and other forms of assisted conception in Qatar. Conclusions: The annual number of births in Qatar has recently shown a significant departure from its previous trend, requiring a radical reassessment of future projections. There has also been a concomitant increase in multiple births which has been associated with the expansion of IVF programs and other forms of assisted conception. A simple quadratic model predicts that there will be ,22,500 births in 2015, of which , 8,000 will be Qatari. A far-term projection for 2025 suggests that this number is likely to rise to , 27,000 but with some small additional increase yet to come. Keywords: Qatar, birth statistics, birth trends, multiple births, birth projections

Submitted: 17 May 2013 Accepted: 03 July 2013 ª 2013 Greer, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Greer W. Trends and projections of annual birth volumes in the State of Qatar: 1970 –2025, Avicenna 2013:3 http://dx.doi.org/10.5339/avi.2013.3

Page 2 of 11 Greer. Avicenna 2013:3

INTRODUCTION In common with most countries in the Arabian Gulf, the ethnic profile of Qatar has evolved to be a combination of its indigenous peoples (Qataris) and non-resident foreigners (non-Qataris), comprising both Arab and non-Arab expatriates from all over the world.1 The population in Qatar has increased dramatically throughout the last thirty years (Figure 1) and on April 30, 2013, it stood at 1,944,9532 (excuding those who were outside the state boundary on that date), of which less than 15% were Qataris. Qatar is therefore a country comprising substantial numbers of different peoples with different biological propensities for different diseases and medical conditions, and who hold different opinions regarding the ideal nature and delivery of healthcare services. From an epidemiological perspective this situation is unique and such a demographic “perfect storm” complicates attempts to simply import North American or European healthcare models as a basis for the further development of the Qatari Heathcare system. In parallel to the incessant increase in the overall population there has naturally been a corresponding increase in the number of in-country births, although this has perhaps been less dramatic because several sectors of the population (such as the migrant construction workers) are predominantly male and usually arrive in Qatar without any accompanying families.1 Nonetheless, the overall number of births has risen substantially during the last 30 years (Figure 2) and has become a clear and important “landmark” in the current wave of healthcare development. However, the predicted total annual number of births for 2015 which was estimated many years ago has already been surpassed by the unexpected surge in the number of births in the country. There is therefore a clear need to reevaluate the rationale for predicting anticipated annual birth numbers in Qatar and to develop more reliable numerical estimates which can be more confidently used to support the many healthcare planning initiatives which are currently underway. There is a considerable amount of national data already available from several different sources within Qatar which can facilitate such a study. The purpose of this paper is to collate these various data, to chart and investigate their visible trends and to develop suitable future projections for the annual number of births which would be expected to emerge later in this decade and beyond. METHODS Data sources The raw data presented here originate primarily from two local sources which are publicly available. The principal source is the set of annual reports of the Qatar National Births and Deaths Registry, which

Figure 1. The Trend in the Total Population of Qatar, 1984 –2010.

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Figure 2. Annual Numbers of Registered Births in Qatar. 1970–2010.

are well-organized and extremely detailed annual summaries of the available birth and death data for Qatar. In recent years, these reports (and their relevant documentation) have all become available on the website of the Qatar Statistics Authority3; the most recent report is for 2010. The ultimate source of these data are the official records of the Supreme Council of Health (note that some individuals do not register births in time and so these births are not registered during their year of birth). All births are registered according to the mother’s usual place of residence at time of birth. Although the title, format and contents of this report have changed over the last 30 years, nonetheless much of the key data remains as an unbroken historical record. The first report of the National Births and Deaths Registry was released in September 1985 under the banner “VITAL STATISTICS: Annual Bulletin (Births and Deaths)”4; this issue is particularly important because it also provides summary data for earlier years – as far back as 1970. The second data-source comprises the set of annual statistical reports which are prepared by the Qatar Hamad Medical Corporation (HMC) and made publicly available on its own website.5 These include birth statistics for the only two HMC hospitals which provide obstetric care (Women’s Hospital and Al Khor Hospital). Until recently, HMC was by far the main healthcare provider in Qatar and effectively the only inpatient facility available. Other local sources are available which can provide supporting data, especially the recent “PEARL” initiative – the new national neonatal registry.6 Data entry and analyses Selected data from the reports described above were entered into the JMP statistics package v8.0 (SAS Corp, USA) where they were collated and reorganized for presentation and analyses purposes. Presentation, comparisons and analyses of trends were then conducted using the Origin scientific plotting and analysis package v8.1 (Originlab Corp, USA). All curve-fitting and future projections were also carried out within Origin. RESULTS The increasing trend in registered births in Qatar between 1970 and 2010 is shown in Figure 3. These data are a composite of information from the annual Births and Deaths Reports of 1970 –1984, 1989, 1997, 2007 and 2009,7 and a publicly-available Excel file from the Qatar Statistics Authority for 2010.8 It is evident that the indigenous population (Qataris) exhibit a gradual linear increase in birth numbers, whereas the expatriate population appears to experience two increased “waves” of births. The first of these runs from around 1977 to 1990 and the second from 2006 to the present. The small

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Figure 3. Trend in Annual Numbers of Registered Births in Qatar Since Official Records Began until 2010. The 2011 Total is from the PEARL Registry.

number of “unregistered” births (i.e. births which are registered in subsequent years) between 1997 and 2010 are shown in Table 1 (along with the small but regular number of Qatari births abroad from 1993). There are no available data which describe non-Qatari women who may have been resident in Qatar during their pregnancy but decided to return home for the birth. Qataris have the highest number of regional births throughout the recent recorded history of births in Qatar (Figure 4). “Other Arabs” and Asians form the next two largest sub-groupings, with the Asians displaying somewhat fewer births; their year-on-year variations also appear to track closely together throughout this period. It is of interest to note that –in contrast–very few GCC nationals have their babies in Qatar. The in-country births numbers for Europeans and “others” are also remarkably small. Table 1. Annual numbers of unregistered births in Qatar7 and Qatari births abroad between 1997 and 2010. (Note that some data are not publicly available). Unregistered Births Year

Qatari

Non-Qatari

Total

Qatari Births Abroad

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

n/a n/a n/a n/a 162 140 153 138 159 123 119 50 64 52 9 266 166 n/a

n/a n/a n/a n/a 28 40 101 50 78 65 51 49 49 32 5 138 104 n/a

n/a n/a n/a n/a 190 180 254 188 237 188 170 99 113 84 14 404 270 n/a

187 n/a 176 172 177 165 147 167 185 169 176 169 n/a 198 207 245 244 276

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Figure 4. Trend in Annual Numbers of Registered Births in Qatar, Stratified by Nationality.

The trends for multiple births (i.e. twins, triplets and higher-order births) in Qatar are visible in Figures 5 and 6 and display a high degree of year-on-year variability due to their relatively small numbers. Note that these data represent the number of individual babies who are twins or triplets (etc.) – they do not show the number of mothers who delivered. For analysis purposes, these data have been divided into two groups: twins (Figure 5) and triplets and higher-order births (Figure 6). It is clear from Figure 5B that although the absolute numbers of both Qatari and non-Qatari twin-births track very closely together throughout the period studied, when these are corrected for the increasing differences in their birth numbers, the Qataris show some evidence of having higher rate of twins since 1990. However the difference between Qataris and non-Qataris is much larger with respect to the numbers of triplets and higher-order births (Figure 6A): although they begin at similarly low levels, their trends quickly diverge, with the non-Qatari births appearing to follow a more linear trend compared to the more complex trend exhibited by the Qataris. This difference is exacerbated when the relative numbers of annual births are taken into consideration (Figure 6B) although it appears to reach a maximum around 2000 and may subsequently decline slightly. Until recently, almost all births in Qatar took place at the HMC Women’s Hospital (Figure 7),5 but since 2006, the annual number of births has also grown significantly due to additional contributions by the new (private) hospitals. In 2007, a second HMC hospital (Al Khor, in northern Qatar) also began to offer obstetric services, increasing the overall HMC number of births. However, in recent years the increase in births in the private sector has far surpassed the additional contribution of Al Khor. In 2010, the combined births from Al Ahli, Al Emadi and Doha Clinic constituted the visible difference between the registered total births and HMC total births, and in 2011 this amounted to 2,671.6 We can make good use of these various data in the prediction of realistic national estimates of birth volume for both the near and mid-term future. From the registry data (Figure 8), it is clear that Qatari births exhibit a linear trend throughout. The parameters and standard-errors for the displayed regression line are: intercept ¼ 2279176.93145 (SE ¼ 9456.29649) and gradient ¼ 142.5621 (SE ¼ 4.73995). This gradual linear increase will produce an annual Qatari number of births of ,8,000 in 2015. Until 1997, the non-Qatari population has displayed less linear behavior, but for the next period of ten years, it did settle into a linear trend and this was used to project numbers forward, leading to a 2015 estimate of ,18,000. However, since 2006 the annual trend in birth numbers among the non-Qatari population has moved to a

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Figure 5. Trend in Annual Numbers of Twins in Qatar (A: Absolute Numbers, B: Birth Percentages).

new phase – a non-linear trajectory – which has significantly impacted the overall number of registered births in Qatar. For near-term projections (until 2015), this recent trend in registered births can be very closely approximated for the 5 years involved by using a simple quadratic equation. The parameters and standard-errors for the displayed regression lines are: Intercept ¼ 2349438500.0 (SE ¼ 69662200.0), b1 ¼ 346719.79985 (SE ¼ 69386.70794) and b2 ¼ -86.0 (SE ¼ 17.27757).

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Figure 6. Trend in Annual Numbers of Triplets & Higher in Qatar (A: Absolute Numbers, B: Birth Percentages).

Unfortunately because there has been no public release of births and deaths reports since 2010, any near-term projections must be based on this relatively small portion of time. Nonetheless, the quadratic function shown in Figure 8 (dotted line) appears to be an excellent fit to these existing data. Therefore we can use this regression to project our near-term annual birth estimate for Qatar to 2015, when it will be , 22,500. Near-term predictions assume that the composition of the Qatar population will remain relatively unchanged over this period while far-term projections require some assumptions regarding the

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Figure 7. Trend Comparison of the Annual Numbers of Registered Births in Qatar, with the Corresponding Numbers at HMC and Subcategorized by Women’s Hospital and Al Khor.

dynamics of the expatriate population. These trends are shown in Figure 4 and strongly suggest that although Western populations may well have made significant inroads in Qatar during recent years, they have had little impact on birth numbers; the two expatriate populations that are likely to shape the dynamics of the birth population over the coming decade will probably remain “other Arabs” and Asians The significant upswing in total births during the last 6 years appears to be primarily associated with these groups although it appears that the rise in these numbers is decreasing. If we assume that the increase in obstetric beds in Qatar is associated with the recent upsurge in private health care (which will be enhanced with the imminent opening of Sidra Women and Children’s Hospital) then this will effectively continue to deplete the reservoir of local births from these two population subgroups. We can then formulate a more “structural” predictive model for birth numbers which is likely to prove more robust for far-term projections. This model recognizes the gradual linear increase of the indigenous Qatari population but also includes a separate term which represents the larger expatriate

Figure 8. Near-Term Projection of Key Birth Statistics to 2015: Total Number of Registered Births and Number of Qatari Registered Births. (the green triangle is the 2011 estimate from the PEARL registry [8]).

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Figure 9. Far-Term Projection of Key Birth Statistics to 2025: Total Number of Registered Births and Number of Qatari Registered Births.

sub-population which would be gradually depleted over the coming years, thereby reducing the year-on-year increase and eventually forcing the number of new annual births to a plateau: x 2 2006 y ¼ 2a0 þ a1 x þ b0 þ b1 1 2 exp 2 T where a0 and a1 are the established Qatari intercept and gradient (see above), b0 is the y-intercept at year 2006: 7347.26994 (1.61588) b1: is the amplitude of the birth “reservoir”: 11096.3131 (41.14453) T: Time constant of the depletion of the birth reservoir: 7.00006 (0.0352) It was noted that fitting a nonlinear function with 3 unknown parameters to the small number of points (5) beyond the linear region of the data (i.e. 2006–2010 inc.) might prove difficult. Therefore, since the quadratic fit (above) proved to be such an excellent fit to the same region, the same quadratic curve was sampled at 100 equally-spaced points and these were used as the basis for the nonlinear fit (hence the small and misleading standard errors for the parameter estimates. This far-term model predicts that the annual birth rate in 2025 could be as much as 27,000 (Figure 9).

DISCUSSION Historical trends Over the last 43 years the Qatari annual birth volumes have grown in a very linear fashion and it is likely that by 2015 the annual number of Qatari births will have reached approximately 8,000. The total annual volume, however (across all nationalities), has been more volatile because it is a strong function of the expatriate population (in terms of numbers, age/gender and lifestyle). Roughlyspeaking, until 2006 the trend in the annual pattern of birth volume among the total population in Qatar can be regarded as two large perturbations superimposed on relatively linear growth. During the periods of linearity it appears that the expatriate birth population has been similar in size to the Qatari birth population and growing at a similar rate. However between 1975 and 1990 the expatriate births exhibited a significant “wave” of increased births which was followed by a rapid decrease – possibly as a result of population upheavals during the first Gulf war. A much larger repeat of this expatriate birth population “surge” would appear to be taking place now, having begun some years ago during 2006. Linear regressions of early population growth models natrurally predicted that the total number of births in Qatar will reach approximately 18,000 per year by 2015.

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Near-term projections During the last five years it appears that Qatar has embarked on a significantly new (curvilinear) period of increased births. A more likely near-term (quadratic) estimate for the annual birth population would now be closer to 22,500 for 2015. Other functional forms of a near-term projection were explored but a simple quadratic fit appears to be the simplest and describes the available data with great precision. This model recently received some validation from the first published annual report of the PEARL project6; when the national number of births for 2011 displayed excellent agreement with the previously estimated fit (Figure 8).

Multiple births The general trend for multiple births in Qatar (i.e. the annual number of live-born twins, triplets etc.) has been increasing steadily since 1985, rising from just over 1% to , 3% in 2005. This is a little more than in the USA, where the number of live births in twin deliveries doubled between 1984 and 2005.9 By contrast, this rate in the more remote southeast region of China stayed roughly constant (averaging 1.2%) during the same period10; this supports the notion that the increase in live twin births during this period is comparable to what is observed in “western” countries and can probably be ascribed to the expansion of IVF programs and other forms of assisted conception in Qatar.5 Of special interest in the trends for multiple births in Qatar is the difference between the Qatari and non-Qatari numbers. The absolute numbers of twins appears very similar for both the Qatari and nonQatari sub-populations, but when corrected for the associated changes in overall birth rate, a small discrepancy appears. In the case of triplets and higher-order births this difference is substantial and clearly visible both in the absolute and the corrected trends. It is tempting to simply believe that this reflects a preponderance of Qataris who make use of assisted conception opportunities in Qatar. However the HMC data available for 2011 would not – by itself – support this view. In 2011, the Assisted Conception Unit (ACU) at HMC treated 1,272 patients but only 45% of these were Qataris.5 Similarly, out of a grand total of 9,781 outpatient visits to the ACU in 2011, only 46% were by Qataris; furthermore, out of 288 female visits, only 31% were Qatari. Out of all the patients treated by the ACU in 2011, there were 335 clinical pregnancies of which 50% were for Qataris.

Figure 10. Trend in Clinical Pregnancies in the HMC Assisted Conception Unit.

Page 11 of 11 Greer. Avicenna 2013:3

The available historical data belies these recent statistics, demonstrating that – at least between 1998 and 2005 – there was actually a wide gap between the number of clinical pregnancies achieved by the ACU for Qataris and non-Qataris (Figure 10) – a gap that has since been completely closed during the last 5 years. However it is also clear from Figures 5 and 6 that this does not provide a complete explanation of the data because during the last five years there has still remained a substantial difference between the Qatari and non-Qatari multiple birth statistics. It may be that to find the answer to this question the statistics of those Qataris who seek treatment elsewhere will have to be explored further. Far-term projections Given the paucity of available data, attempting a far-term projection to 2025 is an ambitious task which is fraught with difficulties, in addition to the usual demographic problems associated with population variability. Because the population in Qatar mainly comprises expatriates, it is especially vulnerable to economic and political upheavals – both in their native countries and in the Gulf region itself. Qatar is also currently embarking on several major infrastructure projects, such as an ambitious rail system, the opening of the new Doha International Airport, hosting the future World Cup and the development of a plethora of new hotels. The implications of these events on birth numbers are difficult to estimate. It should also be emphasized that although these statistics have strong planning value in the area of birth and newborn services, they might need to be supplemented to some extent for planning activities in the areas of maternity, pediatrics and some other services, since there are currently no reliable data concerning expatriate women who give birth in their home countries and subsequently return with the baby to Qatar. However, the projected estimate for 2025 of 27,500 births has been calculated by assuming that the linear trend in Qatari births will continue unabated and that the dynamics of the birth projection will primarily be governed by a gradually depleting annual reservoir of expatriate births (due to national increases in obstetrics facilities). Nonetheless, this estimate should be continually updated every few years. REFERENCES [1] Zahlan R.S. The creation of Qatar. 1979. ISBN-10:0064979652. ISBN-13:978-0064979658. Barnes and Noble Books. [2] Qatar Statistics Authority: Total Population in Qatar on 30th April 2013. http://www.qsa.gov.qa/eng/ PopulationStructure.htm (Accessed May 11, 2013). [3] Qatar Statistics Authority. Births and Deaths Annual Reports. http://www.qix.gov.qa/portal/page/portal/qix/ subject_area/Publications?subject_area¼182 (Accessed May 11, 2013). [4] First Report of National Births and Deaths Registry. http://www.qix.gov.qa/portal/page/portal/QIXPOC/Documents/ QIX%20Knowledge%20Base/Publication/Population%20Statistics/Vital/Source_QSA/Births_Deaths_ QSA_AnBu_AE_1985.pdf (Accessed May 11, 2013). [5] Hamad Medical Corporation. Annual Health Reports. http://site.hmc.org.qa/msrc/ahr.htm (Accessed May 11, 2013). [6] Pearl Neonatal Outcomes Research Study in the Araban Gulf. Annual Report. Doha, Qatar: Pediatrics Department, Hamad Medical Corporation; 2011. [7] Annual Births and Deaths Reports 1970-1984, 1989, 1997, 2007 and 2009. http://www.qix.gov.qa/portal/page/portal/ qix/subject_area/Publications?subject_area¼182 (Accessed May 11, 2013). [8] Excel file. Births_Deaths_2010.xlsx http://www.qix.gov.qa (Accessed March 25, 2012). [9] Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Munson ML, Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System. Births: Final Data for 2005. Natl Vital Stat Rep. 2007 Dec 5;56(6):1–103. [10] Lu X, Zhang J, Lio Y, Wang R, Lu Y, Li Z. Epidemiology of Twin births in Southeast china 93–2005. Twin Res Hum Genet. 2013 Apr;16(2):608–613. doi: 10.1017/thg.2013.7. Epub Feb 21, 2013.

OPEN ACCESS

Research article

Role of prostaglandins in colorectal tumorigenesis: Localization and expression of COX-1, COX-2, microsomal Prostaglandin E Synthase-1 and the EP2 receptor Lars Hedin1,*, Katarina Rask2, Yihong Zhu3, Anna Wickman2, Wanzhong Wang4, Hans Brevinge5, Magnus Tho¨rn6, Fredrik Ponte´n7, Karin Sundfeldt3 1

The Primary Health Care Center, Sandvaktaregtan 15, 296 35 A˚hus, Sweden 2 Center for Physiology and Bio-Imaging (CPI), The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3 Department of Obstetrics and Gynecology, The Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 4 Department of Urology, The Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 5 Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 6 Department of Surgery, Stockholm South General Hospital, 118 83 Stockholm, Sweden 7 Department of Pathology, Uppsala University Hospital, Uppsala, Sweden *Email: larsfhedin@gmail.com

ABSTRACT Background: Prostaglandins, in particular prostaglandin E2 (PGE2), are elevated in adenomas and colorectal cancers (CRC). Experimental and epidemiological studies have demonstrated reduced incidence of adenomas and CRC by inhibitors of prostanoid synthesis (NSAIDs). This study aimed to characterize the expression and localization of key enzymes/receptors for PGE2 synthesis in adenomas and CRC in comparison to normal colon. Methods: Immunoblotting and immunohistochemistry were used for semi-quantitative and qualitative analysis of COX-1, COX-2, mPGES-1 and the EP2 receptor in biopsies from patients undergoing resection of adenomas or surgery for CRC (Dukes’ A-C). Normal colon served as control for the corresponding tumor in each of the CRC patients. Results: COX-1 was decreased significantly in all groups of CRC (Dukes’ A-C) compared to normal colon. In contrast, COX-2 was increased, but only in the combined group of CRC. Microsomal PGES-1 was increased in CRC (Duke’s B), and EP2 was augmented in adenomas and CRC. The localization was predominantly epithelial in normal colon and in adenomas, while in CRC both epithelial- and stromal expression was demonstrated. Conclusions: The results support the PGE2- pathway, with epithelial- stromal interactions, in the evolvement of adenomas and in the progression of CRC. Co-expression of COX-1 and COX-2 is in line with the preventive effects of non-specific NSAIDs on adenoma formation. The decrease of COX-1, in combination with an increase of COX-2, favors the potential use of selective COX-2 inhibitors as an adjunct therapy in CRC.

http://dx.doi.org/ 10.5339/avi.2013.5 Submitted: 20 May 2013 Accepted: 7 June 2013 ª 2013 Hedin, Rask, Zhu, Wickman, Wang, Brevinge, Tho¨rn, Ponte´n, Sundfeldt, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Hedin L, Rask K, Zhu Y, Wickman A, Wang W, Brevinge H, Tho¨rn M, Ponte´n F, Sundfeldt K. Role of prostaglandins in colorectal tumorigenesis: Localization and expression of COX-1, COX-2, microsomal Prostaglandin E Synthase-1 and the EP2 receptor, Avicenna 2013:5 http://dx.doi.org/10.5339/avi.2013.5

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INTRODUCTION Colorectal cancer (CRC) ranks as one of the top three malignancies in most Western populations.1 Earlier studies from the Middle East reported that CRC was less common than in the West.2 However, the association between diet, a sedentary lifestyle and overweight makes it more likely that the incidence of CRC will increase substantially in Qatar, as well as in other parts of the Middle East. An additional risk factor in this region for CRC is consanguinity that is demonstrated to be strongly associated with the development of CRC.3 In fact, studies from several countries in the Middle East reports an increasing incidence in CRC, and several characteristics of Western populations, e.g. earlier age of incidence.4 – 6 The present model of colon tumorigenesis involves the conversion of adenomas to the malignant phenotype.7 Prostaglandins (PGs), in particular PGE2, have been implicated in the growth of both adenomas and cancer.8 The cyclooxygenases (COX), COX-1 and COX-2, are key enzymes in the synthesis of prostanoids. COX-1 is considered to produce PGs to maintain tissue homeostasis, e.g. integrity of the gastrointestinal mucosa, whereas COX-2 is induced by hormones, growth factors and cytokines, and generates PGs responsible for inflammatory responses, angiogenesis, cell proliferation and apoptosis.8 The importance of PGs for malignancy is demonstrated by epidemiological studies where the use of non-steroidal anti-inflammatory drugs (NSAIDs) resulted in a substantial reduction of the risk to develop tumors, in particular CRC.9,10 Previous studies have demonstrated low or non-detectable levels of COX-2 in normal colon tissue and increased contents in tumors, while COX-1 was expressed at low levels in both normal and malignant cells.11 Multiple reports have focused on COX-2 in CRC9 and recently, a trial with a COX-2 specific inhibitor, celecoxib, reduced the frequency of colorectal polyps in patients with an earlier history of colorectal adenomas.12 The final conversion to PGE2 is mediated by prostaglandin E synthase (PGES). Two microsomal isoforms are described, mPGES-1 and mPGES-2; and both forms were found to be over-expressed in CRC.13 There are four receptors for PGE2 (EP1 –EP4); all demonstrated to participate in experimental carcinogenesis.9 Interestingly, activation of the EP2 receptor by PGE2 was demonstrated to interact with the axin/b-catenin signaling in human colon cancer cells in vitro.14 Alteration of this pathway by mutations in the APC gene is a crucial event in colorectal tumorigenesis, both in humans and experimental animal models.15 An additional role for PGE2 in tumorigenesis is the activation of the cyclic AMP signaling pathway in “tumor associated stromal cells”, e.g. immune cells, where an altered function might result in a defective anti-tumor response.16 The aim of this study was to characterize the expression, cellular localization and contents of key enzymes for the synthesis of PGE2 (COX-1, COX-2, mPGES-1), and the EP2 receptor, in normal tissue, in adenomas, and in CRC.

MATERIALS AND METHODS Tissues of adenomas, normal colon and CRC Adenomas were from (surgical pathology files, Sahlgrenska University Hospital, Go¨teborg, Sweden) six patients with sporadic adenomatous polyposis (1 tubular, 5 tubulovillous). Five were of mild to moderate dysplasia and one of severe dysplasia.17 Biopsies of normal colon and CRC were obtained from patients (surgical pathology files, the University Hospital, Uppsala, Sweden) undergoing routine surgical procedures with colonic or rectal resection. Non-neoplastic tissue adjacent to the cancer was obtained from all patients with CRC and served as control tissue (normal colon) for the corresponding tumor of the same patient. The tumors were classified according to Dukes’ stages.18 Tissue samples were snap frozen and kept at 2 708C until analysis.

Homogenization of tissues and immunoblotting Preparation of tissue extracts and the procedure for immunoblotting/visualization (Tropix, Bedford, UK) were described previously in detail.19 The primary antibodies were from Cayman Chemical Co. (Ann Arbor, MI, USA): COX-1 (monoclonal, dilution 1:1,000), COX-2 (rabbit polyclonal, 1:1,000), mPGES-1 (rabbit polyclonal, 1:500), EP2 receptor (rabbit polyclonal, 1:500). Proliferating cell nuclear antigen (PCNA) (monoclonal, 1:1,000) was from Santa Cruz Biotechnology (San Diego, CA, USA). Electrophoresis standards for COX-1 and COX-2 (Cayman Chemical Co.) were used as positive controls. Each blot contained an identical sample (see below) as an internal control in order to compare the levels of expression between blots.

