This rigorous and timely review has several important contributions. First, wide geographical and temporal variations were observed globally. Second, North America, Northern Europe and the UK have the highest incidence worldwide. The incidences of IBD in Southern and Eastern Europe and the Southern Hemisphere also appeared to be high, whereas the incidence was lower, but climbing, in Africa, South America, and Asia. Third, the incidence of IBD is substantially increasing in worldwide regions; however, data published during the previous two decades demonstrate the plateauing incidence of IBD in the Western world after a previously documented increase[22,29-38], but incidence remains high. Currently, the incidence might be sharply increasing in Southern and Eastern Europe and in Oceania. IBD is emerging in other parts of the world (i.e., certain parts of Asia/the Middle East, Africa) approaching the rates reported in westernized nations, but given the accelerating incidence found in many of these areas, the incidence is expected to increase. These trends clearly parallel those of the West that occurred along with the increasing development more than four decades ago indicating an emerging epidemic of IBD worldwide. This gap is considerably less pronounced in 2018, and the narrowing differential gap may have important implications for the worldwide IBD sequelae. The incidence has increased in recent decades up to 23 for IBD in Finland, 13.9 for CD in Canada, 15 for UC in Finland, and 3.6/100000 for IBD-U in the Netherlands. Few studies using north-south/west-east gradients have demonstrated particularly high rates in the north[39-42], except for northern France and Spain. Although our review did not specifically investigate disease incidence gradients, this phenomenon has been less prominent over the last three decades[45-51].
The global incidence rates of IBD have risen during the 20th century but data obtained during the previous two decades are conflicting. The incidence of IBD has increased mainly due to pediatric CD[42,51,52], whereas the incidence of UC has remained stable, although an inverse distribution of CD and UC has been reported[2,4,20,31,32,38,53-57]. Since 1950, 60% of CD and 20% of UC pediatric studies have shown a significant increase in incidence. 75% of CD and 60% of UC studies show increasing incidence in adults. In our systematic review, since 1985, 67% of studies investigating CD, 46% of studies investigating UC, and 11 % of studies investigating IBD-U have reported significant increasing in incidence worldwide. Thus, the incidence rates might be increasing in virtually all regions worldwide. However, the increase in UC was more modest. We intriguingly suggest that the rising incidence of UC may be attributable to the fact that in the emerging areas with a low incidence of IBD, UC has emerged first, followed by CD after a variable period, similar to trends in earlier studies from the West[4,56,59-63].
CD predominates over UC and IBD-U in areas with a high IBD incidence. Recent data indicate higher rates of pediatric CD than UC in Europe and North America, except in Scandinavia[64-66], Northern California, Southern and Eastern Europe, where the incidence of UC exceeds that of CD. The reasons for these striking differences in the rates among the three subtypes of IBD remain uncertain[28,68,69]. IBD-U is more frequently found in children than adults (children 12.7% vs adults 6.0%, P < 0.0001).
Considerable geographical diversity in IBD is observed. Moreover, several studies have reported different incidence rates within a country[31,65], highlighting the role of the environment. Global data exploring the similarities and differences might call for future studies to extensively study genetic-environment interactions providing an opportunity to further identify the contributing factors in locations where IBD is emerging rapidly. Rates among ethnical/racial groups raise further questions regarding why the children of immigrants from the developing world have increased rates of IBD. For example, the incidences of IBD among immigrants of SA origin in Canada[18,25], the UK[16,27], and in immigrants of Middle-Eastern descent in Australia have been reported. In the state of Georgia, the highest incidence of CD in African American children was reported. The key factor of migration influencing disease onset is likely exposure to a different environment than that in the country of origin[7,73]. Additionally, indigenous populations in developed countries have a much lower IBD incidence.
