Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring : the Pune Maternal Nutrition Study Aims/hypothesis Raised maternal plasma total homocysteine -LRB- tHcy -RRB- concentrations predict small size at birth , which is a risk factor for type 2 diabetes mellitus . We studied the association between maternal vitamin B12 , folate and tHcy status during pregnancy , and offspring adiposity and insulin resistance at 6 years . Introduction The ` thrifty phenotype ' hypothesis -LSB- 1 -RSB- introduced a new paradigm in the aetiology of chronic disease and stimulated research into the relationship between maternal nutrition , fetal growth and offspring risk of type 2 diabetes mellitus . India has the largest number of diabetic patients in the world -LSB- 2 -RSB- and this may be related to the fact that Indian babies are amongst the smallest in the world -LSB- 3 -RSB- . We were the first to demonstrate that low birthweight of Indian babies predicts insulin resistance and adiposity in childhood -LSB- 4 -RSB- . Subsequently we demonstrated that the apparently small Indian newborn babies are relatively adipose , hyperinsulinaemic and hyperleptinaemic compared with white babies -LSB- 5 , 6 -RSB- . These babies grow into shorter , thinner -LRB- low BMI -RRB- but more adipose -LRB- higher body fat per cent and higher central fat -RRB- adults compared with whites , and have a many times higher risk of type 2 diabetes -LSB- 7 -RSB- . Thus , in addition to the role of putative genetic and modern day lifestyle factors , the intrauterine environment may also influence the risk of type 2 diabetes mellitus . The Pune Maternal Nutrition Study -LRB- PMNS -RRB- is the first study in India to investigate the relationship between maternal nutrition and offspring risk of type 2 diabetes and cardiovascular disease . Data were collected on the mother 's size , diet , micronutrient status and physical workload during pregnancy -LSB- 6 , 8 , 9 -RSB- , and the newborns were measured in detail at birth and every 6 months thereafter . At 6 years of age , the offspring were investigated for risk of type 2 diabetes and cardiovascular disease . We have reported that a higher frequency of maternal intake of green leafy vegetables -LRB- GLVs -RRB- , milk and fruit and higher erythrocyte folate concentrations are associated with larger newborn size -LSB- 8 -RSB- . In a small sub-sample we found that higher maternal circulating total homocysteine -LRB- tHcy -RRB- predicted low offspring birthweight -LSB- 10 -RSB- . Other studies in Pune have shown that vitamin B12 deficiency is common and contributes to hyperhomocysteinaemia , while folate deficiency is rare -LSB- 11 , 12 -RSB- . We therefore hypothesised that vitamin B12 and folate deficiency in the mother during pregnancy would predict greater adiposity and insulin resistance in the offspring . Methods The recruitment of mothers and follow-up of the children in the PMNS -LRB- Fig. 1 -RRB- has been described -LSB- 6 , 8 , 9 -RSB- . The study started in 1993 . Non-pregnant married women living in six villages near Pune had detailed anthropometric measurements every 3 months and menstrual dates were recorded monthly . Women who became pregnant were assessed at 18 ± 2 and 28 ± 2 weeks of gestation for anthropometry , physical workload , dietary intake -LRB- 24 h recall and food frequency questionnaire -LSB- FFQ -RSB- -RRB- and measurement of circulating nutrients . According to the National Nutritional Anemia Control Programme , women were given 100 tablets of iron -LRB- 60 mg per tablet -RRB- and folic acid -LRB- 500 μg per tablet -RRB- from 18 weeks of gestation . Newborn babies were measured within 72 h of birth -LRB- 1994 -- 1996 -RRB- , and the children were followed up post-natally with repeat anthropometry every 6 months . Fig. 1The PMNS : a flow diagram to describe data collection and exclusions from the study . LMP Last menstrual period At 6 years of age -LRB- December 2000 -- February 2003 -RRB- the children were investigated for body size , body composition and risk factors for type 2 diabetes mellitus and cardiovascular disease . Families were instructed to continue their usual diet and activity prior to the study , and were transported to the Research Unit the previous evening . They were provided with a standard dinner and then water only until the next morning . A fasting blood sample was collected , followed by a 1.75 g/kg body weight oral anhydrous glucose load and a further blood sample 120 min later . The family 's socioeconomic status -LRB- SES -RRB- was assessed using the Standard of Living Index devised by the National Family Health Survey -LSB- 13 -RSB- . Weight and height were measured using standardised protocols . Whole-body dual-energy X-ray absorptiometry -LRB- DEXA -RRB- scans -LRB- Lunar DPX-IQ 240 ; Lunar Corporation , Madison , WI , USA ; paediatric software -RRB- were carried out to measure total , truncal and leg fat mass , percentage body fat and lean mass . Standard quality assurance tests were performed every day . The DEXA machine was installed 3 months after the study started , and therefore 59 children had DEXA measurements later than the other investigations . Plasma glucose was measured using an Hitachi 911 automated analyser -LRB- Hitachi , Tokyo , Japan -RRB- by the glucose oxidase peroxidase method . Plasma insulin was measured using a Delfia technique -LRB- Victor 2 ; Wallac , Turku , Finland -RRB- -LSB- 14 -RSB- . Insulin resistance was calculated using the fasting insulin and glucose concentrations -LRB- homeostatic model assessment of insulin resistance -LSB- HOMA-R -RSB- -RRB- -LSB- 15 -RSB- . As previously described , maternal erythrocyte folate concentrations were measured at the time of the original study -LRB- 1993 -- 1996 -RRB- , taking all necessary precautions in the collection , transport and storage of samples -LSB- 8 -RSB- . Based on the findings of a preliminary study -LSB- 10 -RSB- , we measured plasma vitamin B12 , tHcy and methylmalonic acid -LRB- MMA -RRB- concentrations in all the stored maternal fasting samples -LRB- − 80 °C -RRB- in February 2004 , as described -LSB- 11 -RSB- . Ethical permission for the study was granted by the KEM Hospital Ethical Committee , and by the local village leaders . Parents gave informed written consent . None of these volunteers were paid for participating in the study . Statistics Skewed variables were transformed to normality using the following transformations : log to the base e -LRB- ln -RRB- -LRB- plasma vitamin B12 -LSB- 18 weeks -RSB- , tHcy and MMA and erythrocyte folate concentrations , maternal fat intake , and the child 's trunk and leg fat mass -RRB- , square root -LRB- maternal energy , protein , and carbohydrate intakes , and the child 's total fat mass -RRB- and reciprocal of square root -LRB- maternal vitamin B12 concentrations at 28 weeks -RRB- . Maternal pre-pregnant fat mass was calculated from the sum of four skinfold thickness measurements -LSB- 16 -RSB- . Maternal intakes of specific foods , based on the FFQ , were analysed as categorical variables . Low vitamin B12 and erythrocyte folate concentrations were defined as < 150 pmol/l and < 283 nmol/l , respectively . Elevated tHcy and MMA concentrations were defined as > 10 and > 0.26 μmol/l -LSB- 17 -RSB- . Correlations between different nutritional measures in the mothers were tested using Pearson correlation coefficients . Relationships between maternal nutritional variables and outcomes in the children were analysed using multiple linear regression . As a final stage of the analysis , we summarised the inter-relationships between maternal factors and outcomes in the children using principal components analysis -LRB- PCA -RRB- and conditional independence analysis . We first performed a PCA to condense the information contained in large groups of variables into a small number of ` component ' variables . These components are independent of each other and therefore can be used in regression analysis without the problem of colinearity -LSB- 18 -RSB- . The groups of variables were : -LRB- 1 -RRB- maternal pre-pregnant size -LRB- height , skinfold thicknesses , head circumference , mid-upper-arm circumference -LSB- MUAC -RSB- and waist and hip