ORIGINAL ARTICLE OPEN. A Barden 1, R Singh 1, B Walters 2, M Phillips 3 and LJ Beilin 1

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1 OPEN Cittion: Nutrition & Dietes (2013) 3, e72; doi: /nutd & 2013 Mcmilln Pulishers Limited All rights reserved /13 ORIGINAL ARTICLE A simple scoring method using crdiometolic risk mesurements in pregnncy to determine 10-yer risk of type 2 dietes in women with gesttionl dietes A Brden 1, R Singh 1, B Wlters 2, M Phillips 3 nd LJ Beilin 1 OBJECTIVE: To exmine if clustering of crdiometolic risk fctors in pregnncy predicts type 2 dietes nd crdiovsculr disese (CVD) risk t 10 yers in women with gesttionl dietes mellitus (GDM). STUDY DESIGN AND SUBJECTS: A prospective cse control study in 150 GDM nd 72 overweight women with norml glucose tolernce (NGT) mesured crdiometolic risk fctors (ody mss index (BMI), systolic lood pressure (SBP), fsting glucose, insulin, nd triglycerides nd high-density lipoprotein (HDL) cholesterol) t 28 weeks gesttion nd 6 months nd 10 yers fter pregnncy. Cluster nlysis of crdiometolic risk fctors in pregnncy ws used to strtify GDM s high nd low risk for dietes nd CVD risk t 10 yers. The dt in pregnncy were used to determine simple method for ssessing risk of future dietes. RESULTS: BMI in the 150 GDM t study entry ws similr to NGT, ut 35% of GDM fell into high-risk cluster with elevted BMI, SBP, glucose, insulin nd triglycerides nd lower HDL levels. At 10 yers, type 2 dietes ws sixfold higher in high-risk GDM (odds rtio (OR) ¼ 6.75, confidence intervl (CI) ¼ 2.0, 22.7, P ¼ 0.002) compred with low-risk GDM nd ws not reported in NGT. The high-risk cluster predicted type 2 dietes etter thn BMI430 (OR ¼ 2.13, CI ¼ 0.71, 6.4, P ¼ 0.179) or fsting glucose 45.5 mmol l 1, (OR ¼ 4.56, CI ¼ 1.50, 13.85, P ¼ 0.007). We determined tht GDM with ny four of the crdiometolic risk fctors (BMI430 kg m 2, fsting glucose45.0 mmol l 1, insulin47.8 mu l 1, triglycerides 42.4 mmol l 1, HDLo1.6 mmol l 1 or SBP4105 mm Hg) in pregnncy would e in high-risk cluster. CONCLUSIONS: A metolic syndrome-like cluster in pregnnt GDM identifies risk for type 2 dietes providing n opportunity to focus on rigorous lifestyle interventions fter delivery to reduce the urden of disese ttriuted to this condition. Nutrition & Dietes (2013) 3, e72; doi: /nutd ; pulished online 3 June 2013 Keywords: lipids; insulin; lood pressure; glucose; ody mss index; metolic syndrome INTRODUCTION Oesity in the ostetric popultion is incresing to epidemic proportions worldwide 1 nd is likely to ffect future incidence of gesttionl dietes mellitus (GDM), susequent type 2 dietes nd crdiovsculr disese (CVD). Pregnncy offers n opportune time to ssess CVD nd dietes risk t n erly ge. Women with GDM hve high rte of complictions in pregnncy including stillirth, mcrosomi nd pre-eclmpsi 2 nd re prone to develop dietes nd vsculr disese in the yers following. 3 5 GDM nd their offspring hve n incresed risk of oesity nd type 2 dietes. 6 Dietes ppers to negte the usul femle crdiovsculr dvntge in women of reproductive ge 7 nd hs een ssocited with n increse in CVD risk in women compred with men It hs een suggested tht pregnncy provides the necessry stress to unmsk ltent elements of the metolic syndrome predisposing to n increse in long-term crdiovsculr risk, 11,12 However, trditionl CVD risk mrkers re not routinely mesured in pregnncy ecuse hormonl chnges tht occur in pregnncy influence the levels of mny CVD mrkers. It is well known tht pregnncy complictions such s GDM nd pre-eclmpsi re ssocited with normlities tht could