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Sep 13, 2007 - Institute of Human Nutrition, University of Southampton, ..... King Samrat Ashok (273 BC) first banned the .... Technical Report Series No. 724.
Diabetologia (2008) 51:29–38 DOI 10.1007/s00125-007-0793-y

ARTICLE

Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study C. S. Yajnik & S. S. Deshpande & A. A. Jackson & H. Refsum & S. Rao & D. J. Fisher & D. S. Bhat & S. S. Naik & K. J. Coyaji & C. V. Joglekar & N. Joshi & H. G. Lubree & V. U. Deshpande & S. S. Rege & C. H. D. Fall

Received: 12 May 2007 / Accepted: 21 June 2007 / Published online: 13 September 2007 # Springer-Verlag 2007

Abstract Aims/hypothesis Raised maternal plasma total homocysteine (tHcy) 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. Methods In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B12, tHcy and methylma-

Electronic supplementary material The online version of this article (doi:10.1007/s00125-007-0793-y) contains supplementary material, which is available to authorised users. C. S. Yajnik : S. S. Deshpande : D. S. Bhat : S. S. Naik : K. J. Coyaji : C. V. Joglekar : N. Joshi : H. G. Lubree : V. U. Deshpande : S. S. Rege Diabetes Unit, KEM Hospital and Research Centre, Pune, Maharashtra, India D. J. Fisher : C. H. D. Fall MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK A. A. Jackson Institute of Human Nutrition, University of Southampton, Southampton General Hospital, Southampton, UK H. Refsum Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

lonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-R]) at 6 years. Results Two-thirds of mothers had low vitamin B 12 (0.26 μmol/l) and 30% had raised tHcy concentrations (>10 μmol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p 21 weeks)

Pregnant women enrolled June 1994–April 1996 n =79 7 Late abortions Late terminations Maternal death

n=12 n=14 n=1

Live births n =762 Major anomalies Ba by not measured Mother diabetic Mother hypertensive

n=9 n=51 n=1 n=1

Ea rly neonatal death Late neonatal death Other infant death Death after infancy

n=3 n=11 n=3 n=9

Included in this analysis n =700

Available for follow-up at 6 years n =67 4 Studied n =653 (97%)

insulin and glucose concentrations (homeostatic model assessment of insulin resistance [HOMA-R]) [15]. As previously described, maternal erythrocyte folate concentrations were measured at the time of the original study (1993–1996), taking all necessary precautions in the collection, transport and storage of samples [8]. Based on the findings of a preliminary study [10], we measured plasma vitamin B12, tHcy and methylmalonic acid (MMA) concentrations in all the stored maternal fasting samples (−80°C) in February 2004, as described [11].

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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 (ln) (plasma vitamin B12 [18 weeks], tHcy and MMA and erythrocyte folate concentrations, maternal fat intake, and the child’s trunk and leg fat mass), square root (maternal energy, protein, and carbohydrate intakes, and the child’s total fat mass) and reciprocal of square root (maternal vitamin B12 concentrations at 28 weeks). Maternal prepregnant fat mass was calculated from the sum of four skinfold thickness measurements [16]. Maternal intakes of specific foods, based on the FFQ, were analysed as categorical variables. Low vitamin B12 and erythrocyte folate concentrations were defined as 0.26 μmol/l [17]. 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 interrelationships between maternal factors and outcomes in the children using principal components analysis (PCA) 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 [18]. The groups of variables were: (1) maternal pre-pregnant size (height, skinfold thicknesses, head circumference, mid-upper-arm circumference [MUAC] and waist and hip circumferences); (2) maternal macronutrient intakes (energy, protein, carbohydrate and fat intakes at 18 and 28 weeks); (3) maternal micronutrient-rich foods in pregnancy (frequency of intake of dairy products, GLV, fruit and non-vegetarian items [meat, fish and eggs] at 18 and 28 weeks of gestation); (4) maternal micronutrient status (vitamin B12, folate, tHcy and MMA concentrations at 18 and 28 weeks); (5) newborn size (birthweight, length, skinfold thicknesses, MUAC, head and abdominal circumferences); and (6) 6 year body composition (height and DEXA measurements of lean mass, and total, truncal and limb fat). Other key variables (maternal SES and physical workload score [mean of 18 and 28 week scores], and HOMA-R in the child at 6 years) remained as single variables. These, and the relevant principal components were included simultaneously in a conditional indepen-

Diabetologia (2008) 51:29–38

dence analysis, which is a method of displaying ‘pathways’ of association between a pre-specified set of variables (in this case, the groups of variables described above). The partial correlation (that is, the correlation while holding the remaining variables constant in the set) of each pair of variables was calculated [19]. A ‘path’ diagram was then drawn, connecting pairs of variables that were significantly correlated (pAlternate day Circulating micronutrients Vitamin B12 (pmol/l) 10 μmol/l, n (%)

Number

18 weeks of gestation

Number

28 weeks of gestation

692 692 692 692 692

7,293 (5,858, 8,774) 1,743 (1,400, 2,090) 313 (257, 376) 44.9 (35.4, 54.8) 32.7 (23.9, 42.9)

670 670 670 670 670

6,803 (5,523, 8,268) 1,626 (1,320, 1,976) 296 (236, 360) 41.7 (33.8, 51.3) 29.6 (22.4, 39.2)

692 692 692 692

15 (2) 139 (20) 277 (40) 261 (38)

671 671 671 671

69 (10) 197 (29) 243 (36) 162 (24)

692 692 692 692

107 141 129 315

(15) (20) (19) (46)

671 671 671 671

96 (14) 137 (20) 144 (21) 294 (44)

692 692 692 692

228 182 182 100

(33) (26) (26) (14)

671 671 671 671

254 (38) 181 (27) 149 (22) 87 (13)

638

135 (103, 175) 380 (60) 874 (687, 1,106) 1 (0.2) 0.80 (0.50, 1.34) 586 (94) 8.1 (6.8, 10.3) 177 (28)

594

122 (94, 160) 423 (71) 961 (736, 1,269) 1 (0.2) 0.73 (0.44, 1.18) 533 (90) 8.6 (6.7, 10.8) 193 (33)

618 636 639

562 594 593

Dairy products refers to whole milk plus milk products (milk in tea and other beverages, yoghurt, buttermilk, ghee, ice cream and other milkbased preparations). Non-vegetarian foods are meat, fish and eggs

calculated because of small numbers. Higher frequency of intake of dairy products and non-vegetarian foods was associated with higher plasma vitamin B12 concentrations (p=0.005 and 0.04, respectively) and lower tHcy (p=0.1 and p=0.04) and MMA concentrations (p=0.01 and p=0.003). Plasma vitamin B12 concentrations were also related to protein intakes (28 weeks, p=0.03) but not to energy intake. Higher frequency of GLV intake predicted higher erythrocyte folate concentrations (p=0.001). 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 [8], lower maternal folate concentrations were associated with smaller newborn weight, MUAC and abdominal circumference (p=0.003, 0.008, 0.008, respectively). Higher tHcy concentrations at 18 weeks were

associated with smaller newborn size (MUAC, p=0.02; abdominal circumference, p=0.02; and subscapular and triceps skinfold thicknesses, p=0.01 and p=0.007). 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 (UK) reference [22] (Table 2); none were overweight or obese as defined by International Obesity Task Force [23] 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 [24], 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 (p