maternal nutrition: effects on health in the next...

Introduction

The concept that longevity is influenced by events in earlylifeisnotnew.In1934,Kermacketal1showedthatdeath rates inEurope from1751 to1930 fellwitheach successiveyear-of-birthcohort.They rejectedonepossibleexplanation,that‘amorehealthyraceofchildrenwasbornineachsuccessivedecade’,andthoughtthatit

Maternalnutrition:Effectsonhealthinthenextgeneration

CarolineFall

MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital Southampton, UK

ReceivedApril24,2009

Nearly 20 years ago, it was discovered that low birthweight was associated with an increased risk of adult diabetes and cardiovascular disease (CVD). This led to the hypothesis that exposure to undernutrition in early life increases an individual’s vulnerability to these disorders, by ‘programming’ permanent metabolic changes. Implicit in the programming hypothesis is that improving the nutrition of girls and women could prevent common chronic diseases in future generations. Research in India has shown that low birthweight children have increased CVD risk factors, and a unique birth cohort in Delhi has shown that low infant weight, and rapid childhood weight gain, increase the risk of type 2 diabetes. Progress has been made in understanding the role of specific nutrients in the maternal diet. In the Pune Maternal Nutrition Study, low maternal vitamin B12 status predicted increased adiposity and insulin resistance in the children, especially if the mother was folate replete. It is not only maternal undernutrition that causes problems; gestational diabetes, a form of foetal overnutrition (glucose excess), is associated with increased adiposity and insulin resistance in the children, highlighting the adverse effects of the ‘double burden’ of malnutrition in developing countries, where undernutrition and overnutrition co-exist. Recent intervention studies in several developing countries have shown that CVD risk factors in the offspring can be improved by supplementing undernourished mothers during pregnancy. Results differ according to the population, the intervention and the post-natal environment. Ongoing studies in India and elsewhere seek to understand the long-term effects of nutrition in early life, and how best to translate this knowledge into policies to improve health in future generations.

Key wordsLowbirthweight-foetalgrowth-maternalnutritionalstatus-underweight

wasbecauseofbetterchildhoodlivingconditionsbroughtaboutbysocialreforms.In1977,Forsdahl2discoveredageographicalcorrelationinNorwaybetweenheartdiseasemortalityin1964-1967andinfantmortalityrates70yearsearlier.Hesuggestedthatgrowingupinpovertycaused‘permanent damage’ perhaps due to a ‘nutritional deficit’, which resulted in ‘life-long vulnerability’ to an affluent adultlifestyleandhighfatintakes.

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Studies by Barker & osmond3,4 in the UK, adecadelater,focusedonpre-natalfactors.Differencesaround the UK in neonatal mortality (a marker forlow birthweight) in 1921-1925 predicted death ratesfrom stroke and heart disease in 1968-19783. Thediscovery of birth records dating from 1911 in thecountyofHertfordshiremadeitpossibletoshowthatlowbirthweightandweightatoneyearwereassociatedwith an increased risk of death from cardiovasculardisease4. There was an approximate doubling ofmortality from the highest to the lowest extremes ofbirthweight. Based on these findings, they put forward thecontroversialhypothesisthatpoorfoetalandearlypost-natalnutritionwasacauseofadultcardiovasculardisease.Hewasconvincedthatfallingmortalityratesinthewesternworldwerebecausemothers,andthereforefoetusesandbabies,werebetternourished,witheachsucceedinggeneration.

Sincethen,studiesaroundtheworldhaveshownthatlowerbirthweightisassociatedwithanincreasedriskofawiderangeofhealthproblems inadult life,including type 2 diabetes5, metabolic syndrome6,chronic lung disease7, osteoporosis8 and mentalillness9. There is also a wealth of data showing thatpoor intrauterine and infant growth and nutrition areassociatedwithreducedcapacityinadultlife,includingreducedstature,lowerphysicalworkcapacity,impairedcognitivefunctionandeducationalattainment,and(forwomen)anincreasedriskoflowbirthweightinthenextgeneration10.Thesestudieshaveledtoanewbranchofscientific research: the developmental origins of health anddisease(DoHaD).

