the search was adapted from a previous study ( 6 ) and comprised search terms for infant feeding consisting of text words ( including breast fed , breast feed , breast feeds , breast feeding , breast milk , bottle fed , bottle feed , bottle feeds , bottle feeding , infant feed , infant feeds , infant feeding , infant nutrition , formula fed , formula feed , formula feeds , formula feeding , infant diet , infant diets , dried milk , and early nutrition ) or medline subject heading key words ( including breast feeding , bottle feeding , milk , human , infant food , and infant formula ) and terms for type 1 diabetes including the text words ( iddm or [ diabetes and type 1 ] ) or the medline subject heading key word  diabetes mellitus , type 1 . the searches were limited to studies on humans published after january 1996 [ to avoid overlap with two previous meta - analyses ( 3,4 ) ] up to 1 may 2011 . titles and then abstracts were screened independently by two investigators ( c.r.c . and c.c.p . ) to establish if the studies were likely to provide relevant data based on the following inclusion criteria : 1 ) they identified a group with type 1 diabetes and a group without type 1 diabetes , and 2 ) they recorded breast - feeding in these groups . studies were excluded if they contained < 20 patients with diabetes or if they were family - based ( because the association between infant feeding and type 1 diabetes may be different in individuals with a strong genetic susceptibility ) . the corresponding author of each included article was asked if they were aware of any additional studies . the corresponding author of each study was contacted to provide individual participant data to allow breast - feeding to be consistently categorized across studies , standardize adjustment of the association with breast - feeding for potential confounders ( including maternal diabetes , birth weight , gestational age , maternal age , birth order , caesarean section , and socioeconomic status ) , and include data from studies that did not report detailed findings . authors were requested to provide raw data or to provide adjusted estimates of the association between breast - feeding and type 1 diabetes after conducting specified additional analyses . details of each study were extracted by one reviewer ( c.r.c . ) and agreed with the study author . a two - stage technique was used to calculate pooled estimates of the association between breast - feeding and diabetes , before and after adjustment for potential confounders ( 7 ) . odds ratios ( ors ) and ses were calculated for the association between diabetes and breast - feeding within each study . unconditional and conditional logistic regression was used to calculate the ors and ses for the unmatched and matched case - control studies , respectively . in cohort studies with varying length of participant follow - up , rate ratios and their ses were used instead of ors , which were not directly calculable . as type 1 diabetes is a rare disease , these measures should be approximately equal . in one study ( 8) with a zero cell count for an exposure category , a correction was added to obtain an estimate and se for use in the meta - analysis . in another study , an additional adjustment was always made for the perinatal cohort entry score to reflect the study design ( 9 ) . finally , in studies for which no author could be contacted or data were not available , if possible , required estimates were extracted from published reports . tests for heterogeneity between studies were conducted and random - effects models used to calculate pooled ors . random - effects models were used , instead of fixed - effects models , because between - study heterogeneity was anticipated from these observational studies . small study effects ( possibly due to publication bias ) were investigated by checking for asymmetry in funnel plots of the study ors against one over the se of the logarithm of the ors . similar methods were conducted to pool adjusted estimates . first , adjusted estimates and ses were calculated within each study using regression models appropriate to the study design including diabetes as the outcome variable and breast - feeding and the potential confounder(s ) of interest as explanatory variable(s ) . the analysis was initially conducted based upon a priori categorizations of nonexclusive and exclusive breast - feeding 2 weeks versus breast - feeding < 2 weeks and was repeated for nonexclusive breast - feeding 3 months versus breast - feeding <3 months in which these data or similar were available . subgroup analyses were also conducted including only studies with a low risk of bias based upon high response rates ( > 70% ) in both cases and controls and the use of randomly selected population - based controls . subgroup analysis was also performed by age at diagnosis of diabetes , geographic region , and incidence rate based upon a published summary of worldwide incidence ( 10 ) . all statistical analyses were performed using stata 11.0 ( stata , college station , tx ) . the search was adapted