reflect predisposition to the metolic syndrome nd oth of these complictions re ssocited with n incresed risk of coronry rtery disese nd stroke. Clustering of crdiovsculr risk fctors tht comprise the metolic syndrome (hypertension, oesity, impired glucose tolernce nd dyslipidemi) hs een recognized since the 1920s. 13 In this report, we descrie prospective cse control study in GDM nd overweight women with norml glucose tolernce (NGT) tht exmined whether strtifying the GDM using cluster nlysis of crdiometolic risk mrkers mesured during pregnncy predicted development of dietes nd CVD risk 10 yers lter. MATERIALS AND METHODS Ptient popultion nd study design One hundred twenty-two pregnnt women were recruited from outptient clinics t King Edwrd Memoril Hospitl, nd Joondlup Helth Cmpus in the metropolitn re of Perth, Western Austrli etween 1998 nd All the women were referred for 75-g orl glucose tolernce t 28 weeks gesttion. One hundred fifty were clssified s GDM using the previling criteri of the Austrlsin Dietes in Pregnncy Society 14 (fsting 1 School of Medicine nd Phrmcology, University of Western Austrli, Perth, Western Austrli, Austrli; 2 The Dietes Service, King Edwrd Memoril Hospitl, Perth, Western Austrli, Austrli nd 3 Western Austrlin Institute for Medicl Reserch, University of Western Austrli, Perth, Western Austrli, Austrli. Correspondence: Professor A Brden, School of Medicine nd Phrmcology, Royl Perth Hospitl Unit, University of Western Austrli, Level 4 MRF Building, PO Box X2213, Perth 6847, Western Austrli, Austrli. E-mil: nne.rden@uw.edu.u Received 10 April 2013; ccepted 28 April 2013

2 2 Risk mrkers in pregnncy nd future CVD risk A Brden et l glucosex5.5 mmol l 1 nd/or 2-h glucosex8.0 mmol l 1, fter 75-g orl glucose tolernce test). The mjority of the GDM (75%) presented with incident GDM. Seventy-two women were clssified s hving NGT. The GDM were further clssified into high- nd low-risk GDM using cluster nlysis of trditionl crdiovsculr fctors t 28 weeks gesttion s descried in the sttisticl methods. All women were studied t 28 weeks gesttion, nd t 6 months nd 10 yers fter their pregnncy in prospective cse control study. The reserch nurse undertking the study ws linded to the GDM cluster lloction when follow-up mesurements were otined. Women were excluded from the study if they hd ny known pre-existing chronic medicl condition. The study ws crried out in ccordnce with the Declrtion of Helsinki. It ws pproved y the institutionl ethics committees nd informed written consent ws otined from ll prticipnts. The women were studied t 28 weeks gesttion, efore ny dietry intervention or hypoglycemic therpy commenced. They hd stndrd clinicl monitoring in the outptient clinic until delivery nd were studied gin t 6 months postprtum nd then 10 yers fter their pregnncy. A comprehensive study of crdiovsculr risk fctors ws crried out t the three time points nd included fsting glucose, insulin, triglycerides, highdensity lipoprotein (HDL) cholesterol nd high sensitivity C-rective protein (Hs-CRP) tht were mesured in the Deprtment of Pthology nd Lortory Medicine t Royl Perth Hospitl. A reserch nurse mesured weight nd height, nd lood pressure (BP) using Dinmp 1846SX oscillometic monitor (Criticon Inc., Tmp, FL, USA). Averge systolic nd distolic BPs were clculted from five mesurements t 1-min intervls fter 5-min seted rest. Questionnires were dministered regrding ostetric nd medicl history, prity nd pre-pregnncy ody weight, mritl sttus, eduction level, ethnic ckground nd fmily history of hypertension nd dietes. After