The foetal programming hypothesis

obviously, it isnot lowbirthweightof itself thatcauses these problems, but what low birthweightrepresents: foetal undernutrition and impaireddevelopment11 (Fig. 1). The foetus depends on thetransfer of nutrients from the mother, and adapts toinadequatenutritioninseveralways:prioritizationofbrain growth at the expense of other tissues such astheabdominalorgans,alteredsecretionandsensitivityto the foetal growth hormones insulin and insulin-likegrowth factor-1 (IGF-I), andupregulationof thehypothalamo-pituitary-adrenal (HPA) ‘stress’ axis.The foetus sacrifices tissues that require high-quality building blocks, like muscle or bone, and insteadlays down less demanding tissue, like fat.Althoughoccurringinresponsetoatransientphenomenon(foetalundernutrition),thesechangescanbecomepermanent

or ‘programmed’ because they occur during criticalperiodsofearlydevelopment.

The mechanisms by which this could occur11-15include simple growth failure, leading to impairedorgansizeandstructure,forexample,reducednumbersof pancreatic beta cells, renal nephrons or brainneurones,andalteredarterialstructure.Theseincludealteredendocrinesettings,forexample,reducedinsulinsecretionandsensitivity,andupregulationoftheHPAaxis and sympathetic nervous system. At a cellularlevel, these include altered epigenetic characteristics–changestotheproteinsandothermoleculesattachedtoDNAwhichcontrolgeneexpression.Eachofthesechanges can lead directly to adult cardiovasculardisease, or render the individual more susceptible totheeffectsofenvironmentalstressorssuchasobesityarisinginlaterlife.

The programming hypothesis is supported bynumerous examples of nutritional programmingin experimental animals. In rats, maternal proteinrestrictioninpregnancyleadstohigherbloodpressure16,impairedglucosetolerance17,insulinresistance18,19,andalteredhepaticarchitectureandfunction20intheadultoffspring.Animalexperimentsallowmoresophisticatedstudyofthemechanismsofprogrammingattissueandcellular levels. For example, insulin resistance and

Fig. 1. The foetal programming hypothesis; flow diagram illustrat-ing proposed effects of intra-uterine nutrition on the foetus, andlong-termeffectsonmetabolismanddiseaserisk.Source:Ref.23.

594 INDIANJMEDRES,NoVEMBER2009

impairedglucosetoleranceinadultoffspringofprotein-deprivedratsresultsfromreducedgeneexpressionforenzymes in the insulin-signalling pathway18. Raisedblood pressure in the offspring of protein-deprivedratshasbeenlinkedtoepigeneticchangesthatcanbepreventedbysupplementingthemotherwithfolate21.

Associationsofcardiovasculardiseaseanditsriskfactors with different body proportions at birth mayreflect undernutrition during critical periods in gestation forthedevelopmentoftissuesandorgansystems11.Maleand female foetuses have different growth priorities,and adapt differently to undernutrition, reflected in sex differences in associations with neonatal bodyproportions11.Thehyperplasticdevelopmentofmanytissuescontinues inearly infancy, andundernutritionduringinfancyisprobablyequallyimportant3.

Research in the Indian scenario

Indianresearchershavemadeamajorcontributionto the DOHaD field and towards its translation into improvedhumanhealth.AstudyofCVDriskfactorsin Indian children was the first in a developing country to examine associations between size at birth andlaterrisk22.Among4yroldchildrenbornintheKEMHospital,Pune,lowerbirthweightwasassociatedwithhigher plasma glucose concentrations after an oralglucose load. When the children were re-studied at 8years, thoseof lowerbirthweighthadhigherLDL-

cholesterol concentrations and subscapular/tricepsskinfoldratios,andafteradjustingfor8-yearweight,highersystolicbloodpressureandinsulinresistance22.Theseriskfactorswerehighestinchildrenwhowerebornsmallbutbecamethebiggest(heaviest,tallestandmostadipose)at8years.