from a previous study ( 6 ) and comprised search terms for infant feeding consisting of text words ( including breast fed , breast feed , breast feeds , breast feeding , breast milk , bottle fed , bottle feed , bottle feeds , bottle feeding , infant feed , infant feeds , infant feeding , infant nutrition , formula fed , formula feed , formula feeds , formula feeding , infant diet , infant diets , dried milk , and early nutrition ) or medline subject heading key words ( including breast feeding , bottle feeding , milk , human , infant food , and infant formula ) and terms for type 1 diabetes including the text words ( iddm or [ diabetes and type 1 ] ) or the medline subject heading key word  diabetes mellitus , type 1 . the searches were limited to studies on humans published after january 1996 [ to avoid overlap with two previous meta - analyses ( 3,4 ) ] up to 1 may 2011 . titles and then abstracts were screened independently by two investigators ( c.r.c . and c.c.p . ) to establish if the studies were likely to provide relevant data based on the following inclusion criteria : 1 ) they identified a group with type 1 diabetes and a group without type 1 diabetes , and 2 ) they recorded breast - feeding in these groups . studies were excluded if they contained < 20 patients with diabetes or if they were family - based ( because the association between infant feeding and type 1 diabetes may be different in individuals with a strong genetic susceptibility ) . the corresponding author of each included article was asked if they were aware of any additional studies . the corresponding author of each study was contacted to provide individual participant data to allow breast - feeding to be consistently categorized across studies , standardize adjustment of the association with breast - feeding for potential confounders ( including maternal diabetes , birth weight , gestational age , maternal age , birth order , caesarean section , and socioeconomic status ) , and include data from studies that did not report detailed findings . authors were requested to provide raw data or to provide adjusted estimates of the association between breast - feeding and type 1 diabetes after conducting specified additional analyses . details of each study were extracted by one reviewer ( c.r.c . ) and agreed with the study author . a two - stage technique was used to calculate pooled estimates of the association between breast - feeding and diabetes , before and after adjustment for potential confounders ( 7 ) . odds ratios ( ors ) and ses were calculated for the association between diabetes and breast - feeding within each study . unconditional and conditional logistic regression was used to calculate the ors and ses for the unmatched and matched case - control studies , respectively . in cohort studies with varying length of participant follow - up , rate ratios and their ses were used instead of ors , which were not directly calculable . as type 1 diabetes is a rare disease , these measures should be approximately equal . in one study ( 8) with a zero cell count for an exposure category , a correction was added to obtain an estimate and se for use in the meta - analysis . in another study , an additional adjustment was always made for the perinatal cohort entry score to reflect the study design ( 9 ) . finally , in studies for which no author could be contacted or data were not available , if possible , required estimates were extracted from published reports . tests for heterogeneity between studies were conducted and random - effects models used to calculate pooled ors . random - effects models were used , instead of fixed - effects models , because between - study heterogeneity was anticipated from these observational studies . small study effects ( possibly due to publication bias ) were investigated by checking for asymmetry in funnel plots of the study ors against one over the se of the logarithm of the ors . first , adjusted estimates and ses were calculated within each study using regression models appropriate to the study design including diabetes as the outcome variable and breast - feeding and the potential confounder(s ) of interest as explanatory variable(s ) . the analysis was initially conducted based upon a priori categorizations of nonexclusive and exclusive breast - feeding 2 weeks versus breast - feeding < 2 weeks and was repeated for nonexclusive breast - feeding 3 months versus breast - feeding <3 months in which these data or similar were available . subgroup analyses were also conducted including only studies with a low risk of bias based upon high response rates ( > 70% ) in both cases and controls and the use of randomly selected population - based controls . subgroup analysis was also performed by age at diagnosis of diabetes , geographic region , and incidence rate based upon a published summary of worldwide incidence ( 10 ) . all statistical analyses were performed using stata 11.0 ( stata , college station , tx ) . 