circumferences -RRB- ; -LRB- 2 -RRB- maternal macronutrient intakes -LRB- energy , protein , carbohydrate and fat intakes at 18 and 28 weeks -RRB- ; -LRB- 3 -RRB- maternal micronutrient-rich foods in pregnancy -LRB- frequency of intake of dairy products , GLV , fruit and non-vegetarian items -LSB- meat , fish and eggs -RSB- at 18 and 28 weeks of gestation -RRB- ; -LRB- 4 -RRB- maternal micronutrient status -LRB- vitamin B12 , folate , tHcy and MMA concentrations at 18 and 28 weeks -RRB- ; -LRB- 5 -RRB- newborn size -LRB- birthweight , length , skinfold thicknesses , MUAC , head and abdominal circumferences -RRB- ; and -LRB- 6 -RRB- 6 year body composition -LRB- height and DEXA measurements of lean mass , and total , truncal and limb fat -RRB- . Other key variables -LRB- maternal SES and physical workload score -LSB- mean of 18 and 28 week scores -RSB- , and HOMA-R in the child at 6 years -RRB- remained as single variables . These , and the relevant principal components were included simultaneously in a conditional independence analysis , which is a method of displaying ` pathways ' of association between a pre-specified set of variables -LRB- in this case , the groups of variables described above -RRB- . The partial correlation -LRB- that is , the correlation while holding the remaining variables constant in the set -RRB- of each pair of variables was calculated -LSB- 19 -RSB- . A ` path ' diagram was then drawn , connecting pairs of variables that were significantly correlated -LRB- p < 0.01 -RRB- . Two-tailed significance was calculated at 5 % level . Analyses were performed using SPSS 11.0 for windows -LRB- SPSS , Chicago , IL , USA -RRB- and STATA 7.0 -LRB- STATA , College Station , TX , USA -RRB- . Results Many of the maternal size and nutritional measurements and their relationship to neonatal size have been described before -LSB- 8 -RSB- . The age -LRB- median -LSB- 25th , 75th centiles -RSB- -RRB- of the mothers when they became pregnant was 21 -LRB- 19 , 23 -RRB- years . They were short -LRB- 152.0 -LSB- 148.5 , 155.4 -RSB- cm -RRB- and had a low pre-pregnant BMI -LRB- 17.8 -LSB- 16.7 , 19.1 -RSB- kg/m2 -RRB- but a relatively high percentage body fat -LRB- 20 % -LSB- 18 , 24 -RSB- -RRB- . Their dietary intakes and micronutrient status during pregnancy are shown in Table 1 . The women 's energy and protein intakes were low compared with the recommended dietary allowances of 10,565 kJ -LRB- 2,525 kcal -RRB- and 65 g/day , respectively -LSB- 20 -RSB- . At 18 and 28 weeks , their energy intakes were 1.57 and 1.43 times their calculated basal metabolic rate -LSB- 21 -RSB- . One-third of women were lacto-vegetarian , and only 15 % of women ate non-vegetarian foods more frequently than once every alternate day . The portion sizes of non-vegetarian foods were small -LRB- < 120 g/day for chicken , fish and meat dishes and ~ 60 g/day for eggs -RRB- . Table 1Maternal nutrition data during pregnancy -LRB- median and 25th and 75th centiles , unless otherwise stated -RRB- Number18 weeks of gestationNumber28 weeks of gestationMacronutrient intakes Energy -LRB- kJ -RRB- 6927,293 -LRB- 5,858 , 8,774 -RRB- 6706,803 -LRB- 5,523 , 8,268 -RRB- Energy -LRB- kcal -RRB- 6921,743 -LRB- 1,400 , 2,090 -RRB- 6701,626 -LRB- 1,320 , 1,976 -RRB- Carbohydrate -LRB- g -RRB- 692313 -LRB- 257 , 376 -RRB- 670296 -LRB- 236 , 360 -RRB- Protein -LRB- g -RRB- 69244.9 -LRB- 35.4 , 54.8 -RRB- 67041.7 -LRB- 33.8 , 51.3 -RRB- Fat -LRB- g -RRB- 69232.7 -LRB- 23.9 , 42.9 -RRB- 67029.6 -LRB- 22.4 , 39.2 -RRB- FFQ , n -LRB- % -RRB- GLVs Never69215 -LRB- 2 -RRB- 67169 -LRB- 10 -RRB- < 1 per week692139 -LRB-20-RRB-671197 -LRB- 29 -RRB- > 1 per week692277 -LRB-40-RRB-671243 -LRB- 36 -RRB- > Alternate day692261 -LRB-38-RRB-671162 -LRB- 24 -RRB- Dairy products , n -LRB- % -RRB- Never692107 -LRB- 15 -RRB- 67196 -LRB- 14 -RRB- < 1 per week692141 -LRB-20-RRB-671137 -LRB- 20 -RRB- > 1 per week692129 -LRB-19-RRB-671144 -LRB- 21 -RRB- > Alternate day692315 -LRB-46-RRB-671294 -LRB- 44 -RRB- Non-vegetarian foods , n -LRB- % -RRB- Never692228 -LRB-33-RRB-671254 -LRB- 38 -RRB- < 1 per week692182 -LRB-26-RRB-671181 -LRB- 27 -RRB- > 1 per week692182 -LRB-26-RRB-671149 -LRB- 22 -RRB- > Alternate day692100 -LRB- 14 -RRB- 67187 -LRB- 13 -RRB- Circulating micronutrients Vitamin B12 -LRB- pmol/l -RRB- 638135 -LRB- 103 , 175 -RRB- 594122 -LRB- 94 , 160 -RRB- < 150 pmol/l , n -LRB- % -RRB- 380 -LRB- 60 -RRB- 423 -LRB- 71 -RRB- Erythrocyte folate -LRB- nmol/l -RRB- 618874 -LRB- 687 , 1,106 -RRB- 562961 -LRB- 736 , 1,269 -RRB- < 283 nmol/l , n -LRB- % -RRB- 1 -LRB- 0.2 -RRB- 1 -LRB- 0.2 -RRB- MMA -LRB- μmol/l -RRB- 6360.80 -LRB- 0.50 , 1.34 -RRB- 5940.73 -LRB- 0.44 , 1.18 -RRB- > 0.26 μmol/l , n -LRB- % -RRB- 586 -LRB- 94 -RRB- 533 -LRB- 90 -RRB- tHcy -LRB- μmol/l -RRB- 6398.1 -LRB- 6.8 , 10.3 -RRB- 5938.6 -LRB- 6.7 , 10.8 -RRB- > 10 μmol/l , n -LRB- % -RRB- 177 -LRB- 28 -RRB- 193 -LRB- 33 -RRB- Dairy products refers to whole milk plus milk products -LRB- milk in tea and other beverages , yoghurt , buttermilk , ghee , ice cream and other milk-based preparations -RRB- . Non-vegetarian foods are meat , fish and eggs Maternal vitamin B12 and folate status Women in whom vitamin B12 , folate and related measurements were not available had similar pre-pregnant weight , SES and weight gain at 28 weeks of pregnancy compared with those who were studied . The majority of women -LRB- > 60 % -RRB- had low plasma vitamin B12 concentrations -LRB- Table 1 -RRB- , over 90 % had elevated MMA concentrations , and one-third were hyperhomocysteinaemic . On the other hand only one woman had a low erythrocyte folate concentration . Between 18 and 28 weeks of gestation , plasma vitamin B12 , MMA and tHcy concentrations remained similar -LRB- p ~ 0.11 , for all -RRB- , while erythrocyte folate concentrations increased -LRB- p < 0.001 -RRB- . Plasma tHcy and MMA concentrations were inversely related to plasma vitamin B12 -LRB- p < 0.001 for both at 18 and 28 weeks of gestation -RRB- . Low vitamin B12 concentration contributed 41 and 24 % to the population attributable risk of hyperhomocysteinaemia , and 40 and 12 % to high MMA at 18 and 28 weeks of gestation , respectively ; the contribution of low folate concentration could not be calculated because of small numbers . Higher frequency of intake of dairy products and non-vegetarian foods was associated with higher plasma vitamin B12 concentrations -LRB- p = 0.005 and 0.04 , respectively -RRB- and lower tHcy -LRB- p = 0.1 and p = 0.04 -RRB- and MMA concentrations -LRB- p = 0.01 and p = 0.003 -RRB- . Plasma vitamin B12 concentrations were also related to protein intakes -LRB- 28 weeks , p = 0.03 -RRB- but not to energy intake . Higher frequency of GLV intake predicted higher erythrocyte folate concentrations -LRB- p = 0.001 -RRB- . All these associations were independent of the energy intake and SES . Maternal nutrition during pregnancy and newborn size Maternal vitamin B12 and MMA concentrations were unrelated to neonatal measurements . As previously described -LSB- 8 -RSB- , lower maternal folate concentrations were associated with smaller newborn weight , MUAC and abdominal circumference -LRB- p = 0.003 , 0.008 , 0.008 , respectively -RRB- . Higher tHcy concentrations at 18 weeks were associated with smaller newborn size -LRB- MUAC , p = 0.02 ; abdominal circumference , p = 0.02 ; and subscapular and triceps skinfold thicknesses , p = 0.01 and p = 0.007 -RRB- . Maternal nutrition during pregnancy and offspring size , body composition and HOMA-R at 6 years At 6 years , the children were light , short and had a low BMI compared with an international -LRB- UK -RRB- reference -LSB- 22 -RSB- -LRB- Table 2 -RRB- ; none were overweight or obese as defined by International Obesity Task Force -LSB- 23 -RSB- criteria . However , skinfold thickness measurements showed that the children were relatively truncally adipose ; the mean SD score for subscapular skinfold thickness was − 0.42 compared with the UK growth standards -LSB- 24 -RSB- , in contrast with − 2.23 for weight and − 1.86 for BMI . Higher fat mass and higher body fat per cent were associated with higher fasting insulin concentrations , higher HOMA-R and higher 120 min plasma glucose concentrations -LRB- p < 