Anotherclearexampleofthedisadvantagesbeingsmall in early life and becoming obese as an adultcamefromastudyofyoungadultsinNewDelhi,whoweremeasuredatbirthandevery6monthsuntil theageof21yr23.Meanbirthweightwasonly2.9kg.Aschildren, many of the cohort were underweight-for-age[53%attheageof2yr,usingNationalCenterforHealth Statistics (NCHS) standards]. When they were re-traced at 26-32 yr, 40 per cent were overweight(BMI >25 kg/m2) and 10 per cent were obese (BMI>30kg/m2).Fourpercentalreadyhadtype2diabetesand15percenthadimpairedglucosetolerance(IGT)(pre-diabetes).Afteradjusting foradultBMI,plasmaglucose concentrations and insulin resistance wereinverselyrelatedtobirthweight,andIGTanddiabeteswere associated with lower weight and BMI at theageof1yr.Incontrast,thechildhoodgrowthofthosewhodevelopedIGTordiabeteswascharacterisedbyacceleratedBMIgainrelativetotherestofthecohort(Fig.2).FrombeingbelowthecohortmeanforBMIat2yearstheywerewellabovethemeanat30years.ThehighestprevalenceofIGTanddiabeteswasinmenand

Fig. 2. Data from the New Delhi birth cohort. Mean sex-specific SD scores for height (left) and BMI (right) at every age from birth to 21 yr, andwhenstudiedat26-32yr,forsubjectswhodevelopedIGTordiabetes.MeanSDscoresareindicatedbythesolidline,and95percentCI’sbydottedlines.ThemeanSDscoreforthewholecohortiszero.[ReprintedwithpermissionfromtheMassachusettsMedicalSociety(TheNewEnglandJournalofMedicine2004;350:865-75)].

Age(yr) Age(yr)

FALL:DEVELoPMENTALoRIGINSoFHEALTH&DISEASE 595

women who had low BMI SD scores in infancy buthighSDscoresat12yearsorlater.

There are a number of possible reasons whyweight gain in childhood, on a background of foetalrestriction, might cause disease. Low birthweightbabies tend to catch-up (compensatory growth), andtherapidityofpost-natalgrowthmaysimplyindicatetheseverityofgrowthretardationatbirth.Alternativelythe process of catch-up may be disadvantageous initself. Itmay imposeexcessdemandonother tissueswhich are not capable of compensatory hyperplasia,suchas thepancreas. Itmayalterbodycomposition;animals can gain excessive fat if they are placed onahighplaneofnutritionafteraperiodofearlypost-natal undernutrition24. McCance suggested that goodnutritionat thisstageemphasisesthedevelopmentoftissueslikefat,whichmaintainthecapacityforgrowththroughout life, but cannot recover tissues such asmuscle,whichdevelopearlierandlosethecapacityforcelldivision24.Anotherpossibilityisthatthehormonesdriving catch-up growth have adverse cardiovascularandmetaboliceffects25.

The Pune Maternal Nutrition Study has giveninsightintofoetaldevelopmentinIndianpopulations.This is a prospective population-based observationalstudyof rural Indianwomenand theiroffsprings26,27.Themotherswereshortand thin (meanpre-pregnantheight and BMI: 152 cm and 18.1 kg/m2) and themeanfulltermbirthweightwasonly2.7kg.DetailedanthropometryofthenewbornsshowedthattheirbodycompositiondifferedfromwhiteCaucasianbabiesbornin the UK27. They were lighter by almost 2 standarddeviations,andleantissuessuchasmuscle(mid-upper-armcircumference)andabdominalviscera(abdominalcircumference) showed a similar deficit. Truncal fat (subscapularskinfolds),however,wasrelatively‘spared’(-0.5SD).Thus,althoughextremelysmallandthin,thebabies were relatively adipose. A similar pattern hasbeen confirmed in urban Indian populations28.