1 . briefly , initial searches identified 238 articles from medline , 393 from web of science , and 609 from embase . of these , 40 articles contained relevant data from 47 studies , as information from 7 centers was taken from 1 article ( 11 ) and information from 2 centers was taken from another ( 12 ) . an investigator from each of the 47 studies was invited to provide raw data ( or estimates from prespecified analyses ) . estimates were obtained from 43 of the 47 identified studies covering 95% ( 9,874 of 10,390 ) of potential patients with type 1 diabetes . individual patient data were obtained from 27 of these studies , 8 supplied prespecified estimates , in 8 studies data could be extracted from published reports , and 4 studies could not be included . table 1 contains the characteristics of the 43 studies from which relevant data were obtained ( see supplemental data for full list of included articles ) . of these , 40 were case - control studies , and 3 were cohort studies . twenty - eight studies were from europe , and in 24 studies , cases were identified using a national or local diabetes register . thirty - seven studies ascertained breast - feeding data using questionnaires or interviews , and in the majority , breast - feeding data were recalled many years after the birth of the child . characteristics of included studies published 20042011 investigating the association between breast - feeding and childhood - onset type 1 diabetes , ordered by publication date the associations between any ( nonexclusive ) breast - feeding and type 1 diabetes from the 43 studies ( including 9,874 patients with type 1 diabetes ) are shown in fig . 1 and table 2 . initially , an analysis was conducted investigating any recorded duration of breast - feeding ( the breast - feeding duration used in this analysis for each study is shown in fig . 1 ) . overall , in studies which investigated any measure of breast - feeding , there was a reduction in the risk of type 1 diabetes in breast - fed children of 18% ( or = 0.81 , 95% ci 0.720.92 ; p < 0.001 ) . there was , however , marked heterogeneity between studies ( i = 63% ; heterogeneity p < 0.001 ) . restricting this analysis to studies with a low risk of bias ( due to high response rates and randomly selected population - based controls , as shown in table 1 ) , there was no evidence of an association ( or = 1.00 , 95% ci 0.891.11 ; p = 0.93 ) and little evidence of heterogeneity ( i = 1% ; heterogeneity p = 0.51 ) . pooled analysis of association between ( nonexclusive ) breast - feeding and childhood - onset type 1 diabetes in studies investigating 2 weeks ( nonexclusive ) breast - feeding and studies investigating any measure of breast - feeding . pooled analyses of the association between breast - feeding and childhood - onset type 1 diabetes in all studies and in studies with a lower risk of bias analyses were also conducted in subgroups of studies recording breast - feeding of 2 weeks duration or more ( see fig . 1 for exact duration of breast - feeding used in each study ) and 3 months duration or more ( see table 1 for exact duration of breast - feeding used in each study ) . in 28 studies , there was little evidence of any difference in the risk of type 1 diabetes in children breast - fed for 2 weeks or more compared with < 2 weeks ( or = 0.93 , 95% ci 0.811.07 ; p = 0.32 ) , but again there was heterogeneity between studies ( i = 54% ; heterogeneity p < 0.001 ) . this heterogeneity was reduced in 15 studies with a low risk of bias ( i = 8% ; heterogeneity p = 0.37 ) , but the overall finding was little altered ( or = 1.00 , 95% ci 0.871.15 ; p = 0.99 ) . in 29 studies , there was also little evidence of a reduction in the risk of type 1 diabetes in children breast - fed for  3 months or more compared with children breast - fed for <3 months ( or = 0.88 , 95% ci 0.781.00 ; p = 0.05 ) , but the heterogeneity between studies persisted ( i = 68% ; heterogeneity p < 0.001 ) . repeating this analysis in 15 studies with a low risk of bias showed no evidence of an association ( or = 0.99 , 95% ci 0.861.14 ; p = 0.92 ) and slightly less , though still significant , heterogeneity ( i = 48% ; heterogeneity p = 0.02 ) . funnel plots ( not shown ) provided little evidence of asymmetry ( potentially caused by publication bias ) . finally , an analysis was conducted in the following approximate categories of ( nonexclusive ) breast - feeding : < 2 weeks , 2 weeks to 4 months , 46 months , and > 6 months . in 24 studies with available data , when compared with children breast - fed for < 2 weeks children breast - fed for 2 weeks to 4 months had a 4% reduction in diabetes risk ( or = 0.96 , 95% ci 0.831.12 ) , children breast - fed for 46 months had a 5% reduction in diabetes risk ( or = 0.95 , 95% ci 0.781.15 ) , and children breast - fed for > 6 months had a 6% reduction in diabetes risk ( or = 0.94 , 95% ci 0.761.17 ) , though none of these differences were significant . these findings were similar when restricted to 13 studies with a low risk of bias . additional analyses ( shown in supplementary table 2 ) in subgroups of studies defined by geographic region ( european , non - european ) and