0.05 for all -RRB- . Table 2Characteristics of the children at 6 years -LRB- n = 653 -RRB- Median -LRB- IQR -RRB- Mean SD scorea -LRB- SD -RRB- Age -LRB- years -RRB- 6.1 -LRB- 6.1 , 6.2 -RRB- Weight -LRB- kg -RRB- 16.0 -LRB- 14.8 , 17.3 -RRB- − 2.23 -LRB- 1.00 -RRB- Height -LRB- cm -RRB- 109.7 -LRB- 106.7 , 112.9 -RRB- − 1.39 -LRB- 0.89 -RRB- BMI -LRB- kg/m2 -RRB- 13.3 -LRB- 12.8 , 14.0 -RRB- − 1.86 -LRB- 0.90 -RRB- Subscapular skinfold thickness -LRB- mm -RRB- 5.0 -LRB- 4.4 , 5.6 -RRB- − 0.42 -LRB- 0.68 -RRB- Triceps skinfold thickness -LRB- mm -RRB- 6.2 -LRB- 5.4 , 7.1 -RRB- − 1.41 -LRB- 0.79 -RRB- Fat mass -LRB- kg -RRB- 3.1 -LRB- 2.4 , 3.7 -RRB- Fat -LRB- % -RRB- 18.8 -LRB- 15.5 , 22.2 -RRB- Leg fat mass -LRB- kg -RRB- 1.3 -LRB- 1.0 , 1.5 -RRB- Trunk fat mass -LRB- kg -RRB- 0.9 -LRB- 0.7 , 1.2 -RRB- Lean mass -LRB- kg -RRB- 12.7 -LRB- 11.7 , 13.7 -RRB- Insulin resistance -LRB- HOMA-R -RRB- 0.70 -LRB- 0.37 , 1.06 -RRB- 120 min glucose -LRB- mmol/l -RRB- 5.49 -LRB- 4.82 , 6.21 -RRB- Vitamin B12 -LRB- pmol/l -RRB- 224 -LRB- 167 , 311 -RRB- aSD scores at 6 years were derived from the UK growth standards -LSB- 26 , 28 -RSB- IQR Interquartile range Higher frequency of maternal intake of GLVs and higher erythrocyte folate concentrations -LRB- 28 weeks -RRB- were associated with higher fat mass and higher per cent body fat in the children -LRB- GLVs : p = 0.02 , 0.08 ; and folate : p = 0.01 , 0.002 ; Table 3 -RRB- . None of the maternal nutritional variables were related to lean mass in the children . Table 3Outcomes in the children at 6 years -LRB- body composition and insulin resistance -RRB- according to maternal vitamin B12 concentrations at 18 weeks , erythrocyte folate at 28 weeks and GLV and dairy product intake at 28 weeks NumberHeight -LRB- cm -RRB- Fat mass -LRB- kg -RRB- Lean mass -LRB- kg -RRB- Insulin resistance -LRB- HOMA-R -RRB- Vitamin B12 at 18 weeks -LRB- pmol/l -RRB- < 103146110.2 -LRB- 4.3 -RRB- 3.3 -LRB- 0.9 -RRB- 12.8 -LRB- 1.6 -RRB- 0.78 -LRB- 0.42 , 1.34 -RRB- 103 -- 134150109.3 -LRB- 4.6 -RRB- 3.0 -LRB- 1.0 -RRB- 12.7 -LRB- 1.5 -RRB- 0.68 -LRB- 0.35 , 0.99 -RRB- 135 -- 174145109.6 -LRB- 4.9 -RRB- 3.1 -LRB- 1.0 -RRB- 12.9 -LRB- 1.7 -RRB- 0.69 -LRB- 0.30 , 0.95 -RRB- ≥ 175151110.0 -LRB- 4.9 -RRB- 3.2 -LRB- 1.0 -RRB- 12.8 -LRB- 1.7 -RRB- 0.61 -LRB- 0.35 , 1.00 -RRB- p valuea0 .80.50.30.03 p valueb0 .60.40.30.04 Erythrocyte folate at 28 weeks -LRB- nmol/l -RRB- < 734129109.2 -LRB- 4.6 -RRB- 3.0 -LRB- 1.0 -RRB- 12.8 -LRB- 1.7 -RRB- 0.52 -LRB- 0.28 , 0.81 -RRB- 734 -- 691136109.8 -LRB- 4.5 -RRB- 3.1 -LRB- 0.9 -RRB- 12.9 -LRB- 1.6 -RRB- 0.65 -LRB- 0.36 , 0.92 -RRB- 962 -- 1,268131109.9 -LRB- 4.7 -RRB- 3.2 -LRB- 1.2 -RRB- 12.7 -LRB- 1.8 -RRB- 0.71 -LRB- 0.39 , 1.12 -RRB- ≥ 1,269127110.7 -LRB- 4.8 -RRB- 3.4 -LRB- 1.1 -RRB- 13.0 -LRB- 1.6 -RRB- 0.85 -LRB- 0.51 , 1.27 -RRB- p valuea0 .020.0010.5 < 0.001 p valueb0 .70.010.4 < 0.001 GLVs at 28 weeks Never63109 .1 -LRB- 5.5 -RRB- 3.0 -LRB- 0.9 -RRB- 12.5 -LRB- 1.7 -RRB- 0.83 -LRB- 0.25 , 1.23 -RRB- < Once per week183109 .5 -LRB- 4.7 -RRB- 3.0 -LRB- 1.0 -RRB- 12.7 -LRB- 1.7 -RRB- 0.73 -LRB- 0.36 , 1.05 -RRB- > Once per week231109 .8 -LRB- 4.6 -RRB- 3.2 -LRB- 1.0 -RRB- 12.8 -LRB- 1.7 -RRB- 0.69 -LRB- 0.34 , 0.99 -RRB- ≥ Alternate days146110 .5 -LRB- 4.1 -RRB- 3.3 -LRB- 1.2 -RRB- 13.0 -LRB- 1.6 -RRB- 0.66 -LRB- 0.41 , 1.00 -RRB- p valuea0 .0020.0010.010.99 p valueb0 .40.020.40.98 Dairy products at 28 weeks Never87108 .4 -LRB- 4.9 -RRB- 2.9 -LRB- 0.9 -RRB- 12.6 -LRB- 1.8 -RRB- 0.60 -LRB- 0.32 , 0.95 -RRB- < Once per week124110 .2 -LRB- 4.1 -RRB- 3.2 -LRB- 1.0 -RRB- 12.8 -LRB- 1.6 -RRB- 0.62 -LRB- 0.37 , 0.99 -RRB- > Once per week134109 .4 -LRB- 4.6 -RRB- 3.2 -LRB- 0.9 -RRB- 12.7 -LRB- 1.7 -RRB- 0.73 -LRB- 0.40 , 1.06 -RRB- ≥ Alternate days278110 .3 -LRB- 4.6 -RRB- 3.2 -LRB- 1.2 -RRB- 12.9 -LRB- 1.7 -RRB- 0.74 -LRB- 0.37 , 1.11 -RRB- p valuea0 .0050.030.30.02 p valueb0 .20.20.80.006 Values are mean -LRB- SD -RRB- or median -LRB- interquartile range -RRB- ap value adjusted for the child 's age and sexbp value adjusted for the above , plus : SES , the mother 's pre-pregnant height and fat mass , the child 's birthweight , skinfold thicknesses and gestation at delivery and the mother 's protein intake at the time of measurement Higher frequency of maternal intake of dairy products at 28 weeks , and lower plasma vitamin B12 -LRB- 18 weeks -RRB- and higher erythrocyte folate concentrations -LRB- 28 weeks -RRB- were associated with higher HOMA-R in the children -LRB- Table 3 -RRB- . The highest HOMA-R was in children whose mothers had the lowest vitamin B12 and highest folate concentrations -LRB- Fig. 2 -RRB- . There was no statistically significant interaction , however , between vitamin B12 and folate concentrations in relation to HOMA-R -LRB- Table 4 -RRB- . The associations remained significant after further adjustment for the child 's own fat mass and plasma vitamin B12 concentrations . None of the other maternal dietary or macronutrient variables were related to HOMA-R in the children . Fig. 2Insulin resistance -LRB- HOMA-R -RRB- in the children at 6 years in relation to maternal vitamin B12 -LRB- 18 weeks -RRB- and erythrocyte folate -LRB- 28 weeks -RRB- Table 4Multiple linear regression models for child 's insulin resistance -LRB- HOMA-R -RRB- at 6 years as the dependent variableIndependent variableModel 1Model 2Model 3Model 4βp valueβp valueβp valueβp valuePlasma vitamin B12 at 18 weeks -LRB- pmol/l -RRB- − 0.160.03 − 0.160.04 Erythrocyte folate at 28 weeks -LRB- nmol/l -RRB- 0.38 < 0.0010.38 < 0.001 Interaction term -LRB- vitamin B12 × folate -RRB- − 0.080.7 The independent variable included maternal plasma vitamin B12 concentration at 18 weeks gestation , erythrocyte folate at 28 weeks gestation , child 's age , sex , fat mass and standard of living index . The models progressively included vitamin B12 , erythrocyte folate , both , and an interaction term -LRB- models 1 to 4 , respectively -RRB- Maternal vitamin B12 concentrations were not related to the child 's insulinogenic index -LRB- a measure of beta cell function -RRB- but 28 week erythrocyte folate concentration was directly related -LRB- p < 0.01 -RRB- . PCA and conditional independence analysis PCA and conditional independence analyses are summarised in Fig. 3 and the Electronic supplementary material -LRB- ESM -RRB- Table 1 . Mothers of higher SES had higher intakes of the micronutrient-rich foods , except non-vegetarian foods -LRB- correlation A -RRB- . Larger maternal body size -LRB- correlation B -RRB- and larger size of the offspring at birth -LRB- correlation C -RRB- were associated with larger 6 year size . None of the maternal nutritional variables were related to 6 year body composition in the children , but the contrast between folate and vitamin B12 concentrations -LRB- micronutrient status , factor 3 : higher maternal folate and MMA and lower vitamin B12 -RRB- was associated with higher HOMA-R in the child at 6 years -LRB- correlation D -RRB- . Fig. 3The groups of variables used in the PCAs are described in Statistical methods . The notation F1 -- F3 indicates the first to third principal components , or factors -LRB- F -RRB- , derived from each group of variables . Lines connecting boxes indicate significant positive correlations -LRB- p < 0.01 -RRB- , and bold lines denote correlations significant at p < 0.001 . Correlations labelled A -- D are explained in the Results -LRB- PCA and conditional independence analysis -RRB- . Veg Vegetables Discussion We have demonstrated for the first time in a purposeful , community-based prospective study an association between maternal nutritional measurements in pregnancy and two major risk factors for type 2 diabetes in the offspring . Among rural mothers in Pune , energy and protein intakes are lower than the recommended daily allowance , vitamin B12 status is poor but folate status is adequate . Maternal macronutrient intakes were unrelated to adiposity and insulin resistance in the offspring . However , higher maternal folate concentrations predicted greater adiposity -LRB- fat mass and body fat per cent -RRB- and higher insulin resistance , and lower vitamin B12 concentrations predicted higher insulin resistance . Children born to mothers with low