1. family and parenting
2. motherhood
3. pregnancy

Review Article
Indian J Med Res 130, November 2009, pp 593-599
Maternal nutrition: Effects on health in the next generation
Caroline Fall
MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital
Southampton, UK
Received April 24, 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 words Low birth weight - foetal growth - maternal nutritional status - underweight
Introduction
was because of better childhood living conditions brought
about by social reforms. In 1977, Forsdahl2 discovered a
geographical correlation in Norway between heart disease
mortality in 1964-1967 and infant mortality rates 70 years
earlier. He suggested that growing up in poverty caused
‘permanent damage’ perhaps due to a ‘nutritional deficit’,
which resulted in ‘life-long vulnerability’ to an affluent
adult lifestyle and high fat intakes.
The concept that longevity is influenced by events in
early life is not new. In 1934, Kermack et al 1 showed
that death rates in Europe from 1751 to 1930 fell with
each successive year-of-birth cohort. They rejected one
possible explanation, that ‘a more healthy race of children
was born in each successive decade’, and thought that it
593
594
INDIAN J MED RES, NOVEMBER 2009
Studies by Barker & Osmond3,4 in the UK, a
decade later, focused on pre-natal factors. Differences
around the UK in neonatal mortality (a marker for
low birthweight) in 1921-1925 predicted death rates
from stroke and heart disease in 1968-19783. The
discovery of birth records dating from 1911 in the
county of Hertfordshire made it possible to show that
low birthweight and weight at one year were associated
with an increased risk of death from cardiovascular
disease4. There was an approximate doubling of
mortality from the highest to the lowest extremes of
birthweight. Based on these findings, they put forward
the controversial hypothesis that poor foetal and early
post-natal nutrition was a cause of adult cardiovascular
disease. He was convinced that falling mortality rates in
the western world were because mothers, and therefore
foetuses and babies, were better nourished, with each
succeeding generation.
Since then, studies around the world have shown
that lower birthweight is associated with an increased
risk of a wide range of health problems in adult life,
including type 2 diabetes5, metabolic syndrome6,
chronic lung disease7, osteoporosis8 and mental
illness9. There is also a wealth of data showing that
poor intrauterine and infant growth and nutrition are
associated with reduced capacity in adult life, including
reduced stature, lower physical work capacity, impaired
cognitive function and educational attainment, and (for
women) an increased risk of low birthweight in the next
generation10. These studies have led to a new branch of
scientific research: the developmental origins of health
and disease (DOHaD).
or ‘programmed’ because they occur during critical
periods of early development. The mechanisms by which this could occur11-15
include simple growth failure, leading to impaired
organ size and structure, for example, reduced numbers
of pancreatic beta cells, renal nephrons or brain
neurones, and altered arterial structure. These include
altered endocrine settings, for example, reduced insulin
secretion and sensitivity, and upregulation of the HPA
axis and sympathetic nervous system. At a cellular
level, these include altered epigenetic characteristics
– changes to the proteins and other molecules attached
to DNA which control gene expression. Each of these
changes can lead directly to adult cardiovascular
disease, or render the individual more susceptible to
the effects of environmental stressors such as obesity
arising in later life.
The programming hypothesis is supported by
numerous examples of nutritional programming
in experimental animals. In rats, maternal protein
restriction in pregnancy leads to higher blood pressure16,
impaired glucose tolerance17, insulin resistance18,19, and
altered hepatic architecture and function20 in the adult
offspring. Animal experiments allow more sophisticated
study of the mechanisms of programming at tissue and
cellular levels. For example, insulin resistance and
The foetal programming hypothesis
Obviously, it is not low birthweight of itself that
causes these problems, but what low birthweight
represents: foetal undernutrition and impaired
development11 (Fig. 1). The foetus depends on the
transfer of nutrients from the mother, and adapts to
inadequate nutrition in several ways: prioritization of
brain growth at the expense of other tissues such as
the abdominal organs, altered secretion and sensitivity
to the foetal growth hormones insulin and insulinlike growth factor-1 (IGF-I), and upregulation of the
hypothalamo-pituitary-adrenal (HPA) ‘stress’ axis.
The foetus sacrifices tissues that require high-quality
building blocks, like muscle or bone, and instead
lays down less demanding tissue, like fat. Although
occurring in response to a transient phenomenon (foetal
undernutrition), these changes can become permanent
Fig. 1. The foetal programming hypothesis; flow diagram illustrating proposed effects of intra-uterine nutrition on the foetus, and
long-term effects on metabolism and disease risk. Source: Ref. 23.
