Female multiple sclerosis and urbanization

Cendrowski Artykuły W. oryginalne Female multiple / sclerosis original and urbanization papers 421 Female multiple sclerosis and urbanization Stwardnienie rozsiane u kobiet a urbanizacja Wojciech Cendrowski Samodzielna Lecznica Centrum w Warszawie Wprowadzenie. Środowiskowe czynniki inicjują stwardnienie rozsiane (SM), aczkolwiek immunologiczne i genetyczne determinanty wpływają na etiopatogenezę choroby. Cel badania. Ustalenie relacji między wskaźnikiem kobiet do mężczyzn (WKM) w kohorcie SM i wskaźnikami urbanizacji. Materiał i metoda. Ogólna kohorta SM obejmowała 14 343 chorych (M 6324, K 8110), którzy zmarli w latach 1971-1990, 2001-2010 w Polsce. Wszystkich chorych na SM podzielono na miejskich (8318) i wiejskich (6116) mieszkańców według miejsca zgony. Wskaźnik K:M w kohorcie SM skorelowano ze wskaźnikami urbanizacji. Dane demograficzne uzyskano z Głównego Urzędu Statystycznego w Warszawie. Wyniki. WKM w całkowitej, miejskiej oraz wiejskiej zbiorowości SM wzrósł w ciągu 40 lat (z przerwą dekady) w Polsce: p<0,001. Długookresowy wskaźnik K:M w miejskiej grupie SM był istotnie wyższy niż odpowiedni wskaźnik w grupie wiejskiej: 1,65 (SD 0,13) vs. 1,40 (SD 0,20), p=0,002. Znaleziono mocną korelację między wzrastającym WKW w SM i zwiększającym się wskaźnikiem urbanizacji w całej kohorcie SM oraz w ogólnej zbiorowości kobiet: r=0,757; r=0,699; p<0,0001. Wnioski. Wyższy wzrost występowania SM u kobiet stwierdzono w miastach w porównaniu do wsi. Znaleziono mocną asocjację pomiędzy zwiększającym się WKM w SM i wskaźnikami urbanizacji. Dane implikują, że urbanizacja wprowadziła dodatkowe czynniki ryzyka SM, szczególnie wśród kobiet. Słowa kluczowe: stwardnienie rozsiane, wskaźnik płci, urbanizacja, Polska Introduction. Environmental factors initiate multiple sclerosis (MS), although immunological and genetic determinants influence upon the aetiopathogenesis of the disease. Aim. To ascertain the relation between the female to male ratio (F:M ratio) in the MS cohort and urbanization indices. Material & Method. The total MS cohort included 14 434 individuals (M 6324, F 8110) who died between 1971-1990, 2001-2010 in Poland. All MS individuals were divided, according to the place of death, into urban (8318) and rural (6116) residents. The F:M ratio in the MS cohort was correlated to urbanization indices. The demographic data were obtained from the Central Statistical Office in Warsaw. Results. The F:M ratio in the entire urban and rural MS assemblage has increased over 40 years (with one decade interval) in Poland: p<0.001. The long-term F:M ratio in the MS urban group was significantly higher than the respective ratio in the MS rural group: 1.65 (SD 0.13) vs. 1.40 (SD 0.20), p=0.002. Strong correlation was found between the rising F:M ratio in MS and increasing urbanization indices in entire MS assemblage as well as in the female general population: r=0.757, r=0.699, p<0001. Conclusions. More rising occurrence of MS in women was ascertained in towns than in rural settlements of the country. A strong association was found between the increasing F:M ratio in the MS cohort and urbanization indices. The data implicate that urbanization has brought forward additional MS risk factors, particularly for females. Key words: multiple sclerosis, sex ratio, urbanization, Poland Probl Hig Epidemiol 2015, 96(2): 421-426 www.phie.pl Nadesłano: 20.04.2015 Zakwalifikowano do druku: 08.05.2015 Adres do korespondencji / Address for correspondence doc. dr med. Wojciech Cendrowski ul. Balladyny 1d/6, 02-553 Warszawa tel. 22 845 28 61, e-mail: chihahi@op.pl Abbreviations F females M males MS multiple sclerosis OR odds ratio P probability SD standard deviation UVB ultraviolet (B radiation) Introduction Environmental, immunological and genetic determinants exist in the aetiology of multiple sclerosis [1-3]. The aetiological factors include deficiency of ultraviolet B radiation (UVB), low serum level of vitamin D 3, late childhood infections, higher level of hygiene and hazardous lifestyle [4-6]. Epidemiological studies showed inconsistent relation between urban residence and prevalence of MS [7]. Some analytical studies pointed out the correlation of urban living with higher prevalence of the disease [8, 9]. Other investigations described equal prevalence of MS in urban or rural residents [7, 10, 11]. A motif of a deleterious urbanization effect on MS incidence in the Mediterranean area was taken up by Katzumani et al. [12]. They found long-term, much higher MS incidence in urban agglomerations than in rural