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Densitometric scanning Semi-quantitative measurements of the immunoblots were made by densitometry (Fluor-Se Multimager, Quantity One ver. 4.1.0., BioRad, Hercules, CA, USA). The optical density (OD) of each band was measured. The internal standard on each blot was set to 100%. A CRC sample (Dukes’ B) was used as an internal standard for COX-2, mPGES-1 and EP2 measurements, while normal colon from a Dukes B patient was used for COX-1. The signal from each band was compared to the standard and the obtained relative value was used for statistical analysis.19 Immunohistochemistry The immunohistochemical analysis is described in detail elsewhere.19 The primary antibodies COX-1 (1:100), COX-2 (monoclonal, 1:100), mPGES-1 (1:50), EP2 (1:50) were from Cayman Chemical Co. (Ann Arbor, MI, USA) and Cytokeratin 8 (CK8, monoclonal, 1:400, marker of epithelial cells) was from DAKO (Copenhagen, Denmark). Primary antibodies were replaced by equal amounts of TBS as negative controls. Statistics Values are given as the mean ^ standard error of the mean (SEM). ANOVA followed by Fischer’s LSD post-hoc test was used for the analysis of the immunoblotting data obtained by densitometric scanning. When comparing normal and CRC samples from the same patient, paired students t-test was used. A p-value less than 0.05 was considered significant. RESULTS COX-1 in normal colon, adenomas and CRC A strong expression of COX-1 was noticed in most of the normal colon samples obtained from patients of all Dukes’ stages. The adenocarcinomas of all stages demonstrated a lower expression compared to the corresponding normal colon tissue from each individual patient (Fig. 1A–C). The decrease was significant for all three stages: Dukes’ A tumors (n ¼ 8) 37% ( p , 0.05), Dukes’ B tumors (n ¼ 9) 32% ( p , 0.05), and in Dukes’ C tumors (n ¼ 10) 31% ( p , 0.05) (Fig. 1A –C). When all normal colon samples (n ¼ 27) and the corresponding CRC samples (n ¼ 27) were compared as groups with the content in adenomas (n ¼ 6), the latter content was in between that of normal samples and the adenocarcinomas and did not significantly differ from either group (Fig. 1D). COX-1 was localized to epithelial cells in the normal colon (Fig. 2A) and in the adenomas (Fig. 2E). No epithelial staining was observed in the CRC, where the expression was confined to the stroma (Fig. 2C). Staining of cells in the stroma was scarce in normal colon and absent in the adenomas (Fig. 2A, E). COX-2 in normal colon, adenomas and CRC COX-2 was low in normal colon samples of CRC patients (n ¼ 32), but a trend towards an increased content was observed in the normal colon obtained from Dukes’ C patients. There was no significant difference between the individual Dukes’ stages and the corresponding normal colon (Fig. 3A – C). However, the COX-2 expression in adenocarcinomas (Dukes’ A-C) combined to one group (n ¼ 32), was significantly elevated compared to the corresponding normal colon samples (n ¼ 32) ( p , 0.05) (Fig. 3D). The levels in adenomas (n ¼ 6) were not significantly different compared to the normal colon or to the CRC (Fig. 3D). Only a few epithelial cells and stromal cells stained positive for COX-2 in normal colon tissue (Fig. 2B). The adenomas exhibited staining limited to epithelial cells (Fig. 2F) whereas a majority of the CRC exhibited staining of both epithelial and stromal cells (Fig. 2D). Microsomal Prostaglandin E Synthase-1 (mPGES-1) in normal colon, adenomas and CRC A slight increase of mPGES-1, although not significant, was observed for Dukes’ A (n ¼ 7) and C (n ¼ 8) tumors (Fig. 4A, C). The content in Dukes’ B (n ¼ 6) tumors was significantly increased compared to the corresponding normal colon tissue (n ¼ 6) (Fig. 4B). The levels in the combined group of CRC (Dukes’ A-C) (n ¼ 21) demonstrated a trend of increase compared to normal colon (n ¼ 21), but this was not significant (Fig. 4D). Neither did the expression in the adenomas (n ¼ 6) significantly differ from the groups of normal colon or adenocarcinomas (Dukes’ A-C) (Fig. 4D). The normal colon demonstrated a weak staining of mPGES-1 in some epithelial cells, as well as sporadic staining of stromal cells (Fig. 5A). A distinct, epithelial staining (cytoplasmic) was observed in

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Duke A

100

50 * 25

COX-1 expression (% of internal control)

50 *

tumor

normal

Duke C

100

50 * 25

COX-1 expression (% of internal control)

normal

COX-1 expression (% of internal control)

Duke B

100

tumor

100

50 a

0 normal

tumor

normal

adenomas

CRC

Fig. 1. COX-1 expression in normal colon, adenomas and CRCs. The semi-quantitative measurements were obtained by densitometric scanning of immunoblots. A–C) The graph demonstrates the content of COX-1 in normal colon and CRC (paired values) from each patient. A) Dukes’ A (n ¼ 8), B) Dukes’ B (n ¼ 9), C) Dukes’ C (n ¼ 10). The bars to the left and right hand sides of the figures represent Mean ^ SEM of COX-1 content in normal colon and CRC. The samples are plotted as percentage of a normal colon tissue from a patient with a Dukes’ B tumor that was used as an internal standard sample on each immunoblot. Paired t-test was used for statistical analysis. An asterisk (*) denotes a statistically significant difference ( p , 0.05) between tumor and normal colon of the same Dukes stage. D) Histogram representing samples of normal colon tissues, adenomas (n ¼ 6) and CRC. ANOVA followed by Fischer’s LSD post-hoc test was used for statistical analysis. (a) p , 0.05 vs. normal samples. All CRC stages were included in the CRC group.

adenomas (Fig. 5E). A positive staining (cytoplasmic), mainly of clusters of stromal cells, was present in the CRC (Fig. 5C). EP2 receptor in normal colon, adenomas and CRC The CRC samples showed a strong expression of the EP2 receptor, and the contents were also increased significantly in the Dukes’ A (n ¼ 7) and C (n ¼ 8) stages compared to the corresponding groups of normal colon ( p , 0.05) (Fig. 6A, C). An increase, but not significant, was also observed in the Dukes’ B (n ¼ 6) tumors (Fig. 6B). The content of EP2 was significantly increased in adenomas (n ¼ 6) compared to the group of normal colon ( p , 0.05) (Fig. 6D). The increase of EP2 was also

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* (b)

(a)

* (d)

(c)

* (e)

(f)

Fig. 2. Staining for COX-1 (a, c and e) and COX-2 (b, d, and f) in colon tissues. Immunohistochemical analysis of normal colon mucosa (a, b), a Duke’s B stage tumor (c, d) and an adenoma (tubulovillous) (e, f). Arrow ¼ epithelial cells, * ¼ stroma cells (magnifications: 200 £ , inserts 400 £ ).

significant in the combined group of CRC (n ¼ 21) compared to the corresponding group of control tissue (n ¼ 21) ( p , 0.05) (Fig. 6D). The EP2 receptor was demonstrated (membrane staining) in both epithelial and stroma cells in normal colon (Fig. 5B). The adenomas exhibited a strong staining (membrane/cytoplasmic) of epithelial cells, while the signal from stromal cells was very weak or undetectable (Fig. 5F). The stromal cells in the adenocarcinomas showed a clear signal (membrane/cytoplasmic), while the staining of epithelial cells was less intense (Fig. 5D). PCNA in normal colon, adenomas and CRC Proliferating cell nuclear antigen (PCNA), an enzyme involved in DNA synthesis, was used as a marker to estimate proliferation. A significant increase of PCNA content was demonstrated by immunoblotting (data not shown) in CRC compared to the corresponding normal colon (normal 20 ^ 3%, tumor 44 ^ 9%, p , 0.01). Interestingly, the contents of PCNA in adenomas were increased even more in comparison to normal colon (76 ^ 9%, p , 0.001). DISCUSSION The importance of PGE2 in colorectal tumorigenesis is supported by experimental and epidemiological studies.20 This study demonstrates that key enzymes for the synthesis of PGE2, i.e. COX-1, COX-2, mPGES-1, and the EP2 receptor, exhibit cell- and stage specific expression patterns in adenomas and CRC. The PGs, generated by COX-1, are involved in the maintenance of barrier functions of the intestinal mucosa and the protection against damage, and are also essential for the survival of intestinal stem cells.21 Our results demonstrated a major localization of COX-1 to epithelial cells of the normal colon, in agreement with earlier studies.22 The content of COX-2 in the normal epithelium was sparse with only a few positive cells. This finding was expected since the COX-2 expression is commonly associated with inflammation.8 Microsomal PGES-1 was also localized to the epithelial cells of the normal colon,

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Duke A

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Fig. 3. COX-2 expression in normal colon, adenomas and CRC. The semi-quantitative measurements were obtained by densitometric scanning of immunoblots. A–C) The graph demonstrates the content of COX-2 in normal colon and CRC (paired values) from each patient. A) Dukes’ A (n ¼ 11), B) Dukes’ B (n ¼ 10), C) Dukes’ C (n ¼ 11). The bars to the left and right hand sides of the figures represent Mean ^ SEM of COX-2 content in normal colon and CRC. The samples are plotted as percentage of a normal colon tissue from a patient with a Dukes’ B tumor that was used as an internal standard sample on each immunoblot. Paired t-test was used for statistical analysis. An asterisk (*) denotes a statistically significant difference ( p , 0.05) between tumor and normal colon of the same Duke stage. D) Histogram representing samples of normal colon tissues, adenomas (n ¼ 6) and CRC. ANOVA followed by Fischer’s LSD post-hoc test was used for statistical analysis. (a) p , 0.05 vs. normal samples. All CRC were included in the CRC group.

similar to the findings by Yoshimatsu and co-workers.13 The EP2, EP3 and EP4 receptors were demonstrated in normal human colon.23 Our study focused on the EP2 receptor, since previous experimental studies in vivo and in vitro showed that this receptor is important for intestinal polyposis24 and proliferation of colon cancer

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Duke A

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Fig. 4. mPGES-1 expression in normal colon, adenomas and CRC. The semi-quantitative measurements were obtained by densitometric scanning of immunoblots. A–C) The graph demonstrates the content of COX-1 in normal colon and tumor tissue (paired values) from each patient. A) Dukes’ A (n ¼ 7), B) Dukes’ B (n ¼ 6), C) Dukes’ C (n ¼ 8). The bars to the left and right hand sides of the figures represent Mean ^ SEM of mPGES-1 content in normal colon and CRC. The samples are plotted as percentage of a normal colon tissue from a patient with a Dukes’ B tumor that was used as an internal standard sample on each immunoblot. Paired t-test was used for statistical analysis. An asterisk (*) denotes a statistically significant difference ( p , 0.05) between tumor and normal colon of the same Dukes’ stage. D) Histogram representing samples of normal colon tissues, adenomas (n ¼ 6) and CRC. ANOVA followed by Fischer’s LSD post-hoc test was used for statistical analysis. (a) p , 0.05 vs. normal samples. All CRC stages were included in the CRC group.

cells.14 The present study demonstrated EP2 receptors in the epithelium and in the stroma of normal colon. The stained stromal cells were not further characterized, but were most likely immune cells.23 COX-1, COX-2, mPGES-1 and the EP2 receptor were mainly confined to epithelial cells of the adenomas, and the contents of COX-1, COX-2 and mPGES-1 were similar to that of normal colon. In contrast, the EP2 receptor demonstrated a significant increase. This suggests that the epithelial cells in adenomas have the potential of an enhanced responsiveness to PGE2. The significance of co-expression of COX-1 and COX-2 in adenomas, as demonstrated in the present study, was analyzed in a rodent model for FAP25

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* * (a)

(b)

* * (c)

(d)

* (e)

(f)

Fig. 5. Staining for mPGES-1 (a, c and e) and EP2 (b, d, and f) in colon tissues. Immunohistochemical analysis of normal colon mucosa (a, b), Dukes’ B stage tumor (c, d) and an adenoma (tubulovillous) (e, f). Arrow ¼ epithelial cells, * ¼ stroma cells (magnifications: 200 £ , inserts 400 £ ).

where COX-2 was expressed only in larger polyps/adenomas, while COX-1 was found in polyps/adenomas of any size. The authors proposed that the presence of COX-1 “secured” basal levels of PGE2 for early growth of polyps to a stage/size when additional expression of COX-2 (and mPGES-1) contributed to an accelerated growth. Indeed, the present study provides support for an accelerated proliferation rate in adenomas, since the expression of PCNA was significantly increased compared to normal colon. A recent study using a human cell line established from early microadenoma of a polyposis patient demonstrated that exogenous PGE2 could stimulate progression of related genes in these cells, e.g. c-fos, the ERK signaling pathway and COX-2.26 We did not observe expression of COX-2 in the stroma of adenomas and there are conflicting results regarding the cellular localization of over-expressed COX-2. Some studies reported an increase of COX-2 in cancerous cells in colon adenomas27 while others demonstrated COX-2 expression predominantly in stromal cells, e.g. macrophages, and only weak expression in epithelial cells.28,29 In polyps from patients with FAP, COX-2 was demonstrated predominantly in stromal fibroblasts and endothelial cells, but to a very small extent in bone-marrow derived cells.30 One study showed active inflammatory signaling in polyps, suggesting that NSAIDs acted, at least in part, on stromal- rather than epithelial cells.31 Expression of COX-2 was observed in epithelial cells and macrophages in sporadic colorectal polyps32 as well as in fibroblasts and endothelial cells of polyps from patients with FAP.24 In addition, COX-2 expression was positively correlated to an increased severity of dysplasia in epithelial cells33 and in size34 of colorectal adenomas. The major stromal expression of COX-2 in adenomas or polyps has been attributed to macrophages.29 This finding suggested that COX-2 was involved in the synthesis of PGs for signaling between macrophages and epithelial cells in polyps in vivo,23 a paracrine signaling pathway demonstrated in experiments in vitro.35 The adenomas examined in the present study, might represent stages of increased growth, but without a phenotype lacking “tumor-antigenicity” to recruit immune cells (macrophages, T-cells) to the stroma. A mechanism for tumor-derived PGE2 to participate in malignant progression could be to convert adaptive, regulatory T-cells (Treg) into a regulatory phenotype.36,37 Treg have been demonstrated to accumulate in tumors where they may impair an effective anti-tumor immune response.38 In fact, an inverse correlation between the percentage of Treg in peripheral blood and disease prognosis was demonstrated in patients with gastrointestinal malignancies.39

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Duke A

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Fig. 6. EP2 expression in normal colon, adenomas and CRC. The semi-quantitative measurements were obtained by densitometric scanning of immunoblots. A–C) The graph demonstrates the content of COX-1 in normal colon and tumor tissue (paired values) from each patient. A) Dukes’ A (n ¼ 7), B) Dukes’ B (n ¼ 6), C) Dukes’ C (n ¼ 8). The bars to the left and right hand sides of the figures represent Mean ^ SEM of mPGES-1 content in normal and CRC tissue. The samples are plotted as percentage of a normal colon tissue from a patient with a Dukes’ B tumor that was used as an internal standard sample on each immunoblot. Paired t-test was used for statistical analysis. An asterisk (*) denotes a statistically significant difference ( p , 0.05) between tumor and normal colon of the same Dukes’ stage. D) Histogram representing samples of normal colon tissues, adenomas (n ¼ 6) and CRC. ANOVA followed by Fischer’s LSD post-hoc test was used for statistical analysis. (a) p , 0.05 vs. normal samples. All CRC stages were included in the CRC group.

Dukes’ stage A demonstrated a reduced content of COX-1 compared to control colon and to adenomas. A similar reduction of the COX-1 protein in CRC, was noted by Kargman and coworkers.11 They also found similar contents of COX-1 in normal colon and in adenomas. Many studies have focused on the involvement of COX-2 in tumorigenesis9 since COX-2 expression stimulates growth, cell survival, angiogenesis and tumor cell invasiveness.8 Furthermore, genes regulating apoptosis, proliferation and

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cell-cell communication were affected by COX-2 expression.26 Taken together, these studies suggested the involvement of COX-2, but not of COX-1, in carcinogenesis. The present study demonstrated also a significant augmentation of COX-2 in the combined group of CRC (Dukes’ A-C). Interestingly, we observed a trend of increase in the corresponding normal colon samples, in particular in samples obtained from patients with Dukes’ C tumors. This finding is most likely due to an increased systemic inflammatory response, with an infiltration of immune cells also into the surrounding normal colon tissue, adjacent to the growing tumor. Clinical studies have also demonstrated elevated levels of C-reactive protein in patients with CRC, and that this marker of a generalized inflammatory response was associated with cancer-specific survival.40 Recent reports have shown the presence of COX-2 expressing immune cells, e.g. macrophages, in the stroma of colon tumors.35 We observed that the content of COX-2 varied between individual CRC stages, and similar variations have been reported earlier.11,41 Sheehan and co-workers showed a correlation between a greater expression of COX-2 with more advanced Dukes’ stage.33 In contrast, Dimberg and collaborators41 were unable to find this correlation, similar to our results. Previous studies have reported an increased content of mPGES-1 in CRC.13 In the present study, a significant elevation of mPGES-1 was demonstrated in Dukes’ stage B tumors. Previous immunohistochemical analysis13 demonstrated low levels of mPGES-1 localized to epithelial cells in normal colon. An increased expression was observed in adenomas and in adenocarcinomas.13,42 All these studies reported an exclusive epithelial localization of mPGES-1. The lack of stromal staining in adenocarcinomas is in contrast to our findings, where mPGES-1 was demonstrated in clusters of stromal cells, a similar pattern to that of COX-2. Two studies13,42 observed an increase of COX-2 in conjunction to mPGES-1 in tumors. In support for a stromal localization of mPGES-1 (as well as for COX-2) are clinical,35 as well as experimental studies,23 demonstrating the importance of macrophages in this compartment. Experimental models have demonstrated a role for all four EP receptors in experimental carcinogenesis.9,23 The present study focused the expression of the EP2 receptor, which similar to EP4, activates the PKA-pathway, but in addition also participates in the b-catenin/axin/APC pathway.9 It was also suggested that the EP2 and EP4 receptors were most likely mediators of the paracrine effects of PGE2 on intestinal epithelial cells, both at early and at late stages of colorectal carcinogenesis.8,43 Targeted deletion of the EP2 receptor gene in apc D 716 knockout mice resulted in a decrease in the number of polyps, and the phenotype resembled the cox-2 2/2 mice.24 In contrast, targeted deletion of the EP1 or Ep3 receptors did not affect polyp formation. These studies also showed that COX-2 expression was boosted by PGE2 through the EP2 receptor, via a positive feedback loop. In both COX-2 and EP2 deficient mice, induction of angiogenesis-related factors was suppressed.24 Other studies have also reported that angiogenic effects of COX-2 may be mediated by the EP2 receptor.44 These results proposed a role for the EP2 receptor in early stages of tumorigenesis. Indeed, our result showed that the EP2 receptor was increased in adenomas and in CRC of all Dukes’ stages, supporting a role in both polyp formation and in the progression of CRC. A study in mice reported an increase of the EP2 receptor in the intestine after radiation injury.21 They could also demonstrate that pro-survival- and anti-apoptotic effects of PGE2 were mediated by the EP2 receptor. These experimental findings, and the observed increase of the EP2 receptor in adenomas and CRC in the present study, suggest participation in cell cycle control and programmed cell death, resulting in an increased growth rate, reflected by elevated levels of PCNA in the present study. The present findings support a role for PGE2 signaling in the growth of adenomas and in the progression of CRC. The contents of COX-2, mPGES-1 and EP2 were significantly elevated in CRC in comparison to the corresponding normal colon. In contrast to the normal colon tissue and adenomas, the level of COX-1 was decreased in CRC. Expression in cells outside of the epithelium, i.e. particular in the stroma of CRC, of COX-2, mPGES-1 and EP2, supports previous experimental studies emphasizing stromal-epithelial interactions in tumor progression.29 Our observation of co-expression of COX-1 and COX-2 in adenomas provides a plausible explanation to the more efficient reduction of adenomas/CRC observed in epidemiological studies of users of non-specific NSAIDs compared to clinical trials with coxibs,9,12 suggesting that non-specific NSAIDs can prevent earlier stages in tumorigenesis.

Acknowledgements Support was provided by the Swedish Cancer Society, the Swedish Society of Medicine, the Swedish Medical Research Council (13475 to K.S. and L.H.), the Norwegian Cancer Society (to L.H), the Novo Nordisk Research Foundation (to L.H.), Syskonen Svenssons, Lars Hiertas foundation, Foundations of Assar Gabrielsson and Foundation King Gustav V Jubilee Clinic Cancer Research.

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OPEN ACCESS

Review article

Examining the links between air quality, climate change and respiratory health in Qatar Kevin Teather1,*, Natacha Hogan2, Kim Critchley1, Mark Gibson3, Susanne Craig3, Janet Hill2 1

University of Calgary â&#x20AC;&#x201C; Qatar, Doha, Qatar 2 University of Saskatchewan, Saskatoon, Canada 3 Dalhousie University, Halifax, Nova Scotia, Canada *Email: klteathe@ucalgary.edu.qa

ABSTRACT Little information exists concerning (i) source contributions to airborne particulate pollution in Qatar, (ii) the potential impact that deteriorating air quality may have on the respiratory health of residents, and (iii) how climate change may affect respiratory health through its impact on air quality. Air quality in Qatar may be negatively affected by naturally occurring contributions including dust/sand originating from adjacent desert regions, microbial communities that may be associated with these particulates, and volatile organic compounds (VOCs) released by blooms of phytoplankton in coastal waters. Of increasing concern are anthropogenic contributions, including emissions from the rapidly growing number of vehicles, from ships travelling in the Persian Gulf, and from industrial and construction activities. We examine the relative importance of these contributions and discuss some of the expected impacts on respiratory health. We conclude by speculating on the impact that climate change may have on air quality and respiratory health around Qatar.

http://dx.doi.org/ 10.5339/avi.2013.9 Submitted: 18 May 2013 Accepted: 27 June 2013 ÂŞ 2013 Teather, Hogan, Critchley, Gibson, Craig, Hill, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Teather K, Hogan N, Critchley K, Gibson M, Craig S, Hill J. Examining the links between air quality, climate change and respiratory health in Qatar, Avicenna 2013:9 http://dx.doi.org/10.5339/avi.2013.9

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BACKGROUND The deterioration of air quality in many regions of the world has generated increasing concern with growing evidence of its impact on human health. While anthropogenic sources of air pollution originating largely from industrial and vehicular emissions have received the most attention, exposure to natural sources of airborne particulate matter, including those generated from fires, volcanic eruptions, and sand/dust storms also impact health. Many areas around the Middle East, including Qatar, have experienced substantial development over the past few decades, funded largely by gas and oil industries, raising concerns about air quality. Compounding problems generated by anthropogenic air pollutants are natural sources of airborne particulates, mainly dust and sand, originating from surrounding arid regions [1 and references therein]. In this article, we first examine some of the sources that may impact air quality in Qatar and review general effects they may have on human health. We then look more specifically at the impact of air quality on respiratory heath. This is not meant to be an exhaustive review of the health issues that may be incurred by exposure to various air pollutants, but rather an initial assessment of the potentially important sources and effects of airborne particulates in the region. CONTRIBUTING SOURCES TO POOR AIR QUALITY Natural sources Air quality is affected by a diverse array of substances including respirable suspended particulates, carbon monoxide, sulphur and nitrous oxides, acid gases, metals, volatile organics, solvents, pesticides, and bioaerosols.2 In the absence of anthropogenic sources of pollutants, air quality can be negatively affected by airborne particulates and chemicals derived from a variety of natural sources. Some natural air pollutants originating from forest fires and sand storms are considered to be as harmful as fossil combustion-related air pollutants.3,4 Volcanic emissions, for example, can contain large amounts of particulates as well as sulphur dioxide, fluorides, hydrogen chloride, and toxic metals.2 Of particular concern in Qatar and other regions of the Middle East are suspended particles of dust/sand. High concentrations of suspended particles are common in desert regions when moistureladen cooler air drops to the surface and is subsequently pushed back up causing wind and eddies, carrying with it particles picked up from the ground. These particles are carried by wind over varying distances, depending largely on the size of the granules and the wind velocity. The concentration of airborne particulates generated in this way can be classified by its impact on visibility where blowing dust, dust storm and severe dust storm refer to times when horizontal visibility is less than 11 km, 1000 m, and 200 m, respectively. Akbari5 noted that in some regions of the Middle East, and for about 30% of the time, dust conditions fall into one of these three categories. Natural mineral and chemical constituents of dust Airborne mineral dust originates from the weathering of surface rocks and soils and subsequent transport via strong surface winds.6 In the absence of other inputs, the initial mineral and chemical properties of the dust are therefore determined by the substrate from which they originated. Dust origination from soil and the evaporation of seawater are the primary sources of airborne particles worldwide.6 Low precipitation in much of the Middle East favours longer-term suspension of these particles in this region. Engelbrecht et al.7,8 provided a comprehensive overview of aerosol dust throughout the Middle East noting that all samples contained silicate minerals, carbonates oxides, sulfates and salts in various proportions. Mineralogical analysis around Qatar suggests that dust in this area contain high amount of calcite, quartz and feldspar.7 Substantial evidence exists concerning the impact of sand/dust storms on human health. Recent studies have shown that hospital admission rates for various respiratory illnesses, including asthma,9 bronchitis,10 pneumonia,11 and general respiratory problems,12,13 increase shortly after exposure to wind-generated dust. In addition, non-respiratory problems such as stroke,14 cardiovascular morbidity13 and congestive heart failure,14 as well as general emergency admissions,15 also increase following such events. It has been suggested that high levels of quartz found in dust in Kuwait City may be associated with a number of health problems, including silicosis.16 While the health costs of these events have not, to our knowledge, been determined, clearly they are substantial. This is expected to be particularly important for countries such as Qatar where dust storms occur on a relatively frequent basis.