FALL: DEVELOPMENTAL ORIGINS OF HEALTH & DISEASE
595
impaired glucose tolerance in adult offspring of proteindeprived rats results from reduced gene expression for
enzymes in the insulin-signalling pathway18. Raised
blood pressure in the offspring of protein-deprived
rats has been linked to epigenetic changes that can be
prevented by supplementing the mother with folate21.
cholesterol concentrations and subscapular/triceps
skinfold ratios, and after adjusting for 8-year weight,
higher systolic blood pressure and insulin resistance22.
These risk factors were highest in children who were
born small but became the biggest (heaviest, tallest and
most adipose) at 8 years.
Associations of cardiovascular disease and its risk
factors with different body proportions at birth may
reflect undernutrition during critical periods in gestation
for the development of tissues and organ systems11. Male
and female foetuses have different growth priorities,
and adapt differently to undernutrition, reflected in
sex differences in associations with neonatal body
proportions11. The hyperplastic development of many
tissues continues in early infancy, and undernutrition
during infancy is probably equally important3.
Another clear example of the disadvantages being
small in early life and becoming obese as an adult
came from a study of young adults in New Delhi, who
were measured at birth and every 6 months until the
age of 21 yr23. Mean birthweight was only 2.9 kg. As
children, many of the cohort were underweight-forage [53% at the age of 2 yr, using National Center for
Health 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
>30 kg/m2). Four per cent already had type 2 diabetes
and 15 per cent had impaired glucose tolerance (IGT)
(pre-diabetes). After adjusting for adult BMI, plasma
glucose concentrations and insulin resistance were
inversely related to birthweight, and IGT and diabetes
were associated with lower weight and BMI at the
age of 1 yr. In contrast, the childhood growth of those
who developed IGT or diabetes was characterised by
accelerated BMI gain relative to the rest of the cohort
(Fig. 2). From being below the cohort mean for BMI at
2 years they were well above the mean at 30 years. The
highest prevalence of IGT and diabetes was in men and
Research in the Indian scenario
Indian researchers have made a major contribution
to the DOHaD field and towards its translation into
improved human health. A study of CVD risk factors
in Indian children was the first in a developing country
to examine associations between size at birth and
later risk22. Among 4 yr old children born in the KEM
Hospital, Pune, lower birthweight was associated with
higher plasma glucose concentrations after an oral
glucose load. When the children were re-studied at
8 years, those of lower birthweight had higher LDL-
Age (yr)
Age (yr)
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,
and when studied at 26-32 yr, for subjects who developed IGT or diabetes. Mean SD scores are indicated by the solid line, and 95 per cent
CI’s by dotted lines. The mean SD score for the whole cohort is zero. [Reprinted with permission from the Massachusetts Medical Society
(The New England Journal of Medicine 2004; 350 : 865-75)].
596
INDIAN J MED RES, NOVEMBER 2009
women who had low BMI SD scores in infancy but
high SD scores at 12 years or later.
There are a number of possible reasons why
weight gain in childhood, on a background of foetal
restriction, might cause disease. Low birthweight
babies tend to catch-up (compensatory growth), and
the rapidity of post-natal growth may simply indicate
the severity of growth retardation at birth. Alternatively
the process of catch-up may be disadvantageous in
itself. It may impose excess demand on other tissues
which are not capable of compensatory hyperplasia,
such as the pancreas. It may alter body composition;
animals can gain excessive fat if they are placed on
a high plane of nutrition after a period of early postnatal undernutrition24. McCance suggested that good
nutrition at this stage emphasises the development of
tissues like fat, which maintain the capacity for growth
throughout life, but cannot recover tissues such as
muscle, which develop earlier and lose the capacity for
cell division24. Another possibility is that the hormones
driving catch-up growth have adverse cardiovascular
and metabolic effects25.
The Pune Maternal Nutrition Study has given
insight into foetal development in Indian populations.
This is a prospective population-based observational
study of rural Indian women and their offsprings26,27.