The incidence of IBD in North America is among the highest in the world and is increasing[4,20,22]. There are no national cohorts of pediatric IBD in the USA because the health system is not ideal for conducting population studies. In general, data have been obtained from single regions and must be extrapolated to other geographical regions of the United States. The incidence of IBD in the entire state of Wisconsin (2000-2007) was 9.5/100000, which is similar to the incidence reported in Ontario, Canada, but the incidence of both CD and UC has remained stable. Regarding the members of the Kaiser Permanente Northern California health plan (KPNC) (1996-2006), the data somewhat differed likely due to the different mix of races/ethnicities than that observed in other parts of the United States. The incidence of UC demonstrated a significant 2.7-fold increase, and CD remained stable. Hispanic and SA children had predominantly UC, suggesting the presence of possible etiological differences among ethnicities. Another study conducted in KPNC reported similar levels of IBD, while the incidence in children of African-American origin in Georgia was much higher (7.1/100000). In a Texas cohort, an increasing incidence of IBD among children with evidence of more CD than UC and IBD-U from 1991 to 2002 has been reported. Caucasians had a higher IBD incidence rate than African-Americans or Hispanics, and African Americans had predominantly CD. Comparable values have been reported in Wisconsin. The mean incidence of CD was double that of UC. An equal IBD incidence was observed among all ethnic groups. In the Olmsted County population, the incidence was 4.8 for CD and 3.2/100000 for UC, and remained stable between 1990 and 2000[36,58]. Data from Texas, Georgia, Wisconsin and from comparable studies in KPNC found rates similar to those in Olmsted County[20,76]. However, the ratio of CD/UC cases was greater in Olmsted County, Atlanta and Wisconsin, compared to the greater incidence of UC in KPNC. These results may be attributable to the ethnic demographics of the respective populations. In contrast, a much higher rat was found in the state of Rhode Island compared with older cohorts from other parts of the U.S.[21,23,36,52].
The incidence of IBD in Canada is among the highest reported to date as documented in previous single-province studies[18,78-82] and large multi-province trials[31,39,83]. The incidence in Ontario has steadily increased from 9.5 (in 1994) to 11.4/100000 (in 2005). However, the incidence of UC was stable, and the incidence significantly increased from 9.4 to 13.2/100000 (1994-2009). Although the incidence of IBD in Ontario decreased from 14.3 to 12.4/100000 in 1997-2006, the incidence of CD nearly doubled, which is similar to another Canadian study. Among the best studies in the region, 3 studies determined the incidence of IBD in five provinces of Canada[31,83,84]. The overall incidence was 9.7/100000, and CD was the predominant form of IBD similar to data from Nordic countries. The incidence of IBD was the lowest in Manitoba and the highest in Nova Scotia. The incidence of IBD remained stable after stratifying into CD and UC during the first decade of the twenty-first century, except for an increase in incidence among the youngest group. By extrapolating the results to the entire country, approximately 650 children are diagnosed with IBD yearly, affecting up to 2695 children (< 16 years) in 2008. Similarly, a study from Ontario observed the most rapid increase in children (< 10 years) between 1994 and 2008. Recent data from Canada suggest that the rate of incidence of pediatric IBD is plateauing, indicating a reversal after a long period of ongoing increase[18,31,78,83].
In Argentina, IBD remains uncommon according to a study conducted from 2012 to 2013. The total incidence was 0.4/100000 ranging from 0.2 to 2.4/100000. We could not find other data related to Argentinian children or children in other countries in Latin America for comparison.
Northern and Western Europe
The incidence rates reported in Scandinavia are among the highest rates published to date indicating higher rates of CD than UC and IBD-U but Finland is among the few countries that reportedly show a predominance of UC, whereas the incidence of CD has become relatively greater than that of UC in North America and the UK[20,64,66]. The incidence of IBD has almost doubled between 1987 and 2003 and tripled between 1987 and 2014, with a steeper increase in the incidence of UC compared to that of CD. The incidence of UC increased from 4 to 9/100000 and that of CD increased from 2 to 5/100000[65,88-90] confirming a strongly increasing trend in Finland since the late 1980s. A Norwegian study covered the period of 1993-2004. The incidence of IBD did not change and a trend towards an increase in CD and reduction in UC was recorded, which is similar to the finding of the IBSEN study of 1990-1994. A subsequent study (2005-2007) performed in the same catchment area showed that the incidence of IBD was 10.6/100000 indicating a marked increase in the incidence of CD although incidence of UC has been stabilized in Southeastern