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Physical, chemical and biological properties of the dust may all play a role in determining the type, frequency and seriousness of illnesses. Particles with diameters of less than 4 mm can penetrate into the bronchioles and alveoli of the lungs17 and it is generally agreed that particles less than 2.5 mm (PM2.5) pose the most serious threat to respiratory function.18 It has also been established that improvements in air quality through a lowering of PM2.5 concentrations can decrease mortality associated with respiratory and cardiovascular problems.19 Larger particles, classified as PM10 and defined as between 2.5–10 mm, are more likely to become trapped along the respiratory tract and subsequently expelled. However, even exposure to these coarse particles is known to increase the rates of hospital admissions for chronic obstructive pulmonary disorder (COPD) and asthma.20,21 In general, chronic exposure to airborne particulate matter can result in an increase in lower respiratory symptoms, COPD, reduction in lung function and reduction in life expectancy.22 Microbial communities Airborne particulates may contain bacteria, viruses, and fungi, as well as a number of allergens including pollens and organic debris. Since desert soils are the source of most of the airborne particulates in arid regions, a number of investigations have attempted to provide information on their biological communities. Griffin [23 and references therein] estimated that one gram of desert topsoil contains approximately 109 bacteria and 108 viruses. Gonzalez-Martin et al.24 found substantial variability in both bacterial and viral estimates in soils taken from different desert environments around the world. Importantly, the harsh ecological conditions of these environments is thought to select for characteristics that increase the effectiveness of long distance atmospheric dispersal by these organisms.23,25 Griffin23 reviewed research that detected bacteria and fungi in dust storms. Sixteen different genera of bacteria and 17 genera of fungi were detected in three studies in which dust had originated in the Middle East.26 – 28 More recently, 11 types of bacteria and two species of fungus were detected in airborne dust samples from various regions around Iraq.29 Bacillus species were the most common type of bacteria, making up just over 40% of all microorganisms identified, while the fungi Aspergillus and Candida made up 14.5% and 7.7% of the microbial community, respectively. Although direct links between human illness and microorganisms identified in dust storms have been difficult to establish, samples typically contain species known to be associated with known health problems. Isolates found in dust samples from Kuwait that are known to be pathogenic included Neisseria, Staphylococcus, Bacillus, Pantoea, Ralstonia, and Cryptococcus.26 Leski et al.30 identified at least five different human pathogens in desert dust samples taken from Kuwait and Iraq. Earlier studies had suggested links between sand-dust storms and pneumonitis,31 bacterial and atypical pneumonia,32 and anaphylactic and non-anaphylactic respiratory problems.27 One of the clearest links between dust-borne pathogens and human illness is that between the bacterium Neisseria and seasonal outbreaks of meningitis observed in regions of North Africa.33 One microbial community that has attracted recent attention in the deserts of Qatar is cyanobacteria. These organisms help bind desert sands and remain dormant until they are activated after rainfalls. The dried crusts and mats in which these communities occur can contribute to airborne dust, particularly if disturbed as a result of traffic. It has been suggested that cyanotoxins released by these organisms might be a risk factor in the development of certain neurological diseases.34,35 Phytoplankton Phytoplankton blooms in the Persian and Arabian Gulf and wider Arabian Sea are a normal ecological phenomenon. However, in recent years, the characteristics of these blooms have changed dramatically, both in terms of phytoplankton abundance and the organisms present.36 – 38 The factors controlling these blooms are numerous and complex, but primarily include natural ocean circulation and seasonal weather patterns,37 anthropogenic stress on marine ecosystems [39 and references therein], and fertilisation of the water column by trace element rich Aeolian dust from surrounding deserts.40 While not comprising a substantial component of airborne particulate matter, these marine phytoplankton are known to emit a large suite of volatile organic compounds (VOCs) including terpenes and organohalogens.41 – 46 Phytoplankton can be grouped into species or size classes that fulfil different ecological functions – commonly referred to as phytoplankton functional types (PFTs) – and PFTs have been shown to emit VOCs variably, both in terms of compound type and emission rate.42,46,47

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These phytoplankton-derived compounds can play an important role in air quality: for example, they may be involved in the formation and loss of tropospheric ozone, alter the lifetime of important atmospheric gases (e.g., stratospheric ozone) and, in the cases of dimethyl sulphide and isoprene, act as precursors to secondary organic aerosol (SOA) formation. Biogenic fluxes from the ocean can, therefore, potentially contribute to the total atmospheric loading of PM2.5 and VOCs around Qatar. Anthropogenic sources Anthropogenic additions to windborne dust are largely dependent on industrial and other pollutantgenerating activity in a region. Fine particles, because they provide more surface area per unit weight, may carry greater concentrations of toxic air pollutants, diffuse to surfaces faster and are far more reactive than larger particles.48 Such pollutants may include metals,49 heavy metals,50 pesticides,51 and a suite of chemicals associated with vehicular emissions.52 In a survey of Middle Eastern countries, Lelieveld53 found that the main nitrous oxide NOx source category is transport (59%), being dominated by road traffic, except in the United Arab Emirates (UAE) where emissions from international shipping are more prominent. The second and third most important NOx emission categories are power generation and industry, respectively. In Qatar, three important anthropogenic sources of air pollutants are vehicular emissions, industry (particularly gas and oil refineries), and construction activities. Vehicular emissions Although few studies have examined the impact of vehicular traffic on air quality in Middle Eastern countries, Waked and Afif54 suggested that road transport is a major contributor to air pollutants in the region. For example, El Raey55 estimated that the transport sector is responsible for about 70% of urban air pollution in Syria. In Doha, rapid population growth, lack of a well-developed transit system, low fuel prices, and high personal incomes combine to influence the high number of personal vehicles on the road; the number of cars more than doubled from 287,500 vehicles in 2000 to 656,686 in 2010.56 In addition, traffic congestion, common in many regions of Doha, adds significantly to vehicular emissions. Sixty air samples collected over a one year period (2006 â&#x20AC;&#x201C;2007) in Qatar revealed average concentrations of total suspended particulates of 282 mg/m3, with PM10 and PM2.5 concentrations of 165 and 67 mg/m3, respectively.7 The observed concentration of PM2.5 in Qatar is more than double the recommended target across Canada57 and Europe58 and four times higher than recommended by the U.S. Environmental Protection Agency.59 Indeed, due to the increasing body of evidence linking fine particles to serious human health issues, the EPA is recommending lowering the exposure level standard to 12 mg/m3 from its current 15 mg/m3. There was a 5.4% annual increase of minute particles between 2007 and 2010, as well as a 9.3% and 2.6% increases in nitrogen oxides and sulphur dioxide levels, respectively; all are at least partially attributed to increasing vehicular use in the area.56 Health problems associated with vehicular emissions are expected to be more pronounced in pedestrians and outdoor labourers as compared to vehicle drivers as the latter are partially shielded from pollutants. However, as outdoor air quality is closely associated with indoor air quality, even people in buildings near heavy traffic areas may be impacted. Emissions that may be of particular concern include sulphur, nitrogen oxides, ozone, carbon monoxide and benzene. Although substantial evidence exists concerning the harmful effects of total emissions, specific causal agents are difficult to identify. The effects of sulphur and nitrogen dioxide on human health, for example, are not well understood.60 Exposure to ozone and carbon monoxide, on the other hand, is known to affect lung and cardiovascular function and result in increased hospital admissions.61 â&#x20AC;&#x201C; 63 Benzene exposure has been associated with an increased incidence of childhood leukemia.64 In addition to emissions from road traffic, ships are known to be an important source of PM2.5 in coastal cities such as Doha.65,66 There have been a number of studies demonstrating that ship emissions significantly impact air quality in port cities.67,68 Corbett et al.66 estimated 60,000 cardiopulmonary and lung cancer deaths annually can be attributed to ship emissions in Europe, East Asia, and South Asia alone. The main ship emissions of health concern are PM2.5 oxides of nitrogen and sulphur dioxide (SO2). Other major air pollutants of health concern found in ship emission plumes include black carbon/elemental carbon (soot), heavy metals, polynuclear aromatic hydrocarbons (PAHs),69 volatile organic compounds (VOCs), ultrafine particles70 and carbon monoxide (CO).66 The VOCs and NO2 generated by ships are precursors to ground-level ozone (O3), which is known to be

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harmful to health and a powerful greenhouse gas.71 Furthermore, because ship pollution travels great distances, many inland populations are also susceptible to marine emissions.72 Industrial emissions Total greenhouse gas emissions (including carbon dioxide, methane, and nitrous oxide) increased by 47% in Qatar over the period between 2001 and 2006.73 This increase was due primarily to increased oil and gas operations (70%) although increased vehicle use accounted for 10% of this increase. Only one study in Qatar has examined suspended particulates originating from the oil industry. Abou-Leila et al.74 examined possible differences in air particulates before and during the burning of oil fields in Kuwait during the Gulf War. They detected aluminium, silicon, sulphur, chlorine, potassium, calcium, iron and zinc of which only zinc and sulphur increased during the war. Clearly, this does not reflect emissions from normal industrial activity. In addition, emissions from gas and oil industries may be less of a concern for human health since they are released in areas away from major urban centers. Of growing concern, however, are emissions of aerial plankton and dust from the cement industry, which has grown substantially in the past decade in response to urban development and increased construction.56 Construction activity Construction-caused environmental pollution has increasingly become a significant cause of poor air quality75 and is of particular concern to human health as it generally occurs in heavily populated regions. Construction activities generate dust from concrete, cement, wood, stone and silica, all of which can contribute to health problems. In addition, they contribute to increased vehicular use that are associated with problems discussed above, as well as noxious vapours arising from glues, paints, plastics, cleaners, etc.. Thus, areas around construction sites are typically exposed to an intense, and often unpredictable, array of hazardous air pollutants. Sand and dust created by the manufacturing industry and the soaring number of construction projects here have all contributed to the deterioration of air quality around Doha.56 Unfortunately, little quantitative data exists concerning the air quality deterioration resulting from construction activities. Air quality and respiratory health Although exposure to various air pollutants can have wide-ranging impacts on human health, of primary concern is respiratory health. Illnesses associated with the respiratory system are important reasons for clinic visitation, hospital admission and drug use in Qatar and in neighbouring countries. The incidence of respiratory illnesses varies across the Middle East and, in most cases, detailed analyses have not yet been done. Asthma is the most common respiratory problem, particularly in children, and often results in hospital admission. The prevalence of asthma in children has been found to be 13% in the UAE,76 16.8% in Kuwait,77 19.6% in Saudi Arabia,78 and just over 20% in Oman.79 Rates are similar for Qatar; Janahi et al.80 found that 19.8% of 6â&#x20AC;&#x201C;14 year old schoolchildren were asthmatic and AlMarri78 reported a hospital admission rate for asthma of 42 per 100,000, of which 35% were less than 15 years of age. While some of these differences may be due to different age cohorts of children studied, they suggest the incidence of asthma in the Middle East is relatively high and likely increasing.78,81 While several studies have focused on the prevalence of asthma, other respiratory problems contribute significantly to hospital admissions in Qatar. Dr. Hussain al Awadhi, a senior consultant at Hamad Medical Corporation (HMC), noted that â&#x20AC;&#x153;While statistics continue to show a steady decrease in reported cases of health conditions such as stroke, hypertension and even cancer, the reverse is the case for COPD diseases commonly referred to as chronic bronchitis and emphysema, as they continued to be on the increaseâ&#x20AC;? (Qatar Tribune, 27/10/10). Janahi et al.80 reported high prevalence of diagnosed allergic rhinitis (30.5%), and chest infection (11.9%) among schoolchildren in Qatar, with the prevalence of each illness being similar in parents. Two other major respiratory problems that may be related directly or indirectly to air quality include tuberculosis (TB) and pneumonia. Unfortunately, there are few published studies concerning the incidence of either in the Middle East. Memish et al.82 reported that TB is a serious illness throughout the region and that its incidence in Saudi Arabia is 17 per 100, 000 people. Tuberculosis has been particularly problematic in Qatar, which has not only the highest incidence of the disease, but is one of the only countries in the region that showed no decline in its incidence between 1990 and 2006.83 Waness et al.84 described the recent increase in community

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acquired pneumonia in the Middle East and prevalence of other types of bacteria responsible for this illness throughout the region. Particulate-induced inflammation is regarded as the main mechanism underlying respiratory health effects.85 Fine and ultrafine particles are more strongly associated with this response due to their ability to deposit deep into the lungs, access the alveolar tissue, and interact with both macrophages and epithelial cells, the principal cells that process airborne particles in the lung.86,87 In fact, there is a link between high levels of inflammatory markers in blood and cardio-respiratory effects in populations exposed to airborne particulates.85,88 The formation of reactive oxygen species (ROS) has been suggested as an important initiating factor of particle-induced inflammation89 as well as being associated with oxidative stress leading to cytotoxicity and DNA damage.90 As previously stated, particulate matter is a complex mixture of compounds of different origin and chemical composition that contribute to its toxicological potential. Several toxicological studies have established an association between some metals in particulate matter and the particulateinduced inflammation in the lungs. Exposure to particulate matter collected near a steel plant in the United Kingdom caused inflammation in the rat lung correlated with the concentration of metals in particulate mass.91 Metals associated with particles in welding fumes induced an inflammatory response in an alveolar cell line.92 Present in almost all combustion-related missions, polycyclic aromatic hydrocarbons (PAHs) are also a significant constituent of particulate matter and may induce inflammatory, cytotoxic, and genotoxic effects. A number of studies93,94 have reported DNA damage in lung epithelial cells exposed to particulate matter sampled in different cities. In fact, levels of vehicular emissions have been correlated with levels of DNA damage with samples from highly urban sites inducing greater DNA damage compared to sites with lower traffic emissions.95 To date, no studies have examined the inflammatory potential and toxicological properties of particulate matter from the Middle Eastern region, despite the high concentration of airborne dust throughout the regions and high level of air pollution in urban centres. Differences in air quality and frequency of dust storm events during certain periods of the year are likely associated with effects on respiratory health but the epidemiological data and experimental studies to this effect are lacking. In terms of mitigating harmful emissions, identifying compounds with the great toxicological activity (i.e. metals, PAHs, microbes) may help to define more efficient strategies to reduce air pollution by focusing on those sources that emit the most harmful particles. Weather and the potential impact of climate change on air quality in Qatar A variety of climatic factors are known to influence respiratory health, usually through their impact on air quality. The region around Qatar is one of the driest on earth with maximum daily average temperatures in August reaching 458C.96 Wind, particularly during the winter months, can carry significant amounts of dust/sand. This results in the dust loading in Qatar and neighbouring countries (200 mg/m2) ranking as the second highest in the world (after Saharan Africa).97 While a relationship between weather patterns and respiratory problems are commonly noted in newspaper articles and websites (e.g., “Weather flux triggers respiratory diseases” – Qatar Tribune; “Residents advised to take health precautions during dust storms” – Qatar is Booming), detailed investigations concerning such links are lacking. Interestingly, Dr. Osama al Dulaimi reported that the number of asthma cases at the Qatar Medical Centre (QMC) increased by as much as 30% during and shortly after very windy conditions (Qatar Tribune, 27/03/11). As weather patterns play an important role in determining air quality, it is important to understand the potential impact of climate change if we are to better evaluate stresses that may be placed on the health care system in the coming decades. The impacts of climate change are most often discussed in light of how changes in temperature, patterns of precipitation, and sea level rise will likely affect a particular region. Differences in topography, vegetation, proximity to water, and natural variability in weather make predictions for specific regions in the Middle East difficult98 although it is widely accepted that climate change will result in even hotter, drier conditions over the next few decades.99,100 Predicted temperature increases range from 1.5–48C98 to 3.5 –78C101 by the end of the century. Changes in precipitation are more difficult to predict, given the extreme inter-annual variability in rainfall throughout much of the region. In general, more northern areas are expected to receive significantly less rainfall, with impacts diminishing as one moves further south.101 Although the region around Qatar may in fact experience a slight increase in rainfall by the end of the century,98 this will likely be offset by more extensive evaporation due to higher temperatures. Expected changes due

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to climate change that may have implications for human health in Qatar are 1) higher temperatures, 2) more frequent extreme weather events, 3) heavy rains leading to local flooding, and 4) more frequent sandstorms.73 While changes in humidity are often not presented in climate change predictions, they may also have important implications for human health as described below. At least one model suggests that, on a global scale, specific humidity will increase but relative humidity is unlikely to change significantly.102 There is already some evidence of the possible effects of climate change in the region. Zhang et al.103 examined data from 75 weather stations in 15 Middle Eastern countries, including Qatar, to determine climate trends that occurred between 1950 and 2003. They found a significant warming trend across the region with an increase in average daily maximum and minimum temperatures as well as in the number of warm days. Rainfall patterns, as expected, were less conclusive and not significant in general. AlSarmi and Washington104 followed up this study by examining climate trends over the last two to three decades. Although they used fewer stations and a shorter time period, the results were similar to those of Zhang et al.103 Fourteen of the 21 stations showed significant warming trends with the greatest responses observed in Oman and the UAE. Doha experienced the second highest monthly temperature increase with a 1.548C increase per decade for February. While the amount of precipitation at most sites declined, the only significant decreases were observed in Saik (Oman) and Tabuk (Saudi Arabia). The few studies that have examined current trends in humidity levels were critically evaluated by Willett.105 The data, while not of the same quality as those for temperature and precipitation, suggest that surface level atmospheric moisture has increased over the latter part of the last century. Climate change is expected to have a direct impact on air quality. The Intergovernmental Panel on Climate Change (IPCC)106 has suggested that air quality in cities is almost certain to decline in response to climate change if remedial actions are not taken. Rising temperatures are associated with reduced air quality, placing people at risk for skin, eye, and respiratory irritation. Most importantly, increased temperatures are positively associated with ozone levels in areas with heavy vehicular traffic, even where the normal temperatures are typically high.107,108 Humidity can affect air quality and subsequently human health in two ways. First, increased humidity may result in heat stress at higher temperatures as it interferes with the bodyâ&#x20AC;&#x2122;s ability to cool effectively through perspiring. Secondly, more humid air can hold greater concentrations of particulates that may be damaging to respiratory health and related illnesses.109 Increased wind speed can have both positive and negative effects on air quality. Good airflow can disperse ground level pollutants in regions where air quality is poor, thus providing a healthier environment. In Qatar, however, increased wind speeds, particularly of those coming from the north and northwest, can result in dusty conditions. Climate change is expected to increase the frequency of extreme weather events; Qatar can expect more sandstorms and the accompanying health problems with which they are associated. SUMMARY Qatar faces a growing risk of health-related problems due to poor air quality originating from both natural and anthropogenic sources. Dust from adjacent deserts can carry both living and nonliving constituents that may be harmful to health while populations of phytoplankton in the surrounding waters can release volatile organic chemicals that have been linked to human illness. Anthropogenic contributions to poor air quality are linked to the rapid development of the country and can originate from vehicular and ship emissions, as well as emissions from industrial and construction activities. While there is a substantial body of evidence linking poor air quality to human health, a number of important questions remain. For example, what are the relative contributions of the various sources in the region? What microorganisms are normally present in airborne dust and do they pose a risk to human health? What are the specific toxicological properties of airborne particulates around Qatar? What are the expected health costs if, as predicted, climate change intensifies the deterioration in air quality in the region? Answers to these and related questions are required to assist in the development of remediation strategies to improve air quality as well as health care strategies to prepare for expected increases in respiratory-related illnesses. COMPETING INTERESTS None of the authors have competing interests or conflicts of interest with respect to the material presented in this paper.

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AUTHOR CONTRIBUTIONS KT organized and wrote a substantial part of the paper. NH contributed to the writing and revising of the manuscript. KC contributed to the writing and revising of the manuscript MG, SC and JH all wrote sections of the paper. All authors have read and approved the final manuscript. REFERENCES [1] Khodeir M, Shamy M, Alghamdi M, Zhong M, Sun H, Costa M, Chen L-C, Maciejczyk P. Source apportionment and elemental composition of PM2.5 and PM10 in Jeddah City, Saudi Arabia. Atmos Pollut Res. 2012;3:331–340. [2] Curtis L, Rea W, Smith-Willis P, Ervin F, Pan Y. Adverse health effects of outdoor air pollutants. Environ Int. 2006;32:815 –830. [3] Naeher L, Brauer M, Lipsett M, Zelikoff JT, Simpson CD, Koenig JQ, Smith KR. Woodsmoke health effects: a review. Inhal Toxicol. 2007;19:67–106. [4] Tolba MK, Saab N. Arab environment: climate change, impact of climate change on Arab countries. Report of the Arab Forum for Environment and Development. 2009. [5] Akbari S. 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OPEN ACCESS

Review article

Barriers and facilitators influencing the physical activity of Arabic adults: A literature review Kathleen Benjamin*, Tam Truong Donnelly University of Calgary – Qatar, Doha, Qatar *Email: kmbenjam@ucalgary.edu.qa

ABSTRACT Physical inactivity is a global health concern. Evidence suggests low levels of physical activity among Arabic adults living in Middle Eastern countries. To help ensure the success of strategies to promote physical activity, a better understanding of the barriers and facilitators to physical activity is needed. The objective of this article is to present a review of the literature that focuses on the barriers and facilitators to physical activity among Arabic adults. A socio-ecological framework was used to guide this review. Following a database search (2002 –2013), a total of 15 studies were included in this review. The findings revealed that barriers (i.e., factors that impede physical activity), occurred at the individual level (e.g., lack of time, health status), social/cultural/policy level (e.g., traditional roles for women, lack of social support, use of housemaids), and the environmental level (e.g., hot weather, lack of exercise facilities). Some of the facilitators (i.e., factors that enable/promote physical activity) were: Muslim religion, desire to have slimmer bodies, and having good social support systems. Future intervention studies aimed at promoting physical activity among Arabic adults need to address these multiple influencing factors. Keywords: physical activity, Middle East, Arab, UAE, barrier, facilitator

http://dx.doi.org/ 10.5339/avi.2013.8 Submitted: 18 May 2013 Accepted: 14 June 2013 ª 2013 Benjamin, Donnelly, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Benjamin K, Donnelly TT. Barriers and facilitators influencing the physical activity of Arabic adults: A literature review, Avicenna 2013:8 http://dx.doi.org/10.5339/ avi.2013.8

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BACKGROUND Physical activity guidelines from the World Health Organization (WHO) suggest that healthy adults 18 –64 years of age should accumulate at least 150 min of moderate intensitya aerobic activity per week.1,2 According to the most recent statistics from WHO, in 2008, 31% of people 15 years of age and older worldwide had insufficient levels of physical activity.3 A study conducted in the Gulf Cooperation Council (GCC) countries revealed that only 40% of men and 27% of women reported that they were physically active for at least 150 min per week.4 Similarly, in the State of Qatar, nearly 50% of young adults 18 –19 years of age had insufficient levels of physical activity and this rate increased substantially with age.5 For example, among people 60–69 years of age, 75% had insufficient levels of physical activity.5 High rates of physical inactivity suggest the existence of underlying barriers to physical activity.6 Changes in activity patterns (e.g., less physical activity and sedentary life style) and diet (e.g., high fat and sugar diets) in the Middle East are important risk factors for conditions such as cardiovascular diseases, type 2 diabetes, breast and colon cancer, and obesity.7 There is a high incidence of cardiovascular diseases, diabetes, colon and breast cancer and obesity among Arabic people living in the Middle East and GCC countries.5,8 – 10 For example, cardiovascular diseases are the leading causes of mortality and morbidity in the State of Qatar.5,10 Diabetes is a recognized risk factor for heart diseases such as myocardial infarction.11 In 2006, about 4% of the population worldwide had diabetes.5 Among GCC countries, Qatar has the highest prevalence of diabetes (16.7%).5,12 Globally, the incidence of obesity is rising rapidly.13 For example, results of a 2006 WHO report indicated that 24% of the people surveyed in Qatar were of normal weight, 39% were overweight, and nearly 29% were obese.5 Contributing factors for obesity in the Middle East and United Arab Emirates (UAE) include diets high in carbohydrates and fats and the lack of social support for exercise, especially among women.14 In the Middle East region, the incidence of breast cancer has increased substantially in the last 24 years.8 For example, in 2006, breast cancer was the leading cancer diagnosis for Qatari women with the incidence, increasing significantly with age.5 Studies support an association between breast cancer and physical inactivity and high fat diets.15 – 19 For seniors, physical inactivity can lead to muscle and balance disturbances which, in turn, place seniors at greater risk of experiencing a fall event.20 Globally, it is estimated that one-in-three seniors, aged 65 years and older, experience one or more falls each year.20 – 22 Considering population aging and the high incidence of falls among seniors, the promotion of physical activity is an important component of fall prevention programs. Lastly, there is growing evidence to support the hypothesis that exercise may be an effective alternative to traditional mental health interventions in cardiac patients who have a high incidence of depression.23 – 26 Results of a recent Cochrane review suggest that among people with depression, exercise may reduce the symptoms of depression.23 In addition, given the high incidence of cardiovascular diseases in the Middle East and GCC countries, and the link between cardiovascular disease and depression, the promotion of physical activity should be an important component of mental health interventions in people with cardiovascular diseases. A socio-ecological model was used to guide the organization and presentation of the barriers and facilitators in this review.27 – 31 This is a useful model because it considers the barriers and facilitators to physical activity and their interconnections at multiple levels of the system (e.g., individual, policy, community, environmental).27 – 31 Based on a socio-ecological model, three categories used in past research are: (1) individual level, (2) organizational, social/cultural, policy level, and (3) environmental level. Other authors have used a similar typology to guide their physical activity studies.6,31 – 33 A fourth category called ‘intersecting barriers’ was used in this review. Intersecting barriers refers to barriers that intersect or converge at more than one level of the ecological system.6,32 The convergence or intersection of barriers creates additional challenges on the ecological system. For example, in a qualitative study conducted in nursing homes in Ontario, Canada, less than optimal conditions for physical activity for residents were created when an organizational barrier (i.e., inadequate staffing) converged with a barrier at the environmental level (i.e., inadequate number of elevators to transport residents in wheelchairs to their activity programs).32 An understanding of the influencing factors and a According to the WHO, the intensity of different types of physical activity varies between people and is dependent on a person’s level of fitness and past exercise history. Typically, moderate-intensity activity requires moderate effort which noticeably accelerates the heart rate. Examples of moderate intensity activities are: brisk walking, dancing, housework, gardening, and general building tasks such as painting.1

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their interconnections is critical to the development of effective interventions to address the problem of sedentary behaviors.6,32 The main objective of this paper is to present an overview of the literature related to the barriers and facilitators to physical activity for Arabic adults. A better understanding of the barriers and facilitators to physical activity is critical to the successful promotion and implementation of physical activity interventions. No previous reviews of the literature related to the barriers and facilitators to physical activity for Arabic adults were found. METHODS Search for articles focusing on ‘barriers’ and ‘facilitators’ An English-language search of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTdiscus, and Middle Eastern and Central Asian Studies was conducted to identify journal articles published from 2002 to 2013. The following keywords were used: physical activity, exercise, Middle East, Arab*, Emirates, Bahrain, Qatar, Kuwait, Gulf Co-Operative Council, GCC, UAE, barriers, challenges, facilitators, enablers, singly and in combination. This search yielded 47 articles. The abstracts of these articles were reviewed using the following inclusion criteria: (1) study focused on the barriers and/or facilitators to physical activity or exercise, (2) study included Arabic adults 18 years of age and older, and (3) qualitative, quantitative or mixed methods study design. Thirty-two articles were eliminated because they did not meet the inclusion criteria (i.e., 11 did not include Arabic adults and 21 did not focus on the barriers/ facilitators to physical activity). Hence, 14 studies that focused on the barriers/facilitators to physical activity were retained for review.34 – 48 Search for RCTs We anticipated that some of the intervention studies may have included a description of the barriers/facilitators encountered during intervention implementation.6 Thus, we also searched for RCTs that contained an exercise or physical activity component. To identify these studies, we conducted a separate English-language MEDLINE database search for articles published from January 2002 to January 2013. Keywords were: physical activity, exercise, Middle East, Arab*, Emirates, Bahrain, Qatar, Kuwait, Gulf Co-Operative Council, GCC, UAE, randomized control trial, singly and in combination. This search yielded 11 articles. The abstracts of these articles were screened using the following inclusion criteria: (1) RCT that included an exercise or physical activity intervention(s), and (2) sample included Arabic adults aged 18 years and older, living in the community. Ten articles were eliminated because they did not meet our inclusion criteria (i.e. six articles did not focus on an exercise or physical activity intervention (e.g., drug study) and four articles did not include Arabic adults. One intervention study was retained.49 Hence a total of 15 studies were included in this review.34 – 49 Fourteen studies focused on the barriers/facilitators to physical activity and one study was a lifestyle intervention study that contained an exercise intervention. Figure 1 provides a flow diagram of the literature search. Assessing the quality of the retrieved articles The Mixed Methods Appraisal Tool (MMAT) was used to assess the methodological quality of our retained studies.50 This multi-faceted tool allows researchers to use only one appraisal tool when assessing the methodological quality of different study designs for a literature review (i.e., qualitative, quantitative descriptive, quantitative randomized controlled trials, quantitative, non-randomized, and mixed methods studies). Reliability and efficiency testing of the pilot MMAT in 2010 found that the inter-rater reliability scores ranged from moderate to perfect agreement.50 – 52 This tool uses two main steps for assessing studies. First, regardless of the study design, all studies are screened by two criteria which are: (1) are there clear objectives? and (2) does the collected data address the research objectives? Three possible response options are provided: (1) yes, (2) no, and (3) can’t tell. Next, each study is assessed using specific criteria related to type of study design. For instance, one of the criteria used to assess RCTs relates to withdrawal and dropout rates (i.e., Is there a low withdrawal/dropout rate? – below 20%). The tool and scoring metrics are available online.50 The first author (KB) assessed the quality of the studies. All of the studies met the first two criteria in step one. In step two, four studies met 100% of the criteria, six studies met 75% of the criteria, and five studies met 50% of the criteria. Hence, the overall methodological quality of the studies was good.