delivery, detils of infnt irth weight nd postntl complictions were otined from hospitl records. At the 10-yer follow-up, dignosed dietes nd hypertension were scertined from medicl records nd mesurement of fsting glucose (X7 mmol l 1 ) nd BP 4140/90 mm Hg mesured using Dinmp 1846SX. Inquiry ws mde out dditionl pregnncies nd pregnncy complictions in the 10 yers. An ssessment of current level of physicl ctivity nd lcohol nd cigrette consumption nd mediction ws otined from questionnire. Sttisticl nlysis Cluster nlysis in GDM. Definitions of the metolic syndrome rely on cut-points for quntittive vriles where ech vrile is linerly relted to CVD risk. The trditionl cut-points for components of the metolic syndrome re not suitle for use in pregnnt women ecuse the hormonl chnges ssocited with pregnncy ffect lipid levels, insulin resistnce nd BP. To overcome the prolem of defining the metolic syndrome in pregnncy, we used k-mens cluster nlysis to define two groups with higher or lower vlues tht constitute the metolic syndrome in non-pregnnt dults. Cluster nlysis is sttisticl method tht uses lgorithms, which minimize within-group vrition nd mximize etween-group vrition of the clustering vriles. 15 Clustering vriles were ody mss index (BMI), systolic BP (SBP), fsting glucose, insulin, HDL cholesterol nd triglycerides mesured t 28 weeks of pregnncy efore commencing dietry intervention or hypoglycemic therpy. Two clusters were identified. We refer to the group with the higher vlues s the high-risk cluster group. Differences in SBP, nd BMI nd fsting glucose, insulin, triglycerides, HDL cholesterol nd Hs-CRP in the high nd low-risk clusters nd NGT t study entry nd 6 months nd 10 yers were ssessed using one-wy nlysis of vrince nd lest squre differences to djust for multiple comprisons. Log trnsformtion ws undertken when necessry to normlize the dt. The study ws designed to hve 80% power t Po0.05 to detect difference of 0.3 mmol l 1 in glucose; 0.35 mml l 1 in triglycerides; 0.14 mmol l 1 in HDL cholesterol; 2.6 unit difference in BMI nd 4 mm Hg difference in SBP etween the clusters nd NGT. Differences in discriminte vriles were ssessed using w 2 nlysis. Logistic regression models with roust stndrd error term were used to predict type 2 dietes 10 yers fter pregnncy, with djustment for differences in ge, fmily history of dietes, level of eduction, pregnncy weight gin, insulin tretment during pregnncy nd smoking. The roust stndrd errors were used to ccommodte the nested dt with clustering of oservtion times within individuls. Byesin Informtion Criterion (BIC) ws used to compre different models, where smller BIC represents etter model fit. 16 The potentil for is resulting from loss to follow-up ws investigted using Heckmn selection model. 17 Determintion of crdiometolic risk fctor cut-points for clinicl use in GDM. Recursive prtitioning developed y Breimn et l. 18 ws used to define suitle cut-points for ech of the clustering vriles in pregnncy. To void the prolem of multi-collinerity tht is inevitle in the nlysis of clusters we rn two recursive prtitioning nlyses, one with insulin, glucose nd BMI nd the other with SBP, triglycerides nd HDLs. We used the resulting cut-points to determine the sensitivity nd specificity for cluster memership depending on whether 6, 5 or 4 of the cluster vriles exceeded the cut-point for ptient clssifiction. RESULTS A totl of 150 GDM nd 72 overweight NGT were studied during pregnncy. Follow-up mesurements were otined in 90% of GDM nd 86% of NGT t 6 months post-prtum nd 75% of GDM nd 70% of NGT t 10 