vitamin B12 concentrations but high folate concentrations were the most insulin resistant . The 18 week vitamin B12 concentration was more strongly associated with insulin resistance than the 28 week value , while the reverse was true for erythrocyte folate . The lifespan of erythrocytes -LRB- 4 months -RRB- means that 28 week erythrocyte folate reflects nutritional status earlier in pregnancy . Thus , early-mid pregnancy may be a critical period for the programming of adiposity and insulin resistance . The PMNS children are short and thin but relatively adipose compared with white children , similar to the situation in Indian newborns -LSB- 5 , 6 -RSB- and adults -LSB- 25 -RSB- . There were no excessively adipose or insulin-resistant children in this cohort , but adiposity measures were strongly related to metabolic risk factors -LRB- glycaemia and insulin resistance -RRB- in the normal range . Other studies have shown that higher levels of risk factors in the normal range in childhood predict an increased risk of disease in later life -LSB- 26 , 27 -RSB- . We have demonstrated that the ` thin-fat ' phenotype of Indians is associated with a higher risk of type 2 diabetes -LSB- 7 -RSB- . This phenotype reflects the simultaneous involvement of two major body compartments -LRB- less lean but more adipose -RRB- , which contribute to the pathogenesis of type 2 diabetes -LSB- 28 -RSB- . Our study suggests that an intrauterine imbalance between two related micronutrients -LRB- vitamin B12 and folate -RRB- may be responsible . A related concept is that of sarcopenic obesity , which increases risk of metabolic and skeletal adverse outcomes -LSB- 29 -RSB- . We did not find an association between maternal vitamin B12 concentrations and size at birth , possibly because so many women had values in the deficient range . However , higher maternal tHcy concentrations -LRB- which were related to low vitamin B12 concentrations -RRB- predicted smaller newborn size . A study in Bangalore , South India , where mothers had higher vitamin B12 concentrations , found that low maternal vitamin B12 concentrations predicted fetal growth retardation -LSB- 30 -RSB- . These findings are consistent with the ` thrifty phenotype hypothesis , ' which proposed that ` poor ' maternal nutritional status increases the risk of type 2 diabetes in the offspring -LSB- 1 -RSB- . On the other hand , the positive associations of maternal folate and intakes of GLVs and dairy products with adiposity or insulin resistance in the children , are contrary to the hypothesis because they predicted larger offspring size at birth . Our results suggest a need for caution in designing nutritional strategies to improve fetal growth and future health based on relationships with birth size alone . Previous studies linking maternal nutrition in pregnancy to cardiovascular risk factors in the offspring did not measure vitamin B12 or folate -LSB- 31 -RSB- . These two vitamins play a crucial role in nucleic acid synthesis and one-carbon metabolism . Low maternal folate status has been implicated in the aetiology of neural tube defects -LSB- 32 -RSB- and high tHcy levels have been associated with poor pregnancy outcomes -LSB- 10 , 33 , 34 -RSB- . This has led to a policy of supplementation with folic acid before and during pregnancy , and fortification of flour with folic acid in some countries . The Indian policy is to provide iron and folic acid -LRB- 60 mg and 500 μg per day -RRB- to all pregnant mothers -LSB- 35 -RSB- . Despite the evidence of widespread deficiency -LSB- 11 -RSB- vitamin B12 supplementation is not a consideration in pregnant Indian women . Vegetarianism and low milk intakes contribute to low vitamin B12 status in Indians -LSB- 36 , 37 -RSB- . Vegetarianism is multigenerational , and influenced by religious and socioeconomic factors . King Samrat Ashok -LRB- 273 bc -RRB- first banned the killing of animals for food and this was institutionalised by three religions : Jainism , Hinduism and Buddhism . The role of socioeconomic factors is evident in the small portion sizes of non-vegetarian foods habitually eaten by our mothers . Adequate folate status in the PMNS indicates adequate dietary intake even before supplementation was started -LRB- 18 weeks of gestation -RRB- , which further increased the levels . In addition , it is our experience that many Indian obstetricians routinely prescribe high doses of folic acid -LRB- 5 mg or more -RRB- in ` early ' pregnancy with the intention of preventing neural tube defects , even though the majority of pregnant women approach the doctor after 12 weeks of gestation , when the neural tube is already closed . Thus religious and socioeconomic factors , and medical practices , contribute to create an imbalance in these two related vitamins . The association of higher maternal intake of dairy products with insulin resistance in the offspring requires further exploration . It is intriguing that higher milk consumption is associated with higher insulin resistance in European children -LSB- 38 -RSB- . We can only speculate about the possible mechanisms for our findings -LRB- Fig. 1 -RRB- . Vitamin B12 deficiency will trap folate as 5-methyltetrahydrofolate -LSB- 39 -RSB- , prevent the generation of methionine from homocysteine and therefore reduce protein synthesis and lean tissue deposition . Elevated methylmalonyl-CoA could contribute to increased lipogenesis by inhibiting carnitine palmitoyltransferase -LSB- 40 -RSB- and thereby inhibit β-oxidation -LSB- 41 -RSB- . An analogous clinical situation is high-dose folic acid treatment of severely vitamin B12-deficient pernicious anaemia patients : anaemia improves but neurological damage worsens , possibly because of accumulation of odd-chain carbon fatty acids -LSB- 42 -RSB- . Epigenetic regulation , involving DNA methylation , may be another mechanism of nutritional programming , as demonstrated in animal models -LSB- 43 -- 45 -RSB- . It would be interesting to study these aspects further . The PMNS has many strengths including a population-based design and high participation and follow-up rates . The nutritional assessment methods were developed specifically for the population . The rural setting is representative of over 70 % of the Indian population , in whom the prevalence of diabetes is rapidly rising -LSB- 46 -RSB- . The lacto-vegetarian food habits of our women are similar to ~ 40 % of Indian households and ~ 10 % of the world population -LSB- 47 -RSB- . Although vitamin B12 was measured in stored frozen samples , it is stable during long-term storage -LSB- 48 -RSB- . In the absence of accepted guidelines for interpreting vitamin B12 status in pregnancy -LSB- 49 -RSB- , we can not define the true extent of vitamin B12 deficiency , but high levels of MMA and tHcy suggested its presence in a majority of the women in our study -LSB- 17 -RSB- . Associations with folate and vitamin B12 concentrations but not with tHcy and MMA could be due to dependence of the latter two on non-nutritional factors that are altered in pregnancy -LRB- haemodilution and elevated glomerular filtration rate -RRB- , although we did find an association between high maternal MMA and insulin resistance in the children in the conditional independence analysis . A limitation of the study is that it is observational , and therefore causality can not be ascertained . In conclusion , our data raise the important possibility that high folate intakes in vitamin B12-deficient mothers could increase the risk of type 2 diabetes in the offspring . This is the first report in humans to suggest that defects in one-carbon metabolism might be at the heart of intra-uterine programming of adult disease . There is a need for further studies to test our findings and to determine the correct management of low vitamin B12 concentrations in Indian mothers . Electronic supplementary material Below is the link to the electronic supplementary material . Figure S1 Suggested metabolic mechanisms for adiposity , insulin resistance and altered gene expression in a situation of dietary vitamin B12 deficiency combined with adequate folate status -LRB- PDF 35.7 kb -RRB- Table S1 Unrotated factor loadings from the PCA -LRB- PDF 75.3 kb -RRB-