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BARRIERS/FACILITATORS ARTICLES Databases (MEDLINE, CINAHL, SPORTdiscus, Middle Eastern and Central Asian Studies) searched for English journal articles published from January 2002-January 2013. Keywords for search: physical activity, exercise, Middle East, Arab*, Emirates, Bahrain, Qatar, Kuwait, Gulf Co-Operative Council, GCC, UAE, barriers, challenges, facilitators, enablers. Search yielded 47 articles

Screening : abstract, title, or full article using inclusion criteria: (1) article focused on the barriers and/or facilitators to physical activity or exercise, (2) sample included Arabic adults18 years of age and older, and (3) qualitative, quantitative or mixed methods study design.

Thirty two articles eliminated: Reasons for exclusion (1) not Arabic or adults (n=11) and (2) not focused on the barriers/facilitators to physical activity or exercise (n=21). Two of the retained articles based on same study–thus counted as one study Retained = 14 studies

Database search of Medline for RCTs published 2002-2013 Inclusion criteria: (1) experimental study that included an exercise or physical activity component and (2) included adults-19 years of age and older. Retained from database search (n=11) 10 studies excluded – reasons for exclusion: (1) not focused on topic (n=6) and (2) sample did not include Arabic adults (n=4). RCTs included in review (n=1) Total number of studies in this review = 15 studies

Figure 1. Flow diagram of literature search.

Design and characteristics of the ‘barriers’ and ‘facilitators’ studies The characteristics of the 14 included barriers/facilitator studies are presented in Table 1. Seven studies were quantitative in design, six were qualitative, and one study was mixed methods. Sample sizes for the quantitative studies ranged from 334 to 2176 participants. Sample sizes for the qualitative studies ranged from 21 to 110 participants. Three studies were conducted in the UAE, three in the USA, two in Saudi Arabia, two in Israel, and one in each of the following countries/states: Qatar, Kuwait, Turkey, and Australia. Participants’ age varied across studies (young, middle aged adults). Only one study focused on seniors44 and six studies included women only.35,38 – 41,46,47 FINDINGS Barriers: Individual level Except for one study,45 the remaining studies reported on barriers at the individual level. The two most common barriers reported in the quantitative studies were: ‘lack of time’ and the ‘presence of health conditions’ (e.g., heart disease, osteoarthritis, asthma). ‘Lack of time’ was related to factors such as competing family demands (e.g., household chores, child care), extra office work for men, frequent

75 Emirita women with pre-diabetic with abdominal obesity Al Ain medical districtrural and urban Age: 20– 60 yrs. (mean age ¼ 39 ^ 12.1 yrs)

2. Ali et al.35 UAE Focus on the barriers and facilitators to weight management (only barriers to exercise reported in this table)

452 patients (15 –80 years 3. AlQuaiz and Tayel36 Saudi Arabia (mean age ¼ 33.3 years Focus- barriers to healthy ^ 13.3yrs) 50% ¼ lifestyle (Physical 15 –29 yrs 32% males, activity and healthy 68% female, eating) Only barrier to 29.4% housewives

390 diabetic patients (mean age 52 ^ 9.9 yrs) Outpatients from AL- Ain District UAE 62% females

Sample

1. Al-Kaabi et al. UAE Focus on barriers to physical activity

Author(s) Country Focus

Quantitative Cross-sectional Self- administered survey Tool adapted from Centre for Disease

Qualitative, Descriptive, Grounded theory Constant comparative analyses Purposive sampling Eight focus groups

Quantitative Face-to-face interview

Research Approach

Organizational, social/cultural, policy

Levels- Barriers and Facilitators

Physical Environment

Barriers Barriers Barriers Presence of diseases 32.1% Cultural reasons 29.2%, Weather 7.9% Lack of time 29.7% especially for women, Parks unavailable 1.5% Family responsibilities 20.8% difficulty of joining gym – only Lack of safe places Exercise is boring 20.3% few centers for women only to walk 0.8% Fear of injury 4.9% Lack of family support 4.1% Laziness 1.0% Cost of joining gym 2.8% Embarrassed to wear exercise clothes 0.5% Belief that exercise makes control of diabetes difficult 0.5% Barriers Barriers Barriers Competing demands- No time for Cultural norms- walking in Lack of indoor space to do exercise- housework and public without a male escort exercise excessive computer/internet use not culturally acceptable for Lack of culturally appropriate Chronic health conditions women exercise facilities (e.g., asthma) Low family support for Hot weather- difficult to walk Facilitators exercise-e.g. discouraged outdoors Presence of health condition acted purchase of treadmill for Street safety-women felt unsafe as a motivator to exercise home use- no space) to walk alone in the city Frequent social gatherings with Facilitators food limited physical activity Living on a farm increased opportunities walking opportunities. Use of housemaids limited Cooler weather promoted physical activity outdoor walking Facilitators Having other women to walk with (walking buddy) Barriers Barriers Barriers Lack of resources 280.5% None reported Lack of energy 2 73.2%- higher Higher in females and in lower among females versus males versus higher income) Lack of willpower-2nd most common Lack of skills 43.5% Limited funding for Saudi women to join sports clubs.

Individual

Table 1. Studies focusing on the barriers and facilitators to physical activity and exercise.

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Sample

5. Berger and Peerson38 Fujairah UAE Focus: identify social and cultural barriers to physical activity

20 Emirati female unmarried college students 18– 27 yrs of age. Islamic, Arabic first language.

82.4% from primary health care clinics King Khalid University Hospital in Riyad 2176 adult Saudi nationals 4. Amin et al.37 Saudi Arabia (men ¼ 55.6%, Focus- barriers toward women-44.4%) leisure related Age: 18–64 (mean physical activity 32.7 ^ 9.8 yrs) All barriers listed by From primary health author under personal centers urban ¼ 61% category rural ¼ 39.0% 10.8% of sample had chronic disease

physical activity included in table.

Author(s) Country Focus

Table 1 – continued

Individual

High cost of gym memberships Lack of social support (higher in females than males)

Organizational, social/cultural, policy

Physical Environment

Barriers Quantitative Barriers Barriers Weather leading barrier (65.9%) Cross sectional Lack of time (44.7%) (domestic Traditions 2nd most common barrier (60.1%) Descriptive chores for women, extra office Lack of places to exercise Survey work for men) (55.4 %) Global physical activity Lack of money (28.2%) Lack of company (29.1%), questionnaire esp. among men esp. among women-could not Lack of interest (22%) go outdoors to exercise esp. among younger age alone –must be escorted by group father, brother or husband. Fear of injury (20%) Approval of family, husband Dislike exercising (13.8%) were important Internet/TV use (13.8%) Chronic illness (13.5%) Old age (7.7%) Qualitative Barriers Barriers Barriers Participatory Action Age & female gender Exercise not considered a Intense heat June to August Research Grooming: efforts might be social activity Some informants did not like to Interviews & focus ruined by exercise, Non- participation of friends sweat, while other did groups Did not like to wear sports Lack of role models among (i.e. belief that it would Content analyses clothes under abayas peers and family increase weight loss). Lack of motivation Putting on makeup at school Dislike for exercise not allowed – makeup Tiredness applied in a.m. at Prefer to watch rather than participants’ home engage Excessive body weight Lack of time Lack of information on the benefits of physical activity Lack of transport to exercise facility

Control (CDC) website

Research Approach

Levels- Barriers and Facilitators

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Qualitative 12 focus groups

50 Arabic Muslim Qualitative 7. Donnelly et al.40,41 Doha, Qatar women with heart Individual Interviews Focus – challenges and disease in Doha Qatar Semi-structured opportunities to $ 30 years (range 32–85 yrs). questionnaire engage in healthy 36% of sample between lifestyle (Physical 50 –59yrs, 28% between activity, diet and 60– 69 years smoking) Four women worked Author mentioned outside of home and ecological model three did not have children

6. Caperchione et al.39 110 women in Australia Australia 55.7% Fillipino Focus on physical 26.8% Sudanese activity behaviours 63.0 % Bosian NB –multi-cultural 39.1% Arabic speaking sample- included Mean age (39.1 ^ 10.4 yrs) common themes across all ethnic groups and ethnic specific themes. Only Arabic- speaking themes will be reported

Barriers Barriers Barriers Ethnic specific Ethnic specific Not ethnic specific –Finding time to be active –partly –Need for public modesty for –Safety concerns –high due to larger than normal family women barrier to outdoor crime areas-would only engage size and cultural norms that activities in outdoor walks in daylight required house work to be done Different perceptions of what by women regardless of external constitutes health compared employment (e.g. in Africa – bigger body Not ethnic specific mass is better- denotes –Family commitments prevented richness, happiness and them from being active/ Women healthy were responsible for most of the Not ethnic specific domestic chores –Do not know where to access –Could exercise alone in home but information about programs not motivated without group support –Health concerns (seen as both a barrier/enabler)- Health “scares” was a motivating factor/Belief that too much exercise associated with tiredness, soreness, and injury. Barriers Barriers Barriers Health conditions (these women Traditional cultural Hot desert climate- people walk had heart disease and some had values and practices for only two months per yr. fatigue and SOB) (2012, 2011) Taboo for females to go out in due to heat Facilitators public places unless Facilitators Religion- Quran supportive of accompanied by male family Low cost and accessible facilities exercise (2012) member (2012) (2012,2011) Feeling healthy and looking younger Priority on caring for family-not were motivators – all participants exercise (2012, 2011) expressed desire for slimmer Family responsibilities (e.g., bodies (2012) caring for children and grandchildren) took precedence over their own health care (2012) Having more servants than one needs which reduces opportunities for women to be active when doing domestic chores (2012)

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Sample

Research Approach

Individual

Organizational, social/cultural, policy

Levels- Barriers and Facilitators

Physical Environment

Facilitators Having a good informal (family friends) and formal (health care provider) support system (2012,2011) 42 334 adults – with 8. Serour et al. Quantitative Barriers Barriers Barriers Kuwait hypertension, and/or type International Physical Lack of time (39%) Use of house maids (54.1%) Weather (27.8%) Intense hot Barriers to adherence to 2 diabetes from family Activity Questionnaire Coexisting disease (35.6%) Lack of exercise partner (3.7%) summers lifestyle management practice health centers used (e.g., osteoarthritis, asthma, and Excessive use of private cars (diet and physical Mean age 53.5 ^ 10.3 range musculoskeletal disease reduced opportunities for activity) (27– 74) physical activity (e.g., walking Female ¼ 62.6% to bus stop, or walking to work) (83.8%) 43 21 Arab American college Qualitative Barriers 9. Kahan Barriers Facilitators USA students Selected for extreme Focus groups Most common barrier -time Overall, lack of parental More active- friendly physical Focus on sociocultutal manifestations of religiosity or Individual interviews management (school work and support, modeling or environments in US. (Bicycles) factors that influence acculturation Thematic analyses family commitments left little encouragement, esp. for Clerics likely to offer some type of physical activity, 9 males 12 females time for physical activity) daughters PA program body composition (9-Muslim & 12 non- Muslim) Facilitators –Mixed messages from and nutrition Age not reported 13 lived off Most common facilitator – health parents Used ecological model – campus without parents, 5 with and wellness outcomes– Women’s traditional role levels wereparents and 3 in college dorms. Improved mental, physical (domestic) intrapersonal, and function) More religious -less likely to be interpersonal, & acculturated and more likely community/organto confirm to Middle Eastern izational/policy beliefs about physical activity. Facilitators Friends exerted a positive influence 44 Seniors ^ 60 years 70% of Quantitative Barriers Barriers Barriers 10. Shemesh et al. Israel sample-female, 89% between Convenience sample Low motivation (47%) Access barriers –high cost of Lack of places to exercise-10% Multiethnic (Hebrew, 60– 79 yrs. Self administered Poor health or disability (32%) exercise facilities Arabic, Russian) Most participated in activity at questionnaire Focus- factors influencing least twice per week health behaviours

Author(s) Country Focus

Table 1 – continued

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314 male /female students mean ¼ 20.6 ^ 1.93 yrs) 60 male/female faculty (mean ¼ 43.3 yrs ^11.3, 71 male/female staff (mean ¼ 36.1 ^ 8.73 years

14. Koc¸ak48 Turkey (university Middle East Technical – Ankara) Focus on barriers to exercise

Quantitative Barriers 12 item questionnaire Lack of time most common barriers (44.4%) Laziness (6.9%) Dislike for exercise (7.3%) Not interested (6.9%) Illness or handicap (4.0%) No past habit (4.9%) Cost (2.5%) Work pressure (1.6%)

22 Arab mothers , 45 years of Mixed methods Barriers age, married, well educated Focus groups Lack of time From 7- Middle Eastern countries Interviews 15 open Facilitators Majority did moderate ended question After exercise the mothers exercise, e.g., brisk walking, using Social stated they felt “good” vacuuming 1 –2 days per wk. Cognitive Theory and had more energy 10 did vigorous activity (e.g. Male Arab- American running) 1 –2 days per week Acculturation Scale used 180 Arabic women mean-age Quantitative Barriers 37.6 ^ 12.9 Cross sectional Not enough time (56%) 46.2 % were sedentary Too stressed (27.8%) Pain when exercising (12.2%) Exercise is boring (8.3%) Not enough money (6.1%) Too old (3.3%)

Qualitative 8-Focus Barriers groups Not reported Purposeful sampling Facilitators Slightly more than Religion- Quran supportive of 50% were female physical activity Most Muslim or Bedouin and lived in rural villages

12. Tami et al.46 USA- Texas Focus on the effect of acculturation on dietary and physical activity NB- only factors related to physical activity included in this table 13. Qahoush et al.47 USA Focus on physical activity

11. Shuval et al.45 45 Arab Israeli physical Israel education students –Ohalo Focus of the role of College culture, environment Age: 18–31 (mean ¼ 21.9yrs) and religion in the Slightly more than 50% were promotion of physical female Most were activity not physically active on a regular basis.

Barriers Barriers Although participants recognized Not reported value of activity – they were Facilitators not active- lived in extended Access to exercise facilities families that deemphasized the value of physical activity Women not permitted to exercise in public Villages receive less funding for sports than urban centers. Facilitators Living in an urban center (sidewalks, gyms, accessible) Living away from extended family structure Barriers Barriers Not reported Not reported Facilitators Low cost (fees) Social support from husband Availability of fitness classes at Islamic center Motivator- seeing people walking in the mall. Barriers Barriers Takes time away from Not reported family (15%) Facilitators Lack of support- family & Safe places to jog or friends (3.9%) walk (73.3%) Facilitators Walking & cycling club- (29.4%) Recreational facilities (31.1%) Barriers Barriers Lack of facilities 0.89% Heavy class schedule 2nd most common barrier (25.2% among students) No partner- 1.7% Family pressure/obligations 1.2%

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social gatherings, and time management challenges related to heavy school workloads. Some participants did not exercise because they believed that exercise would be painful or that it would make diabetic control more difficult.34,47 Fatigue and tiredness was a barrier reported in studies, especially among women.36,38 Other reported barriers were: lack of interest, motivation, and information about the benefits of exercise, fear of injury, stress, excessive internet and computer usage, and no past ‘habit’ of exercise. Similar findings were found in the qualitative studies. For instance, in a study among 21 Arab college students in the US, family commitments and school work left little time for exercise.43 In a study among 20 female Emirati college students, barriers related to grooming and traditional dress for women were reported.38 The female students in the study did not like to wear sports clothes under their abayasb and some did not like to exercise because they felt that exercising would ruin their makeup. They explained that they were not allowed to apply makeup at school.38 Barriers: organizational, cultural/social, policy level Most of the qualitative and quantitative studies reported on barriers related to ‘cultural and social norms’.34 – 41,43,45,47 Traditionally, women in many Islamic countries need to be accompanied by a male family member (e.g., husband, father, or brother) when going outdoors which reduces opportunities for physical activities. To preserve public modesty, many Arabic women wear traditional dress (e.g., abayas) in public which may make it difficult for them to participate in certain types of physical activities.53 Cultural norms and expectations regarding women’s roles were also viewed as barriers to physical activity. Similar to many other cultures and societies, women were expected to care for the family and household and their exercise needs were afforded low priority. In an Australian study, Arabic women reported that they had less time for physical activity because they do all of the household tasks (e.g., cooking, cleaning) even if they are employed outside of the home.39 Another barrier reported across the studies was a general lack of social support for exercise, especially for women.34 – 37,43,45,47 For women, family obligations (e.g., caring for children and husband) took precedence over engagement in physical activity. Another barrier was a general lack of parental support and peer role modelling.43 In a US study, participants reported that parents did not support physical activity, partly due to the fact that education was afforded higher priority than physical activity.43 They also reported receiving mixed messages. For example, mothers expressed their concerns to their daughters regarding weight gain, but provided only conditional support for physical activity.43 Barriers reported in two Middle Eastern studies were difficulties in finding an exercise ‘partner’ and a belief that exercise was not considered a social activity.38,48 Another reported barrier was the use of housemaids.35,40,42 For example, in a study conducted in Qatar, female participants recommended that women should do more housework with less dependency on housemaids as a mean of doing more physical activity at home.40 At the policy level, barriers were related to the allocation of funding for sports, especially for women. In a study conducted in Saudi Arabia, participants reported that there was limited funding for Saudi women to join sports clubs and, typically, gym memberships were expensive.36 In an Israeli study, participants indicated that compared to urban centres, villages received less funding for sport programs.45 Barriers: environmental level Several studies cited barriers at the environmental level.34,35,37,41 – 44 The two most common barriers at the environmental level were the ‘weather’ and ‘lack of exercise facilities’. The Middle East is noted for it hot summer climate (30 –50 degree Celsius), which restricts outdoor activities like walking, cycling and jogging. Overall, there was a lack of culturally appropriate and affordable exercise facilities or outdoor spaces for activities (e.g., parks), especially for women. A barrier reported in a US study was the lack of places to jog because of high crime rates.39 In a UAE study, the women reported that they felt unsafe to walk on the street alone in the city.35 Lastly, in a study conducted in Kuwait, most of the participants (83.8%) agreed that the excessive daily use of private driver/cars interfered with their physical activities.42 The excessive use of private drivers/cars is likely due to factors such as: a hot desert climate which makes outdoor walking difficulty; a lack of adequate public transport systems, and a lack b An ‘abaya’ is a traditional loose fitting outer garment that is worn by some women in parts of the Islamic world. It is typically black in color.

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of ‘walkable’ neighbourhoods. Typically, private cars transport clients from door to door which reduces the need to walk outdoors in intense hot temperature. Intersecting barriers None of the studies included an explicit reference to the presence of intersecting barriers. As mentioned previously, intersecting barriers are barriers that converge or intersect at more than one ecological level. However, some of the studies implicitly described instances where barriers intersected or converged. For instance, in a qualitative study, a woman explained that her ‘family’ discouraged her from buying a treadmill for home use (barrier – social level) because there was not enough ‘space’ for it in the home (barrier – environmental level).35 Facilitators Six studies reported on the facilitators to physical activity.35,40,41,43,45 – 47 At the individual level, the most common facilitators were the presence of a ‘health condition’ and ‘religion’. For some participants, the presence of a health condition or health ‘scare’, such as a cardiac event, acted as a ‘motivator’ for them to be more physically active. Similarly, in a study conducted among 50 Arabic women with heart disease in Qatar, ‘feeling younger’ and ‘more healthy’ acted as motivators for these women to engage in healthy lifestyles.40,41 A few studies cited religion as a facilitator to physical activity.40,45 In a qualitative study among Arab Israeli college students, religion was seen as a facilitator because the scriptures in the Quranc encourage physical activities, especially swimming and horseback riding.45 However, although physical activity was viewed as extremely important, some students believed that it doesn’t affect life expectancy because only God determines this.45 Although several studies reported a lack of social support as a barrier to physical activity, two American studies43,46 and two Middle Eastern studies35,40,41 reported that ‘supportive social systems’ acted as facilitators to physical activity. For instance, in a study conducted in Doha, Qatar, having ‘good’ informal (family members and friends) and formal support (government, health care professionals) systems acted as opportunities for Qatari women with heart disease to engage in healthy lifestyles. The findings indicated that daughters were often the most effective supporters because, in addition to offering simple encouragement, they took an active role in supporting their mothers. For instance, daughters would ask their mothers to accompany them to the gym.41 Other informal supports reported included having supportive husbands and other women to walk with.41 Formal supports reported in this study included government and physician support. The Qatari government encouraged healthy lifestyles by building accessible and affordable exercise facilities for women.41 Physicians supported their female patients to maintain healthier lifestyles after their cardiac event by offering them advice on how to exercise and be more active.41 Although several studies reported a general lack of culturally appropriate and affordable exercise facilities, two US studies43,46 and two Middle Eastern studies40,41,45 reported that the availability of exercise facilities acted as a facilitator to physical activity. For example, Qatari women reported that there were several affordable facilities where women could go to be active, such as the Aspire Zone in Doha, capital of Qatar.40 In an UAE study, participants explained that living on a farm provided opportunities for physical activity.35 Participants in a US study reported that having active friendly physical environments (e.g. bicycles paths) encouraged them to be more active.43 Findings: RCTs One RCT that met the inclusion criteria was included in this review.49 Characteristics of this study are provided in Table 2. Two hundred and one Arab women (age 35–54 years) with one or more components of metabolic syndrome (see Table 2 for details of the sample health characteristics) were randomized to an intervention group and received 22 sessions of dietary counselling and 22 sessions of physical activity or to a control group and received five dietary sessions only. The dropout rate in the intervention group was 14% versus 6% in the control group. The average attendance rate in the intervention group was 40% for the activity sessions and 95% for the dietary sessions. The lower attendance rate in the activity sessions may have been due to frequent turnover of fitness instructors (i.e. three instructors in one year), and/or low motivation among participants. Although the authors c

The Quran is a book containing the sacred writings of Islam.

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Table 2. Intervention study. Did authors discuss barriers related to implementation?