Norway compared with the rates over the previous 15 years[60,93-96]. Similarly, Canada had high a incidence of 9.7/100000. The incidence of CD between 1984 and 1985 was 2.5/100000, whereas the incidence of UC was 4.3/100000 with a lower incidence of UC in Western Norway compared to that in Southeastern Norway, which is similar to the results reported in a subsequent study in Southeastern Norway (1990-1994). An increase in the incidence of CD was observed in Northern Stockholm (1990-2001), while the incidence of UC was stable, and a significant increase was observed in the overall incidence of IBD. In a follow-up paper (2002-2007), the incidence of IBD had plateaued. The incidence rate was 9.2 for CD and 2.8/100000 for UC and the incidence of UC significantly increased but not of CD. The incidence of IBD significantly increased between 2000 and 2007 compared to that reported in an earlier study conducted in the same region (1990-2001). These rates are relatively higher than those reported in other studies on pediatric IBD, although the rates are similar to those reported in studies conducted in Canada[54,81], Norway, and Finland. Lindberg et al suggested that the incidence of UC increased (from 1.4 to 3.2/100000), whereas that of CD and IBD-U remained stable (1984-1995), which is similar to the results of a study conducted from 1963-1987. The incidence of IBD, CD, UC and IBD-U was 6.9, 3.8, 2.1, and 1.1/100000, respectively, in Northern Stockholm (1990-1998). After more than a decade of a stable incidence of IBD in Scandinavia, the incidence of CD significantly increased from 1990 to 1998, while the corresponding incidence of UC and IBD-U remained unchanged. As a part of the Swedish ICURE study (2005-2009), the incidence of pediatric IBD in Uppsala County, just north of Stockholm, was among the highest reported in Europe[100,101]. In Denmark, the incidence of IBD has steadily increased from the 1960s until 2013[102-104], except for in one study. An increase in IBD from the 1980s to 2013 was observed, but the incidence rates increased the most in patients (< 15 years) with CD. The incidence rate of UC increased from 1962 to 1987 in the county of Copenhagen, and Fonager et al discovered an increasing incidence of CD but a rather stable incidence of UC with a tendency towards decreasing from 1987 to 1992. Compared to earlier Danish investigations, the incidence of CD had increased nearly 15-fold, whereas the incidence of UC remained stable between 1962 and 2006[34,102,108]. Another study observed an insignificant increase in the incidence of IBD between 1998 and 2004, indicating that the previously observed increasing incidence might be levelling. A significant increase in the incidence of IBD was also reported in recent Danish nationwide comparisons from 1995 to 2013 [109-111]. The IBD incidence (< 19 years) has increased in isolated regions as the Faroe Islands (part of the Danish realm) (1960-2014 with the predominance of UC comparable to findings obtained in the Nordic countries[64,66,105]. The incidence among Icelandic children is closest to that observed in Denmark and Sweden but lower than that observed in Norway[54,92]. Between 1980 and 2010, a sharp increase in IBD incidence was observed, however, the incidence levelled from 2000 to 2010[29,112] similar to the findings in Denmark and Wisconsin[22,34] but lower compared to other Northern countries.
Sawczenko et al discovered an incidence of 5.3/100000 in the British Isles; CD was twice as common as UC, accounting for approximately 700 new cases/year in the UK and the Republic of Ireland. A greater proportion of SA children had UC than non-immigrants. In Scotland, incidence data spanning over 40 years showed a dramatic increase in IBD with a marginal decrease in the incidence of UC but an increasing incidence of CD from 1968 to 1983. In follow-up studies, the increase in CD continued between 1990 and 1992[61,113]. In contrast, the incidence of CD continues to increase, and the incidence of UC is also apparently increasing from 1981 to 1995. Other Scottish studies showed an increase in the incidence of CD from 1981 to 1995 but no difference was observed in the incidence of UC[16,114,115]. By comparing the periods 1990-1995 to 2003-2008, significant increases were observed in the incidence of IBD, CD and UC. Data obtained in Wessex, England reported an incidence of 9.37/100000 which significantly increased from 2002 to 2012. The most recent figures (2013-2017) were reported and compared to previously published Wessex data, demonstrating the most contemporary incidence and trend over 16 years. Similar findings have been observed among Welsh children and appears to have plateaued between 1995 and 1997. In 1995-2003, the overall incidence of IBD was 5.4/100000 and had reached a plateau[30,118], but data obtained during 1996-2005 show that the incidence of CD is continuing to slowly increase in Cardiff. An increasing incidence of IBD in Irish children was observed between 1998 and 2014[16,120,121], which is consistent with the global trends[2,4]. Another study also confirms the continuous increase in the incidence of IBD, particularly UC.