yers fter pregnncy. BMI in GDM t the study entry ws similr to NGT, 30.2±5.0 nd 30.2±7.5 kg m 2, respectively. Identifiction of high-risk metolic cluster in GDM Cluster nlysis using trditionl crdiometolic risk fctors mesured t 28 weeks gesttion identified, high-risk cluster representing 35% of GDM. The high-risk cluster hd significntly elevted SBP, BMI, fsting lood glucose, triglycerides, insulin nd lower HDL cholesterol. The degree of seprtion of the min fetures of the high- nd low-risk clusters re shown in Tle 1. The high-risk cluster hd elevted Hs-CRP 9.7±1mgl 1 compred with the low-risk cluster 5.5±0.4 mg l 1. At 28 weeks gesttion, NGT were comprle to the low-risk cluster with respect to fsting glucose 4.46±0.04 mmol l 1 ; insulin 8.9±0.6 mu l 1 ; triglycerides 2.36±0.1 mmol l 1, HDL cholesterol 1.75±0.04 mmol l 1 nd Hs-CRP 6.56±0.66 mg l 1. SBP nd BMI in NGT were 107±1 mm Hg nd 30.2±0.9 kg m 2, respectively, nd lower thn the high-risk cluster (P ¼ 0.001) ut higher thn the low-risk cluster (P ¼ 0.02, P ¼ 0.001, respectively; Figure 1). Tle 1. Comprison of the differences in cluster vriles etween the high- nd low -risk cluster GDM nd women with NGT t 28 weeks of pregnncy Vrile High-risk GDM Low-risk GDM N NGT Fsting glucose (mmol l 1 ) 5.6± ± ±0.4 BMI (kg m 2 ) 35.5± ± ±7.6 Fsting insulin (mu l 1 ) 15.7± ± ±5.3 SBP (mm Hg) 112±9 103±7 107±10 Fsting triglycerides 3.0± ± ±0.8 (mmol l 1 ) Fsting HDL cholesterol (mmol l 1 ) 1.5± ± ±0.4 Arevitions: ANOVA, nlysis of vrince; BMI, ody mss index; GDM, gesttionl dietes mellitus; HDL, high-density lipoprotein; NGT, norml glucose tolernce; SBP, systolic lood pressure. Dt shown re men nd s.d. Differences etween the ech of the clusters nd NGT were nlyzed using one-wy ANOVA. Po0.01 compred with low-risk cluster nd NGT. Po0.05 compred with NGT. Nutrition & Dietes (2013) 1 6 & 2013 Mcmilln Pulishers Limited

3 Risk mrkers in pregnncy nd future CVD risk A Brden et l BMI SBP 3 (Kg/m 2 ) 20 (mmhg) wk 6mthPP 10y 28wk 6mthPP 10y (mmol/l) Glucose (mu/l) Insulin (mmol/l) wk 6mthPP 10y 28wk 6mthPP 10y HDL-cholesterol 28wk 6mthPP 10y (mmol/l) Triglycerides 28wk 6mthPP 10y Figure 1. BMI, SBP, fsting glucose, insulin, triglycerides nd HDL cholesterol in the high-risk (lck rs) low-risk clusters (grey rs), nd NGT group (white rs) t 28 weeks gesttion, 6 months nd 10 yers post-prtum. Vlues re men±s.e.m., Po0.01 compred with low-risk cluster nd NGT, Po0.05 compred with low-risk cluster. Demogrphics, ostetric history nd fmily history of CVD risk fctors t study entry At entry to the study the high-risk cluster ws younger thn the low-risk cluster ut similr to NGT. The distriution of ethnic ckgrounds ws similr to the low-risk cluster nd NGT nd ws comprised minly of women with Cucsin ckground (Tle 2). The high-risk cluster were less educted thn the low-risk cluster nd NGT, completing yer 12 high school (Po0.001) nd otining tertiry qulifiction (P ¼ 0.025) less often (Tle 2). Prity ws similr etween clusters nd NGT (Tle 2). Dignosed GDM or pre-eclmpsi, in previous pregnncy ws 20% nd 19%, respectively, in the GDM clusters (Tle 2) nd ws reported infrequently in NGT. Fmily history of hypertension ws similr etween the clusters nd NGT (Tle 2). Fmily history of dietes ws reported more often in the highrisk cluster (P ¼ 0.006; Tle 2). Neontl outcomes nd pregnncy complictions in the index pregnncy Birth weight, irth length nd hed circumference of the ies ws similr in ll groups (Tle 2). The incidence of pre-eclmpsi ws 10% in GDM nd not different etween the clusters. Pre-eclmpsi ws not reported in