Kalter-Leibovici et al. (Israel)49 Sample: women 35 –54 years of age living in 2 Muslim Arab communities in the center of Israel with BMI of 30–40 and 1 or more component of the metabolic syndrome. Components of syndromes were: waist circumference greater than 88 cm, blood pressure of at least 130/85 mm Hg, fasting plasma glucose level of at least 110/mg/dL, triglycerides of at least 150 mg/dL, and high –density liproprotein cholesterol less than 50 mg/Dl. Focus: 12 month experimental lifestyle intervention study Group A- 22 dietary sessions per year – plus exercise Group B -5 dietary sessions, no exercise. Dietary sessions provided in both group and individual format. Sample: 110 obese, non diabetic Arabic women, 35 –54 yrs of age

Yes: focus was to provide a culturally sensitive intervention. Participants face ‘familial and societal barriers toward dietary modification, physical activity’. No further details provided Initial refusal during recruitment – 38% (81/209) Modest dropout rate group A (14%) –reasonspersonal reasons (n ¼ 9); lack of motivation (n ¼ 5) Low dropout rate group B (7%)-lost to follow up (n ¼ 1); lack of motivation (n ¼ 6) High attendance rate to both individual and group dietary session

commented that in participants faced ‘familial’ and ‘societal’ barriers towards physical activity and dietary modification, they did not provide further details or explanations. DISCUSSION Although the presence of a health condition or disease was reported as a barrier to physical activity, some participants explained that the presence of a health condition/disease acted as a motivator for them to exercise because of the beneficial outcomes (e.g., feeling more healthy). Similar results have been reported in prior research.32,33 For instance, it is well recognized that exercise can improve joint flexibility and may help to decrease the stiffness and pain associated with arthritis.54 – 57 This type of information is valuable when considering the design of intervention strategies. It may be especially important that exercise programs for people with health conditions be tailored so that they are ‘doable’ which, in turn, may help to promote long-term adherence.6,32 The most commonly-reported barrier in the natural environment was the hot summer temperature, which impeded most outdoor activities. One potential solution would be to use existing air-conditioned buildings for exercise. For instance, shopping malls could offer walking programs for people. Mallwalking programs are popular in North America, especially for seniors because they provide accessible, safe and user friendly (benches, washrooms) options to outdoor walking.58 Since the concept of ‘family’ plays an important role in Islamic Arabic speaking countries, mall-walking programs could provide walking programs for family units. Other facilities built specifically for family, women, and children would be needed as well. To address environmental barriers, an interdisciplinary approach will be needed. People such as city planners, architects, building inspectors, policy makers, and health care planners will need to work together to address the multiple levels of influence.32 For instance, evidence suggests that the use of signage and spatial factors in the built environment (e.g., distance of stairwell from main building entrance) can increase stair use in public buildings.59 – 63 Architects could incorporate this knowledge into the design of new buildings and building inspectors could ensure that stairs/stairwells in public buildings meet current safety recommendations (e.g., handrails, stair height/depth, adequate lighting).64,65 As mentioned previously, a ‘lack of exercise facilities’ was a barrier cited in this review. This lack may partly be related to the Islamic teaching about public modesty, which means that women must find exercise facilities that cater to women only, or facilities that offer specific hours for women.66 Having separate facilities for men and women may not always be feasible. A potential solutions is having internally segregated facilities and programs in one building.66 Although not as common as in Western societies, there are independent fitness clubs in the Middle East, in addition to those established in major hotels.67 Both types of fitness clubs may be

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cost-prohibitive for some individuals. Less costly alternatives are needed. For instance, subsidized exercise programs can be provided in workplaces and local community centers. Wellness centres could be established in existing shopping malls. Another practical strategy that could help to offset the costs associated with formal exercise programs is the promotion of active living.d Active living can be done at home, as well as in formal exercise spaces. Given that public modesty is important in Islamic countries, the use of home gyms (e.g., treadmills, hand weights) could offer people exercise options in the privacy of their homes. The Islamic faith plays an important role in the lives of Arabic people. Muslims are expected to care for their bodies and to engage in healthy lifestyles.53,68 The Quran is supportive of Muslims engaging in physical activity provided it does not violate certain principles such as the Islamic dress code. This represents a potential opportunity to promote physical activity. Health promotion messages could be linked to religious teachings and religious leaders could play a supportive role in encouraging Muslims to adapt more active lifestyles.40,41 Physicians and other health care providers can also play a pivotal role in promoting and assisting their clients to be physically active.6,40,41,69 For instance, the results of a Canadian study among seniors revealed that those who were advised to exercise by their physicians were 7.8 times more likely to be in the ‘high’ active group as opposed to the ‘low’ active group.69 However, evidence suggests that the majority of physicians do not routinely advise their patients to exercise.70 – 72 One study reported that the strongest predictor of patients receiving advice from their physicians to exercise and eat a less fat diet was high body mass index and having high cholesterol, respectively.73 Similar to the West, in the Middle East, physicians’ advice is typically valued and trusted. There is a critical need for physicians and other health care providers to take a proactive role in promoting physical activity in order to prevent and/or reduce the heavy burden of lifestyle related diseases.40,41,69 LIMITATIONS First, this review was limited to an English-language search of published articles that focused on the barriers and facilitators to physical activity for Arabic adults living in the community. We did not do any hand searching for published articles or internet searching for unpublished work. Thus, important studies may have been missed. However, similar to another previous review,6 we did attempt to augment this review by including RCTs that included a discussion of implementation barriers. Hence, we believe that this literature review gives insight on the barriers and facilitators to physical activities among Arabic adults. CONCLUSION Despite the paucity of research in the area, this literature review still provides insights as to the barriers/facilitators influencing the physical activity of Arabic adults. A socio-ecological model was used to frame this review. Barriers and facilitators occur at the individual, social/cultural/policy and environmental levels. Future physical activity intervention studies and health promotion strategies aimed at increasing physical activity will need to consider these multiple influences.6 Because of their influence in the Arab world, health care professionals, religious leaders, and role models could play a pivotal role in promoting more active lifestyles. Separate exercise facilities for both sexes, and accessible and affordable community programs using existing physical spaces such as schools and shopping malls could be developed to promote physical activity among Arabic adults. COMPETING INTERESTS The authors declare that they have no competing interests. AUTHOR CONTRIBUTIONS KB contributed to the conception of this manuscript, revised it critically for content, and gave final approval of the manuscript version submitted for publication. TD contributed to the conception of this manuscript, revised it critically for content, and gave final approval of the manuscript version submitted for publication. All authors read and reviewed the final manuscript. d Active living refers to a way of life that incorporates physical activity into daily life, for example, using the stairs rather than taking an elevator.

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Acknowledgement The authors wish to thank BC for helping us to format this article.

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[25] Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour KA, Herman S, Craighead WE, Brosse AL, Waugh R, Hinderliter A, Sherwood A. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007;69(7):587–596. [26] Blumenthal JA, Babyak MA, Moore KA, Craighead WE, Herman S, Khatri P, Waugh R, Napolitano MA, Forman LM, Appelbaum M, Doraiswamy PM, Krishnan KR. Effects of exercise training on older patients with major depression. Arch Intern Med. 1999;159(19):2349–2356. [27] Green LW, Richard L, Potvin L. Ecological foundations of health promotion. Am J Health Promot. 1996;10(4):270–281. [28] Richard L, Potvin L, Kishchuk N, Prlic H, Green LW. Assessment of the integration of the ecological approach in health promotion programs. Am J Health Promot. 1996;10(4):318–328. [29] Sallis JF, Owen N. Ecological models. In: Glanz K, ed. Health Behaviour and Health Education: Theory, Research and Practice. 2nd ed. San Francisco, CA: Jossey-Bass; 1997:403–424. [30] Sallis JF, Owen N, Fisher EB. Ecological models of health behaviour. In: Glanz K, Rimer B, Viswanath K, eds. Health Behaviour and Health Education: Theory, Research, and Practice. 4th ed. San Francisco, CA: Jossey-Bass; 2008:465–482.

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[31] Sallis JF, Cervero RB, Ascher W, Henderson KA, Kraft MK, Kerr J. An ecological approach to creating active living communities. Annu Rev Public Health. 2006;27:297–322. [32] Benjamin K, Edwards N, Guitard P, Murray MA, Caswell W, Perrier MJ. Factors that influence physical activity in long-term care: perspectives of residents, staff, and significant others. Canadian J Aging. 2011;30(2):1–12. [33] Chen YM. Perceived barriers to physical activity among older adults residing in long-term care institutions. J Clin Nurs. 2010;19(3-4):432 –439. [34] Al-Kaabi J, Al-Maskari F, Saadi H, Afandi B, Parkar H, Nagelkerke N. Physical activity and reported barriers to activity among type 2 diabetic patients in the United Arab Emirates. Rev Diabet Stud. 2009;6(4):271–278. [35] Ali HI, Baynouna LM, Bernsen RM. Barriers and facilitators of weight management: perspectives of Arab women at risk for type 2 diabetes. Health Soc Care Commun. 2010;18(2):219–228. [36] AlQuaiz AM, Tayel SA. Barriers to a healthy lifestyle among patients attending primary care clinics at a university hospital in Riyadh. Ann Saudi Med. 2009;29(1):30–35. [37] Amin TT, Suleman W, Ali A, Gamal A, Al Wehedy A. Pattern, prevalence, and perceived personal barriers toward physical activity among adult Saudis in Al-Hassa, KSA. J Phys Act Health. 2011;8(6):775–784. [38] Berger G, Peerson A. Giving young Emirati women a voice: participatory action research on physical activity. Health Place. 2009;15(1):117–124. [39] Caperchione CM, Kolt GS, Mummery WK. Physical activity in culturally and linguistically diverse migrant groups to Western society: a review of barriers, enablers and experiences. Sports Med. 2009;39(3):167–177. [40] Donnelly TT, Al Suwaidi J, Al Enazi NR, Idris Z, Albulushi AM, Yassin K, Rehman AM, Hassan AH. Qatari women living with cardiovascular diseases – challenges and opportunities to engage in healthy lifestyles. Health Care Women Int. 2012;33(12):1114–1134. [41] Donnelly TT, Al-Suwaidi J, Al Bulushi A, Al Enazi N, Yassin K, Rehman AM, Abu Hassan A, Idris Z. The influence of cultural and social factors on healthy lifestyle of Arabic women. Avicenna. 2011;2011(3):1–13, [http://www.qscience. com/doi/full/10.5339/avi.2011.3]. [42] Serour M, Alqhenaei H, Al-Saqabi S, Mustafa AR, Ben-Nakhi A. Cultural factors and patients’ adherence to lifestyle measures. Br J Gen Pract. 2007;57(537):291–295. [43] Kahan D. Arab American college students’ physical activity and body composition: reconciling Middle East-West differences using the socioecological model. Res Q Exerc Sport. 2011;82(1):118–128. [44] Shemesh AA, Rasooly I, Horowitz P, Lemberger J, Ben-Moshe Y, Kachal J, Danziger J, Clarfield AM, Rosenberg E. Health behaviors and their determinants in multiethnic, active Israeli seniors. Arch Gerontol Geriatr. 2008;47(1):63–77. [45] Shuval K, Weissblueth E, Araida A, Brezis M, Faridi Z, Ali A, Katz DL. The role of culture, environment, and religion in the promotion of physical activity among Arab Israelis. Prev Chronic Dis. 2008;5(3):A88. [http://www.cdc.gov/pcd/issues/ 2008/jul/07_0104.htm]. [46] Tami SH, Reed DB, Boylan M, Zvonkovic A. Assessment of the effect of acculturation on dietary and physical activity behaviors of Arab mothers in Lubbock, Texas. Ethn Dis. 2012;22(2):192–197. [47] Qahoush R, Stotts N, Alawneh MS, Froelicher ES. Physical activity in Arab women in Southern California. Eur J Cardiovasc Nurs. 2010;9(4):263–271. [48] Koc¸ak S. Perceived barriers to exercise among university members. ICHPER – SD J. 2005;41(1):34–36. [49] Kalter-Leibovici O, Younis-Zeidan N, Atamna A, Lubin F, Alpert G, Chetrit A, Novikov I, Daoud N, Freedman LS. Lifestyle intervention in obese Arab women: a randomized controlled trial. Arch Intern Med. 2010;170(11):970–976. [50] Pluye P, Robert E, Cargo M, Bartlett G, O’Cathain A, Griffiths F. Proposal: A Mixed Methods Appraisal Tool for Systematic Mixed Studies Reviews. : McGill University; 2011. [http://mixedmethodsappraisaltoolpublic.pbworks.com/f/MMAT% 202011%20criteria%20and%20tutorial%202011-06-29.pdf] [http://mixedmethodsappraisaltoolpublic.pbworks.com; Archived by WebCitew at http://www.webcitation.org/5tTRTc9yJ] [accessed Apr. 2, 2013]. [51] Pace R, Pluye P, Bartlett G, Macaulay AC, Salsberg J, Jagosh J, Seller R. Testing the reliability and efficiency of the pilot mixed methods appraisal tool (MMAT) for systematic mixed studies review. Int J Nurs Stud. 2012;49(1):47–53. [52] Pluye P, Gagnon MP, Griffiths F, Johnson-Lafleur J. A scoring system for appraising mixed methods research, and concomitantly appraising qualitative, quantitative and mixed methods primary studies in mixed studies reviews. Int J Nurs Stud. 2009;46(4):529 –546. [53] Nakamura Y. Beyond the hijab: female Muslims and physical activity. WSPAJ. 2002;11(2):21–48. [54] Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones J, Van den Ende EC. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database Syst Rev. 2009; (4):CD006853. [55] Hagen KB, Dagfinrud H, Moe RH, Osteras N, Kjeken I, Grotle M, Smedslund G. Exercise therapy for bone and muscle health: an overview of systematic reviews. BMC Med. 2012;10:167. [56] Kelley GA, Kelley KS, Hootman JM, Jones DL. Effects of community-deliverable exercise on pain and physical function in adults with arthritis and other rheumatic diseases: a meta-analysis. Arthritis Care Res (Hoboken). 2011;63(1):79–93. [57] Levy SS, Macera CA, Hootman JM, Coleman KJ, Lopez R, Nichols JF, Marshall SJ, Ainsworth BA, Ji M. Evaluation of a multi-component group exercise program for adults with arthritis: fitness and exercise for people with arthritis (FEPA). Disabil Health J. 2012;5(4):305–311. [58] Stephenson LE, Culos-Reed SN, Doyle-Baker PK, Devonish JA, Dickinson JA. Walking for wellness: results from a mall walking program for the elderly. J Sport Exerc Psychol. 2007;29:S204. [59] Boen F, Maurissen K, Opdenacker J. A simple health sign increases stair use in a shopping mall and two train stations in Flanders, Belgium. Health Promot Int. 2010;25(2):183–191. [60] Lee KK, Perry AS, Wolf SA, Agarwal R, Rosenblum R, Fischer S, Grimshaw VE, Wener RE, Silver LD. Promoting routine stair use: evaluating the impact of a stair prompt across buildings. Am J Prev Med. 2012;42(2):136–141. [61] Howie EK, Young DR. “Step It UP”: a multicomponent intervention to increase stair use in a university residence building. Am J Health Promot. 2011;26(1):2 –5. [62] Nicoll G. Spatial measures associated with stair use. Am J Health Promot. 2007;21(4):346–352.

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[63] Boutelle KN, Jeffery RW, Murray DM, Schmitz MK. Using signs, artwork, and music to promote stair use in a public building. Am J Public Health. 2001;91(12):2004–2006. [64] Pauls JL. Review of stair-safety research with an emphasis on Canadian studies. Ergonomics. 1985;28(7):999 –1010. [65] Christina KA, Cavanagh PR. Ground reaction forces and frictional demands during stair descent: effects of age and illumination. Gait Posture. 2002;15(2):153 –158. [66] Taylor J. The changing health of the Middle East population through oil and automobiles: Jennifer Taylor talks to Abdulrahman O. Musaiger, BSc, DR Ph, Director of Arab Center for Nutrition, Bahrain. Eur Heart J. 2009;30(11):1291–1293. [67] McKechnie DS, Grant J, Shabbir Golawala F, Ganesh P. The fitness trend moves east: emerging market demand in the UAE. Eur Sport Manage Quart. 2006;6(3):289 –305. [68] Yosef AR. Health beliefs, practice, and priorities for health care of Arab Muslims in the United States. J Transcult Nurs. 2008;19(3):284 –291. [69] Benjamin K, Edwards NC, Bharti VK. Attitudinal, perceptual, and normative beliefs influencing the exercise decisions of community-dwelling physically frail seniors. J Aging Phys Act. 2005;13(3):276 –293. [70] Stengel MR, Kraschnewski JL, Hwang SW, Kjerulff KH, Chuang CH. “What my doctor didn’t tell me”: examining health care provider advice to overweight and obese pregnant women on gestational weight gain and physical activity. Womens Health Issues. 2012;22(6):e535–e540. [71] Bull FC, Jamrozik K. Advice on exercise from a family physician can help sedentary patients to become active. Am J Prev Med. 1998;15(2):85–94. [72] Glasgow RE, Eakin EG, Fisher EB, Bacak SJ, Brownson RC. Physician advice and support for physical activity: results from a national survey. Am J Prev Med. 2001;21(3):189–196. [73] Kreuter MW, Scharff DP, Brennan LK, Lukwago SN. Physician recommendations for diet and physical activity: which patients get advised to change? Prev Med. 1997;26(6):825–833.

OPEN ACCESS

Review article

Role of growth factors in preeclampsia: Early detection and treatment Sadia Munir* University of Calgary â&#x20AC;&#x201C; Qatar, Doha, Qatar *Email: munirs@ucalgary.edu.qa

ABSTRACT Preeclampsia is a pregnancy specific condition characterized by hypertension and proteinuria. It complicates about 10% of all pregnancies. It is a major cause of maternal and fetal morbidity and mortality. Interestingly, preeclampsia may have an impact on the health of the mother or infant, beyond the pregnancy. It is believed that several ligands and receptors of different families of growth factors have been involved in the development of preeclampsia. We performed a systematic search of PubMed including combination of terms such as preeclampsia, growth factors, treatment, vascular endothelial growth factor A, activin A, inhibin A, placental growth factor, transforming growth factor b-1, Nodal, placenta, trophoblast cells, biomarkers and detection. In this review we have summarized current knowledge on the role of growth factors in early detection and treatment of preeclampsia. Although these growth factors have significant roles in normal and complicated pregnancies, the current value of these growth factors as biomarkers, for the precise prediction of preeclampsia, has its limitation. Therefore, future studies need to be done to support some of the very promising and interesting data to develop affordable and widely available tests for early detection and treatment of preeclampsia. Keywords: preeclampsia, growth factors, placenta, bio markers, treatment, detection, vascular endothelial growth factor A, activin A, inhibin A, placental growth factor, transforming growth factor b-1, Nodal

http://dx.doi.org/ 10.5339/avi.2013.4 Submitted: 18 May 2013 Accepted: 29 June 2013 ÂŞ 2013 Munir, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Munir S. Role of growth factors in preeclampsia: Early detection and treatment, Avicenna 2013:4 http://dx.doi.org/10.5339/avi.2013.4

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INTRODUCTION Preeclampsia is the contributor to the world wide maternal mortality of approximately 100,000 deaths a year.1 It complicates about 10% of all pregnancies and it is the first cause of maternal admission to intensive care units.2 It is a very challenging disease with associated high risk of perinatal mortality; it is the reported cause of 10% stillbirths and 15% of preterm deliveries.1,3 There is a five folds increase in the death rate of infants born to mothers affected with preeclampsia. In a retroscopic study involving one million Canadian women, it was shown that women, who suffer from preeclampsia or other placental diseases, are twice as likely to have premature cardiovascular disease when compared to women with no placental syndrome.3 – 6 No recent data is reported about the prevalence of preeclampsia in Qatar. However, in a populationbased study carried out in UAE, preeclampsia was the leading cause of maternal morbidity. It has been recently reported that 59.5% women out of 926 cases of severe acute maternal morbidity were preeclamptic. The frequency of preeclampsia was significantly higher among Indian subcontinent populations as compared to Arab populations.7 Preeclampsia is a pregnancy-specific condition characterized by hypertension ($140/90 mm Hg) and protienuria ($300 mg) after 20 weeks of gestation. Clinical symptoms of preeclampsia include headaches, excess and rapid weight gain, nausea and vomiting, stomach ache, edema and vision problems.8 If left untreated, preeclampsia can develop into eclampisa, which is acute and life threatening occurrence of seizure activity and/or unexplained coma during pregnancy or postpartum.9 Preeclampsia may also impact women’s health beyond their pregnancies. Increasing evidence suggest that preeclampsia is the risk factor of many diseases including cardiovascular diseases and diabetes.4 – 6,10 Two different disease entities of preeclampsia are described based on number of articles published in early 1980s and late 1970s: early onset preeclampsia (that develops before 34 weeks of gestation) and late onset preeclampsia (that develop at or after 34 weeks of gestation).3,11 – 15 Different genetic and environmental risk factors, prognosis, heritability, biochemical, histological and clinical features are associated with early or late onset of preeclampsia. Early onset preeclampsia is associated with dysfunction in placenta, reduction in placental volume, intrauterine growth restriction, low birth weight and adverse maternal and fetal outcomes. On the other hand, in general, placental involvement is minimally present in late onset preeclampsia and is the result of maternal constitutional disorder. Furthermore, normal fetal growth, normal birth weight and favourable maternal and fetal outcomes have also been reported in late onset preeclampsia.16,17 Predicting preeclampsia is a major challenge in obstetrics.17,18 More importantly, no major progress has been achieved in the treatment of preeclampsia. As the placenta is the main cause of the disease, the only way to treat the disease is to extract the placenta and deliver the baby. In developed countries, the cost of an average case of preeclampsia is estimated at £9000.19 In developing countries, where emergency care is often inadequate or lacking, the importance of preeclampsia is even more stressed, when confidential enquiries are analysed showing that a significant proportion of cases of fetal deaths is due to preeclampsia.20 Therefore, there is an increasing need of an affordable and widely applicable test that could permit early presymptomatic detection of preeclampsia to identify and monitor high-risk pregnant mothers to provide the best prenatal care for them and for their child. There are multiple markers of preeclampsia that are available in the first trimester and would allow early diagnosis of high-risk pregnant women to reduce the morbidity. These markers can also open an area to carry out further studies looking at therapeutic medications.12,14,18,20 – 24 In this review we will briefly discuss the pathophysiology of preeclampsia, current biomarkers in preeclampsia and prospects of use of these markers for early detection and treatment of preeclampsia. PATHOPHYSIOLOGY OF PREECLAMPSIA Preeclampsia is a multisystem disorder commonly called as gestational hypertension with protienuria or defective placental angiogenesis.3,5,12,16,25 It is the leading cause of maternal and fetal mobidity and mortality. Prediction of development of preeclampsia is often too difficult, leading the Greeks to name ‘eklampsis’ means lightening.3 Severity of preeclampsia is variable. It ranges from mild hypertension and proteinuria to severe disease with endothelial dysfunction and end organ damage. Preeclampsia is investigated for more than a decade now, but most of its pathogenesis is still unknown.26

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Increasing evidence suggest that preeclampsia is the result of placental dysfunction in the first trimester. This placental dysfunction is because of the shallow invasion of extravillous trophoblast cells in the placental bed.11,17 Placenta is a transient organ, which is critically involved in the growth and development of the fetus. During placental development, trophoblast is the first cell lineage, differentiated into two major pathways, the villous pathway and extravillous pathway (Figure 1). In normal pregnancy, during the first trimester, extravillous trophoblast cells invade the maternal spiral arteries of the uterus, into and across the deciduas up to the one third of the myometrium.27 This results in the formation of maternal placental vessels that supply oxygen and nutrients to the developing fetus. Trophoblast cells also abolish the response of maternal vessels to the vasoconstrictors by clearing the smooth muscle structure that surrounds these vessels, therefore facilitating placental blood flow. On the other hand, in preeclampsia, invasion of myometrium by extravillous trophoblast is reduced to around 50% of normal, resulting in incomplete modification of maternal spiral arteries, placental ischemia and hypoxia which impairs fetal growth (Figure 1).27 â&#x20AC;&#x201C; 29 Shallow invasion of the uterus also produces a Trophoblast cells (progenitor cells)

Undifferentiated cytotrophoblast cells

Anchoring villi

Villous pathway

Reduced EVT PE

EVT cells Functions: Nutrient and waste exchange. Hormone production Interstitial EVT Shallow invasion PE

Migrate into 1/3rd of myometrium.