B I O B O O B O B I O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O B O O B B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O B I O B O O O O O B O O O B O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O B I O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O B O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O B I O B O O O O O O O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O O O O O O O B O B I O O B O O O O O B O O O B O O O O O O O O O O O B I O O O B I O O O B I O O O O O O O B I O O O B O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O B O O O O B O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O B O B I O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O B O O O B I O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O B I O O O O B O O O O O O O O O O O O O O O O O O O

adiposity
folate
insulin resistance
maternal nutrition
offspring
pregnancy
vitamin b12


Abuse

in

Women

and

Men

with

and

without

Functional

Gastrointestinal

Disorders

We

aimed

to

investigate

the

history

of

abuse

in

childhood

and

adulthood

and

health-related

quality

of

life

-LRB-

HRQL

-RRB-

in

women

and

men

with

FGID

in

the

general

adult

population

A

cross-sectional

study

in

a

random

population

sample

-LRB-

n

years

-RRB-

living

in

Östhammar

municipality

Sweden

in

was

performed

Persons

with

FGID

-LRB-

n

-RRB-

and

a

group

of

abdominal

symptom-free

controls

-LRB-

SSF

n

-RRB-

were

selected

by

means

of

a

validated

questionnaire

assessing

gastrointestinal

symptoms

-LRB-

the

ASQ

-RRB-

Abuse

anxiety

and

depression

-LRB-

the

HADS

-RRB-

and

HRQL

-LRB-

the

PGWB

-RRB-

were

measured

Women

with

FGID

had

a

higher

risk

of

having

a

history

of

some

kind

of

abuse

as

compared

with

the

SSF

controls

-LRB-

vs.

OR

CI

SSF

-RRB-

in

contrast

to

men

-LRB-

vs.

n.s.

-RRB-

Women

with

a

history

of

abuse

and

FGID

had

reduced

HRQL

-LRB-

CI

-RRB-

as

compared

with

women

without

abuse

history

-LRB-

CI

P

healthy

on

PGWB

-RRB-

Childhood

emotional

abuse

was

a

predictor

for

consulting

with

OR

-LRB-

CI

-RRB-

Thus

previous

abuse

is

common

in

women

with

FGID

and

must

be

considered

by

the

physician

for

diagnosis

and

treatment

of

the

disorder

Introduction

Maltreatment

threats

or

violence

from

another

person

often

an

intimate

partner

is

psychosocially

traumatic

and

a

growing

problem

in

society

During

the

last

decade

the

number

of

assaults

reported

to

the

police

in

Sweden

increased

by

to

inhabitants

and

the

number

of

sexual

offences

increased

by

to

of

which

rapes

increased

by

to

The

latter

high

percentage

is

partly

attributable

to

a

change

in

the

Swedish

legislation

that

lowered

the

threshold

at

which

sexual

offence

is

classified

as

rape

For

children

-LRB-

years

-RRB-

the

number

of

assaults

reported

to

the

police

has

increased

by

to

and

the

number

of

rapes

has

increased

during

the

last

decade

by

to

-LSB-

-RSB-

About

half

of

the

women

in

Canada

and

Sweden

have

been

described

as

having

experienced

at

least

one

incident

of

violence

by

a

man

since

the

age

of

-LSB-

-RSB-

and

in

a

Japanese

study

three

quarters

of

the

women

said

they

had

experienced

sexual

physical

or

emotional

intimate

partner

violence

-LSB-

-RSB-

A

population

survey

in

Los

Angeles

reported

a

childhood

-LRB-

lifetime

for

age

years

-RRB-

sexual

assault

prevalence

of

in

women

and

in

men

-LSB-

-RSB-

and

in

adults

-LSB-

-RSB-

Functional

gastrointestinal

disorders

-LRB-

FGIDs

-RRB-

are

a

group

of

digestive

diseases

with

a

chronic

or

recurrent

course

in

the

absence

of

organic

illness

likely

to

explain

the

symptoms

-LSB-

-RSB-

The

most

frequent

FGIDs

are

irritable

bowel

syndrome

-LRB-

IBS

-RRB-

with

an

average

estimated

prevalence

of

and

functional

dyspepsia

with

a

prevalence

of

in

the

general

adult

population

but

with

a

considerable

proportion

of

persons

with

overlapping

symptoms

-LSB-

-RSB-

Most

studies

on

IBS

report

more

sufferers

among

women

than

men

-LSB-

-RSB-

The

difference

in

prevalence

of

dyspepsia

between

women

and

men

is

inconsistent

some

studies

report

a

higher

prevalence

of

symptoms

of

dyspepsia

in

women

than

in

men

-LSB-

-RSB-

whereas

others

do

not

find

any

sex

difference

-LSB-

-RSB-

Although

FGID

is

common

only

about

of

people

who

have

symptoms

of

dyspepsia

ever

seek

medical

attention

for

it

-LSB-

-RSB-

while

the

consulting

figures

for

IBS

are

somewhat

higher

-LSB-

-RSB-

FGIDs

constitute

about

of

all

consultations

in

primary

care

-LSB-

-RSB-

and

only

a

minority

is

referred

to

secondary

care

-LSB-

-RSB-

Nevertheless

FGID

accounts

for

up

to

of

all

gastroenterology

consultations

-LSB-

-RSB-

The

pathogenesis

of

FGID

is

at

present

often

explained

using

the

biopsychosocial

model

in

which

biologic

and

psychosocial

factors

participate

in

the

origin

of

symptoms

-LSB-

-RSB-

An

overrepresentation

of

a

history

of

past

abuse

has

been

reported

in

both

patients

and

non-patients

with

IBS

and

among

non-patients

with

functional

dyspepsia

-LSB-

-RSB-

However

investigating

abuse

is

difficult

among

patients

with

abdominal

distress

since

sexual

and

physical

abuses

are

seldom

reported

to

doctors

by

their

patients

-LSB-

-RSB-

Our

aims

were

to

investigate

the

occurrence

of

a

history

of

sexual

physical

or

emotional

abuse

experienced

in

childhood

or

later

in

life

among

women

and

men

with

FGID

in

the

general

population

and

the

possible

association

with

consultation

rate

as

compared

with

subjects

free

from

FGID

controlling

for

age

sex

education

and

psychological

distress

Methods

Setting

and

sampling

A

population

sample

-LRB-

n

-RRB-

drawn

from

the

National

Swedish

Population

Registry

in

involved

men

and

women

years

of

age

born

on

day

or

of

each

month

living

in

Östhammar

municipality

The

sampling

method

is

equivalent

to

random

sampling

since

there

is

no

reason

to

believe

that

date

of

birth

is

associated

with

the

variables

measured

The

subjects

were

sent

a

validated

postal

questionnaire

called

The

Abdominal

Symptom

Questionnaire

-LRB-

ASQ

-RRB-

-LSB-

-RSB-

The

responders

-LRB-

n

-RRB-

in

the

population

sample

were

classified

according

to

their

responses

in

the

ASQ

as

having

either

functional

gastrointestinal

disorder

-LRB-

FGID

n

-RRB-

i.e.