NGT. Crdiovsculr risk profile 6 months fter pregnncy Using the clusters ssigned in pregnncy, BMI, fsting glucose, SBP nd triglycerides were significntly elevted in the high-risk cluster compred with the low-risk cluster nd NGT. In contrst, HDL ws significntly reduced in the high-risk cluster (Figure 1). The differences in triglycerides, HDL cholesterol, BMI, insulin, glucose nd SBP etween the clusters were still present fter djusting for differences in ge nd eductionl ckground. At 6 months post-prtum, BMI in NGT ws significntly lower thn the high-risk cluster nd higher thn the low-risk cluster. SBP, glucose, triglycerides, HDL nd insulin differed significntly from the high-risk cluster ut not the low-risk cluster (Figure 1). Follow-up t 10 yers At 10 yers type 2 dietes, ws reported more frequently in the high-risk cluster (38.6%) compred with the low-risk cluster (6.2%, P ¼ 0.001) nd ws not reported in NGT (Tle 3). Reporting of dignosed hypertension nd hypercholesterolemi ws similr etween the clusters (Tle 3). Susequent pregnncies in the 10 yers, were reported in B50% of women. The high-risk cluster reported more irths thn the low-risk cluster P ¼ 0.03 (Tle 3). Reporting of recurrence of GDM or hypertension in susequent & 2013 Mcmilln Pulishers Limited Nutrition & Dietes (2013) 1 6

4 4 Risk mrkers in pregnncy nd future CVD risk A Brden et l Tle 2. Demogrphics, ostetric nd fmily history of dietes nd hypertension nd neontl outcomes of the groups otined t the index pregnncy High-risk Low-risk NGT (n ¼ 53) (n ¼ 97) (n ¼ 72) Age (yers) 31.3± ± ±0.4 Ethnic ckground Cucsin 67.9% 78.4% 84.9% Asin/originl/middleestern 32.1% 21.6% 15.1% Level of eduction Completed yer % 71.1% 61% Tertiry qulifiction 17% 37.1% 31% Ostetric history Prity Nulliprous % 15.1% 20.6% 20.6% Multiprous % 84.9% 79.4% 79.4% Previous gesttionl 23.5% 18.3% 2.9% dietes % Previous pre-eclmpsi % 27.9% 15.4% 0% Fmily history Hypertension % 62.3% 53.7% 57.5% Dietes % 75.5% 52.6% 53.4% Ostetric nd neontl outcomes Pre-eclmpsi % 17% 7.3% 0% Birth weight (g) 3321± ± ±57 Birth length (cm) 49.7± ± ±0.3 Hed circumference (cm) 34.6± ± ±0.2 Gender of ies % Boys 56.9% 48.4% 44.4% % Girls 43.1% 51.6% 55.6% Arevitions: ANOVA, nlysis of vrince; NGT, norml glucose tolernce. Vlues re men±s.e.m. Po0.01 compred with high-risk cluster. Po0.05 compred with high-risk cluster using one-wy ANOVA for continuous vriles nd w 2 nlysis for descriptive vriles. pregnncy ws similr etween the GDM clusters. Reporting of these complictions in NGT ws infrequent (Tle 3). Although mesurements were not otined from ll women t 10 yers, those not studied hd similr cluster distriution to the originl cohort (30% high-risk cluster) nd similr seline BMI, lipids, glucose, insulin nd SBP to their cluster (dt not shown). The Heckmn selection model produced n inverse Mills rtio of 0.52, P ¼ 0.263, which suggests tht loss to follow-up is not relted to development of dietes. The high-risk cluster reported reduced prticiption in exercise (wlking, grdening nd sport; Tle 3). Reporting of tocco nd te consumption ws similr etween the clusters ut coffee drinkers were less prevlent in the high-risk cluster (P ¼ 0.019) nd these women reported consumption of less lcohol (Tle 3). In NGT, reporting of exercise ws similr to the low-risk cluster (Tle 3). Alcohol nd te consumption of NGT were not different to either cluster, ut coffee, ws consumed y 79% of NGT nd ws similr to the lowrisk cluster (Tle 3). Crdiovsculr risk profile nd CVD risk score 10 yers fter pregnncy At 10 yers, the pttern of CVD risk fctors in oth the