Theaetiologyofthemuscle-thinbutadipose‘thin-fat’ phenotype of Indian newborns is unknown. Theadiposity is related to maternal adiposity and lipid,glucose and insulin concentrations, but the low leanmassisunexplained.Thephenotypemaybe‘adaptive’andcarrysurvivaladvantage;forexample,inthefaceofa nutritional deficit, muscle growth may be sacrificed, andfatlaiddownpreferentiallyasasubstrateforbraingrowth and/or immune function. Its consequencesfor later health are unknown; however it echoes the

well-describedadult Indianphenotype(lowermusclemass,higherpercentagebodyfat,andgreatertendencyto central adiposity than white Caucasians) that isstronglyassociatedwithtype2diabetes29. The findings highlight the fact that birthweight provides only acrudesummaryoffoetalgrowthandfailstodescribepotentiallyimportantdifferencesinthedevelopmentofspecific tissues.

Studies in India have also highlighted problemsassociated with maternal diabetes, which causesextremehighratherthanextremelowbirthweight.InarecentstudyofcontemporarywomengivingbirthinMysore30, the prevalence of gestational diabetes washigh (6%) despite a low average maternal age andBMI. As expected, babies born to diabetic motherswereheavier(meanbirthweight3339g)thanbabiesofmothers with normal glucose tolerance (2956 g). When studiedattheageof5yr,theyweremoreadiposeandhadhigherinsulinconcentrations,thanchildrenofnon-diabeticmothers30.

The role of nutrition

Foetalgrowthdependsontheuptakeofnutrients,whichoccursat theendofacomplexmaterno-foetalsupply line31. This includes intake, i.e., the mother’sappetite,dietandabsorption.Thenutrientsarrivingattheplacenta,andhowtheyaretransferredtothefoetus,dependonmaternalmetabolism:herendocrinestatus,herpartitioningofnutrientsbetweenstorage,utilizationor circulation, and her cardiovascular adaptations topregnancy, such as plasma volume expansion whichincreases uterine blood flow. These are influenced by maternalnutritioninwaysthatarepoorlyunderstood.Thelinkbetweenmaternalandfoetalnutritionisthusindirectandexplainswhythefullimpactofmaternaldietonfoetalgrowthremainsunclear.

Foetal growth can be readily restricted inexperimental animals by reducing maternal intakesofenergyandproteinduringpregnancy31.Energyandprotein deficiency in the mother is also associated withintrauterinegrowthretardationinhumans,sizeatbirthisstronglyrelatedtomaternalbodymassindex,and during acute famine birthweight falls by severalhundredgrams32,33.However,randomisedclinicaltrials(RCTs) of energy and/or protein supplements haveshown only small effects on birthweight34. There isevidence that supplementingundernourishedmotherswith micronutrients, or improving the diet quality,increasesfoetalgrowth.ThePuneMaternalNutritionStudy showed that mothers with higher intakes of


micronutrient-rich foods like green leafy vegetables,fruitandmilkhadbabiesthatwerelargerinallbodydimensions26. Several recent RCTs have also shownincreased newborn size after maternal micronutrientsupplementation,althoughtheincreasewassmall35,36.Foetal growth is related to maternal height andbirthweight. This suggests that undernutrition of themotherduringherownfoetallifeandchildhoodgrowthlimitsthegrowthofherfoetus.Effectsofthemother’scurrent nutritional status are therefore influenced by herownpastnutritionandthatofearliergenerations.