422 Probl Hig Epidemiol 2015, 96(2): 421-426 settlements. The question arises whether urban setting brings about conditions for higher occurrence of MS, especially in young women who have relocated from villages to large towns. This study investigates whether MS occurrence, particularly in women, was higher in the Polish towns than in the countryside. The aim of this study was to ascertain possible association between the sex ratio in MS assemblage and urbanization indices. The epidemiology of MS might change because of migration of young residents from rural to urban areas. Urbanization is a continuously developing, widespread, demographic process that sets up the existing MS risk factors for city-born and newcomers in larger towns. Material and method The study analysed the relation of urban to rural MS assemblages as well as an existing connection between the female to male ratio in MS and urbanization indices in Poland. The total cohort of MS individuals included 14 434 patients (M 6324, F 8110) who died between 1971-1990 and 2001-2010 in Poland. The MS diagnosis was established according to codes from the International Classification of Diseases: 6/7 10, 345, G-35. The average F:M ratio in MS assemblage was calculated in particular years considering the annual number of death among females and males. The entire MS cohort was divided, according to the place of death, into urban and rural assemblage. No information was available whether the place of death was identical either with the place of birth or residence prior to the onset of the disease. The index of demographic urbanization was determined by the ratio of urban to rural assemblage in a particular population over one year. The data concerning the number of deceased MS individuals, gender of patients, year and location of death were obtained from the Central Statistical Office in Warsaw. The sex ratio, urbanization index in MS assemblages and in the general population between 1971-1990 were compared to respective variables during the period of 2001-2010. The Student t test was used in comparisons. The relationship between the F:M ratio in the entire MS cohort and the urbanization index population was sought over 3 decades. The correlation between the above mentioned variables was performed according to the test by Pearson. Results The entire cohort consisted of 14 434 deceased MS individuals (M 6324, F 8110), tab. I. That large group was divided into 8318 urban residents and 6116 rural residents. The F:M ratio in the entire cohort, in urban and rural assemblages, was respectively 1.27 (SD 0.22), 1.37 (SD 0.25), 1.16 (SD 0.16). The point in question is that all ratios significantly increased over the periods of 1971-1990, 2001-2010, p<0.001. Looking at the F:M ratio in urban MS residents one may note a strong correlation between that ratio and 40 calendar years (with one decade interval), fig. 1. The relation between the long-term F:M ratio in urban to rural MS assemblages arouses particular interest. A comparison of the urban to rural MS ratio (1.37 vs. 1.16) showed a significantly higher proportion of MS females in towns, p=0.002. In addition the range of the sex ratio between 1971 and 2010 increased more in urban than in rural MS residents (difference 0.69 vs. 0.41), tab. I. The findings are particularly noteworthy, because they demonstrated greater accumulation of MS females in cities than in villages. However, the rural F:M ratio also increased during the same time confirming the obvious existence of MS risk factors in the countryside. The relation between the urban and rural sex ratio in MS between 1972-1990, 2001-2010 is presented in figure 2. Noteworthy is that the F:M ratio in urban MS residents was more marked between 2001-2010 than between 1971-1990 (1.65 v. 1.23), tab. I. That suggests a strong influence of modern urban setting on MS developing in the latter decade. A somewhat weaker influence of rural environment was found in the sex ratio (1.40 vs. 1.05). 2,0 1,0 F:M urban 0 0 10 20 30 40 50 Fig. 1. Graphic presentation of linear correlation test between F:M ratio in MS urban assemblage (y-axis) and calendar years (x-axis) over three decades. Note increasing relationship between variables: correlation coefficient r was 0.789, p<0.0001 2,0 1,44 1,5 1,5 1,36 1,46 1,38 1,24 0,93 0,99 1,16 1 1,14 0,96 0,87 0,95 1,0 0,5 1,58 1,24 1,55 1,1 1,51 1,63 1,59 1,41 0 1972 1975 1978 1981 1984 1987 1990 1993 1997 2001 2004 2007 2010 The F:M ratio in MS urban residents The F:M ratio in MS rural residents Fig. 2. Diagram showing relation the F:M ratio in urban to rural MS assemblage in Poland. Data are presented on every third year (1972 1990, 2001-2010). Noteworthy is that F:M ratio was higher in urban MS residents than in rural ones except in 1987 and 2007