Extravillous pathway

Syncytiotrophoblast

Reduced migration and invasion of endovascular EVT PE Penetration and remodelling of maternal spiral artery Endovascular EVT

Low resistance and high capacity of utero-placental arteries will increase the blood flow to placenta. Figure 1. A schematic flow chart to illustrate pathways of normal placental trophoblast differentiation vs. preeclampsia formation. Trophoblast progenitor cells give rise to cytotrophoblast, which are mononucleated and undifferentiated cells. Cytotrophoblasts differentiate into multinucleated syncytiotrophoblasts, in the villous pathway. In the extravillous pathway, cytotrophoblast cells detach from the anchoring villi, called Extravillour trophoblast cells (EVT) and migrate into the decidua. These cells reach up to one third of the myometrium and are called interstitial extravillous trophoblast cells. Endovascular extravillous trophoblast cells penetrate the uterine spiral artery and causes remodelling of spiral artery to increase the blood flow in placenta. Red coloured boxes indicate pathological changes in normal pregnancy that leads to preeclampsia.

series of modulators of angiogenesis by the placenta which crosses the materno-placental barrier and adversely affects the mother in the later stages of pregnancy. Thus, the response by the mother appears late, the origin of preeclampsia is early, local and placental.5,6 Several growth factors are involved in the normal placental development. The functions, location and expression of these growth factors are very important in the regulation of placental development, and are thoroughly reviewed in various studies (Table 1). CURRENT BIOMARKERS IN PREECLAMPSIA There are multiple markers of preeclampsia and are reported to be connected to the pathophysiology of the disease. Some are directly involved in the symptoms of disease while others are situated in the

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Table 1. The expression, specific location in placenta and main function of various growth factors in normal pregnancy. Name

Placental location

Expression rd

VEGF

STB, iEVT

Rises in 3 trimester

PIGF TGF-b

CTB, STB, EVT STB, CTB

Rises in 3rd trimester Rises in 1st trimester

Activin A

CTB, EVT

Rises in 1st trimester

Inhibin A

STB

Endoglin Nodal

STB, CTB STB, EVT

Expressed throughout pregnancy Rises in 1st trimester Expressed throughout pregnancy

Function

Induction of endothelial cell migration, division and survival. Induce trophoblast cell invasion Inhibit trophoblast cell proliferation and differentiation toward the invasive EVT pathway. Stimulate hCG and progesterone secretion and CTB proliferation and increases EVT migration. Trophoblast cell endocrine and vascular development Angiogenesis Inhibit proliferation and induce apoptosis in EVT cells

References 30 31,32 33,34

35 â&#x20AC;&#x201C; 37

37 38,39 40,41

STB, syncytiotrophoblast; CTB, cytotrophoblast; EVT, extravillous trophoblast; iEVT, interstitial trophoblast

upstream of pathophysiological cascade. Studies have focussed on cytokines, indicators of endothelial dysfunction, markers of oxidative stress and angiogenic factors.12,14,18,21 â&#x20AC;&#x201C; 24 In this review, we will only discuss studies on growth factors that are especially associated with early onset preeclampsia, which contributes to adverse maternal and perinatal outcomes. Activin A and Inhibin A Activin is one of the members of TGF-b superfamily. Activin A is a pleurotropic cytokine that plays a very important role in many developmental processes.42,43 Mature Activin A is a dimer consisting of disulphide linked inhibin subunits. Activin A signals by binding and activating serine threonine kinase type II receptor (ActRIIA and ActRIIB).35 Activation of type II receptor in turn recruits type I receptor (ALK4) which then activates smad 2 and smad 3 proteins to induce target genes.35,36 Activin A and its receptors are expressed in placental deciduas and uterine tissues during pregnancy.44 In vitro studies have indicated that cell migration and invasion of trophoblast cells was induced by Activin A. Furthermore, Activin A also induces production of several hormones including GnRH, hCG, progesterone and matrix metalloproteinase (MMP2) by trophoblast cells. Studies have shown an increase in the maternal serum and placental inhibin A and Activin A levels in the pregnancies that subsequently developed preeclampsia.37 Evidence has also suggested that Activin A is a promising biomarker for the detection of preeclampsia in Chinese populations. It is also reported that treatment of trophoblast cells with high doses of Activin A promotes apoptosis and therefore affects invasion of extravillous trophoblasts in the myometrium.26 Transforming growth factor b 1 and endoglin Transforming growth factor b1 (TGF b1) is a multifunctional cytokine and is involved in several physiological processes including embryonic growth and development, repair-inflamation and angiogenesis.33,45 It is reported that maternal symptoms of preeclampsia are produced by the release of TGF b1 from endothelial cells in response to phagocytosis of necrotic trophoblasts in preeclamptic placentae. Therefore, TGF b1 is involved in the pathogenesis of preeclampsia.34 Endoglin is the co-receptor for TGF b1 and TGF b3 and modulates TGF b signalling by interacting with type I and type II receptors of TGF b (Table 2).38 Endoglin is expressed by vascular endothelium and syncitiotrophoblasts. It is involved in the process of angiogenesis.39 An increase in soluble endoglin is detected few weeks before the symptoms of preeclampsia; however, levels of TGF b1 do not show any significant difference in normal vs. preeclamptic women.38 There is an evidence of increase in the concentrations of endoglin with severity of the symptoms of preeclampsia.18 Interestingly, elevation in the levels of endoglin is also reported in pregnancies with intrauterine growth restriction without maternal syndrome, suggesting that soluble endoglin is not a promising marker for preeclampsia.46

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Table 2. Receptors involved in the downstream signal pathway of various growth factors. Name of growth factor

Receptors

TGF b Activin A

Serine threonine kinase receptor (type I and type II) Serine theronine kinase receptor (ActRII A and ActRIIB ¼ type II receptors and ALK4 ¼ type I receptor) Serine threonine kinase receptor (ALK7 and ALK4 ¼ type I receptors) Two tyrosine kinase receptor isoforms (VEGF-R1 ¼ Flt1 and VEGF-R2)

Nodal VEGF A

ActRII, activin receptor type II; ALK, Activin receptor like kinase; VEGF-R, vascular endothelial growth factor receptor

Vascular endothelial growth factor A (VEGF-A) VEGF-A produces many functions in endothelial cells including induction of angiogenesis, reduction of apoptosis and increase of vascular permeability.47 It binds with high affinity to two tyrosine kinase receptors expressed on vascular endothelial cells (Table 2).48 Hypoxia stimulates the expression of VEGF-A mRNA expression.49 Fms-like tyrosine kinase receptor (FLT-I) is a receptor which binds with VEGF-A and placental growth factor (PIGF) with high affinity and is expressed in many human tissues, including placental trophoblasts. Its expression is also up-regulated by hypoxia conditions.50 Literature review shows contradictory findings about the expression of VEGF family angiogenic growth factors in the placenta during pregnancy. The inconsistent results are due to the probes used in in situ hybridization studies and many cross react with other growth factors resulting in false-positive data.51 Preeclampsia is associated with early placentation defects and inadequate maternal spiral artery remodelling. In preeclampsia, shallow endovascular invasion is the result of failure of cytotrophoblast differentiation into vascular phenotype. It is reported by in vivo and in vitro studies that preeclamptic placentae retain some adhesion molecules while fail to up-regulate others, which are normally expressed by most differentiated and invasive trophoblasts.52,53 Studies have shown that cytotrophoblasts are regulated by VEGF and blocking of VEGF ligand significantly decreases the expression of integrin a1 and induces apoptosis in these cells.54 Increasing evidence has suggested that a decrease in the expression of VEGF-A and FLT-1 is noticed in severe preeclampsia, as compared to normal placentae.51 Recent studies have also reported that shallow invasion of extravillous trophoblast and impaired spiral artery remodelling not only lead to defective utero-placental circulation but also causes damage to chorionic villi, leading to clinical features of pre-eclampsia.55 There is consistent evidence of increase in maternal serum and placental expression of FLT-1 in preeclamptic women as compared to normal pregnant women.47,56 Moreover, levels of FLT-1 are directly proportional to the degree of proteinuria.56 Although, VEGF-A plays a promising role in normal pregnancy and in the pathogenesis of preeclampsia, it has a limited clinical role in the prediction of preeclampsia due to extremely low circulating levels of free VEGF-A, below the detection level of ELISA kits. The potential use of VEGF family in the treatment of preeclampsia is explored by using many animal models. Infection of pregnant rats with overexpressed FLT adenovirus resulted in hypertension and proteinuria, with renal lesions associated with preeclampsia in pregnant women. Reduction in hypertention and proteinuria and improvement in glomerular endotheliosis was also noticed by induction of recombinant VEGF-A in these rats.57 Recently, potential use of the VEGF family in the treatment of preeclampsia is being explored and many findings have suggested that VEGF-A may have a therapeutic potential in the management of preeclampsia. However further studies on the possibility of potential adverse effects of VEGF-A therapy will be beneficial to completely understand the value of VEGF-A in early diagnosis and treatment of preeclampsia.51 Placental growth factor (PIGF) There is 42% amino acid sequence identity between VEGF-A and PIGF.58 PIGF promotes angiogenesis and the level of maternal serum PIGF is inversely proportional to FLT-1 levels. In preeclampsia, levels of PIGF are lower as compared to normal pregnancy, with the most pronounced difference observed 5 weeks before the clinical onset of the disease.31,32,59,60 PIGF is a small molecule (30KD), freely filtered by glomerulus and can be found in urine. It can easily be detected by dipstick technology.61 It is proposed in many studies that the ratio between PIFF and FLT-1 in early-mid pregnancy is a screening tool for preeclampsia that led to these biomarkers being validated for routine clinical use in some countries. However, highest predictive values have not been achieved.51 One scenario is to screen all women with low PIGF urine concentration and to consider all those with low levels as high-risk women.

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Serial serum measurements of FLT-1 and PIGF could then be performed to identify more precisely women at high risk.31 However, studies have suggested that prediction of preeclampsia by comparing ratios of FLT-1 to PIGF have highest predictive values during second trimester screening.51 A screening test has been launched by Roche in Europe, as a diagnostic screening procedure for preeclampsia in the second trimester.18 This test can significantly separate healthy women and women with preeclampsia when screening was performed after 20 weeks of gestation.62 However, sensitivity and accuracy of test need to be improved to decrease the number of false positive and false negative patients. This can prevent over-diagnosis/over-treatment, reduce cost of monitoring by reducing unnecessary hospital admissions and improve earlier detection and appropriate management.1 Nodal Nodal is a member of transforming growth factor beta superfamily. Nodal signals through type II and type I serine/threonine kinase transmembrane receptor proteins. Nodal has been reported to act through two type I receptors (activin receptor-like kinase 4 and 7) (ALK4 and ALK7) (Table 2).40,63 A preeclampsia susceptibility locus is located on chromosome 2q22 along with type II receptor and ALK7, suggesting an association of these receptors with preeclampsia.64,65 Several studies have suggested that Nodal is important for placental development. Abnormal placentation is reported due to a mutation of the Nodal gene, which leads to expansion of giant cells and spongiotrophoblast layers and decreases the labyrinthine development.66 Nodal also inhibit precocious differentiation of trophoblast stem cells by acting on extraembryonic stem cells.67 In human placenta, Nodal and its receptor ALK7 has been expressed. It is also reported that Nodal signals through ALK7, inhibits trophoblast proliferation and induces apoptosis.40,41 Recently spatial and temporal expression patterns of Nodal and ALK7 in human placenta were examined and level of expression of Nodal and ALK7 were found to be up-regulated in severe early-onset preclamptic placenta. Furthermore, Nodal and ALK7 signals were also detected in the villous mesenchyme surrounding the paravascular capillary network of the intermediate villi, suggesting a potential role of Nodal in angiogenesis or vascular control. It is also reported that overexpression of Nodal and ALK7 significantly decreases trophoblast cell migration and invasion. Most promising data came from a study on human placental explants. Placental explants cultures showed expansion of explants and migration of extravillous trophoblast cells, when treated with Nodal small-interferring RNA. Invasion of EVT cells also depend on the degradation of extracellular matrix by MMP-2 and MMP-9, and their activity is controlled by Tissue inhibitor of matrix metalloproteinases 1(TIMP 1). It was also determined that Nodal inhibits trophoblast cell invasion and migration partly by acting through TIMP1-MMP-2/MMP-9 pathway. Increased expression of Nodal/ALk7 in extravillous trophoblast cells may result in defective cytotrophoblast differentiation, shallow invasion of uterus, excessive apoptosis and imbalance of MMP2/TIMP1 ratio.68 It is also reported that increased level of Activin A in preeclamptic placenta enhances Nodal signalling,which induces apoptosis of trophoblast cells.26 All these findings suggest that Nodal/ALK7 pathway is involved in the regulation of placental development and function and that defective signalling of Nodal may contribute to the pathogenesis of preeclampsia. DISCUSSION Preeclampsia is a serious and complicated disease. Although its causes are not entirely clear, shallow trophoblast invasion and excessive apoptosis along with dysfunction in spiral artery remodelling leads to preeclampsia.1,11,12,18,25,68 Many of the studies summarized here support the idea that various protein biomarkers are known and their level of expressions and roles in pregnancy complications have studied, mainly in preeclampsia.12 However, researchers found no widely acceptable and promising marker for the early detection and prevention/treatment of disease. There is an increasing need of an affordable and widely applicable test that could permit early detection of preeclampsia to identify and monitor high risk pregnant mothers and to provide the best prenatal care for them and for their child. Extensive preclinical and clinical studies have demonstrated that FLT 1, VEGF-A, PIGF and their ratios play important roles and may be useful markers in prediction of preeclampsia.11,12,18,69 The biggest challenge is limitations in their clinical utility, since high precision tests can only be performed in second trimester of gestation. There is an increasing interest in combining several variables, as no single test can predict preeclampsia with accuracy. Recent studies on Nodal and its role in placental development have suggested the need of future studies to focus on the expression pattern and function of Nodal in the placentae of other populations.

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It will provide interesting insights into the clear and well defined role of Nodal and its signalling in preeclampsia. Identification of women at risk for preeclampsia is important not only to develop and evaluate preventive treatments but also to improve the structure of antenatal care. Further studies need to be carried out to find affordable and precise methods of early detection of preeclampsia. These studies are also needed to suggest therapeutic potential in the management of preeclampsia. COMPETING INTERESTS The author of this manuscript has no personal or financial relationship with an individual or organization that may influence her interpretation of literature review mentioned in this article. REFERENCES [1] Scazzocchio E, Figueras F. Contemporary prediction of preeclampsia. Curr Opin Obstet Gynecol. 2011;23:65–71. [2] Tang LC, Kwok AC, Wong AY, Lee YY, Sun KO, So AP. Critical care in obstetrical patients: an eight-year review. Chin Med J (Engl). 1997;110(12):936–941. [3] Hawfield A, Freedman BI. Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection. Ther Adv Cardiovasc Dis. 2009;3:65–73. [4] Tomsin K, Mesens T, Molenberghs G, Peeters L, Gyselaers W. Characteristics of heart, arteries, and veins in low and high cardiac output preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2013;, pii: S0301-2115(13)00146-2. doi: 10.1016/j.ejogrb.2013.03.016. [Epub ahead of print]. [5] Garovic VD, August P. Preeclampsia and the future risk of hypertension: the pregnant evidence. Curr Hypertens Rep. 2013;15:114–121. [6] Berks D, Hoedjes M, Raat H, Duvekot JJ, Steegers EA, Habbema JD. Risk of cardiovascular disease after pre-eclampsia and the effect of lifestyle interventions: a literature-based study. BJOG. 2013;120(8):924–931, doi: 10.1111/14710528.12191. Epub Mar 26, 2013. [7] Ghazal-Aswad S, Badrinath P, Sidky I, Safi TH, Gargash H, Abdul-Razak Y, Mirghani H. Severe acute maternal morbidity in a high-income developing multiethnic country. Matern Child Health J. 2013;17(3):399–404. [8] Jido TA, Yakasai IA. Preeclampsia: a review of the evidence. Ann Afr Med. 2013;12:75–85. [9] Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000;182:307–312. [10] Masuyama H, Nobumoto E, Segawa T, Hiramatsu Y. Severe superimposed preeclampsia with obesity, diabetes and a mild imbalance of angiogenic factors. Acta Med Okayama. 2012;66:171–175. [11] Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv. 2011;66:497–506. [12] Hasko M, Biringer K, Biskupska BK, Danko J. Selected markers in early prediction of preeclampsia. Ceska Gynekol. 2011;76:135–139. [13] Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med. 2008;59:61–78. [14] Than NG, Romero R, Hillermann R, Cozzi V, Nie G, Huppertz B. Prediction of preeclampsia – a workshop report. Placenta. 2008;29:S83–S85. [15] Thangaratinam S, Langenveld J, Mol BW, Khan KS. Prediction and primary prevention of pre-eclampsia. Best Pract Res Clin Obstet Gynaecol. 2011;25:419–433. [16] Beaufils M. Pregnancy hypertension. Nephrol Ther. 2010;6:200–214. [17] Boulanger H, Flamant M. New insights in the pathophysiology of preeclampsia and potential therapeutic implications. Nephrol Ther. 2007;3:437–448. [18] Grill S, Rusterholz C, Zanetti-Da¨llenbach R, Tercanli S, Holzgreve W, Hahn S, Lapaire O. Potential markers of preeclampsia–a review. Reprod Biol Endocrinol. 2009;7:70. doi: 10.1186/1477-7827-7-70. [19] Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, Roberts TE, Mol BW, van der Post JA, Leeflang MM, Barton PM, Hyde CJ, Gupta JK, Khan KS. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling. 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[26] Yu L, Li D, Liao QP, Yang HX, Cao B, Fu G, Ye G, Bai Y, Wang H, Cui N, Liu M, Li YX, Li J, Peng C, Wang YL. High levels of activin A detected in preeclamptic placenta induce trophoblast cell apoptosis by promoting nodal signaling. J Clin Endocrinol Metab. 2012;97(8):E1370–E1379. [27] Pijnenborg R, Robertson WB, Brosens I, Dixon G. Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta. 1981;2:71–91. [28] Pijnenborg R, Bland JM, Robertson WB, Dixon G, Brosens I. The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy. Placenta. 1981;2(4):303–316.

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[29] Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L, van Assche A. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol. 1991;98(7):648–655. [30] Pietro L, Daher S, Rudge MV, Calderon IM, Damasceno DC, Sinzato YK, Bandeira C, Bevilacqua E. Vascular endothelial growth factor and VEGF-receptor expression in placenta of hyperglycaemic pregnant women. Placenta. 2010;31:770–780. [31] Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, Blink AL, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Urinary placental growth factor and risk of preeclampsia. JAMA. 2005;293:77–85. [32] Akolekar R, Zaragoza E, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11 þ 0 to 13 þ 6 weeks of gestation in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol. 2008;32:732–739. [33] Tossidou I, Schiffer M. TGF-beta/BMP pathways and the podocyte. Semin Nephrol. 2012;32:368 –376. [34] Chen Q, Chen L, Liu B, Vialli C, Stone P, Ching LM, Chamley L. The role of autocrine TGFbeta1 in endothelial cell activation induced by phagocytosis of necrotic trophoblasts: a possible role in the pathogenesis of pre-eclampsia. J Pathol. 2010;221(1):87 –95. [35] Walton KL, Makanji Y, Harrison CA. New insights into the mechanisms of activin action and inhibition. Mol Cell Endocrinol. 2012;359:2–12. [36] Robertson DM. Inhibins and activins in blood: predictors of female reproductive health? Mol Cell Endocrinol. 2012;359:78–84. [37] Morris JM, Gopaul NK, Endresen MJ, Knight M, Linton EA, Dhir S, Angga˚rd EE, Redman CW. Circulating markers of oxidative stress are raised in normal pregnancy and pre-eclampsia. Br J Obstet Gynaecol. 1998;105(11):1195–1199. [38] Lim JH, Kim SY, Park SY, Lee MH, Yang JH, Kim MY, Chung JH, Lee SW, Ryu HM. Soluble endoglin and transforming growth factor-beta1 in women who subsequently developed preeclampsia. Prenat Diagn. 2009;29:471–476. [39] ten Dijke P, Goumans MJ, Pardali E. Endoglin in angiogenesis and vascular diseases. Angiogenesis. 2008;11:79 –89. [40] Munir S, Xu G, Wu Y, Yang B, Lala PK, Peng C. Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. J Biol Chem. 2004;279:31277–31286. [41] Fu G, Ye G, Nadeem L, Ji L, Manchanda T, Wang Y, Zhao Y, Qiao J, Wang YL, Lye S, Yang BB, Peng C. MicroRNA-376c impairs transforming growth factor-beta and nodal signaling to promote trophoblast cell proliferation and invasion. Hypertension. 2013;61:864–872. [42] Florio P, Gabbanini M, Borges LE, Bonaccorsi L, Pinzauti S, Reis FM, Boy Torres P, Rago G, Litta P, Petraglia F. Activins and related proteins in the establishment of pregnancy. Reprod Sci. 2010;17(4):320 –330. [43] McNeilly AS. Diagnostic applications for inhibin and activins. Mol Cell Endocrinol. 2012;359:121–125. [44] Peng C, Mukai ST. Activins and their receptors in female reproduction. Biochem Cell Biol. 2000;78:261–279. [45] Feizollahzadeh S, Taheripanah R, Khani M, Farokhia B, Amani D. Promoter region polymorphisms in the transforming growth factor beta-1 (TGFbeta1) gene and serum TGFbeta1 concentration in preeclamptic and control Iranian women. J Reprod Immunol. 2012;94:216–221. [46] Yinon Y, Nevo O, Xu J, Many A, Rolfo A, Todros T, Post M, Caniggia I. Severe intrauterine growth restriction pregnancies have increased placental endoglin levels: hypoxic regulation via transforming growth factor-beta 3. Am J Pathol. 2008;172(1):77–85. [47] Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res. 2000;55:15–35, ; discussion 35 –6. [48] de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992;255:989–991. [49] Purwosunu Y, Sekizawa A, Yoshimura S, Farina A, Wibowo N, Nakamura M, Shimizu H, Okai T. Expression of angiogenesis-related genes in the cellular component of the blood of preeclamptic women. Reprod Sci. 2009;16:857–864. [50] Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem. 1997;272:23659–23667. [51] Andraweera PH, Dekker GA, Roberts CT. The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update. 2012;18:436–457. [52] Many A, Hubel CA, Fisher SJ, Roberts JM, Zhou Y. Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia. Am J Pathol. 2000;156:321 –331. [53] Zhou Y, Genbacev O, Damsky CH, Fisher SJ. Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia. J Reprod Immunol. 1998;39:197–213. [54] Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest. 1997;99:2152 –2164. [55] Verdonk K, Visser W, Steegers EA, Kappers M, Danser AH, van den Meiracker AH. New insights into the pathogenesis of pre-eclampsia: the role of angiogenesis-inhibiting factors. Ned Tijdschr Geneeskd. 2011;155:A2946. [56] Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Gonc¸alves LF, Gomez R, Edwin S. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol. 2004;190(6):1541–1547, ; discussion 1547–50. [57] Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50:686–692. [58] De Falco S, Gigante B, Persico MG. Structure and function of placental growth factor. Trends Cardiovasc Med. 2002;12:241–246. [59] Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–683.

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[60] Poon LC, Zaragoza E, Akolekar R, Anagnostopoulos E, Nicolaides KH. Maternal serum placental growth factor (PlGF) in small for gestational age pregnancy at 11(þ0) to 13(þ 6) weeks of gestation. Prenat Diagn. 2008;28:1110–1115. [61] Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, Hodges-Savola C. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol. 2010;202:40e1–40e7. [62] Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG, Pape J, Dudenhausen JW, Denk B, Stepan H. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol. 2010;202:161e1 –161e11. [63] Xu G, Zhong Y, Munir S, Yang BB, Tsang BK, Peng C. Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. J Clin Endocrinol Metab. 2004;89:5523–5534. [64] Roten LT, Johnson MP, Forsmo S, Fitzpatrick E, Dyer TD, Brennecke SP, Blangero J, Moses EK, Austgulen R. Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study). Eur J Hum Genet. 2009;17:250–257. [65] Fitzpatrick E, Johnson MP, Dyer TD, Forrest S, Elliott K, Blangero J, Brennecke SP, Moses EK. Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia. Mol Hum Reprod. 2009;15:195–204. [66] Ma GT, Soloveva V, Tzeng SJ, Lowe LA, Pfendler KC, Iannaccone PM, Kuehn MR, Linzer DI. Nodal regulates trophoblast differentiation and placental development. Dev Biol. 2001;236:124–135. [67] Guzman-Ayala M, Ben-Haim N, Beck S, Constam DB. Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment. Proc Natl Acad Sci U S A. 2004;101:15656–15660. [68] Nadeem L, Munir S, Fu G, Dunk C, Baczyk D, Caniggia I, Lye S, Peng C. Nodal signals through activin receptor-like kinase 7 to inhibit trophoblast migration and invasion: implication in the pathogenesis of preeclampsia. Am J Pathol. 2011;178:1177 –1189. [69] Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM. Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet Gynecol. 2008;111:1403–1409.

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Evidence-based healthcare

Evidence-based healthcare practice in Qatar: A need to move forward Kyle Wilby1,*, Khalid Al-Siyabi2 1

Qatar University, Doha, Qatar Hamad Medical Corporation, Doha, Qatar 2

*Email: kjw@qu.edu.qa

http://dx.doi.org/ 10.5339/avi.2013.7 Submitted: 11 June 2013 Accepted: 18 July 2013 ÂŞ 2013 Wilby, Al-Siyabi, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Evidence-based medicine (EBM) is considered the gold standard approach to therapeutic decisionmaking in modern medicine. It was first described in the 1990s as a way to improve patient outcomes by promoting rational therapeutic decision-making through translation of high quality clinical studies.1 It was originally defined as the conscientious, explicit, and judicious use of the best available evidence to make decisions regarding the care of individual patients.1 By translating results of high quality clinical trials into the therapeutic management of patients, better outcomes can be achieved.2 Additionally, it allows for standardized therapeutic management of disease and evaluation using audit and feedback. The practice of EBM goes hand on hand with individual clinical expertise and the use of available evidence. The five steps of evidence-based practice are summarized in Table 1.3 The initial step in the process involves the creation of a specific clinical question, commonly referred to as a PICO (Patient or Problem, Intervention, Comparator, Outcomes) question. Using the elements contained within the PICO question, a systematic search of available evidence would then occur (Step 2). Subsequently, critical appraisal of identified literature occurs with assessment for relevance, internal quality, interpretation of findings and applicability to the patient or problem defined by the original clinical question (Step 3). Finally, the practitioner makes an informed decision based on the evidence identified and appraised (Step 4). While these steps complete the EBM process for patient care, a final stage of evaluation and feedback may occur by auditing individual clinicianâ&#x20AC;&#x2122;s practices to benchmark evidence-based practice among peers (Step 5). There is a traditional belief that high quality evidence refers to only randomized controlled trials, or systematic reviews with meta-analysis. When well conducted, these studies usually represent high internal validity but may lack external validity, or generalizability to real-life patients. Therefore, other types of evidence (epidemiological studies, population based studies, case-series and even case reports) cannot always be ignored. The type of evidence selected for appraisal and therapeutic decision-making is largely based on the patient of interest or the problem at hand. For instance, a public health authority searching for evidence regarding immunization programs for influenza may be better suited to appraise epidemiological and population-based studies, rather than randomized controlled trials of individual patients. Another example would be a question relating to management of a rare adverse drug reaction or diseases, for which only case reports are available. Although this type of evidence is not ideal due to high susceptibility to bias and confounding, it may be the only existing source available. Any chosen evidence must be appraised and assessed for quality and relevance, prior to incorporation into clinical decision-making. Sources of evidence range from online medical literature databases such as PubMed4 to international organizations offering evidence summaries and appraisals of published studies. The Cochrane Collaboration5 is a commonly cited source of high quality systematic reviews that are synthesized using objective, standardized methods. Additionally, organizations such as the Britainâ&#x20AC;&#x2122;s Centre for Reviews and Dissemination at the University of York6 strive to standardize reporting and dissemination of high quality evidence reviews. Publications from these organizations can greatly

Cite this article as: Wilby K, Al-Siyabi K. Evidence-based healthcare practice in Qatar: A need to move forward, Avicenna 2013:7 http://dx.doi.org/10.5339/avi.2013.7

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Table 1. The five steps of evidence-based practice.3 Number

Step

Description

Asking Focused Questions (PICO)

Finding the Evidence

Critical Appraisal

4 5

Making a Decision Evaluating Performance

Must include the patient or problem, intervention being considered, comparison intervention, and clinical outcomes of interest Systematic search and identification of the best evidence to answer the focused question (utilizing primary, secondary, and tertiary literature sources) Assessing and interpreting evidence through validity, clinical relevance, and applicability Translating results into practice by applying to a clinical scenario Auditing practice and giving feedback through peers or other evaluation mechanisms

assist clinicians when creating evidence-based practices. However, for topics with little information available or if no review has been completed, a traditional systematic search using medical literature databases is warranted. The need for EBM dissemination and training has been well documented in Qatar. A recent cross-sectional survey determining the knowledge, attitudes and practices of EBM of 182 primary care physicians found 98.4% welcomed promotion of EBM and believed their colleagues welcomed it too.7 A total of 96.2% agreed practicing EBM improves patient care, 84.6% disagreed that EBM was of limited value in primary care but 56.6% agreed EBM places high demand on overloaded physicians. Surprisingly, only 68.7% stated to actively practice EBM. Investigators also sought to identify barriers to practicing EBM. A total of 75.3% indicated lack of free personal time, 62.6% stated limited resources and facilities, and 61.0% identified lack of training workshops and courses interfered with their ability to incorporate EBM into daily practice.7 In order to overcome these barriers, strategies can be developed to facilitate incorporation of EBM into routine patient care. Three other studies were identified assessing EBM and healthcare professionals within the Gulf Cooperation Council (GCC) countries.8 – 10 Two studies from Saudi Arabia assessed attitudes of physicians towards EBM and incorporation into practice.8,9 One study assessed attitudes of evidence-base medicine among 559 primary health care physicians. The study found most practitioners welcomed EBM and agreed that it may improve patient care.8 However, there was a low level of awareness regarding the skills and procedures for extracting evidence and assessing for quality. Similar to the Qatar study, overload and time constraints were the most common barriers associated with incorporating EBM into routine decision-making. A study employing the same methodology in a different group of primary care physicians (N ¼ 272) in Saudi Arabia found very similar results.9 Interestingly, it was documented that the most commonly read journals were those sponsored by pharmaceutical companies, a potential source of bias. Lastly, a study assessing EBM knowledge and attitudes of dentists in Kuwait (N ¼ 120) found 60.9% stated they practiced EBM but only 40.8% had a reasonable understanding of major principles.10 The author’s stated that clinical decisions appeared to be based mostly on clinician’s own judgment (73.3%) versus sources such as PubMed (28.3%) or the Cochrane Library (6.7%). These studies reflect both a desire and need for EBM training throughout the GCC. EBM is the current gold standard for therapeutic decision-making and clinical care for patients worldwide. Time constraints and lack of familiarity with EBM concepts and processes have been demonstrated as barriers to adoption in Qatar and the GCC. Therefore, there is much room to improve EBM practices in this region. In future issues of Avicenna, we will strive to facilitate incorporation of EBM into clinical practice in Qatar, through dissemination of high quality evidence-based summaries of topics relevant to local patient populations. REFERENCES [1] Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. Brit Med J. 1996;312:71–72. [2] Lewis SJ, Orland BI. The importance and impact of evidence-based medicine. J Manage Care Pharm. 2004;10(5 Suppl A):S3 –S5. [3] What is EBM? http://www.cebm.net/index.aspx?o¼1914. Accessed May 31, 2013. [4] PubMed. www.ncbi.nlm.nih.gov/pubmed. Accessed May 31, 2013.