low and high incidence rate countries ( < 15 cases of type 1 diabetes per 100,000 person - years and > 15 per 100,000 person - years , respectively ) did not reveal any marked differences in association . there was little evidence of a difference in the association between childhood type 1 diabetes and ( nonexclusive ) breast - feeding in early diagnosed diabetes ( i.e. , < 5 years old ) and later diagnosed diabetes ( i.e. , between 5 and 15 years old ) in studies in which both age groups were available ( shown in supplementary table 3 ) . specifically , in 22 studies , the or for breast - feeding for 2 weeks or more was 0.84 ( 95% ci 0.651.08 ) in early diagnosed disease and 0.95 ( 95% ci 0.821.11 ) for later diagnosed disease . similarly , in 23 studies , the or for breast - feeding for 3 months or more was 0.86 ( 95% ci 0.691.08 ) in early diagnosed disease and 0.90 ( 95% ci 0.791.02 ) for later diagnosed disease . supplementary table 1 shows the findings for ( nonexclusive ) breast - feeding for 2 weeks or more after adjustment for potential confounders . the association between type 1 diabetes and breast - feeding was little altered after individual adjustment for maternal diabetes , birth weight , gestational age , maternal age , birth order , caesarean section delivery , or socioeconomic status , where possible . there was also little change in the estimate when adjustment for all available variables simultaneously was conducted . similar analyses were conducted for the associations between exclusive breast - feeding and type 1 diabetes ( investigated by 33 studies including 7,621 patients with type 1 diabetes ) that are shown in fig . 2 ( which contains the duration of exclusive breast - feeding used in each study ) and table 1 . overall , in studies which investigated any measure of exclusive breast - feeding , there was a reduction in the risk of type 1 diabetes in exclusively breast - fed children of 26% ( or = 0.74 , 95% ci 0.640.84 ; p < 0.001 ) , but there was marked heterogeneity between studies ( i = 67% ; heterogeneity p < 0.001 ) . when restricting this analysis to 13 studies with a low risk of bias , the association was no longer significant ( or = 0.89 , 95% ci 0.781.02 ; p = 0.09 ) , and there was less heterogeneity ( i = 6% ; heterogeneity p = 0.38 ) . pooled analysis of association between exclusive breast - feeding and childhood - onset type 1 diabetes in studies investigating 2 weeks exclusive breast - feeding and studies investigating any measure of exclusive breast - feeding . as before , analysis was conducted in subgroups of studies recording 2 weeks or more ( see fig . 1 for definition ) and 3 months or more of exclusive breast - feeding ( see table 1 for definition ) . in 20 studies , children exclusively breast - fed for 2 weeks or more had a 25% reduction in their risk of type 1 diabetes ( or = 0.75 , 95% ci 0.640.88 ; p = 0.001 ) compared with children exclusively breast - fed for < 2 weeks , but there was marked heterogeneity between studies ( i = 58% ; heterogeneity p < 0.001 ) . this association was slightly attenuated but remained significant in 12 studies with a low risk of bias ( or = 0.86 , 95% ci 0.750.99 ; p = 0.04 ) , but in these studies , there was less heterogeneity ( i = 0% ; heterogeneity p = 0.44 ) . there was less evidence of a reduction in diabetes risk ( in 30 studies ) in children exclusively breast - fed for 3 months or more ( or = 0.87 , 95% ci 0.751.00 ; p = 0.06 ) compared with children exclusively breast - fed for <3 months but there was marked heterogeneity ( i = 76% ; heterogeneity p < 0.001 ) . in 13 studies with a low risk of bias , the heterogeneity remained ( i = 43% ; heterogeneity p = 0.03 ) , and there was little evidence of an association ( or = 1.13 , 95% ci 0.961.33 ; p = 0.15 ) . insufficient data were available to conduct an analysis of exclusive breast - feeding in finer duration categories . funnel plots for these associations ( not shown ) provided little evidence of asymmetry ( potentially caused by publication bias ) . additional analyses ( shown in supplementary table 2 ) in subgroups of studies defined by geographic region ( european , non - european ) and incidence rates of type 1 diabetes ( low incidence , high incidence ) did not reveal any marked differences in association . as before , a comparison of the associations with exclusive breast - feeding by early diagnosed diabetes ( i.e. , < 5 years old ) and later diagnosed diabetes ( i.e. , between 5 and 15 years old ) showed little evidence of a difference in studies in which both age groups were available ( shown in supplementary table 3 ) . specifically , in 18 studies , the or for exclusive breast - feeding for 2 weeks or more was 0.73 ( 95% ci 0.580.91 ) in early diagnosed disease and 0.75 ( 95% ci 0.600.95 ) for later diagnosed disease . similarly , in 24 studies , the or for exclusive breast - feeding for 3 months or more was 0.86 ( 95% ci 0.711.03 ) in early diagnosed disease and 0.90 ( 95% ci 0.761.05 ) for later diagnosed disease . supplementary table 1 shows the findings for exclusive breast - feeding for 2 weeks or more after adjustment for potential confounders . the association between type 1 diabetes and exclusive breast - feeding was little altered after adjustment for any of these confounders individually , where possible , or when adjustments were conducted for all available confounders simultaneously . 