A relatively un-researched time is the peri-conceptional period. Before the mother even knowsshe is pregnant, and before placentation occurs,sufficient nutrients must be present in the embryo’s immediate environment. The importance of peri-conceptional nutrition has been demonstrated by thereductioninneuraltubedefectswithpre-conceptionalfolate supplementation37. In experimental animals,peri-conceptional undernutrition alters the allocationofcellsintheblastocystandpermanentlychangesthefoetalgrowthtrajectory.Latereffectsintheoffspringincludepre-termdeliveryandadulthypertension38,39.

Severalmicronutrients, especially those involvedin1-carbonmetabolism(suchasfolicacidandvitaminB12)actasco-factorsormoleculardonorsforepigeneticprocessessuchasDNAmethylation,whichmodulategene expression, and therefore cellular proliferationand apoptosis, during foetal development. Genome-wide demethylation occurs just after fertilization,followed by re-methylation at different stages ofembryonicdevelopment40.Epigeneticchangesinducedat this time may become permanent and heritable,determining outcomes in later life and in the nextgeneration. Maternal diet, and especially folate andvitamin B12 intakes influences these processes. For example, thephenomenon in rats by which maternalproteinrestrictionleadstohypertensionintheoffspring,anditspreventionbymaternalfolatesupplementation,have been linked to the de-methylation (by proteinrestriction) and re-methylation (by folate) of specific genes41.

Maternal nutritional status and disease risk in the offspring

Ifthefoetalprogramminghypothesisisright,andmaternalnutritionhasimportanteffectsonadulthealth,correlationswouldbe expectedbetweenmeasuresofmaternalnutrition anddisease in theoffspring.Untilrecently,theonlydatatotestthiswerefromolddietary

surveys and famine studies. For example, the DutchFaminestudieshaveshownthatmaternalexposuretofamine in late gestation was associated with glucoseintoleranceandinsulinresistanceintheoffspring42.

The current focus on developmental origins ofhealth and disease has led to the setting up of newprospective studies in which detailed information onmaternal nutrition in pregnancy has been collected.oneofthese,thePuneMaternalNutritionStudy,hasshownthatlowmaternalcalciumintakeisassociatedwith lower bone mineral content in the children43.Thismaybeasimpleexampleofinadequate‘buildingblocks’ for the tissueconcerned.Thesamestudyhasalsoprovidedevidenceoftheimportanceof1-carbonmetabolism in programming processes. Vitamin B12deficiency in the mother, especially if she was folate replete, was associated with increased body fat andinsulinresistanceinthechildren(Fig.3)44.

We are now beginning to see the DOHaD hypothesistestedininterventionstudies,byfollowingup the children of undernourished women who tookpart in randomized controlled trials of nutritionalsupplementation in pregnancy.A follow up study ofadults born during the INCAP trial in Guatemala, inwhich villages were randomized to receive Atole45(a high-energy, high-protein drink) or Fresco (lowerenergy, no protein) found higher HDL-cholesteroland lower triglyceride concentrations in thosewhosemothers had Atole45. Among adolescents in India,whose pregnant mothers received food-based energyandproteinsupplementsaspartofapackageofpublichealth interventions, insulin resistance and arterialstiffnesswerereducedcomparedtocontrols46.Systolic

Fig. 3.Insulinresistance(HoMA)inchildrenaged6yrfromthePuneMaternalNutritionStudy,inrelationtomaternalvitaminB12(18wk)anderythrocytefolate(28wk).[ReprintedwithpermissionfromSpringer(Diabetologia2008;51:29-38)].


blood pressure was lower (-2.5 mmHg) in 2-yr oldNepali children whose mothers received multiplemicronutrientsinpregnancyratherthanstandardiron/folatetablets47. However, there were negative findings inatrialofhigh-energybiscuitsintheGambia48.Theinterventionreducedtheincidenceoflowbirthweightby 40 per cent and halved perinatal mortality, but atfollow up there was difference in blood pressurebetween children born to women who received theintervention during pregnancy compared to womenwhoreceiveditduringlactation.