functional

dyspepsia

or

irritable

bowel

syndrome

but

not

predominant

symptoms

on

gastroesophageal

reflux

or

being

strictly

symptom

free

-LRB-

SSF

n

-RRB-

i.e.

having

reported

no

gastrointestinal

-LRB-

GI

-RRB-

symptoms

and

also

no

GI

symptoms

reported

by

subjects

who

also

participated

in

two

previous

population

studies

in

-LSB-

-RSB-

In

the

FGID

-LRB-

n

-RRB-

and

SSF

-LRB-

n

-RRB-

sample

groups

were

invited

by

mail

to

an

appointment

at

one

of

their

six

local

health

centres

About

-LRB-

-RRB-

with

FGID

and

-LRB-

-RRB-

SSF

accepted

the

invitation

At

the

health

centre

they

filled

in

the

ASQ

once

again

together

with

other

questionnaires

about

health-related

quality

of

life

-LRB-

HRQL

-RRB-

and

their

abuse

history

A

nurse

assisted

only

when

needed

With

the

same

criteria

for

FGID

applied

to

this

ASQ

response

with

FGID

-LRB-

IBS

and

dyspepsia

only

dyspepsia

only

IBS

-RRB-

and

SSF

remained

and

thus

constituted

the

study

groups

Thus

the

FGID

symptomatics

were

classified

as

FGID

twice

in

and

and

the

symptom-free

SSF

group

up

to

four

times

in

and

This

sampling

procedure

assured

persistent

symptom

status

in

the

two

study

groups

as

has

been

presented

earlier

-LSB-

-RSB-

and

in

Fig.

Fig.