In Austria, the overall incidence of CD and UC have increased from 1997 to 2007. This finding is in contrast to Germany and the Netherlands. For example, a German study did not show any significant change in the IBD incidence. Worldwide, strikingly, the high proportion of IBD-U was observed in the Netherlands and the incidence of IBD cases is comparable with that reported in other European countries. In France, the incidence of CD significantly increased, while the incidence of UC remains unchanged from 1988 to 2011[32,43,125-128]. The most remarkable observation (the EPIMAD Registry) has been a striking increase from 1988 to 2008 in the incidence of CD (< 19 years), and the rates also significantly rose from 1988 to 2011[32,126,127] Surprisingly, in Corsica, using the same registry (EPIMAD), the incidence of CD was close to that observed in other metropolitan French regions; however, the incidence of IBD for UC in Corsica is two-fold higher than that reported in other French regions. In Brittany, the incidence of IBD in childhood was similar to data obtained in Northern France and Nord-Pas-de-Calais[129,130]. Between 1988 and 2011, a dramatic increase was observed in the incidence of both UC and CD in French adolescents. Other than the Swiss IBD Cohort Study (SIBDCS) and the Belgian registry for pediatric CD (BELCRO), up-to-date data regarding the incidence and trends are lacking.
A registry in Italy (1996-2003) showed a significant increase in the incidence of IBD from 0.89 to 1.39/100000 in all 3 pathologies, which is comparable to the incidence in Lombardia (1990-1993). Of note, Italy had a low incidence of IBD earlier, with an initial increase in UC exceeding CD and IBD-U, followed by an increase in the CD incidence, while the UC incidence was stable from 1998-2003. In contrast, the incidence of IBD in central Italy (1978-1992) was comparable to that in the Nordic countries[135,136]. The incidence of IBD was shown to have significantly increased in Spain[44,137]. The SPIRIT (1996-2009) and EXPERIENCE registries (1985-1995) contribute to the complete description of the changes in pediatric IBD in Spain. A three-fold collective increase in IBD (1996-2009) was observed, with another three-fold increase in CD and a two-fold increase in UC, while a lower proportion of IBD-U was described. According to the two latter studies extending the trends to a full 25-year period, these registries showed a sixteen-fold increase in Spain[42,51]. Notably, the incidence of IBD (mainly CD) (18.3/100000) in the Vigo area was the highest compared to that in former Spanish pediatric cohorts. In Malta, UC showed an almost significant increasing trend, but no significant trend in CD was observed.
Central and Eastern Europe
A sharp increase in the incidence of IBD is particularly noticeable in the Czech Republic, Hungary, Slovenia and Croatia, but not in Poland. The results of the 3 studies conducted in the Czech Republic are comparable to the West. Pozler et al showed a five-fold increase in the incidence of CD. Kolek et al published results from Moravia (the eastern part of the Czech Republic) showing increasing incidence of CD and UC between 1999 and 2001. The Czech Republic has among the highest rates of IBD worldwide as recently observed by our group (2000-2015) (10.0, 6.2, 2.8 and 1.0/100000 for IBD, CD, UC and IBD-U, respectively) and have been shown to be increasing in future projections. In neighboring Poland, UC incidence was higher than that of CD with significant regional differences, but the incidence was markedly lower than that observed in the West. Of note the incidence of IBD-U was surprisingly high. An increasing incidence of IBD has been reported in Hungary[46,141,142] comparable to the rate of Slovenia from 1994 to 2010[48,49,143]. One other publication reported much higher rates in Croatia (2000-2004) compared to previous reports[144,145].
Expectedly, knowledge regarding the incidence of IBD in the entire African pediatric population is limited, but the incidence of IBD increased from 0.0/100000 in 1997 to 0.2/100000 in 2002 and 0.9/100000 in 2006 in Libya.