There are many good reasons for improvingthe diets of undernourished mothers. The Gambiasupplement produced an impressive reduction inperinatal mortality, and in Guatemala, early-lifeexposure to Atole improved childhood growth andadult economic productivity49. Clearly, at present,there is inadequate evidence that such interventionsimprove adult health in the offspring. The findings from these trials suggest that there may be beneficial effectsonsomecardiovascularriskfactors,thatthesearecomplex,anddifferaccordingtothepopulation,theinterventionandthepost-natalenvironment.Giventheneedformuchdeeperunderstanding,itistobehopedthat the investigators will follow up their subjectsfurthertodeterminethefullextentofanyeffects,andthat other trials of enhanced materno-foetal nutritionwilladddatatothecurrentlymeagreevidence-baseonthisimportantissue.

Acknowledgment TheworkreportedinthisreviewwassupportedbytheMedicalResearch Council, UK, the Wellcome Trust, UK, the British Heart FoundationandtheParthenonTrust.

References1. Kermack WO, McKendrick AG, McKinlay PL. Death rates in

GreatBritainandSweden;somegeneralregularitiesandtheirsignificance. Lancet1934;i:698-703.

2. Forsdahl A. Are poor living conditions in childhood andadolescence an important risk factor for arterioscleroticdisease?Br J Prev Soc Med1977;31:91-5.

3. BarkerDJP,osmondC.Infantmortality,childhoodnutrition,and ischaemic heart disease in England and Wales. Lancet1986;i:1077-81.

4. Barker DJP, Osmond C, Winter PDW, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet1989;ii:577-80.

5. EARLYREAD Collaboration. Birthweight and risk of type2 diabetes: a quantitative systematic review of publishedevidence.JAMA2008;300:2885-97.

6. RamadhaniMK,GrobbeeDE,BotsML,CastroCabezasM,VosLE,orenA,et al.Lowerbirthweightpredictsmetabolic

syndromeinyoungadults:theAtherosclerosisRiskinYoungAdults(ARYA)study.Atherosclerosis2006; 184:21-7.

7. Barker DJP, Godfrey KM, Fall CHD, Osmond C, Winter PD, Shaheen S. The relation of birthweight and childhoodrespiratory infection to adult lung function and death fromchronicobstructiveairwaysdisease.BMJ1991;303:671-5.

8. Cooper C, Westlake S, Harvey N, Javaid K, Dennison E, Hanson M. Developmental origins of osteoporotic fracture.Osteoporosis Int2006;17:337-47.

9. Landon J, Davison M, Breier B. The developmentalenvironment: influences on subsequent cognitive function and behaviour.In:GluckmanP,HansonM,editors.Developmental origins of health and disease. Cambridge: CambridgeUniversityPress;2006.p.370-8.

10. VictoraCG,AdairL,FallC,HallalPC,MartorellR,RichterL, et al and the Maternal and Child Undernutrition StudyGroup.Maternalandchildundernutrition:consequences foradulthealthandhumancapital.Lancet2008;371:340-57.

11. BarkerDJP.Mothers, babies and health in later life.London:ChurchillLivingstone;1998.

12. Lucas A. Programming by early nutrition in man. CibaFoundation Symposium No. 156, Chichester, UK: John Woley andSons;1991.p.38-50.

13. Waterland RA, Garza C. Potential mechanisms of metabolic imprintingthatleadtochronicdisease.Am J Clin Nutr1999;69:179-97.

14. Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KMK. Epigeneticcontroloffetalgeneexpression.Br J Obstet Gyncol2008;115:158-68.

15. FallCHD.Fetalandmaternalnutrition.In:StannerS,editor.Cardiovascular disease: Diet, nutrition and emerging risk factors.oxford,UK:BritishNutritionFoundationTaskForce.BlackwellPublishing;2005.