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[5] The Cochrane Collaboration: Working together to provide the best evidence for health care. http://www.cochrane.org. Accessed May 31, 2013. [6] The University of York Centre for Reviews and Dissemination. http://www.york.ac.uk/inst/crd/. Accessed May 31, 2013. [7] Al-Kubaisi NJ, Al-Dahnaim LA, Salama RE. Knowledge, attitudes and practices of primary health care physicians towards evidence-based medicine in Doha, Qatar. East Mediterr Health J. 2010;16(11):1189–1197. [8] Al-Ansary LA, Khoja TA. The place of evidence-based medicine among primary health care physicians in Riyadh region, Saudi Arabia. Fam Pract. 2002;19(5):537–542. [9] Khoja TA, Al-Anar LA. Attitudes to evidence-based medicine of primary care physicians in Asir region, Saudi Arabia. East Mediterr Health J. 2007;13(2):408–419. [10] Haron M, Sabti MY, Omar R. Awareness, knowledge and practice of evidence-based dentistry amongst dentists in Kuwait. Eur J Dent Educ. 2012;16(1):e47–e52.

OPEN ACCESS

Perspectives in Arabic healthcare

Pharmaceutical care in the Arabic-speaking Middle East: literature review and country informant feedback Nadir Kheir1,*, Doua Al Saad2, Shaikha Al Naimi2 1

Qatar University, Doha, Qatar Hamad Medical Corporation, Doha, Qatar 2

*Email: nadirk@qu.edu.qa

ABSTRACT Background: The philosophy and practice of pharmaceutical care (PC) has challenged Middle Eastern

pharmacists to embrace a new paradigm that focuses on outcomes of care rather than products or tasks. Although the application of PC was found to be associated with a reduction in adverse drug reactions, length of hospital stay and cost of care in the developed world, the status and application of the practice remains less clear in the Arabic-speaking Middle East (ME). The aim of this project was to describe the current status of PC services in a number of Arabic-speaking ME countries. Methods: We conducted literature search to identify what had been published on the status of PC in the ME. We also invited individuals who have good understanding of the pharmacy environment in the respective country. The individuals identified were asked to respond to a set of standardized questions relating to PC services in their countries. Results: The literature search generated 12 publications in total. Ten country informants agreed to provide information on PC practice and pharmacy practice in general in their respective countries and they ultimately provided information related to these areas. Conclusions: The PC concept is still often confused with clinical pharmacy, which remains to be a priority in several countries in the region. Pharmacy education is rapidly changing change in many of the ME. These changes are hoped to reflect a wider recognition and application of PC services in the hospital and community settings.

http://dx.doi.org/ 10.5339/avi.2013.2 Submitted: 07 May 2013 Accepted: 29 June 2013 ÂŞ 2013 Kheir, Al Saad, Al Naimi, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Kheir N, Al Saad D, Al Naimi S. Pharmaceutical care in the Arabic-speaking Middle East: literature review and country informant feedback, Avicenna 2013:2 http://dx.doi.org/10.5339/avi.2013.2

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BACKGROUND In the Middle East, which encompasses countries between Western Asia and Northern Africa, pharmacy practice continues to evolve, although its progress is hampered by many challenges. While the impact of Arabs on medicine and pharmacy in Europe, and the rest of the world, cannot be overstated, the development in pharmacy education and practice in Arabic-speaking Middle Eastern countries slowed down and centered around traditional curricula and apothecary pharmacy for decades. This recession could be attributed to multiple factors, including past and current periods of conflict, occupation, social and economical pressures, and political instability.1 Meanwhile, in the west, and in particular the United States, the 1960s and 1970s witnessed the introduction of new forms for drug distribution in hospitals, including pharmacy-based unit-dose and intravenous drug admixture programs. These new services marked the introduction of clinical pharmacy, and clinical pharmacists in these countries started to participate in patient rounds, provide drug information, and use medication profiles to document patients’ drug therapies.2 However, just few decades later, Hepler and Strand launched the philosophy and practice of pharmaceutical care which was aimed at taking clinical pharmacy and pharmacy practice as a whole, to a new level marked by more focus on the patient than on drug products.2 Like in other countries in the world, the emergence of pharmaceutical care challenged Middle Eastern pharmacists to embrace this new paradigm, which focuses on outcomes of care rather than products or tasks.2 Indeed, the application of pharmaceutical care services was found to be associated with a reduction in adverse drug reactions, length of hospital stay, and cost of care.2 However, while evidence exists regarding the development and the application of clinical pharmacy in this region,3 – 5 the status of pharmaceutical care remains less clear. Therefore, the aim of this project was to describe the current status of pharmaceutical care services in a number of Arabic-speaking Middle Eastern countries.

METHODS Country selection The following nine countries in the Arabic-speaking Middle Eastern region were selected for this review: Egypt, Jordan, Kuwait, Lebanon, Oman, Qatar, Kingdom of Saudi Arabia (KSA), Sudan, and the United Arab Emirates (UAE). Of these countries, five (Kuwait, Oman, KSA, Qatar, and UAE) constitute most of the countries that form the Gulf Cooperation Council (GCC), and they are in close geographical and cultural proximity to each other. Two countries (Egypt and Sudan) are situated in the neighboring continent of Africa, and both countries lie in the Eastern Mediterranean region).6 The nine countries spread over a wide geographical area across two continents, Asia and Africa. Other Arabic-speaking countries in North Africa (Libya, Tunisia, and Morocco) were not included in this snapshot.

Literature review We conducted a literature search using PubMed and Google Scholar with keywords and terms that included ‘pharmaceutical care’, ‘patient-centered care’, and ‘medication management’ (all often used interchangeably to denote a patient-centered, outcome-oriented service that adopts a structured procedure including patient consultation and information gathering, analysis, care planning and monitoring), in conjunction with the name of each of the selected countries. Publications that focus on pharmaceutical care services were identified and retrieved.

Country informants feedback We used personal contact, the websites of universities and other relevant pharmacy organizations in the selected countries to identify individuals who, at the time of information collection, were working for at least 5 years in the respective country, in pharmacy academia and/or practice, and who had good understanding of the pharmacy environment in the respective country. The individuals identified were invited by email and asked to respond to a set of standardized questions, developed and reviewed by the authors, relating to pharmacy practice in general and pharmaceutical care services in particular (see Table 1).

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Table 1. The 12 questions emailed to country informants. Question

1 2 3 4 5 6 7 8 9 10 11 12

What is the status of pharmaceutical care in your country? If pharmaceutical care does exist, what is the historical development of the services in your area? What qualifications do the practitioners who provide pharmaceutical care services have? What type of formal and informal training to prepare practitioners is occurring in your country? How many practices, how many pharmacists involved, how many patients are receiving the service? Describe the acceptance level by pharmacists, patients and physicians (as well as other patient care providers)? Describe the settings in which pharmaceutical care services are delivered. How have colleges of pharmacy changed their curricula to accommodate pharmaceutical care? Has your government recognized the service? Are they paying pharmacists’ salary to deliver the service or are they paying for the service to be delivered? Are other payers providing reimbursement for the service? If so, how are they paying for the service? What are the rates of payment? What do you think will be the future of pharmaceutical care services in your area? Specifically, where is the practice headed, where are education, research and legislation going to be in two, five or ten years? What other information would you like to share on this subject?

RESULTS AND DISCUSSION Our literature search for the term ‘pharmaceutical care’ in conjunction with the names of the countries selected generated 12 publications in total. Three articles described the practice in each of Jordan,7 – 9 KSA,10 – 12 and UAE. 13 – 15 One article described pharmaceutical care in each of Oman,16 Kuwait,17 and Sudan.18 Twelve country informants agreed to provide information on pharmaceutical care practice and pharmacy practice in general in their respective countries and they ultimately provided information related to these areas. Egypt Egypt is the most populous of the countries investigated.19 The College of Pharmacy at Cairo University is considered the oldest pharmacy program among all other programs in the Middle East, and is considered a major exporter of graduates to GCC countries.1 While pharmacy curricula were totally dominated by traditional chemistry-based courses, recent years have seen the introduction of several undergraduate clinical pharmacy courses, which is a significant development considering the slow pace at which the practice of pharmacy was moving. The healthcare system in Egypt has been criticized for not doing enough to move the pharmacy profession forward. Lack of funding, as a consequence of the unhealthy economy, is a major issue confronting Egypt’s healthcare in general, and pharmacy in particular. As a result, contemporary pharmacy practices, like pharmaceutical care, are not currently widely practiced in Egypt. However, pharmacists in a few hospitals including the National Cancer Institute and Children’s Cancer Hospital are making concerted efforts towards providing pharmaceutical services at the individual patient’s level separate from the routine dispensing process. This being said, these could be considered personal, rather than structured and planned, organizational efforts. Individual attempts to practice pharmaceutical care services are made by a small number of US-trained pharmacists, as well as a few pharmacists who were able to seek certification such as those offered by the American College of Clinical Pharmacy (ACCP) e.g. Board Certified Oncology Pharmacists (BCOP). To date, no formal training is offered to equip pharmacists with the skills for providing pharmaceutical care in the country, and experiential training is not well organized yet. On a governmental level, there was resistance to create a larger role for pharmacists in health care settings, although there were some attempts to establish hospital and clinical pharmacy departments at the Egyptian Drug Authority and the Ministry of Health to set the grounds for such practice. Presently, a good proportion of pharmacists resist practicing any form of clinical pharmacy and pharmaceutical care services as a compulsory service before the development of clear legislation, terms of reference, and scope of practice. Jordan In Jordan, pharmacy education is provided by two public and six private faculties of pharmacy graduating about 1000 pharmacists per year.8 The two public schools offer a Doctor of Pharmacy (PharmD) degree and a Master of Science (M.Sc) degree in clinical pharmacy, making Jordan the third

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country in the Middle East, after Lebanon and KSA, to run a PharmD program.20 Although the introduction of some pharmaceutical care courses started to take place in Jordan universities, the B.Sc pharmacy curricula still have a weak emphasis on pharmaceutical care education and training.8 In the last few years, the clinical pharmacist involvement in providing pharmaceutical care services for selected patient groups started to emerge in Jordan.9,21,22 Despite this, pharmaceutical care is still considered a new concept in Jordan, and its implementation is limited to some governmental and private hospitals, and fewer community pharmacy outlets. So far, most providers of the services are holders of PharmD or Master of clinical pharmacy degrees. In terms of physician acceptance to these new roles of the pharmacist, hospital-based physicians were found to be more likely to accept or recognize traditional pharmacy services than newer services. This suggests a need for more professional awareness of the role of the pharmacists and physicians, and interaction between the members of the health care team if this perception is to change.23 Kuwait Kuwait has one public pharmacy school and it offers a 5-year bachelor degree.1 In undergraduate pharmacy education, the concept of pharmaceutical care is widely introduced in the curriculum, and the teaching methods combine traditional didactic lecturing and problem-based learning.20 In the third year of the faculty of pharmacy, the students use their communication skills and therapeutics knowledge in conducting simple medication reviews, dispensing medications and providing patient counseling. Clinical pharmacy services are limited, but efforts are being made to increase direct patient responsibilities of the hospital pharmacists.1 Community pharmacies are not being fully utilized as sources for quality healthcare provision, and as such provide product-centered services dominated by selling drug products with little counseling and little patient-centered care. In practice, pharmaceutical care services are not provided systematically by all practicing pharmacists, however, these services are provided on an individual basis by ambitious pharmacists. Most of these individuals are Kuwait University graduates or holders of graduate degrees such a Master’s degree in clinical pharmacy or PharmD degree. In a study published in 2006, Awad et al reported lack of uniformity in the responses of hospital pharmacists regarding the focus and objectives of pharmaceutical care which indicated a lack of appropriate understanding of the practice of pharmaceutical care.17 As in Jordan and Egypt, junior pharmacists are now taking the lead in trialing these new services, while most of the ‘older’ pharmacists find their safety zone in the traditional roles of compounding and dispensing medications. In time, this could help in changing the public’s view of what pharmacists can do, and allow other healthcare practitioners to accept the pharmacist into the healthcare team. Currently, physicians vary in their acceptance level; some are more comfortable than others with the pharmacist taking a more clinical role. Lebanon Five universities offer pharmacy programs in Lebanon. Two of the five universities, the Saint-Joseph University and the Lebanese University, follow the French system in which students graduate with a five-year license degree (equivalent to a bachelor’s degree) or a six-year degree, “Doctorat d’exercice en pharmacie”. The school of pharmacy at the Lebanese American University (LAU) was opened in 1995 and its program is consistent with the American pharmacy educational system.24 In 2002, the PharmD degree program offered by LAU secured accreditation from the Accreditation Council for Pharmacy Education (ACPE), making it the first and only PharmD degree program outside of the United States to have ACPE accreditation. Despite the fact that all these universities follow similar curricula, variation in emphasis exists, with some placing more emphasis on basic science, and others on pharmaceutical science, or clinical pharmacy.25 The practice of pharmacy in Lebanon, especially in the community, is still centered around dispensing and selling medications, a phenomenon shared by several neighboring countries. While some universities like LAU and Lebanese International University (LIU) are actively preparing their students to provide pharmaceutical care by delivering pharmacy courses that mirror the US undergraduate and PharmD courses, many of their graduates are either leaving the country to seek job overseas (especially in the more affluent Gulf countries, or in North America) or are working as medical representatives with pharmaceutical companies, mainly focusing in detailing and selling limited medicinal products to private clinics and community pharmacies.

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United Arab Emirates As in other neighboring Gulf countries, pharmacy practice in the United Arab Emirates (UAE) is in a state of evolution, though still dominated by traditional pharmacy and inconsistent service provision. There are some attempts to provide pharmaceutical care activities for selected populations of patients13 – 15; however, the full implementation of pharmaceutical care services is still restricted, especially in the community sector due to workload, shortage of qualified staff, level of acceptance by patients and physicians, and lack of remuneration. Furthermore, because there is still no detailed legislation to organize the practice of pharmacy, no specific level of competency is needed to provide cognitive services, and all that pharmacists need is to obtain a license from the Ministry of Health to practice pharmacy. There is now, however, a requirement to obtain a set number of continuous education units for renewal of licensure. In some private hospitals in the UAE, pharmaceutical care services can be provided only by licensed pharmacist with evidence of clinical training. Several other hospitals now recruit holders of PharmD and advanced degrees from the UK and the US, and these hospitals are introducing, or have introduced, advanced clinical pharmacy services to their patient populations.26 Currently, pharmacy colleges are helping to draft standards of practice and they are taking an active role in advancing the practice in the country. Qatar Qatar’s only national pharmacy program was opened in 2007 in Qatar University. The College had secured provisional international accreditation from the Canadian Council on Accreditation of Pharmacy Programs (CCAPP) in 2008, making it the first and only accredited pharmacy program by the CCAPP outside Canada. The College had its plans for PharmD degree approved in early 2007, and its first candidates started their degree in September 2011, and graduated in July 2012, after 8 months of advanced clinical rotations. Pharmaceutical care features prominently in this college, and is introduced early in the course of study, then continues as a thread in the following years.27 There is good awareness of pharmaceutical care in Qatar, though the term is often used interchangeably with clinical pharmacy. However, like in other ME countries, no structured pharmaceutical care services exist in the non-government sector in Qatar apart from a few individual initiatives by pharmacists who completed online, distance-learning courses on the service. Qatar’s National Health Strategy of 2011 –2016, which articulates its goal of developing a comprehensive world-class healthcare system, describes the introduction of disease management, health insurance, and greater integration between government and private sector.28 These policies and plans exemplify the political will that will be necessary to provide the impetus for an improved pharmacy practice, complete with effective patient-centered services, like pharmaceutical care, run by Qatar’s pharmacists in the next few years. Saudi Arabia Population-wise, the oil-rich Kingdom of Saudi Arabia is the third largest Arab country. Formal education of pharmacy in KSA started in 1952 with the establishment of the College of Pharmacy at King Saud University (KSU) as a four-year pharmacy program.29 As in other countries in the region, basic and foundation sciences dominated the curriculum during the early years, and students graduated with Bachelor of Pharmacy and Medicinal Chemistry.20 From 1970 onward, the College of Pharmacy at KSU –and subsequently other colleges of pharmacy –started and maintained links with certain US universities for the purpose of curriculum improvement.29 These strategies led to two landmark results, introducing clinical pharmacy courses, and years later (in 2008) the initiation of the first PharmD degree program in Saudi Arabia. Pharmaceutical care is taught as a 3 credit hour course in the 4th and 5th year on the BSc. Pharm and PharmD programs, respectively. As in several other countries in the region, most pharmacy graduates in this country join the hospital sector where services are progressive and clinical pharmacists are well paid.20 Saudi has an active professional pharmacy society (The Saudi Pharmaceutical Society) which has an established a pharmacy continuous education program and publishes pharmacy-related periodicals and a peer-reviewed journal.30 According to a study that assessed pharmacists’ understanding and attitudes towards pharmaceutical care in Saudi Arabia, most pharmacists had a favorable understanding of pharmaceutical care and believed the future of pharmacy depends on its implementation.10

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Clinical pharmacy services dominate the practice and grabs the interest of pharmacists. Indeed, some pharmaceutical care activities, such as individually assessing the appropriateness of each medication for patients, is well established in many large Saudi hospitals. While the pharmaceutical care idea is widely recognized, especially by fresh graduates, it is clear that, so far, pharmaceutical care that utilizes the full spectrum of the concept does not exist and will require years to be a recognized practice. Sudan Until recently (before it became two countries), Sudan was considered the largest country in Africa and the Arab world, and tenth largest in the world by area.31 Like Egypt, Sudan is one of the major sources of pharmacists working in the oil-rich Gulf countries, which has a recognizable impact on the pharmacy workforce at the national level. The concept of pharmaceutical care was introduced in Sudan very late, possibly in 2004, and now only about 40% of the existing colleges of pharmacy include aspects of pharmaceutical care in their curricula. While some of these colleges have reasonably well-established pharmacy practice departments, only a few have qualified faculty members to deliver courses with pharmaceutical care concepts as their main focus. An international meeting about pharmaceutical care was held in 2010 in Khartoum, the capital of Sudan, in an attempt to raise awareness about pharmaceutical care among pharmacy academicians. As a result of this and other such initiatives, several pharmacy programs started to target recruiting faculty with expertise in pharmaceutical care teaching or course development. There is currently a realization among many Sudanese pharmacy graduates that they were not adequately prepared during their undergraduate years for provision of pharmaceutical care. A number of workshops and training courses on diverse professional skills and competencies are offered by the General Directorate of Pharmacy of Khartoum State, which has started to advocate and support clinical pharmacy practices in hospitals, including pharmaceutical care services of some sort, in a hospital setting. Some Sudanese pharmacists who have advanced degrees and who live and work outside Sudan had started organizing continuous education workshops on pharmaceutical care and other pharmacy practice subjects in coordination with non-Governmental health care Sudanese groups and organizations. These are usually well attended, but do not provide recognized qualifications. Only a handful of community pharmacists started their own pharmaceutical care practice (that is separate from the dispensing process) through personal initiatives. The health problems mostly targeted are diabetes, dermatology, asthma, and hypertension. Oman Pharmacy education in Oman is provided by two colleges of pharmacy, which were established within the last decade. Their respective curricula had already been oriented towards patient care, away from a product-biased program. The M.Sc degree in clinical pharmacy is offered in Oman, and currently, the two schools of pharmacy are considering developing a PhamD program. Pharmaceutical care in Oman is provided by clinical pharmacist working in tertiary health care institutes. A number of hospitals have very active clinical pharmacy services, like in the Royal Hospital,16 while other hospitals offer limited clinical pharmacy services. Clinical pharmacy services are provided by clinical pharmacists who are holders of a M.Sc degree in clinical pharmacy. However, only one quarter to a third of the admitted patients in the hospitals with active clinical pharmacy services receive some sort of pharmaceutical care service. The early stages of involving clinical pharmacists in these services faced some opposition from other healthcare providers, but the medical team soon started to favor the pharmacists’ involvement in patient care services. Clinical pharmacists’ activities are recognized by the government in Oman through the Civil Service regulations. Pharmaceutical care services are less developed in community pharmacies. There are plans for developing regulation to control the practice of pharmacy that would affect clinical pharmacists’ role at a community pharmacy, and would benefit ambulatory patients – especially those visiting community pharmacies. CONCLUSIONS We provide this synopsis of the status of pharmaceutical care in a region that has significance not only in terms of the size of its population, but also in terms of its political and social importance in the world (Table 2). Our selection of nine countries in the region provided as wide a representation as possible,

8 pharmacy schools: -BSc - PharmD 9 pharmacy schools: -BSc - PharmD 1 pharmacy school: -BSc 5 pharmacy schools: -BSc - PharmD 2 private pharmacy schools: -BSc 1 pharmacy school: -BSc - PharmD 15 pharmacy schools: -BSc 7 pharmacy schools: -BSc

Jordan

Slow introduction of some clinical pharmacy services PC in some community pharmacy outlets Slow pharmacy services in both hospital and community sectors No PC services provided

Well-developed clinical pharmacy services in large hospitals No PC services provided Some clinical pharmacy services in some hospitals, PC in some clinics on individual initiatives

No clinical pharmacy practiced in hospital No PC services provided Well-established clinical pharmacy services in some hospitals No PC services provided

PC: Pharmaceutical Care, 2BSc: Bachelor of Pharmacy, 3PharmD: Doctor of Pharmacy, 4KSA: Kingdom of Saudi Arabia, 5UAE: United Arab Emirates.

UAE5

Sudan

Qatar

Oman

Lebanon

Kuwait

Well advanced clinical pharmacy services in several large hospitals, but limited PC

Apart from few individuals initiatives in few hospitals, no PC services are provided Some clinical pharmacy activities exist in hospitals Some structured PC services provided in few hospitals and the community pharmacy

24 pharmacy schools:-BSc2

Egypt

KSA4

PC1 and practice

Education

Country

Table 2. Summary of status and future indicators of pharmaceutical care in nine Middle Eastern countries.

Started PharmD program

Initiation of postgraduate degrees in clinical pharmacy

Started PharmD and opportunity for practicing pharmacists to join on part time bases

Plan to start PharmD and residency programs

Well-established PharmD programs

Plan to offer a PharmD program and to introduce clinical pharmacy

Initiation of pharmacy residency programs

Active research and rapidly developing practice

Initiation of a PharmD3 program and a new clinical pharmacy degree

Indicators for future practice

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while excluding only few countries where our we were unable to recruit country representatives due to geopolitical reasons and other logistics, such as access to information. Because the pharmaceutical care concept has been introduced relatively recently to many ME countries, we found that it is still often confused with clinical pharmacy, which remains a priority in several countries in the region. Evidently, pharmacy education is witnessing rapid change in many Middle East countries, and several pharmacy programs either had introduced, or are planning to introduce, the PharmD degree to replace the traditional Bachelor of Pharmaceutical Science degree. It is hoped that these changes reflect a wider recognition and application of pharmaceutical care in its many forms, like medication management services, in hospital and community settings. A lot of the information presented in this study came through contacting individuals rather than from the published literature, and this was a major limitation. Ironically, the lack of published literature on PC in the Middle East was one of the reasons why we had to adopt the strategy of using country representatives in the first place. We tried to minimize the subjectivity of information as much as possible through a triangulation approach where we accessed other sources of information like relevant web sites and published literature where available. COMPETING INTERESTS The authors declare no competing interest involved in the work leading to this publication. AUTHORS CONTRIBUTIONS NK conception of the study’s idea, study design, data analysis and interpretation, wrote the manuscript. DA data acquisition, communication with external sources (mainly country informants), revised the manuscript, assisted in data analysis, and organizing the reference list. SA helped in data acquisition, analysis and interpretation, revised the manuscript, helped in organizing the reference list.