Cendrowski W. Female multiple sclerosis and urbanization 423 Table I. Number of deceased patients, female to male ratio and urbanization index in multiple sclerosis assemblage (Poland, 1971-1990, 2001-2010) Year The annual number of deceased MS men The annual number of deceased MS women urban area rural area urban area rural area The F:M ratio in MS individuals in urban area The F:M ratio in MS individuals in rural area The F:M ratio in entire MS assemblage The annual urbanization index in MS assemblage The annual index of urban to rural females in the general population 1971 124 127 116 115 0.93 0.90 0.92 0.99 1.22 1972 94 113 136 106 1.44 0.93 1.16 1.05 1.22 1973 100 112 118 122 1.18 1.08 1.13 0.93 1.21 1974 95 112 143 121 1.50 1.08 1.27 1.02 1.23 1975 131 121 130 117 0.99 0.96 0.98 1.09 1.29 1976 130 123 140 113 1.07 0.91 1.00 1.14 1.38 1977 121 134 128 124 1.05 0.92 0.98 0.96 1.38 1978 124 125 154 109 1.24 0.87 1.05 1.18 1.39 1979 114 120 155 118 1.35 0.98 1.16 1.12 1.43 1980 152 114 145 117 0.95 1.02 0.98 1.28 1.46 1981 138 129 161 129 1.16 1.00 1.08 1.15 1.39 1982 132 111 160 113 1.21 1.01 1.12 1.30 1.42 1983 150 134 172 147 1.14 1.09 1.12 1.15 1.46 1984 126 103 190 118 1.50 1.14 1.35 1.37 1.55 1985 143 108 170 121 1.18 1.12 1.15 1.36 1.57 1986 111 127 161 143 1.45 1.12 1.27 1.00 1.59 1987 120 81 164 119 1.36 1.46 1.40 1.42 1.61 1988 123 109 160 133 1.30 1.22 1.26 1.16 1.63 1989 141 90 166 109 1.17 1.21 1.19 1.54 1.66 1990 145 116 201 111 1.38 0.95 1.19 1.52 1.68 1971-1990 2410 2209 3070 2402 Mean (SD) 1.23 (0.18) 1.05 (0.14) 1.14 (0.21) 1.18 (0.39) 1.44 (0.15) 2001 117 69 185 86 1.58 1.24 1.45 1.94 1.68 2002 116 62 178 86 1.53 1.38 1.44 1.92 1.68 2003 100 56 183 87 1.83 1.55 1.73 1.54 1.67 2004 92 68 143 75 1.55 1.10 1.37 1.66 1.66 2005 116 68 174 93 1.50 1.36 1.45 1.80 1.66 2006 105 64 181 91 1.72 1.42 1.60 1.84 1.66 2007 119 52 180 85 1.51 1.63 1.55 2.18 1.65 2008 101 73 185 83 1.83 1.13 1.37 1.83 1.64 2009 101 61 184 106 1.82 1.73 1.79 1.70 1.63 2010 107 58 171 82 1.59 1.41 1.53 1.98 1.62 2001-2010 1074 631 1764 874 Mean (SD) 1.65 (0.13) 1.40 (0.20) 1.53 (0.14) 1.84 (0.18) 1.66 (0.02) Total 3484 2840 4834 3276 1.37 (0.25) 1.16 (0.23) 1.27 (0.22) 1.40 (0.36) 1.51 (0.16) The annual urbanization index in the entire MS cohort has risen over 40 years (except the interval); p<001. The urbanization index strongly increased in MS assemblage from 1.18 to 1.84 (tab. I). That shows an enlarging group of MS residents in the Polish towns. Further findings of the study proved the association between the F:M ratio in patients and the urbanization index in the entire MS cohort. The correlation coefficient by Pearson was strong: r=0.757; p<0.0001. The outcome points out that the higher the urbanization index in MS, the greater the proportion of women with MS. As might be expected the urbanization index in the female general population was also correlated to the F:M ratio in the entire MS cohort: r=0.699, p<0.0001. The correlation indicates significant relationship between these variables. Putting in order the former results one has to consider inconsistency in the rising sequence of the sex ratio in the female general population. Although there was a strong association between the F:M ratio in MS and urbanization index in the female general population between 1971-1990, no association was found between these variables between 2001-2010: r=- 0.242, p=ns. That outcome may somewhat question the role of urbanization in the MS occurrence after the year 2000. However, a long-term urbanization index in Poland proves a changing introduction of

424 Probl Hig Epidemiol 2015, 96(2): 421-426 diversified, city bound MS risk factors in residents. Some of these factors, not yet fully identified, are in the long run particularly hazardous for the female MS development. Discussion MS is a multifactorial disease strongly determined by environmental and genetic factors [13, 14]. The risk of the disease is increased by birth in springtime in higher latitude, female gender, white race, deficiency of solar radiation, adolescent or early adult age, higher hygiene level and by other determinants [15-19]. A remarkable increase of MS prevalence, particularly in women, has been documented by epidemiological studies in a major part of the world [16, 20-22]. Most analytical investigations considered that MS prevalence was higher in urban than in rural areas, but some surveys found equal prevalence or even lower occurrence of the disease in towns [7, 8, 10, 11, 23]. In a historical cohort of the American veterans Kurtzke and Page [15] ascertained a much higher ratio of 134 urban MS women to 8 rural MS females (ratio=16.7), although the significance of odds ratio (OR) was not stated because of small assemblage. That ratio in MS male group was also increased (7.6), OR 1.36; p<0.05 [15]. Further data from the literature pointed out that more MS individuals had resided in the USA cities than in rural areas (94 vs. 73) [23]. Generally there was a significant correlation between the urbanization index and MS prevalence; p=0.01 [23]. Undoubtedly urban setting introduced many occupational, social, lifestyle and cultural factors. MS patients relocated from villages to towns