16. LangleySC,JacksonAA.Increasedsystolicbloodpressureinadultrats inducedbyfetalexposuretomaternal lowproteindiets.Clin Sci1994;86:217-22.

17. ozanneSE,HalesCN.Thelong-termconsequencesofintra-uterine protein malnutrition for glucose metabolism. Proc Nutr Soc1999;58:615-9.

18. Ozanne SE, Dorling MW, Wang CL, Nave BT. Impaired PI 3-kinaseactivationinadipocytesfromearlygrowth-restrictedrats.Am J Physiol2001;280:E534-9.

19. vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertensionand postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab2000;279:E83-7.

20. HalesCN,DesaiM,ozanneSE,CrowtherNJ.Fishinginthestreamofdiabetes: frommeasuring insulin to thecontroloffetalorganogenesis.Biochem Soc Trans1996;24:341-50.

21. Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, JacksonAA,et al.Folatesupplementationduringpregnancyimproves offspring cardiovascular dysfunction induced byproteinrestriction.Hypertension2006;47:982-7.

22. Bavdekar A, Yajnik CS, Fall CHD, Bapat S, Pandit AN,DeshpandeV,et al.Theinsulinresistancesyndrome(IRS)ineight-year-oldIndianchildren:smallatbirth,bigat8yearsorboth?Diabetes2000;48:2422-9.


23. BhargavaSK,SachdevHPS,FallCHD,osmondC,LakshmyR,BarkerDJP,et al.Relationofserialchangesinchildhoodbody mass index to impaired glucose tolerance in youngadulthood.N Engl J Med2004;350:865-75.

24. McCance RA. Food, growth and time. Lancet 1962; ii :621-6.

25. LeverAF, Harrap SB. Essential hypertension: a disorder ofgrowth with origins in childhood? J Hyperten 1992; 10 :101-20.

26. RaoS,YajnikCS,KanadeA,FallCHD,MargettsBM,JacksonAA, et al. Intakeofmicronutrient-richfoods inrural Indianmothersisassociatedwiththesizeoftheirbabiesatbirth;thePuneMaternalNutritionStudy.J Nutr2001;131:1217-4.

27. Yajnik CS, Fall CHD, Coyaji KJ, Hirve SS, Rao S, BarkerDJP,et al.Neonatalanthropometry:thethin-fatIndianbaby;thePuneMaternalNutritionStudy.Int J Obesity2003;27 :173-80.

28. Krishnaveni GV, Hill JC, Veena SR, Leary SD, Saperia J,ChachyammaKJ,et al.Truncaladiposity ispresentatbirthandinearlychildhoodinSouthIndianchildren.Indian Pediatr2005;42:527-38.

29. Yajnik CS. obesity epidemic in India: intra-utrine origins?Proc Nutr Soc2004;63:1-10.

30. Krishnaveni GV, Hill JC, Leary S, Veena SR, Saperia J,SarojaA,et al.Anthropometry,glucosetoleranceandinsulinconcentrations in Indian children: relationships to maternalglucoseandinsulinconcentrationsduringpregnancy. Diabetes Care2005;28:2919-25.

31. HardingJE.Thenutritionalbasisofthefetaloriginsofadultdisease.Int J Epidemiol2001;30:15-25.

32. Leary S, Fall CHD, osmond C, Lovel H, Campbell D,Eriksson J, et al. Geographical variation in relationshipsbetweenparentalbodysizeandoffspringphenotypeatbirth. Acta Obstet Scand2006;85:1066-79.

33. SusserM,SteinZ.Timinginprenatalnutrition:arepriseoftheDutchFamineStudy.Nutr Rev1994;52:84-94.

34. Kramer MS. Balanced protein/energy supplementation inpregnancy.In: The Cochrane Library,Issue3.2001oxford:Updatesoftware.

35. HaiderBA,BhuttaZA.Multiple-micronutrientsupplementationforwomenduringpregnancy.Cochrane Database Syst Rev(4),CD004905,2006.