Asia/the Middle East
In Israel, the estimated incidence of CD and UC was 3.7 and 0.9/100000, respectively[147,148], which are comparable, but at the lower end, with those in the West[16,21]. 2 studies reported that the IBD incidence (0.5/100000) is lower than that in Western countries among children in Saudi Arabia from 1993 to 2012[149,150]. A higher incidence was reported in Kuwait and Bahrain (states neighboring Saudi Arabia). In Kuwait, the incidence was more than triple that reported in neighboring Saudi Arabia. This finding provides an annual incidence of 2.16/100000 for IBD, whereas the incidence of CD is 1.53, UC is 0.6 and IBD-U is 0.03/100000. A remarkable finding reported in the Arabian Gulf region is the high incidence of CD in Bahrain, which is comparable to Western areas. The lower incidence of IBD in Asia compared with that in Western countries is not universal, and the incidence in China is higher than that in other regions in Asia. This incidence is considered low compared to that in North America and the Nordic countries but not that low compared to the incidence in Scotland[53,113,114] and France and is higher than that in Italy. In China, a multicenter audit of over a decade of experience with childhood IBD between 2000 and 2010 in Shanghai has shown a steadily increasing trend (< 14 years). The incidence of IBD in 2010 was 6.1/100000, which is 12-fold higher than the incidence in 2001. Recent data on Taiwan also demonstrated a substantial increase in the incidence of IBD, which is mainly attributable to CD, while the incidence of UC did not change significantly. Singapore also witnessed a remarkable increase from 2000-2008; the incidence rates were 5.2-fold greater than those assessed 9 years earlier (from 2.2 to 11.4/100000), which is similar to a report from Scandinavia. The incidence of IBD has been increasing in Korea recently[156,157].
Early studies conducted in Australia and NZ (collectively termed Australasia) mirror the incidence observed in the Northern Hemisphere[54,65]. Two Victorian studies from the same area of Australia clearly show increasing rates of both CD and UC. The incidence of CD increased 10-fold over 30 years until 2001. Additionally, an eleven-fold increase was seen in UC with particular increases in the early 1990s, and the incidence has yet to plateau. Using the 1983-1998 population data, the incidence was estimated to be 2.01/100000 for CD among Victorian children with a documented increase. A study conducted in the Sydney area showed much higher rates of IBD in children of Middle-Eastern descent. In contrast, low rates of IBD were observed in the following indigenous populations: Aborigines and Maori. Yap et al calculated the incidence of IBD, CD and UC to be 2.9, 1.9 and 0.5/100000, respectively in NZ, which is at the lower end compared with the incidence in Europe. Recently, Lopez et al provided important data pertaining to the incidence of pediatric IBD in NZ. The incidence of IBD, CD, UC and IBD-U in NZ in 2015 were 5.2, 3.5, 1.0 and 0.7/100000, respectively. A 4-fold increase was observed in the incidence of childhood IBD in the Canterbury Province of NZ between 1996 and 2015. The annual incidence rate was 7.18/100000 with the preponderance of CD over UC (8.4:1)[160,161].
Limitations of the study
Limitations include heterogeneity in population characteristics among the different studies which were also conducted at different times. Most countries lack accurate estimates of the incidence of pediatric IBD. A direct inter-region comparison may be limited due to the use of different diagnostic criteria and geographic distribution. Also, study quality, case ascertainment, different database capture systems, and methodological problems demonstrated heterogeneity, emphasizing the importance of nationwide registries for retrieval of specific health data including a well-established referral system with uniform criteria. This recommendation underlines the need for uniform diagnostic guidelines for the accuracy of comparison among populations[38,162]. Some studies observed crude incidence rates, while other studies reported age- and/or sex-adjusted rates. Some studies did not reflect the countries’ true incidence, because selected areas of the country were sampled instead of the entire country. We should target large databases at the national/international levels providing a more comprehensive analysis. The other limitation rests with the retrospective design of a number of studies and a better categorisation of migrants. The differences in the various age brackets with great impact on incidence rate should be considered as studies involving a higher defined age limit had higher incidence figures. Despite these limitations, these considerations are unlikely to have had major effects on the reporting the changes in the incidence of IBD across time and geography.
The incidence of pediatric IBD (mainly CD) has recently dramatically increased emerging as a globally important changing pediatric disease. In a rapidly changing world, the dramatically increasing incidence of IBD has been observed in the Western world, Oceania and Eastern and Southern Europe, despite a stabilization of incidence rates in the West. The incidence appears to be rising both in newly industrialized and developing countries, and among first-generation of immigrants. Regarding IBD, knowledge of its etiology is limited, and awareness of the patterns of its global incidence could offer new clues, but the complex interplay of genetic and environmental factors remains unclear. Investigations of IBD performed where it is rapidly emerging provide an opportunity to identify the contributing factors. Efforts at global co-ordination for more prospective, population-based studies in children should be encouraged.