1 . briefly , initial searches identified 238 articles from medline , 393 from web of science , and 609 from embase . of these , 40 articles contained relevant data from 47 studies , as information from 7 centers was taken from 1 article ( 11 ) and information from 2 centers was taken from another ( 12 ) . an investigator from each of the 47 studies was invited to provide raw data ( or estimates from prespecified analyses ) . estimates were obtained from 43 of the 47 identified studies covering 95% ( 9,874 of 10,390 ) of potential patients with type 1 diabetes . individual patient data were obtained from 27 of these studies , 8 supplied prespecified estimates , in 8 studies data could be extracted from published reports , and 4 studies could not be included . table 1 contains the characteristics of the 43 studies from which relevant data were obtained ( see supplemental data for full list of included articles ) . of these , 40 were case - control studies , and 3 were cohort studies . twenty - eight studies were from europe , and in 24 studies , cases were identified using a national or local diabetes register . thirty - seven studies ascertained breast - feeding data using questionnaires or interviews , and in the majority , breast - feeding data were recalled many years after the birth of the child . characteristics of included studies published 20042011 investigating the association between breast - feeding and childhood - onset type 1 diabetes , ordered by publication date the associations between any ( nonexclusive ) breast - feeding and type 1 diabetes from the 43 studies ( including 9,874 patients with type 1 diabetes ) are shown in fig . 1 and table 2 . initially , an analysis was conducted investigating any recorded duration of breast - feeding ( the breast - feeding duration used in this analysis for each study is shown in fig . 1 ) . overall , in studies which investigated any measure of breast - feeding , there was a reduction in the risk of type 1 diabetes in breast - fed children of 18% ( or = 0.81 , 95% ci 0.720.92 ; p < 0.001 ) . there was , however , marked heterogeneity between studies ( i = 63% ; heterogeneity p < 0.001 ) . restricting this analysis to studies with a low risk of bias ( due to high response rates and randomly selected population - based controls , as shown in table 1 ) , there was no evidence of an association ( or = 1.00 , 95% ci 0.891.11 ; p = 0.93 ) and little evidence of heterogeneity ( i = 1% ; heterogeneity p = 0.51 ) . pooled analysis of association between ( nonexclusive ) breast - feeding and childhood - onset type 1 diabetes in studies investigating 2 weeks ( nonexclusive ) breast - feeding and studies investigating any measure of breast - feeding . pooled analyses of the association between breast - feeding and childhood - onset type 1 diabetes in all studies and in studies with a lower risk of bias analyses were also conducted in subgroups of studies recording breast - feeding of 2 weeks duration or more ( see fig . 1 for exact duration of breast - feeding used in each study ) and 3 months duration or more ( see table 1 for exact duration of breast - feeding used in each study ) . in 28 studies , there was little evidence of any difference in the risk of type 1 diabetes in children breast - fed for 2 weeks or more compared with < 2 weeks ( or = 0.93 , 95% ci 0.811.07 ; p = 0.32 ) , but again there was heterogeneity between studies ( i = 54% ; heterogeneity p < 0.001 ) . this heterogeneity was reduced in 15 studies with a low risk of bias ( i = 8% ; heterogeneity p = 0.37 ) , but the overall finding was little altered ( or = 1.00 , 95% ci 0.871.15 ; p = 0.99 ) . in 29 studies , there was also little evidence of a reduction in the risk of type 1 diabetes in children breast - fed for  3 months or more compared with children breast - fed for <3 months ( or = 0.88 , 95% ci 0.781.00 ; p = 0.05 ) , but the heterogeneity between studies persisted ( i = 68% ; heterogeneity p < 0.001 ) . repeating this analysis in 15 studies with a low risk of bias showed no evidence of an association ( or = 0.99 , 95% ci 0.861.14 ; p = 0.92 ) and slightly less , though still significant , heterogeneity ( i = 48% ; heterogeneity p = 0.02 ) . funnel plots ( not shown ) provided little evidence of asymmetry ( potentially caused by publication bias ) . finally , an analysis was conducted in the following approximate categories of ( nonexclusive ) breast - feeding : < 2 weeks , 2 weeks to 4 months , 46 months , and > 6 months . in 24 studies with available data , when compared with children breast - fed for < 2 weeks children breast - fed for 2 weeks to 4 months had a 4% reduction in diabetes risk ( or = 0.96 , 95% ci 0.831.12 ) , children breast - fed for 46 months had a 5% reduction