Acknowledgements The authors wish to acknowledge the following individuals for the information that they provided in respect to the pharmaceutical care practice and other relevant issues in their respective countries: Dr. Nirmeen Sabry (Egypt), Dr. Sherief Khalifa (Egypt), Dr. Mahmoud Elmahdawy (Egypt), Dr. Linda Tahaineh (Jordan), Dr. Abdelmoneim Awad (Kuwait), Dr. Maguy Al Hajj (Lebanon), Dr. Abduelmula Abduelkarem (United Arab Emirate), Dr. Maha Al-Draimly (Saudi Arabia), Dr. Abdalla ElKhawad (Sudan), Dr. Abdelrahman Hamed (Sudan), Dr. Mohammed Eltayeb (Sudan), and Mr. Kassim Riyami (Oman).

REFERENCES [1] Kheir N, Zaidan M, Younes H, El Hajj M, Wilbur K, Jewesson P. Pharmacy education and practice in 13 Middle Eastern countries. Am J Pharm Educ. 2008;72(6):133. [2] Hepler C, Strand L. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm. 1990;47(3):533–543. [3] Tuffaha H, Abdelhadi O, Omar S. Clinical pharmacy services in the outpatient pediatric oncology clinics at a comprehensive cancer center. Int J Clin Pharm. 2012;34(1):27–31. [4] Aburuz S, Bulatova N, Yousef A, Al-Ghazawi M, Alawwa I, Al-Saleh A. Comprehensive assessment of treatment related problems in hospitalized medicine patients in Jordan. Int J Clin Pharm. 2011;33(3):501 –511. [5] Al-Hajje A, Atoui F, Awada S, Rachidi S, Zein S, Salameh P. Drug-related problems identified by clinical pharmacist’s students and pharmacist’s interventions. Ann Pharm Fr. 2012;70(3):169–176. [6] World Health Organization (WHO) [http://www.who.int/about/regions/en/] [accessed 1 December 2012]. [7] Aburuz S, Al-Ghazawi M, Snyder A. Pharmaceutical care in a community-based practice setting in Jordan: where are we now with our attitudes and perceived barriers? Int J Pharm Pract. 2012;20(2):71–79. [8] Albsoul-Younes A, Wazaify M, Alkofahi A. Pharmaceutical care education and practice in Jordan in the new millenium. Jordan J Pharm Sci. 2008;1(1):83–90. [9] Jarab A, Alqudah S, Khdour M, Shamssain M, Mukattash T. Impact of pharmaceutical care on health outcomes in patients with COPD. Int J Clin Pharm. 2012;34(1):53 –62. [10] Al-Arifi M, Al-Dhuwaili A, Gubara O, Al-Omar H, Al-Sultan M, Saeed R. Pharmacists’ understanding and attitudes towards pharmaceutical care in Saudi Arabia. Saudi Pharm J. 2007;15(2):146–159. [11] Al-Arifi N. Pharmacy students’ attitudes toward pharmaceutical care in Riyadh region Saudi Arabia. Pharm World Sci. 2009;31(6):677–681. [12] Dib J, Abdulmohsin S. Establishing a pharmaceutical care clinic in a Saudi Arabian health center. Am J Health Syst Pharm. 2007;64(1):107–109. [13] AlMazroui N, Kamal M, Ghabash N, Yacout T, Kole P, McElnay J. Influence of pharmaceutical care on health outcomes in patients with Type 2 diabetes mellitus. Br J Clin Pharmacol. 2009;67(5):547–557. [14] Elnour A, El Mugammar I, Jaber T, Revel T, McElnay J. Pharmaceutical care of patients with gestational diabetes mellitus. J Eval Clin Pract. 2008;14(1):131–140.

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[15] Sadik A, Yousif M, McElnay J. Pharmaceutical care of patients with heart failure. Br J Clin Pharmacol. 2005;60(2):183 –193. [16] Al Salmi Z. Clinical audit of pharmaceutical care provided by a clinical pharmacist in cardiology and infectious disease in-patients at the Royal hospital, Muscat/Oman. Oman Med J. 2009;24(2):89–94. [17] Awad A, Al-Ebrahim S, Abahussain E. Pharmaceutical care services in hospitals of Kuwait. J Pharm Pharm Sci. 2006;9(2):149 –157. [18] Ibrahim A, Scott J. Community pharmacists in Khartoum State, Sudan: their current roles and perspectives on pharmaceutical care implementation. Int J Clin Pharm. 2013;35(2):236–243. [19] World Health Statistics 2012, World Health Organization (WHO) [http://www.who.int] [Accessed 1 December 2012]. [20] Al-Wazaify M, Matowe L, Albsoul-Younes A, Al-Omran O. Pharmacy Education in Jordan, Saudi Arabia, and Kuwait. Am J Pharm Educ. 2006;70(1):18. [21] Jarab A, Alqudah S, Mukattash T, Shattat G, Al-Qirim T. Randomized controlled trial of clinical pharmacy management of patients with type 2 diabetes in an outpatient diabetes clinic in Jordan. J Manag Care Pharm. 2012;18(7):516 –526. [22] Hammad E, Yasein N, Tahaineh L, Albsoul-Younes A. A randomized controlled trial to assess pharmacist-physician collaborative practice in the management of metabolic syndrome in a university medical clinic in Jordan. J Manag Care Pharm. 2011;17(4):295–303. [23] Tahaineh L, Wazaify M, Albsoul-Younes A, Khader Y, Zaidan M. Perceptions, experiences, and expectations of physicians in hospital settings in Jordan regarding the role of the pharmacist. Res Social Adm Pharm. 2009;5(1):63–70. [24] Dib J, Saade S, Merhi F. Pharmacy practice in Lebanon. Am J Health Syst Pharm. 2004;61(8):794–795. [25] Khachan V, Saab Y, Sadik F. Pharmacy education in Lebanon. Currents Pharm Teach Learn. 2010;2(3):186 –191. [26] Dajani S. Gold, golf, and pharmacy in the Gulf. PJ. 2011;273:930 –931. [27] The College of Pharmacy, Qatar University [http://www.qu.edu.qa/pharmacy/] [Accessed 8 December 2012]. [28] Qatar National Health Strategy 2011-2016 [http://www.nhsq.info/] [Accessed 28 November 2012].. [29] Asiri Y. Emerging frontiers of pharmacy education in Saudi Arabia: the metamorphosis in the last 50 years. Saudi Pharm J. 2011;19:1–8. [30] Saudi Pharmaceutical Journal [http://www.journals.elsevier.com/saudi-pharmaceutical-journal] [Accessed 1 January 2013]. [31] Nations Online [http://www.nationsonline.org] [Accessed 28 June 2013].

OPEN ACCESS

Perspectives in Arabic healthcare

Patient- and family-centered care in Qatar: A primary care perspective Mohamud A. Verjee1,*, Suzanne Robertson-Malt2 1

Department of Medical Education, Weill Cornell Medical College in Qatar, Qatar Foundation – Education City, P.O. Box 24144, Doha, Qatar 2 Faculty of Health Sciences, School of Translational Health Science, The Joanna Briggs Institute, The University of Adelaide, North Terrace, SA 5005, Australia *Email: mov2002@qatarmed.cornell.edu

ABSTRACT Healthcare policies in Qatar place a high value on the concept of patient and family-centered care (PFCC) in primary care. The Institute of Medicine raised the concern of patient care in 2001 and Davis et al. advocates of PFCC, promoted the concept. The Primary Health Care Corporation (PHCC) and Hamad Medical Corporation (HMC) in Qatar provide all the government health services of the country at this time. They have sought to integrate PFCC into its systems, while preserving the traditional Qatari way of life. Families in times past were excluded from healthcare involvement as medical specialization progressed, but the undervalued importance of families contributing to healthcare was later realized. Twenty-one established health centers in 2013, are to be augmented by thirty more within five years. By 2011, all Qatar’s major hospitals and its Ambulance Service had achieved JCI accreditation. Entitlement to government healthcare is free for Qatari nationals, or at a small charge for expatriates who maintain a valid health card. Patients have access to a physician at health centers, but have to be referred for hospital consultant appointments. A range of services is available, including a pharmacy, at every health center. A Charter of Patient, Family, and Children’s Rights is in place for HMC supporting family participation in care. The Center for Health Care Improvement (CHCI) was launched in 2008 and focuses on PFCC. Eight core objectives of the CHCI are outlined. Effective patient education with the adoption of sound healthcare policies and fiscal responsibility should help Qatar attain the goals it requires. Keywords: patient- and family-centered care, primary care, Qatar National Vision, JCI accreditation, sustainable, community, patient education

http://dx.doi.org/ 10.5339/avi.2013.1 Submitted: 19 September 2012 Accepted: 20 June 2013 ª 2013 Verjee, Robertson-Malt, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 3.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Verjee MA, Robertson-Malt S. Patient- and family-centered care in Qatar: A primary care perspective, Avicenna 2013:1 http://dx.doi.org/10.5339/avi.2013.1

Page 2 of 5 Verjee and Robertson-Malt. Avicenna 2013:1

INTRODUCTION Placing the patient at the center of clinical decision-making seems a fundamental right of what it means to be a patient. The State of Qatar, in the Middle East, is no exception. Ask any graduating student of medicine, nursing or an allied health profession if the patient should be involved in the decisionmaking regarding their care – the immediate response would be: “Why, of course!” Sadly, this has not been the cultural norm for the majority of healthcare facilities throughout the developed world. Instead, the typical experience for both the patient and loved ones is to answer questions when spoken to and be “told” a plan of care. The concept of PFCC is changing this practice. Thanks to landmark reports such as the Institute of Medicine’s Crossing the Quality Chasm1 in 2001, these paternalistic systems of care have been challenged. In primary care, Qatar strives to inculcate patient and family centered care in the development of its rapidly evolving healthcare system, with determination in its approach. The Institute of Medicine’s report raised a major concern that . . . a chasm exists between the kind of care that patients receive and the kind of care they should have, and calls for fundamental change in the system of care. It further argues that these changes would both be better for patients and make the provision of care more satisfying for clinicians.1

With the advent of patient advocacy groups such as the Picker Institute; Health Consumer Networks; Disease Specific Support Groups, the needs and expectations of patients are now heard. Add to this the increased access that patients have to evidence-based information about their illness and provider/hospital performance, they expect to be involved in determining their plan of care and have their questions answered. Healthcare accreditation organizations, such as the Joint Commission, formerly the Joint Commission on Accreditation of Health Care Organizations2 and the Joint Commission International Accreditation (JCI)3 are establishing performance standards to guide healthcare administrators in their efforts to make their healthcare environment and practices more “patient-centered”. The Institute of Medicine also made patient-centered care one of its six domains of patient safety and quality of care. Patient-centered: providing care that is respectful of and responsive to individual patient preferences, needs, and values, and ensuring that patient values guide all clinical decisions.1

In 2005, Davis et al.4 proposed seven attributes of patient-centered primary care practices, now actively pursued by Qatar: 1. Superb access to care – versatility of appointments, quick responses, efficient use of physician’s time, electronic prescription refills, and a full out of hours service. 2. Patient engagement in care – participation as partners in care, advocates for the needy, access to medical records, patient education, and parent counseling for health and development. 3. Clinical information systems that support high quality care, practice based learning, and quality improvement – health registries, easy access to laboratory and diagnostic tests, information on treatment plans, and information on health risks, services, and outcomes. 4. Care coordination – with referrals, prompt feedback after consultations, communication and prevention of errors between multiple physicians, test result tracking, and appropriate prescribing. 5. Integrated, comprehensive care and smooth information transfer across a fixed or virtual team of providers – proper use of the healthcare team, and avoiding duplication of tasks and testing. 6. Ongoing, routine patient feedback to a practice – patient centered surveys leading to practice improvements, engaging patients to understand their conditions, and improving the quality of life. 7. Publicly available information on practices – enabling a patient to choose their physician after access to physician directories, office location, hours of operation, patient experiences, and peer assessment of physicians. The American Academy of Pediatrics updated a 1992 policy statement in 2003.5 It included the belief “that the medical care of infants, children, and adolescents ideally should be accessible, continuous, comprehensive, family-centered, coordinated, compassionate, and culturally effective.”

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The Primary Health Care Corporation in Qatar provides the bulk of family medicine services in primary care. Hamad Medical Corporation is a national government healthcare institution in Qatar, providing tertiary care. Both have sought to integrate the concept of PFCC towards improving the benefits of the country’s comprehensive health service. Additionally, they want to incorporate this philosophy uniquely, by identifying and celebrating the respected and distinctive style of the Qatari way of life. The leadership in Qatar has reiterated that family units are the cornerstones of Qatari society. Recognition and respect for the significant role of the family in healing means that patients and families must become partners in designing new models of care. BACKGROUND Pormann6 states that Middle Eastern culture was foundational in the establishment of medical science. The western world had led the rapid technological advances for over 150 years. Domiciliary care began in people’s homes. Hospitals were developed, but initially, families had no access to the “care teams”. There was even a time when parents could not see their children in hospital more than once a week.7 The exclusion of families from healthcare teams went hand-in-hand with medical specialization and the use of technology and rising professionalism.8 In more recent times, a veritable body of work brought the family back together with doctors, nurses and allied health professionals as partners in the care team.9 The Institute for Family-Centered Care in North America10 has been a pioneer in this field, spurred on by the recognition that families have much to contribute in the form of better facilities and systems. The importance of addressing both patient and family centered needs is paramount across the world. PRIMARY CARE IN QATAR Primary healthcare services started in 1954 with additional specialty services added in 1978. Tertiary care services have developed at an unprecedented rate since then. The government of Qatar has already constructed twenty-one primary healthcare centers throughout Qatar, predominately in Doha itself, with PFCC a major objective at all sites. Care centers operate in other significant outlying enclaves. In June 2013, the Minister of Health announced that thirty new health centers would be constructed within the next five years. All five major tertiary care hospital complexes in Qatar – Hamad General Hospital, Women’s Hospital, Al Amal Hospital (now the National Center for Cancer Care and Research), and Al Khor Hospital received Joint Commission International accreditation in 2010. In addition, Hamad Medical Corporation’s Ambulance Service also achieved JCI accreditation in 2011.11 These achievements confirmed the high standards of care sought by the government in targeting quality healthcare. Considerable expansion of family medicine took place with its recognition as a specialty in 1995. Access to health centers or hospitals is available to all who maintain a health card, purchased annually by expatriates for a fee of 100 Qatari Riyals (Approximately US$ 27.50), or provided by employers. Qatari national citizens have full entitlement to fully subsidized Government healthcare. Prioritized care in the community includes well women, maternity, and childcare clinics. Otolaryngology, ophthalmology, dermatology, oral hygiene, dental care, and a chronic diseases program are other health center activities. Despite this rapid modernization, the family remains the primary socioeconomic decision making unit. This makes the concept of PFCC an expectation. It actively embraces and integrates the knowledge and information from western medicine into paradigms of Qatar’s healthcare.12 It also provides ongoing support and continued respect for family participation. Features implemented to demonstrate PFCC in Qatar’s health centers include access to a physician whenever required, and automated confirmation of an appointment to hospital outpatients by Short Message Service (SMS). Consultants are based at health center sites as well as hospitals for full assessments; health center appointments are open access for phlebotomy services, radiology, dental care, and chronic disease management. All health centers have a full pharmacy team, who provide guidance as well as medications on an approved formulary between the PHCC and HMC. Hamad Medical Corporation has a Charter of Patient, Family, and Children’s Rights13 supporting the participation of families from the cradle to end-of-life care (Novotny et al.).14 New facilities designed with the integral involvement of patients and families encourage their contribution to prepare for and deliver better healthcare. The stresses and pressures of modern life consolidate the validity of the family unit and its cultural values. Service provision should be provided in such a way that families

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achieve their most highly valued social roles, the care and upbringing of children, looking after the elderly, and caring for the disabled and chronically ill in any community. When HMC launched the Centre for Health Care Improvement in 2008, the journey toward PFCC began.15 The Centre’s primary objective is to focus on patient- and family-centered care, whilst exploring the culturally meaningful and appropriate ways to more effectively engage the family within the care team.

CORE ACTIVITIES OF THE CHCI IN MEETING THE PRIMARY OBJECTIVES 1. Recognition and building upon the societal elements already in place. Feedback from individuals and the community is crucial because it continually helps to improve care. 2. An established comprehensive and universal newborn screening program used to test for thirty-two potentially debilitating endocrine or inborn metabolic disorders e.g. homocystinuria, and medium chain acyl Co-A dehydrogenase (MCAD) deficiency. Qatar is one of only four countries in the world that screens for many potentially harmful conditions that may affect a child’s health, or life, if not diagnosed and treated early. A collaborative partnership exists between the University of Heidelberg in Germany and Qatar for this purpose.16 Treatment for many conditions requires a committed relationship between clinicians of all disciplines, and excellent communication with patients’ families. Since the establishment of newborn screening in December 2003, over 133,000 newborn children have been screened up to and inclusive of August 2012, with high-dividend yield. Qatar will acquire its own screening capacity as early as the end of 2013. New parents will no longer have to suffer time delays with the anguish of uncertainty, and should obtain a diagnosis expeditiously. 3. Collaboration with other people-centered organizations such as government ministries, academic institutions, and civil society associations locally, regionally and internationally, will raise awareness of PFCC. Leading all of this is Qatar Foundation, a semi-private, non-profit organization, founded in 1995. Its foremost aim is – to support Qatar on its journey from a carbon economy to a knowledge economy by unlocking human potential.17 4. To continue to develop an existing agreement of collaborative partnership with the Hospital for Sick Children in Toronto, Canada. This will help build high quality pediatric care in Qatar, and build awareness of the importance of the family setting in the host community. 5. Planned to open in 2014, Sidra Medical and Research Center (Sidra) is a women and children’s tertiary care teaching hospital. The principle of PFCC will be an integral concept in all of Sidra’s activities, inclusive of the design of the hospital and the electronic documentation system. Complementing such activities is the international designation of “Baby Friendly”, which includes but is not limited to exclusive breast-feeding and 24-hour rooming-in of newborns, recognizing the power of both communication and parental bonding from birth. The Qatar National Vision 2030 document details the idea of having one program in multiple sites. The care of women and children will be provided collaboratively by the Primary Health Care Corporation, Hamad Medical Corporation, and Sidra, sharing women and children’s programs and is an example of forward planning to achieve this objective.18 6. Integration of a full “Home Care Program” that expands its services more widely in the community. Families are extremely useful in the safety of communities with long-term medical conditions and elderly people. Ensuring “carers” remain in the community, and enabling patients to remain in their home environments, is evident. Currently, home care services are available for eight hours a day on weekdays. Certified staff carers plan home visits according to care needs. Most patients seen have long-term needs over a wide age range. 7. Recognizing the importance of community based services that help families, such as community midwives and early childhood development programs for children with developmental delays. Dedicated work needs to continue, focusing on initial and continuing care services with other community agencies, to improve these services within Qatar. 8. Learning from recognized exemplars: Organizations and groups that have been walking this road for some time have much to share with Qatar. Role modeling, the Ontario Medical Association policy paper on patient centered care19 thoroughly discusses integration and access to healthcare. Patient and Family Centered Care in Primary Care20 has prospered on the belief that “the family plays a vital role in ensuing the health and well-being of patients of all ages”.21

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CONCLUSION When patient demand exceeds supply, a country’s healthcare system may fail to achieve its objectives, even with the best of intentions. However, healthcare resources are not infinite. Qatar has invested intellect and resources in its healthcare system, and has thoroughly investigated and adopted health policies with financial accountability. Fried22 talks about “economically sustainable” medicine with a long-term purpose of “maximizing health”. In primary care, for patient and family centered care to thrive in Qatar, the basis will lie in a sustainable doctor-patient relationship. Fiscally-responsible professional policies will be required, eliminating redundant consultations and investigations, and reducing any waste of medical resources. It follows that patient education on these aspects needs to be effective to achieve the ultimate goals that Qatar desires. Patients in Qatar must also have the opportunity to understand their conditions, be aware of the risks of non-compliance, obtain investigative and laboratory tests expeditiously, and receive appropriate prescriptions. They should know about their healthcare practitioners, be aware of the facilities offered at both primary and tertiary care levels, and have access to quality out of hours services. Qatar has made a determined start to achieve these goals. REFERENCES [1] Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Vol. 6. Washington, DC: National Academy Press; 2001. [2] Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Facts about Primary Care Medical Home Certification. 2011. http://www.jointcommission.org/assets/1/18/PCMH.pdf [Accessed February 5, 2013]. [3] Joint Commission International (JCI) 2013. Accreditation for Primary Care Centers. http://www.jointcommissioninternati onal.org/Primary-Care/ [Accessed February 3, 2013). [4] Davis K, Schoenbaum SC, Audet A-M. A 2020 vision of patient-centered primary care. J Gen Intern Med. 2005;20(10):953–957. [5] American Academy of Pediatrics. Family-centered care and the pediatrician’s role. Committee on hospital care. Pediatrics. 2003;112(3):691–696. [6] Pormann PE. Female patients and practitioners in medieval Islam. Lancet. 2009;373(9675):1598–1599. [7] van der Horst FC, van der Veer R. Changing attitudes towards the care of children in hospital: a new assessment of the influence of the work of Bowlby and Robertson in the UK, 1940–1970. Attach Hum Dev. 2009 Mar;11(2):119 –142. [8] Waddington I. The movement towards the professionalization of medicine. Br Med J. 1990;301(6754):688–690. [9] Ahmann E, Dokken D. Strategies for encouraging patient/family member partnerships with the health care team. Pediatr Nurs. 2012 Jul-Aug;38(4):232–235. [10] Institute for Family Centered Services http://www.ifcsinc.com/welcome.aspx [Accessed February 2, 2012]. [11] HMC’s Ambulance Service achieves JCI accreditation, October 2011 http://www.qatarisbooming.com/2011/10/26/hm c’s-ambulance-service-achieves-jci-accreditation [Accessed May 15, 2013]. [12] Abyad A, Al-Baho AK, Unluoglu I, Tarawneh M, Al Hilfy TK. Development of family medicine in the Middle East. Fam Med. 2007;39(10):736–741. [13] Government of Qatar – National Health Strategy, 2011 –2016 http://www.gsdp.gov.qa/portal/page/portal/gsdp_en/ knowledge_center/Tab/NDS_ENGLISH_SUMMARY.pdf [Accessed February 4, 2012]. [14] Novotny JM, Lippman DT, Sanders NK, Fitzpatrick JJ. Hospice and Palliative Care Nursing: 101 Careers in Nursing. New York: Springer Publishing Company; 2008. [15] Hamad Medical Corporation. Hamad Medical Corporation launches Center for Healthcare Improvement. Press release 12 May 2008. http://www.ameinfo.com/156383.html [Accessed February 4, 2012]. [16] Lindner M, Abdoh G, Fang-Hoffman J, Shabeck N, Al-Sayrafi M, Al-Janahi M, Ho S, Abdelrahman MO, Ben-Omran T, Bener A, Schulze A, Al-Rifai H, Al-Thani G, Hoffman GF. Implementation of extended neonatal screening and a metabolic unit in the state of Qatar: developing and optimizing strategies in cooperation with the neonatal screening center in Heidelberg. J Inherit Metab Dis. 2007;30(4):522 –529, Epub 2007. [17] Qatar Foundation – homepage. http://www.qf.org.qa [Accessed June 17, 2013]. [18] General Secretariat for Developmental Planning, July 2008. Qatar National Vision, 2030. http://www.gsdp.gov.qa/ portal/page/portal/gsdp_en/qatar_national_vision/qnv_2030_document/QNV2030_English_v2.pdf [Accessed February 3, 2012]. [19] Ontario Medical Association, Policy Paper. Patient Centered Care, 2010, pages 34–49. https://www.oma.org/ Resources/Documents/Patient-CentredCare,2010.pdf [Accessed June 17, 2013]. [20] Institute for Family and Patient Centered Care, 2004. http://www.ipfcc.org/pdf/getting_started.pdf [Accessed February 4, 2012]. [21] Institute for Patient and family-Centered Care. A Hospital Self-Assessment Inventory, 2004. www.familycenteredcare. org [Accessed February 4, 2012]. [22] Fried, R. Sustainable Medicine at the Kimberton Clinic, 2010. http://kimbertonclinic.com/what.htm [Accessed March 3, 2012].

Call for submissions Your research, review, or viewpoints can be submitted to Avicenna through our online submission system: http://www.editorialmanager.com/avi We focus on healthcare innovation in the Gulf and Arabian Peninsula and are particularly interested in the following article types: Research Articles Primary research in basic science or applied healthcare Review Articles Heavily-referenced, comprehensive overviews of a particular field or subfield Perspectives Unique viewpoints from around the region on one aspect of healthcare. These can be thought of as extended editorials, but should be referenced. Evidence-based Healthcare As outlined in Wilby & Al-Siyabiâ&#x20AC;&#x2122;s article in this issue, articles in this section highlight incorporation of EBM into clinical practice in the region. We always welcome discourse on previously published articles in the form of Letters to the Editor. We would also be interested in receiving proposals for special issues on thematic topics of relevance. We look forward to receiving your contributions. http://www.editorialmanager.com/avi Dr Bill Greer Managing Editor Sidra Medical & Research Centre Doha, Qatar bgreer@sidra.org

TABLE OF CONTENTS Avicenna – The innovation in healthcare! William Greer

Correlates of early motherhood in slum areas of Rajshahi City, Bangladesh Md. Mahfuzur Rahman, Md. Abdul Goni, Md. Rizvi Akhter

Trends and projections of annual birth volumes in the State of Qatar: 1970–2025 William Greer

Role of prostaglandins in colorectal tumorigenesis: Localization and expression of COX-1, COX-2, microsomal Prostaglandin E Synthase-1 and the EP2 receptor Lars Hedin, Katarina Rask, Yihong Zhu, Anna Wickman, Wanzhong Wang, Hans Brevinge, Magnus Thörn, Fredrik Pontén,Karin Sundfeldt

Examining the links between air quality, climate change and respiratory health in Qatar Kevin Teather, Natacha Hogan, Kim Critchley, Mark Gibson, Susanne Craig, Janet Hill

Barriers and facilitators influencing the physical activity of Arabic adults: A literature review Kathleen Benjamin, Tam Truong Donnelly

Role of growth factors in preeclampsia: Early detection and treatment Sadia Munir

Evidence-based healthcare practice in Qatar: A need to move forward Kyle Wilby, Khalid Al-Siyabi

Pharmaceutical care in the Arabic-speaking Middle East: literature review and country informant feedback Nadir Kheir, Doua Al Saad, Shaikha Al Naimi

Patient- and family-centered care in Qatar: A primary care perspective Mohamud A. Verjee, Suzanne Robertson-Malt

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