The mothers were short and thin (mean pre-pregnant
height and BMI: 152 cm and 18.1 kg/m2) and the
mean full term birthweight was only 2.7 kg. Detailed
anthropometry of the newborns showed that their body
composition differed from white Caucasian babies born
in the UK27. They were lighter by almost 2 standard
deviations, and lean tissues such as muscle (mid-upperarm circumference) and abdominal viscera (abdominal
circumference) showed a similar deficit. Truncal fat
(subscapular skinfolds), however, was relatively ‘spared’
(-0.5 SD). Thus, although extremely small and thin, the
babies were relatively adipose. A similar pattern has
been confirmed in urban Indian populations28.
The aetiology of the muscle-thin but adipose ‘thinfat’ phenotype of Indian newborns is unknown. The
adiposity is related to maternal adiposity and lipid,
glucose and insulin concentrations, but the low lean
mass is unexplained. The phenotype may be ‘adaptive’
and carry survival advantage; for example, in the face of
a nutritional deficit, muscle growth may be sacrificed,
and fat laid down preferentially as a substrate for brain
growth and/or immune function. Its consequences
for later health are unknown; however it echoes the
well-described adult Indian phenotype (lower muscle
mass, higher percentage body fat, and greater tendency
to central adiposity than white Caucasians) that is
strongly associated with type 2 diabetes29. The findings
highlight the fact that birthweight provides only a
crude summary of foetal growth and fails to describe
potentially important differences in the development of
specific tissues.
Studies in India have also highlighted problems
associated with maternal diabetes, which causes
extreme high rather than extreme low birthweight. In
a recent study of contemporary women giving birth in
Mysore30, the prevalence of gestational diabetes was
high (6%) despite a low average maternal age and
BMI. As expected, babies born to diabetic mothers
were heavier (mean birthweight 3339 g) than babies of
mothers with normal glucose tolerance (2956 g). When
studied at the age of 5 yr, they were more adipose and
had higher insulin concentrations, than children of nondiabetic mothers30.
The role of nutrition
Foetal growth depends on the uptake of nutrients,
which occurs at the end of a complex materno-foetal
supply line31. This includes intake, i.e., the mother’s
appetite, diet and absorption. The nutrients arriving at
the placenta, and how they are transferred to the foetus,
depend on maternal metabolism: her endocrine status,
her partitioning of nutrients between storage, utilization
or circulation, and her cardiovascular adaptations to
pregnancy, such as plasma volume expansion which
increases uterine blood flow. These are influenced by
maternal nutrition in ways that are poorly understood.
The link between maternal and foetal nutrition is thus
indirect and explains why the full impact of maternal
diet on foetal growth remains unclear.
Foetal growth can be readily restricted in
experimental animals by reducing maternal intakes
of energy and protein during pregnancy31. Energy and
protein deficiency in the mother is also associated
with intrauterine growth retardation in humans, size at
birth is strongly related to maternal body mass index,
and during acute famine birthweight falls by several
hundred grams32,33. However, randomised clinical trials
(RCTs) of energy and/or protein supplements have
shown only small effects on birthweight34. There is
evidence that supplementing undernourished mothers
with micronutrients, or improving the diet quality,
increases foetal growth. The Pune Maternal Nutrition
Study showed that mothers with higher intakes of
FALL: DEVELOPMENTAL ORIGINS OF HEALTH & DISEASE
micronutrient-rich foods like green leafy vegetables,
fruit and milk had babies that were larger in all body
dimensions26. Several recent RCTs have also shown
increased newborn size after maternal micronutrient
supplementation, although the increase was small35,36.
Foetal growth is related to maternal height and
birthweight. This suggests that undernutrition of the
mother during her own foetal life and childhood growth
limits the growth of her foetus. Effects of the mother’s
current nutritional status are therefore influenced by
her own past nutrition and that of earlier generations.
A relatively un-researched time is the periconceptional period. Before the mother even knows
she is pregnant, and before placentation occurs,
sufficient nutrients must be present in the embryo’s
immediate environment. The importance of periconceptional nutrition has been demonstrated by the
reduction in neural tube defects with pre-conceptional
folate supplementation37. In experimental animals,
peri-conceptional undernutrition alters the allocation
of cells in the blastocyst and permanently changes the
foetal growth trajectory. Later effects in the offspring
include pre-term delivery and adult hypertension38,39.