in diabetes risk ( or = 0.95 , 95% ci 0.781.15 ) , and children breast - fed for > 6 months had a 6% reduction in diabetes risk ( or = 0.94 , 95% ci 0.761.17 ) , though none of these differences were significant . these findings were similar when restricted to 13 studies with a low risk of bias . additional analyses ( shown in supplementary table 2 ) in subgroups of studies defined by geographic region ( european , non - european ) and low and high incidence rate countries ( < 15 cases of type 1 diabetes per 100,000 person - years and > 15 per 100,000 person - years , respectively ) did not reveal any marked differences in association . there was little evidence of a difference in the association between childhood type 1 diabetes and ( nonexclusive ) breast - feeding in early diagnosed diabetes ( i.e. , < 5 years old ) and later diagnosed diabetes ( i.e. , between 5 and 15 years old ) in studies in which both age groups were available ( shown in supplementary table 3 ) . specifically , in 22 studies , the or for breast - feeding for 2 weeks or more was 0.84 ( 95% ci 0.651.08 ) in early diagnosed disease and 0.95 ( 95% ci 0.821.11 ) for later diagnosed disease . similarly , in 23 studies , the or for breast - feeding for 3 months or more was 0.86 ( 95% ci 0.691.08 ) in early diagnosed disease and 0.90 ( 95% ci 0.791.02 ) for later diagnosed disease . supplementary table 1 shows the findings for ( nonexclusive ) breast - feeding for 2 weeks or more after adjustment for potential confounders . the association between type 1 diabetes and breast - feeding was little altered after individual adjustment for maternal diabetes , birth weight , gestational age , maternal age , birth order , caesarean section delivery , or socioeconomic status , where possible . there was also little change in the estimate when adjustment for all available variables simultaneously was conducted . similar analyses were conducted for the associations between exclusive breast - feeding and type 1 diabetes ( investigated by 33 studies including 7,621 patients with type 1 diabetes ) that are shown in fig . 2 ( which contains the duration of exclusive breast - feeding used in each study ) and table 1 . overall , in studies which investigated any measure of exclusive breast - feeding , there was a reduction in the risk of type 1 diabetes in exclusively breast - fed children of 26% ( or = 0.74 , 95% ci 0.640.84 ; p < 0.001 ) , but there was marked heterogeneity between studies ( i = 67% ; heterogeneity p < 0.001 ) . when restricting this analysis to 13 studies with a low risk of bias , the association was no longer significant ( or = 0.89 , 95% ci 0.781.02 ; p = 0.09 ) , and there was less heterogeneity ( i = 6% ; heterogeneity p = 0.38 ) . pooled analysis of association between exclusive breast - feeding and childhood - onset type 1 diabetes in studies investigating 2 weeks exclusive breast - feeding and studies investigating any measure of exclusive breast - feeding . as before , analysis was conducted in subgroups of studies recording 2 weeks or more ( see fig . 1 for definition ) and 3 months or more of exclusive breast - feeding ( see table 1 for definition ) . in 20 studies , children exclusively breast - fed for 2 weeks or more had a 25% reduction in their risk of type 1 diabetes ( or = 0.75 , 95% ci 0.640.88 ; p = 0.001 ) compared with children exclusively breast - fed for < 2 weeks , but there was marked heterogeneity between studies ( i = 58% ; heterogeneity p < 0.001 ) . this association was slightly attenuated but remained significant in 12 studies with a low risk of bias ( or = 0.86 , 95% ci 0.750.99 ; p = 0.04 ) , but in these studies , there was less heterogeneity ( i = 0% ; heterogeneity p = 0.44 ) . there was less evidence of a reduction in diabetes risk ( in 30 studies ) in children exclusively breast - fed for 3 months or more ( or = 0.87 , 95% ci 0.751.00 ; p = 0.06 ) compared with children exclusively breast - fed for <3 months but there was marked heterogeneity ( i = 76% ; heterogeneity p < 0.001 ) . in 13 studies with a low risk of bias , the heterogeneity remained ( i = 43% ; heterogeneity p = 0.03 ) , and there was little evidence of an association ( or = 1.13 , 95% ci 0.961.33 ; p = 0.15 ) . insufficient data were available to conduct an analysis of exclusive breast - feeding in finer duration categories . funnel plots for these associations ( not shown ) provided little evidence of asymmetry ( potentially caused by publication bias ) . additional analyses ( shown in supplementary table 2 ) in subgroups of studies defined by geographic region ( european , non - european ) and incidence rates of type 1 diabetes ( low incidence , high incidence ) did not reveal any marked differences in association . as before , a comparison of the associations with exclusive breast - feeding by early diagnosed diabetes ( i.e. , < 5 years old ) and later diagnosed diabetes ( i.e. , between 5 and 15 years old ) showed little evidence of a difference in studies in which both age groups were available ( shown in supplementary table 3 ) . specifically , in 