clusters nd NGT ws similr those in pregnncy nd t 6 months post-prtum with the exception of SBP tht ws not different etween the Tle 3. Dignosed type 2 dietes, hypertension nd hypercholesterolemi t 10 yers, ostetric history since the index pregnncy, nd consumption of lcohol, tocco, te nd coffee nd level of exercise t 10 yers in the high nd low -risk cluster GDM nd NGT High-risk Low-risk NGT (n ¼ 40) (n ¼ 72) (n ¼ 48) Dignosed conditions since index pregnncy Type 2 dietes 38.6% 6.2% 0% Hypertension 10.3% 4.8% 2.2% Hypercholesterolemi 26.9% 12.9% 8.3% Ostetric history since index pregnncy Susequent pregnncies Yes % 62.5% 47.0% 60.4% No % 37.5% 53.0% 39.6% No. of irths 1.56± ± ±0.18 GDM in susequent 41.7% 53.6% 10.3% pregnncy Hypertension in susequent pregnncy 8.3% 10.3% 6.9% Self-reported everge consumption nd smoking t 10 yers Te drinkers % 67.5% 70.8% 63% Coffee drinkers % 55.0% 76.9% 79% Consumed lcohol in 35% 59.1% 54.2% lst week Quntity of lcohol 19.8± ± ±6.5 consumed (g) Smokers % 25% 16.7% 14.6% Self-reported exercise t 10 yers Once month 32.5% 9.1% 8.3% 1 2 times per week 17.5% 37.9% 54.2% 3 6 times per week 32.5% 31.8% 16.7% Dily 17.5% 21.2% 20.8% Arevitions: ANOVA, nlysis of vrince; GDM, gesttionl dietes mellitus; NGT, norml glucose tolernce. Vlues re men±s.e.m. Po0.01 or Po0.05 compred with high-risk cluster using one-wy ANOVA for continuous vriles nd w 2 nlysis for descriptive vriles. clusters (Figure 1). After djusting for differences in ge, eductionl level nd the numer of susequent pregnncies the significnt differences (Po0.001), were still found in triglycerides HDL cholesterol nd BMI insulin nd glucose. Hs-CRP remined elevted in the high-risk cluster t 10 yers (7.0±1.3 mg l 1 ) compred with the low-risk cluster (3.1±0.6 mg l 1 ) nd NGT (3.7±1.1 mg l 1, Po0.01). Predictors of type 2 dietes t 10 yers in GDM Logistic regression nd the BIC were used to exmine whether cut-points for BMIX30 kg m 2 or fsting glucose 45.5 mmol l 1 in pregnncy were etter predictors of type 2 dietes t 10 yers thn memership of the high-risk cluster. The high-risk cluster predicted the development of type 2 dietes t 10 yers (odds rtio (OR) ¼ 6.75, 95% confidence intervl (CI) ¼ 2.0, 22.7, P ¼ 0.002, BIC ¼ 88.5). BMIX30 kg m 2 did not predict dietes (OR ¼ 2.13, CI ¼ 0.71, 6.4, P ¼ 0.179, BIC ¼ 97.7). Fsting glucose 45.5 mmol l 1 t dignosis lso predicted type 2 dietes (OR ¼ 4.56, CI ¼ 1.50, 13.85, P ¼ 0.007, BIC ¼ 92.4) ut the lrger BIC indictes the model contining the high-risk cluster is etter model, correctly predicting development of dietes in 12 women s opposed to 8 women using fsting glucose 45.5 mmol l 1. Nutrition & Dietes (2013) 1 6 & 2013 Mcmilln Pulishers Limited

5 Tle 4. Crdiometolic risk fctor defining levels for determining GDM t high-risk of future dietes nd crdiovsculr disese Risk fctor Four or more of the six risk fctors Defining level Body mss index (kg m 2 ) 430 Fsting Glucose (mmol l 1 ) 45.0 Insulin (mu l 1 ) 47.8 Triglycerides (mmol l 1 ) 42.4 HDL cholesterol (mmol l 1 ) o1.6 Systolic lood pressure (mm Hg) 4105 Arevitions: GDM, gesttionl dietes mellitus; HDL, high-density lipoprotein. Exceeding the cut-point for ny 4 of these mesurements will plce GDM in the high-risk pregnncy cluster nd t significnt risk for development of type 2 dietes nd crdiovsculr disese. Smoking, weight chnge in pregnncy, insulin tretment in pregnncy nd gesttion t delivery were exmined s confounders in the logistic regression nlysis. Insulin tretment in pregnncy ppered to protect ginst development of dietes t 10 yers OR ¼ 0.124, CI ¼ 0.003, 0.461, P ¼ ut did not chnge the reltionship etween the high-risk cluster nd dietes t 10 yers OR ¼ 6.88, CI ¼ 1.7, 28.7, P ¼ A simple method for determining high-risk GDM for clinicins We recognized it would e cliniclly useful if simple method could e used for future identifiction of GDM tht fitted our definition of high-risk cluster memership. Using recursive prtitioning of crdiometolic risk fctors mesured in GDM t 28 weeks gesttion, we defined cut-points for ech of the risk fctors. (Tle 4). We determined tht exceeding the defining level for ny four of the crdiometolic risk fctors provided the gretest sensitivity 88.7% (CI ¼ 77 95%) nd specificity 95.9% (CI ¼ %) for lloction of GDM to the high-risk cluster. DISCUSSION In this prospective cse control study of overweight women with GDM, we identified 35% of women with GDM who hd sustntilly higher BMI, BP, fsting glucose, insulin nd triglycerides, nd lower HDL. This high-risk cluster prlleled severl fetures of the metolic syndrome in non-pregnnt dults nd t 10 yers hd incresed rtes of dietes nd worse CVD risk profile thn the low-risk GDM nd overweight NGT. We hve shown for the first time tht metolic syndrome-like profile in GDM is etter predictor of incidence of dietes t 10 yers thn high fsting glucose or elevted BMI. We hve formulted simple, sensitive, specific method sed on crdiometolic risk mesurements otined t dignosis of GDM to id clinicins in ssessment of future risk of developing dietes nd CVD. The high-risk cluster differed from low-risk GDM in tht they were slightly younger, less educted nd reported fmily history of dietes more often. Their metolic syndrome-like CVD profile remined significntly different fter djusting for ge, level of eduction nd fmily history of dietes. In keeping with their metolic syndrome-like profile the high-risk cluster hd higher Hs-CRP levels compred with the low-risk cluster nd NGT during pregnncy. Pre-eclmpsi hs een shown to e ssocited with n incresed CVD risk fter pregnncy, 4,19 ut in our study the incidence of pre-eclmpsi in two clusters ws not different. An elevted 2-h glucose in the glucose tolernce test distinguished Risk mrkers in pregnncy nd future CVD risk A Brden et l the low-risk GDM cluster from NGT, who were otherwise similr in most respects. At 6 months post-prtum, fter the hormonl influences of pregnncy hd resolved the metolic syndrome profile of the high-risk cluster ws still evident. These differences persisted ten yers fter the index pregnncy, with the exception of SBP tht no longer differed etween the clusters. Hs-CRP remined significntly higher in the high-risk cluster t 10 yers. This finding is in keeping with reports of incresed low-grde inflmmtion in non-pregnnt women with previous GDM 20,21 nd women with the metolic syndrome. 22 In regression nlysis, memership of the high-risk cluster tht incorported numer of crdiovsculr normlities, ws etter predictor of type 2 dietes t 10 yers thn high fsting glucose (45.5 mmol l 1 ) mesured t the time of dignosis of GDM. Interestingly, oesity (BMI430) t study entry did not predict the development of dietes t 10 yers, suggesting tht this component of the high-risk cluster ws not on its own the driver for development of dietes. This oservtion is supported y the sence of reported dietes in the overweight NGT whose BMI were consistently higher thn the low-risk cluster GDM. Previous studies hve identified tht women with pst history of GDM re more likely to hve impired glucose regultion nd the metolic syndrome 1 10 yers fter pregnncy. 