in Crete at a younger age in comparison to controls: 24.5 yr. vs. 30.9 yr.; p=0.006 [12]. The MS incidence rate in the urban population of Crete had risen faster and higher than in the rural one: from 2.1 to 7.0/10 5 vs. 1.0 to 3.0/10 5 (1980-2008) [12]. However, about 17 years earlier no difference was found between the MS prevalence in Salonica and adjacent rural area [24]. In southern Greece the F:M ratio in urban residents at the MS onset was 1.77, whereas that ratio in rural residents was 1.36 [12]. These data suggest a marked effect of urban environment on MS risk in women. This study in Poland confirmed previous findings showing predominance of MS women in towns. Temporal change of the urbanization index demonstrated relocation of rural residents to towns and a local increase of urban inhabitants. Analytical studies considered weak association between the quantity of urban population and MS prevalence (r=+0.53, p<0.05) [8]. There was no increased MS risk by population density of birth county in the USA [15]. The data suggest that metropolitan environment has limited concentration of MS risk factors. A higher proportion of citified inhabitants in North America have had a higher education score and a better socioeconomic score. These factors increased the MS risk: OR=1.95, OR=4.96 [15]. Urban professionals had mainly indoor occupation and experienced shorter exposure to solar radiation [25]. In addition, girls and young women in towns presumably use more cosmetics protecting skin from insolation. It seems likely that citified girls care more for personal hygiene removing protective microbiome from the skin. Moreover, children in towns are more frequently overweight than the rural ones. Obesity is known to reduce the serum vitamin D 3 level [26]. Working night shifts (which is more common in towns) is another MS risk factor [27]. Female residents in the Polish towns have fewer children than rural residents: the reproduction rate 1.20 vs. 1.65 (the year 2000) [28]. MS urban women have been on the average older at the first childbirth than controls [12]. Lower reproduction (parity) before the MS onset is recognized as MS risk factor [29-31]. Citified families are on the average smaller and there was a report that lower exposure of children to infant siblings at pre-school age might increase risk of MS [32]. The present data documented the rising F:M ratio also in rural assemblage. Rural residents, especially women, showed lower MS risk because of higher residential (OR=0.7) and occupational (OR=0.5) exposure to solar radiation [25]. The greater was the group using mechanized tools in the agriculture the lower was MS prevalence in rural population [8]. In contrast to large towns air pollution in the countryside was less imminent and thereby decreasing the MS risk in rural residents [33]. Women in comparison with men show greater susceptibility to MS risk factors [14, 16, 34, 35]. Despite that predisposition partial prevention of the disease is possible. Infants born by natural delivery, breastfed for at least 7 months, nursed in average hygienic milieu and exposed to other siblings are less prone to develop MS in the future [13, 32, 36]. Longer childhood exposure to UVB radiation, diet supplementation with vitamin D 3 especially in adolescent girls, higher parity, spending leisure time or weekends outside of town in the open air and avoidance of tobacco or marihuana smoking may contribute to prevention of the disease [6, 13, 17, 26, 37-40]. The current study has at least three limitations. Firstly, epidemiological investigation is reliant exclusively on death statistics. Secondly, urban residence of the deceased MS patients may be not identical with the place of birth and subsequent living. Thirdly, the effect of migration between rural and urban areas confounds the outcome. Nevertheless,

Cendrowski W. Female multiple sclerosis and urbanization reliance of the study on a very large MS cohort, longterm examination of data and use of more than one correlation yielded convincing evidence that urban living, particularly for women, introduces considerable MS risk. In conclusion, the present study shows evidence supporting the role of urbanization in female MS. Data implicate that urbanization brought forward a number of risk factors particularly for women. A long-term 425 female to male ratio was significantly higher in the MS urban than in the rural group. An increase of MS female occurrence in towns was more pronounced between 2001-2010 as compared with the occurrence between 1971-1990. A strong association was found between the increasing F:M ratio in MS cohort and urbanization indices in Poland. Praca finansowana ze środków własnych Piśmiennictwo / References 1. Ascherio A, Munger K. The initiation and prevention of multiple sclerosis. 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