and

sampling

procedure

for

the

study

groups

from

the

population

of

Östhammar

Questionnaires

The

Abdominal

Symptom

Questionnaire

-LRB-

ASQ

-RRB-

has

previously

been

validated

and

found

reliable

and

reproducible

-LSB-

-RSB-

The

definition

of

FGID

used

in

this

study

is

dyspepsia

IBS

or

both

as

taken

from

the

ASQ

Solitary

heartburn

and/or

regurgitations

were

symptoms

not

included

in

our

definition

of

dyspepsia

which

is

in

agreement

with

the

current

ROME

III

definition

-LSB-

-RSB-

In

the

Abuse

Questionnaire

the

questions

about

sexual

abuse

were

those

initially

developed

for

the

National

Population

Survey

of

Canada

-LSB-

-RSB-

from

survey

questionnaires

that

fulfill

reliability

criteria

-LSB-

-RSB-

The

questions

were

translated

into

Swedish

and

back-translated

into

English

for

validation

Questions

were

written

separately

for

childhood

years

and

adulthood

-LRB-

-RRB-

including

six

categories

of

abuse

sexual

physical

and

emotional

each

as

a

child

or

as

an

adult

-LSB-

-RSB-

The

Psychological

General

Well-Being

-LRB-

PGWB

-RRB-

index

is

a

health-related

quality

of

life

instrument

including

items

divided

into

six

domains

anxiety

depressed

mood

positive

well-being

self-control

general

health

and

vitality

Items

are

scored

on

a

six-grade

Likert

scale

with

higher

scores

indicating

better

HRQL

The

total

score

with

a

high

responsiveness

and

validity

for

dyspepsia

-LSB-

-RSB-

was

used

in

this

study

HRQL

values

varying

between

and

have

been

observed

in

a

normal

healthy

population

-LSB-

-RSB-

The

total

score

was

dichotomized

at

the

median

with

a

cut-off

point

at

the

upper

CI

for

functional

dyspepsia

Consequently

a

good

HRQL

was

considered

to

be

a

total

score

of

or

more

which

was

reached

by

subjects

-LRB-

score

mean

SD

-RRB-

while

a

poor

HRQL

was

reached

by

subjects

-LRB-

score

mean

SD

-RRB-

The

Hospital

Anxiety

and

Depression

Scale

-LRB-

HADS

-RRB-

is

a

validated

reliable

instrument

with

subscales

for

measuring

anxiety

and

depression

-LSB-

-RSB-

The

questionnaire

has

seven

items

graded

with

possible

ranges

of

for

each

subscale

-LRB-

total

minimum

score

of

total

maximum

score

of

-RRB-

A

score

of

or

less

on

each

subscale

-LRB-

out

of

a

maximum

of

-RRB-

denotes

a

non-case

a

doubtful

case

and

or

more

a

definite

case

of

anxiety

or

depression

The

cut-off

point

was

set

for

identifying

sufferers

in

this

study

All

participants

per

definition

completed

the

ASQ

-LRB-

-RRB-

the

Abuse

Questionnaire

-LRB-

-RRB-

the

PGWB

questionnaire

and

-LRB-

-RRB-

the

Hospital

Anxiety

and

Depression

Questionnaire

Educational

background

was

registered

at

five

levels

and

dichotomized

with

low

including

elementary

comprehensive

secondary

level

and

high

upper

secondary

university

level

Data

of

previous

consultations

for

GI

symptoms

and

educational

background

were

taken

from

questions

added

to

the

ASQ

This

study

was

approved

by

the

Ethics

Committee

of

the

Medical

Faculty

Uppsala

University

on

June

Statistical

analyses

A

Spearman

rank

correlation

test

was

performed

for

the

variables

anxiety

depression

and

quality

of

life

A

multiple

logistic

regression

analysis

was

performed

with

FGID/SSF

and

consulters/non-consulters

as

outcome

variables

each

of

the

abuse

variables

as

exposure

variables

and

the

possible

confounding

factors

age

-LRB-

years

-RRB-

sex

-LRB-

female/male

-RRB-

education

level

anxiety

-LRB-

subscale

subscale

-RRB-

depression

-LRB-

subscale

subscale

-RRB-

and

HRQL

score

-LRB-

-RRB-

as

explanatory

variables

In

order

to

adjust

for

the

influence

of

explanatory

variables

the

variables

were

added

one

by

one

with

a

forward

stepwise

multiple

logistic

regression

technique

-LSB-

-RSB-

and

if

the

variable

affected

the

odds

ratios

of

the

outcome

variables

less

than

and

with

P

the

variable

was

eliminated

from

the

model

The

Hosmer

Lemeshow

goodness-of-fit

test

was

performed

for

each

model

and

model

improvements

were

tested

with

the

likelihood-ratio

test

Tests

for

interactions

were

completed

between

the

abuse

variables

and

age

sex

and

HRQL

No

significant

interactions

were

found

STATA

version

statistical

package

-LSB-

-RSB-

was

used

for

the

analyses

Results

Demography

and

sexual

physical

and

emotional

abuse

The

distribution

of

age

sex

education

GI

consultation

anxiety

depression

HRQL

and

sexual

physical

and

emotional

abuse

for

persons

with

FGID

and

SSF

is

presented

in

Table

Forty-one

percent

of

those

with

FGID

had

experienced

some

kind

of

abuse

as

compared

with

-LRB-

P

-RRB-

among

SSF

controls

Impaired

anxiety

and

HRQL

were

significantly

more

common

among

subjects

exposed

to

prior

abuse

while

depression

was

not

Table

of

age

sex

education

previous

GI

consultation

and

abuse

for

women

and

men

with

functional

gastrointestinal

disorder

-LRB-

FGID

-RRB-

and

strictly

GI

symptom

free

-LRB-

SSF

-RRB-

and

previous

consulters/non-consulters

for

FGIDFGID

-LRB-

n

-RRB-

n

-LRB-

-RRB-

SSF

-LRB-

n

-RRB-

n

-LRB-

-RRB-

Statistic

PConsulters

GI

-LRB-

n

-RRB-

n

-LRB-

-RRB-

Non-consulters

GI

-LRB-

n

-RRB-

n

-LRB-

-RRB-

Statistic

PMean

age

years

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

high

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Consulted

for

GI

-LRB-

-RRB-

-LRB-

-RRB-

Not

relevantNot

relevantPsychological

general

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Childhood

abuseChildhood

sexual

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Childhood

physical

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Childhood

emotional

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

childhood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Adulthood

abuseAdult

sexual

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Adult

physical

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Adult

emotional

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

adulthood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

childhood

not

adulthood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

adulthood

not

childhood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

abuse

-LRB-

child

or

adult

-RRB-

Sexual

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Physical

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Emotional

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aPearson

b

Student

's

t-test

Women

There

were

women

with

FGID

and

SSF

in

the

study

Almost

half

of

the

women

out

of

-LRB-

-RRB-

with

FGID

had

a

history

of

abuse

in

contrast

to

the

out

of

-LRB-

P

-RRB-

SSF

controls

Women

with

FGID

had

a

higher

prevalence

than

SSF

women

for

sexual

physical

and

emotional

abuse

in

childhood

and

for

sexual

and

emotional

abuse

in

adulthood

as

presented

in

Table

Table

number

of

people

and

the

proportion

of

individuals

-LRB-

-RRB-

with

a

history

of

sexual

physical

and

emotional

abuse

in

women

and

men

with

a

functional

gastrointestinal

disorder

-LRB-

FGID

-RRB-

and

strictly

GI

symptom

free

-LRB-

SSF

-RRB-

The

total

number

of

FGID/SSF

for

both

childhood

and

adulthood

abuse

in

women

was

and

in

menChildhood

abuse

number

FGID/SSF

n

-LRB-

-RRB-

PAdulthood

abuse

number

FGID/SSF

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

P

value

computed

with

Fisher

's

exact

two-sided

test

Out

of

the

women

with

a

history

of

abuse

-LRB-

FGID

n

SSF

n

P

-RRB-

had

experienced

sexual

physical

or

emotional

abuse

both

in

childhood

and

as

adults

In

the

FGID

group

-LRB-

-RRB-

women

reported

abuse

in

childhood

and/or

adulthood

as

compared

with

-LRB-

P

-RRB-

in

the

SSF

group

Moreover

in

the

FGID

group

-LRB-

-RRB-

women

had

a

history

of

childhood

abuse

as

compared

with

-LRB-

P

-RRB-

in

the

SSF

group

Men

In

contrast

to

the

women

the

men

had

no

significant

difference

for

a

history

of

abuse

out

of

-LRB-

-RRB-

men

with

FGID

versus

out

of

-LRB-

P

-RRB-

SSF

men

Similarly

no

statistically

significant

difference

was

found

for

a

history

of

sexual

physical

or

emotional

abuse

in

the

subgroups

childhood

and

adulthood

for

men

see

Table

Anxiety

and

depression

Women

and

men

with

FGID

significantly

more

often

reported

anxiety

-LRB-

P

-RRB-

consultations

for

GI

problems

-LRB-

P

-RRB-

childhood

abuse

-LRB-

P

-RRB-

and

adulthood

abuse

-LRB-

P

-RRB-

than

SSF

women

and

men

In

contrast

depression

had

no

significant

univariate

association

with

FGID

GI

consulting

childhood

abuse

or

adulthood

abuse

FGID

-LRB-

OR

CI

-RRB-

and

anxiety

-LRB-

OR

CI

-RRB-

were

the

only

remaining

independent

predictors

for

abuse

when

adjusted

for

age

sex

education

and

depression

when

tested

with

the

multiple

logistic

regression

technique

Quality

of

life

Subjects

with

FGID

had

a

significant

reduction

in

HRQL

as

measured

by

the

PGWB

with

a

mean

value

of

-LRB-

CI

-RRB-

as

compared

with

SSF

controls

who

scored

-LRB-

CI

-RRB-

There

was

no

significant

difference

in

HRQL

between

women

and

men

either

for

the

FGID

subjects

-LRB-

women

CI

men

CI

-RRB-

or

for

the

SSF

group

-LRB-

women

CI

men

CI

-RRB-

Women

with

a

history

of

some

kind

of

abuse

and

FGID

had

significantly

reduced

HRQL

with

a

mean

value

of

-LRB-

CI

-RRB-

as

compared

with

a

mean

value

of

-LRB-

CI

-RRB-

for

women

without

abuse

history

Similarly

men

with

a

history

of

some

kind

of

abuse

and

FGID

had

significantly

reduced

quality

of

life

with

a

mean

value

of

-LRB-

CI

-RRB-

as

compared

with

a

mean

value

of

-LRB-

CI

-RRB-

for

men

without

abuse

history

The

HRQL

for

FGID

consulters

and

non-consulters

was

the

same

both

groups

had

a

mean

value

of

with

CI

and

respectively

However

FGID

consulters

with

a

history

of

abuse

had

significantly

lower

HRQL

with

a

mean

value

of

-LRB-

CI

-RRB-

than

FGID

consulters

without

a

history

of

abuse

with

a

mean

value

of

-LRB-

CI

P

-RRB-

There

was

a

significant

negative

correlation

between

HRQL

and

anxiety

-LSB-

r

-LRB-

P

-RRB-

-RSB-

and

between

HRQL

and

depression

-LSB-

r

-LRB-

P

-RRB-

-RSB-

Multivariate

risk

modeling

Persons

with

FGID

had

higher

odds

ratio

-LRB-

CI

-RRB-