18 studies , the or for exclusive breast - feeding for 2 weeks or more was 0.73 ( 95% ci 0.580.91 ) in early diagnosed disease and 0.75 ( 95% ci 0.600.95 ) for later diagnosed disease . similarly , in 24 studies , the or for exclusive breast - feeding for 3 months or more was 0.86 ( 95% ci 0.711.03 ) in early diagnosed disease and 0.90 ( 95% ci 0.761.05 ) for later diagnosed disease . supplementary table 1 shows the findings for exclusive breast - feeding for 2 weeks or more after adjustment for potential confounders . the association between type 1 diabetes and exclusive breast - feeding was little altered after adjustment for any of these confounders individually , where possible , or when adjustments were conducted for all available confounders simultaneously . this pooled analysis suggests that breast - feeding exclusively in the early weeks of life could reduce the risk of childhood onset type 1 diabetes by 15% , based upon the highest quality studies . this pooled analysis provides little evidence that longer exclusive or nonexclusive breast - feeding has a protective effect . however , firm conclusions are difficult to reach because of the marked heterogeneity in the observed associations between studies and the weaknesses inherent in many of the included studies . the observed association between exclusive breast - feeding and type 1 diabetes could not be explained by confounding from established risk factors for diabetes including maternal diabetes , birth weight , gestational age , maternal age , birth order , or caesarean section delivery . this is , to our knowledge , the first pooled analysis of individual participant data on breast - feeding and diabetes . the main strengths of using individual participant data in this study was that it allowed analysis to be conducted in similar categories of breast - feeding duration between studies and enabled adjustment of associations for various confounders . this analysis contains data from 43 studies and includes 9,874 patients with type 1 diabetes allowing the power to identify associations of relatively small magnitude . also , the analyses benefited from coverage of 95% of eligible cases from studies identified by the comprehensive search strategies . however , it remains possible that studies with relevant data were not identified by the searches . a weakness of this pooled analysis was that the majority of studies were questionnaire - based case - control studies , and their findings are based upon breast - feeding information usually recalled over many years , potentially resulting in recall and other biases . there were only two cohort studies ( 8,9 ) that prospectively recorded breast - feeding at 2 weeks and 3 months , but these contained relatively few patients with type 1 diabetes , 31 and 24 cases , respectively . consequently , there is a need for further studies prospectively or routinely recording breast - feeding in early life . although attempts were made to identify studies with lower risk of bias ( with higher response rates and randomly selected population - based controls ) , even in these studies , response rates varied , and in many , recall bias is possible . as with all observational studies , it is impossible to rule out the effect of unmeasured confounding , for example , by other infant food intake . this could reflect real differences in the association in different populations or biases specific to each study . in studies with a low risk of bias , less heterogeneity was observed , allowing more confidence to be placed on the resulting pooled estimates . the findings of our pooled analysis of individual participant data differ from two published literature - based meta - analyses ( 3,4 ) . the first meta - analysis ( 3 ) ( containing studies conducted prior to 1994 ) demonstrated a reduction in diabetes risk of 30% with breast - feeding > 3 months , and a 35% reduction with exclusive breast - feeding for > 3 months . the second meta - analysis ( containing studies conducted prior to 1996 , many of which were in the first meta - analysis ) demonstrated a reduction in diabetes risk of 20% with breast - feeding for 3 months and 40% for exclusive breast - feeding for > 3 months ( 4 ) . in our pooled analysis , there was little evidence of any reduction in the risk of diabetes after 3 months of breast - feeding ( exclusive or nonexclusive ) . unfortunately , neither of the two earlier meta - analyses presented estimates for breast - feeding in the first 2 weeks of life to allow comparison with our results . both these meta - analyses were largely based upon questionnaire - based case - control studies , and the second meta - analysis ( 4 ) highlighted that the observed association could reflect methodological weaknesses , particularly recall bias . the authors suggested that mothers of children with diabetes may more critically remember occasions when they deviated from the breast - feeding recommendations of health care personnel ( 4 ) . as previously discussed , the majority of studies included in this pooled analysis were questionnaire - based