20,22 24 Post-prtum elevted CRP hs een lso een reported to coincide with these fetures. Reports tht pre-pregnncy weight nd insulin secretion predict glucose tolernce 5 yers fter GDM 25 suggest tht mny of these fetures my e constitutionl. A lrge retrospective popultion-sed cohort study looking t glucose intolernce in pregnncy showed tht women with GDM hd higher risk of crdiovsculr events over 12.3 yers with n djusted hzrd rtio of 1.66 compred with women who hd NGT in pregnncy. 26 Tht study lso showed tht even mild glucose intolernce in pregnncy conferred n incresed risk for CVD. 26 We postulte tht the incresed risk for CVD in women with mild glucose intolernce my e due to normlities in other CVD risk fctors such s lipids nd insulin tht were not mesured in tht study. Our findings suggest tht su-set of women with GDM hve numer of other metolic normlities including tendency to greter oesity, dyslipidemi, low-grde inflmmtion nd elevted BP tht together predispose to incresed CVD risk nd dietes. This hypothesis is supported y our oservtion tht overweight women who hd NGT test in pregnncy were similr to the low-risk cluster in terms of their lipid profile, insulin levels, mrkers of inflmmtion, fmily history nd level of eduction. In our study, 70% of the originl cohort ws re-studied t 10 yers. Although incomplete follow-up could e seen s wekness in our study, our nlysis for is ecuse of the incomplete follow-up showed tht there ws no significnt is in our findings tht could hve occurred s result of loss to follow-up. Lifestyle mesures recorded t 10 yers indicted tht the highrisk cluster exercised significntly less thn the other groups with 32% of women reporting tht they exercised only once month. Alcohol consumers were similr etween the clusters ut lcohol consumption ws lower in the high-risk cluster. Te consumption ws similr cross the groups ut coffee consumption in the highrisk cluster ws reported less often thn the low-risk cluster or NGT. These findings re interesting in view of the ccumulting epidemiologicl evidence suggesting tht physicl ctivity, 27 coffee drinking nd lcohol consumption 31,32 protect ginst type 2 dietes. In conclusion, we hve shown tht the crdiometolic risk profile s ssessed y cluster nlysis in pregnncies with GDM strongly correltes with the development of dietes nd persistence of CVD risk 10 yers lter. Our dt suggest tht in spite of the hormonl effects of pregnncy, mesurement of trditionl CVD risk fctors in conjunction with detiled fmily 5 & 2013 Mcmilln Pulishers Limited Nutrition & Dietes (2013) 1 6

6 6 history in pregnnt women with GDM my offer etter opportunities to identify women with GDM who re t incresed risk of susequent dietes nd CVD. A strength of this study is tht mesurement of trditionl CVD risk fctors t dignosis of GDM hs enled us to derive simple formul tht should significntly id clinicins in identifiction of those women who should e trgeted for intervention fter pregnncy. CONFLICT OF INTEREST The uthors declre no conflict of interest. ACKNOWLEDGEMENTS Risk mrkers in pregnncy nd future CVD risk A Brden et l We thnk Jckie Ritchie for her excellent ssistnce with recruitment nd follow-up of the women studied. This study ws funded y project grnt from the Ntionl Hert Foundtion of Austrli. REFERENCES 1 Knglingm MG, Forouhi NG, Greer IA, Sttr N. Chnges in ooking ody mss index over decde: retrospective nlysis from Glsgow Mternity Hospitl. Brit J Ostet Gynecol 2005; 112: Suhonen L, Termo K. Hypertension nd preeclmpsi in women with gesttionl glucose-intolernce. 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