of

a

history

of

some

kind

of

abuse

-LRB-

in

childhood

or

adulthood

sexual

physical

or

emotional

-RRB-

as

compared

with

the

SSF

controls

adjusted

for

age

sex

and

HRQL

-LRB-

main

model

adding

the

variable

anxiety

or

education

did

not

improve

the

model

-RRB-

Some

kind

of

abuse

in

adulthood

had

odds

ratio

-LRB-

CI

-RRB-

with

the

same

strategy

Emotional

abuse

in

adulthood

had

the

highest

-LRB-

and

only

significant

-RRB-

odds

ratio

-LRB-

CI

-RRB-

while

sexual

abuse

did

not

reach

significance

In

childhood

physical

abuse

seems

to

have

the

highest

odds

ratio

-LRB-

CI

-RRB-

for

future

FGID

although

significance

was

not

reached

in

this

study

-LRB-

data

not

shown

-RRB-

With

the

main

model

women

had

significantly

high

odds

ratios

for

FGID

from

some

kind

of

abuse

-LRB-

CI

-RRB-

emotional

abuse

-LRB-

CI

-RRB-

physical

abuse

-LRB-

CI

-RRB-

and

sexual

abuse

-LRB-

CI

-RRB-

the

latter

two

types

of

abuse

did

not

reach

significance

as

presented

in

Table

There

were

significant

high

odds

ratios

in

women

with

the

crude

model

for

FGID

from

all

types

of

abuse

in

childhood

and

adulthood

except

adult

physical

abuse

-LRB-

probably

owing

to

the

small

number

of

observations

-RRB-

Similarly

with

the

main

model

there

were

high

odds

ratios

in

women

but

they

did

not

reach

significance

see

Table

Table

ratio

and

confidence

interval

-LRB-

CI

-RRB-

for

having

a

functional

gastrointestinal

disorder

-LRB-

FGID

-RRB-

-LRB-

logistic

regression

-RRB-

in

different

groups

of

abuse

women

and

men

in

crude

model

and

main

model

adjusted

for

age

and

HRQLVariableCrude

modelMain

model

-LRB-

adjusted

for

age

and

HRQL

-RRB-

WomenMenWomenMenChildhood

abuseNo

childhood

sexual

sexual

-LRB-

-RRB-

-LRB-

-RRB-

No

childhood

physical

physical

abuse

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

childhood

emotional

emotional

abuse

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

childhood

childhood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Adulthood

abuseNo

adult

sexual

sexual

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

adult

physical

physical

abuse

-LRB-

-RRB-

-LRB-

-RRB-

No

adult

emotional

emotional

abuse

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

adulthood

adulthood

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Any

abuse

-LRB-

child

or

adult

-RRB-

No

sexual

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

physical

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

emotional

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Reference

too

few

observations

In

contrast

men

did

not

have

the

same

elevation

of

odds

ratio

for

FGID

from

any

type

of

abuse

as

compared

to

women

The

highest

odds

ratio

in

men

for

FGID

was

for

some

kind

of

adulthood

abuse

and

was

-LRB-

CI

-RRB-

while

adult

emotional

abuse

was

-LRB-

CI

-RRB-

but

neither

were

significant

see

Table

Consulters

and

non-consulters

with

FGID

Consulters

with

FGID

more

often

-LRB-

of

them

-RRB-

had

a

history

of

abuse

as

compared

with

non-consulters

-LRB-

P

-RRB-

although

it

did

not

reach

significance

as

shown

in

Table

Some

kind

of

abuse

in

childhood

was

more

prevalent

in

consulters

versus

in

non-consulters

-LRB-

P

-RRB-

and

correspondingly

for

childhood

emotional

abuse

and

-LRB-

P

-RRB-

and

for

childhood

physical

abuse

and

-LRB-

P

-RRB-

Moreover

there

was

a

significantly

higher

prevalence

of

physical

abuse

in

childhood

or

adulthood

in

consulters

versus

non-consulters

P

Female

consulters

with

a

history

of

some

kind

of

abuse

had

an

odds

ratio

of

-LRB-

CI

-RRB-

and

with

a

history

of

childhood

emotional

abuse

this

was

significant

-LRB-

CI

-RRB-

in

contrast

to

male

consulters

with

an

odds

ratio

of

-LRB-

CI

-RRB-

for

some

kind

of

abuse

and

-LRB-

CI

-RRB-

for

childhood

emotional

abuse

Discussion

Women

but

not

men

with

longstanding

FGID

often

have

a

history

of

abuse

Women

with

FGID

reported

past

sexual

physical

or

emotional

abuse

in

of

the

cases

as

compared

with

for

women

without

FGID

in

men

with

FGID

and

in

men

without

FGID

In

this

study

emotional

and

sexual

abuse

are

the

most

common

type

of

threats

to

women

's

health

related

to

FGID

This

study

also

shows

that

childhood

emotional

abuse

is

a

predictor

for

consulting

for

GI

problems

Moreover

longstanding

FGID

is

associated

with

a

significantly

reduced

HRQL

and

a

history

of

abuse

further

reduces

the

HRQL

in

women

and

men

The

findings

reveal

that

a

history

of

abuse

is

an

important

psycho-social

factor

linked

to

FGID

in

women

In

contrast

the

association

in

men

is

less

clear

although

men

with

a

history

of

some

kind

of

abuse

and

FGID

had

significantly

reduced

HRQL

as

compared

with

men

with

FGID

without

any

history

of

abuse

Our

study

does

not

support

the

idea

that

consulters

with

FGID

generally

have

a

poorer

HRQL

than

non-consulters

but

a

history

of

abuse

had

a

negative

effect

on

HRQL

for

consulters

with

FGID

Most

studies

that

investigate

FGID

use

a

technique

that

implies

questioning

the

subjects

of

the

experiment

at

a

single

point

in

time

One

of

the

strengths

of

this

study

is

the

repetitive

sampling

procedure

which

makes

it

possible

to

compare

individuals

with

longstanding

FGID

with

persistently

symptom-free

individuals

in

the

same

population

We

consider

that

our

findings

can

be

generalized

to

the

general

population

as

the

study

groups

were

sampled

from

a

well-defined

and

thoroughly

investigated

population

-LSB-

-RSB-

The

individuals

answered

the

abuse

questionnaire

in

a

quiet

safe

environment

in

reality

anonymously

with

the

support

of

a

nurse

only

when

needed

which

was

an

advantage

since

patients

tend

to

underreport

abuse

when

asked

face

to

face

by

a

doctor

-LSB-

-RSB-

The

abuse

questionnaire

has

not

been

thoroughly

validated

in

a

Swedish

population

but

the

questions

are

straightforward

and

the

questionnaire

was

translated

into

Swedish

and

back-translated

into

English

The

definition

of

functional

dyspepsia

and

IBS

used

is

not

exactly

the

same

as

the

now

recommended

Rome

III

criteria

-LSB-

-RSB-

The

definitions

of

dyspepsia

and

IBS

used

in

this

study

were

those

used

in

the

original

study

from

-LSB-

-RSB-

before

current

recommendations

were

available

We

opted

to

retain

our

original

study

definition

since

our

IBS

definition

was

in

accordance

with

the

Rome

III

criteria

and

our

definition

of

dyspepsia

was

more

restricted

in

terms

of

symptoms

but

wider

in

terms

of

abdominal

location

We

consider

the

overall

prevalence

of

FGID

in

this

study

and

the

concordance

on

an

individual

level

to

be

applicable

within

the

current

definition

-LSB-

-RSB-

and

thus

we

consider

our

results

conclusive

Previous

studies

in

the

field

have

reported

that

about

half

the

patients

referred

to

a

gastroenterology

clinic

had

a

history

of

sexual

or

physical

abuse

-LSB-

-RSB-

Moreover

of

women

who

reported

domestic

violence

to

the

police

had

FGID

according

to

Perona

et

al.

-LSB-

-RSB-

In

the

literature

a

history

of

childhood

or

adult

abuse

characterizes

patients

who

present

with

a

variety

of

functional

symptoms

apart

from

FGID

-LSB-

-RSB-

headaches

-LSB-

-RSB-

pelvic

pain

-LSB-

-RSB-

panic

disorders

-LSB-

-RSB-

non-epileptic

attack

disorders

-LSB-

-RSB-

and

back

pain

-LSB-

-RSB-

Psychological

factors

such

as

anxiety

-LSB-

-RSB-

as

well

as

physiological

factors

such

as

enhanced

visceral

sensitivity

all

contributed

to

a

poor

health

outcome

-LSB-

-RSB-

Only

a

few

studies

have

focused

on

abuse

and

FGID

in

the

general

population

where

Koloski

et

al.

-LSB-

-RSB-

found

abuse

to

be

significantly

associated

with

IBS

and/or

functional

dyspepsia

but

less

important

when

psychosocial

factors

were

controlled

for

a

finding

confirmed

by

others

-LSB-

-RSB-

The

same

research

team

-LSB-

-RSB-

found

that

past

sexual

physical

and

emotional

abuse

was

not

a

significant

predictor

for

seeking

health

care

in

contrast

to

our

finding

that

a

history

of

childhood

emotional

abuse

was

associated

with

consulting

and

anxiety

and

FGID

were

independent

predictors

for

previous

abuse

It

is

clear

from

our

study

that

many

subjects

with

traumatic

memories

and

uncomfortable

symptoms

never

seek

health

care

and

that

when

they

do

it

is

important

to

take

a

thorough

medical

history

There

is

a

bi-directional

communication

between

the

gut

and

the

brain

through

the

autonomic

nervous

system

and

the

hypothalamic

pituitary

adrenal

axis

-LSB-

-RSB-

that

can

mediate

an

emotional

trauma

such

as

previous

abuse

Common

links

suggested

are

neuroticism

-LSB-

-RSB-

generally

diminished

pain

threshold

-LSB-

-RSB-

and

current

depression

-LSB-

-RSB-

There

is

a

higher

incidence

of

childhood

abuse

reported

for

women

than

for

men

in

this

study

as

in

others

-LSB-

-RSB-

This

could

explain

the

significant

relation

of

consulting

and

childhood

emotional

abuse

for

women

but

not

for

men

found

in

this

study

suggesting

that

FGID

in

some

patients

might

be

a

sequel

of

previous

abuse

The

treatments

available

to

date

for

FGIDs

are

of

limited

value

Creed

et

al.

-LSB-

-RSB-

have

reported

that

psychological

treatment

and

antidepressants

are

effective

in

patients

with

IBS

and

a

history

of

sexual

abuse

which

stresses

the

importance

of

discovering

past

abuse

in

patients

with

FGID

Future

studies

must

focus

on

how

the

knowledge

of

a

patient

's

previous

exposure

to

different

kinds

of

abuse

and

the

effects

of

different

kind

of

psychotherapy

can

improve

the

treatment

for

at

least

a

subset

of

FGID

sufferers

Conclusions

We

conclude

that

women

with

longstanding

FGID

in

many

cases

have

a

history

of

physical

emotional

or

sexual

abuse

in

childhood

or

adulthood

which

is

associated

with

a

poor

HRQL

and

increased

health

care

seeking

This

is

important

for

physicians

to

consider

when

diagnosing

and

treating

FGID

in

women

O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

functional gastrointestinal disorders
irritable bowel syndrome