case - control studies and would also be subject to this bias . in 2007 , the agency for healthcare research and quality reviewed the evidence of the effect of breast - feeding on type 1 diabetes ( 13 ) . however , the report did not contain a meta - analysis because their searches identified only 6 studies after 1996 ( up to 2007 ) when the previous meta - analyses were conducted , in contrast to the 43 studies included in our pooled analysis between 1996 and 2011 . the estimated or of 0.75 for any breast - feeding for 3 months from the agency for healthcare research and quality report ( 13 ) ( based solely on the two previous meta - analyses ) has since been used to estimate the cost - effectiveness of breast - feeding in the u.s . our results would suggest that this or of 0.75 may overestimate any protective effect against type 1 diabetes and that consequently the cost - effectiveness of breast - feeding with respect to type 1 diabetes could also be exaggerated . a recent narrative review ( 15 ) commenting on the effects of breast - feeding and complementary feeding noted that the associations were controversial and that contradictory outcomes had been observed . studies have also been conducted into -cell autoimmunity and breast - feeding , but the results have been mixed , with some studies observing protective effects of breast - feeding , whereas others have observed no association [ see knip et al . ( this pooled analysis suggests that initial exclusive breast - feeding may reduce diabetes risk , indicating that the introduction of formula feeding may explain any association . the responsible mechanism is unclear , but researchers have speculated ( 15 ) that breast - feeding could protect against type 1 diabetes risk by increasing gut permeability ; previous studies have shown that gut permeability decreases faster in breastfed children ( 16 ) or by reducing the risk of enterovirus infections ( 17 ) , which have been associated with increased diabetes risk ( 18 ) . alternatively , any increased risk of diabetes associated with formula feeding could reflect early exposure to a variety of cow s milk proteins [ studies have shown children with type 1 diabetes have increased concentrations of antibodies to dietary antigens ( 19 ) ] , modification of the gut microflora ( 15 ) , and increased weight gain in early life [ although one study suggested that any effect of breast - feeding was independent of weight gain ( 20 ) ] . in our analysis , an association was only observed for initial exclusive breast - feeding ( for 2 weeks ) but not for exclusive breast - feeding for 3 months . this distinction may be real or could reflect the relatively accurate maternal recall of initial breast - feeding but less accurate recall of the duration of feeding , as previously suggested ( 3 ) . if early introduction of formula feeding is responsible then ongoing efforts to investigate alternative formula , such as the trial to reduce insulin - dependent diabetes mellitus in the genetically at risk ( 21 ) , may be productive . in conclusion , our pooled analysis suggests that children who are initially exclusively breast - fed have a small reduction in their risk of type 1 diabetes . this finding is difficult to interpret because the associations varied markedly between studies and because the results are based primarily upon questionnaire - based case - control studies , which could have been affected by recall and other biases .
objectiveto investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.research design and methodsrelevant studies were identified from literature searches using medline , web of science , and embase . 
 authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses . 
 meta - analysis techniques were used to combine odds ratios ( ors ) and investigate heterogeneity between studies.resultsdata were available from 43 studies including 9,874 patients with type 1 diabetes . 
 overall , there was a reduction in the risk of diabetes after exclusive breast - feeding for > 2 weeks ( 20 studies ; or = 0.75 , 95% ci 0.640.88 ) , the association after exclusive breast - feeding for > 3 months was weaker ( 30 studies ; or = 0.87 , 95% ci 0.751.00 ) , and no association was observed after ( nonexclusive ) breast - feeding for > 2 weeks ( 28 studies ; or = 0.93 , 95% ci 0.811.07 ) or > 3 months ( 29 studies ; or = 0.88 , 95% ci 0.781.00 ) . 
 these associations were all subject to marked heterogeneity ( i2 = 58 , 76 , 54 , and 68% , respectively ) . in studies with lower risk of bias , the reduced risk after exclusive breast - feeding for > 2 weeks remained ( 12 studies ; or = 0.86 , 95% ci 0.750.99 ) , and heterogeneity was reduced ( i2 = 0% ) . 
 adjustments for potential confounders altered these estimates very little.conclusionsthe pooled analysis suggests weak protective associations between exclusive breast - feeding and type 1 diabetes risk 
 . however , these findings are difficult to interpret because of the marked variation in effect and possible biases ( particularly recall bias ) inherent in the included studies .