36. Bhutta Z, Ahmad T, Black RE, Cousens S, Dewey K,GiuglianiE,et alandtheMaternalandChildUndernutritionStudy Group. What works? Interventions to affect maternal andchildundernutritionandsurvivalglobally.Lancet2008;371:417-40.

37. Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins forpreventingneuraltubedefects.Cochrane Database Syst Rev2001;3:CD001056.

38. Bloomfield F, Oliver M, Harding JE.The late effect of fetal growthpatterns.Arch Dis Child Fetal Neonatal Ed2006;91:299-304.

39. Watkins AJ, Wilkins A, Cunningham C, Perry vH, Seet MJ, osmondC,et al.Lowproteindietfedexclusivelyduringmouseoocyte maturation leads to behavioural and cardiovascularabnormalitiesintheoffspring.J Physiol2008;586:2231-44.

40. GodfreyKM,LillycropKA.Epigeneticmechanismsandthemismatchconceptofthedevelopmentaloriginsofhealthanddisease.Ped Res2007;61:5R-9R.

41. LillycropKA,PhillipsES,JacksonAA,HansonMA,BurdgeGC.Dietaryproteinrestrictionofpregnantratsinduces,andfolic acid supplementation prevents, epigenetic modification ofhepaticgeneexpressionintheoffspring.Br J Nutr2005;135:1382-6.

42. RavelliACJ,vanderMeulenJHP,MichelsRPJ,osmondC,BarkerDJP,HalesCN,et al.Glucosetoleranceinadultsafterprenatalexposuretofamine.Lancet1998;351:173-7.

43. GanpuleA,YajnikCS,FallCHD,RaoS,FisherDJ,KanadeA,et al.BonemassinIndianchildren;relationshipstomaternalnutritionalstatusanddietduringpregnancy;thePuneMaternalNutritionStudy. J Clin Endocrinol Metab 2006;91 : 2994-3001.

44. Yajnik CS, Deshpande SS, JacksonAA, Refsum H, Rao S,FisherDJ,et al.VitaminB12andfolateconcentrationsduringpregnancyand insulin resistance in theoffspring:ThePuneMaternalNutritionStudy.Diabetologia2008;51:29-38.

45. Stein AD, Wang M, Ramirez-Zea M, Flores R, Grajeda R, Melgar P, et al. Exposure to a nutrition supplementationintervention in early childhood and risk factors forcardiovasculardiseaseinadulthood:evidencefromGuatemala.Am J Epidemiol2006;164:1160-70.

46. KinraS,SarmaKVR,Ghafoorunissa,MenduVVR,RavikumarR, Mohan V, et al. Effect of integration of supplementalnutrition with public health programmes in pregnancyand early childhood on cardiovascular risk in rural Indianadolescents:longtermfollow-upofHyderabadnutritiontrial.BMJ2008;337:1-10.

47. VaidyaA,SavilleN,ShresthaBP,CostelloAM,ManandharDS, osrin D. Effects of a maternal multiple micronutrientsupplement on children’s weight and size at 2 years of ageinNepal;follow-upofadoubleblindrandomisedcontrolledtrial.Lancet2008;371 :452-4.

48. Hawkesworth S, PrenticeA, FulfordA, Moore S. Maternalprotein-energy supplementation does not affect adolescentblood pressure in the Gambia. Int J Epidemiol 2009; 38 :119-27.

49. Hoddinot J, Maluccia JA, Behrman JR, FloresR,MartorellR. Effect of a nutrition intervention in early childhood oneconomic productivity in Guatemalan adults. Lancet 2008;371:411-6.

Reprint requests:Prof.CarolineHD,MRCEpidemiologyResourceCentre,UniversityofSouthampton,SouthamptonGeneralHospitalTremonaRoad,Southampton,UKSo166YD

e-mail:[email protected]


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