Several micronutrients, especially those involved
in 1-carbon metabolism (such as folic acid and vitamin
B12) act as co-factors or molecular donors for epigenetic
processes such as DNA methylation, which modulate
gene expression, and therefore cellular proliferation
and apoptosis, during foetal development. Genomewide demethylation occurs just after fertilization,
followed by re-methylation at different stages of
embryonic development40. Epigenetic changes induced
at this time may become permanent and heritable,
determining outcomes in later life and in the next
generation. Maternal diet, and especially folate and
vitamin B12 intakes influences these processes. For
example, the phenomenon in rats by which maternal
protein restriction leads to hypertension in the offspring,
and its prevention by maternal folate supplementation,
have been linked to the de-methylation (by protein
restriction) and re-methylation (by folate) of specific
genes41.
597
surveys and famine studies. For example, the Dutch
Famine studies have shown that maternal exposure to
famine in late gestation was associated with glucose
intolerance and insulin resistance in the offspring42.
The current focus on developmental origins of
health and disease has led to the setting up of new
prospective studies in which detailed information on
maternal nutrition in pregnancy has been collected.
One of these, the Pune Maternal Nutrition Study, has
shown that low maternal calcium intake is associated
with lower bone mineral content in the children43.
This may be a simple example of inadequate ‘building
blocks’ for the tissue concerned. The same study has
also provided evidence of the importance of 1-carbon
metabolism in programming processes. Vitamin B12
deficiency in the mother, especially if she was folate
replete, was associated with increased body fat and
insulin resistance in the children (Fig. 3)44.
We are now beginning to see the DOHaD
hypothesis tested in intervention studies, by following
up the children of undernourished women who took
part in randomized controlled trials of nutritional
supplementation in pregnancy. A follow up study of
adults born during the INCAP trial in Guatemala, in
which villages were randomized to receive Atole45
(a high-energy, high-protein drink) or Fresco (lower
energy, no protein) found higher HDL-cholesterol
and lower triglyceride concentrations in those whose
mothers had Atole45. Among adolescents in India,
whose pregnant mothers received food-based energy
and protein supplements as part of a package of public
health interventions, insulin resistance and arterial
stiffness were reduced compared to controls46. Systolic
Maternal nutritional status and disease risk in the
offspring
If the foetal programming hypothesis is right, and
maternal nutrition has important effects on adult health,
correlations would be expected between measures of
maternal nutrition and disease in the offspring. Until
recently, the only data to test this were from old dietary
Fig. 3. Insulin resistance (HOMA) in children aged 6 yr from the
Pune Maternal Nutrition Study, in relation to maternal vitamin B12
(18 wk) and erythrocyte folate (28 wk). [Reprinted with permission from Springer (Diabetologia 2008; 51 : 29-38)].
598
INDIAN J MED RES, NOVEMBER 2009
blood pressure was lower (-2.5 mmHg) in 2-yr old
Nepali children whose mothers received multiple
micronutrients in pregnancy rather than standard iron/
folate tablets47. However, there were negative findings
in a trial of high-energy biscuits in the Gambia48. The
intervention reduced the incidence of low birthweight
by 40 per cent and halved perinatal mortality, but at
follow up there was difference in blood pressure
between children born to women who received the
intervention during pregnancy compared to women
who received it during lactation.
There are many good reasons for improving
the diets of undernourished mothers. The Gambia
supplement produced an impressive reduction in
perinatal mortality, and in Guatemala, early-life
exposure to Atole improved childhood growth and
adult economic productivity49. Clearly, at present,
there is inadequate evidence that such interventions
improve adult health in the offspring. The findings
from these trials suggest that there may be beneficial
effects on some cardiovascular risk factors, that these
are complex, and differ according to the population, the
intervention and the post-natal environment. Given the
need for much deeper understanding, it is to be hoped
that the investigators will follow up their subjects
further to determine the full extent of any effects, and
that other trials of enhanced materno-foetal nutrition
will add data to the currently meagre evidence-base on
this important issue.
Acknowledgment
The work reported in this review was supported by the Medical
Research Council, UK, the Wellcome Trust, UK, the British Heart
Foundation and the Parthenon Trust.
References
1.
Kermack WO, McKendrick AG, McKinlay PL. Death rates in
Great Britain and Sweden; some general regularities and their
significance. Lancet 1934; i : 698-703.
2.
Forsdahl A. Are poor living conditions in childhood and
adolescence an important risk factor for arteriosclerotic
disease? Br J Prev Soc Med 1977; 31 : 91-5.
3.
Barker DJP, Osmond C. Infant mortality, childhood nutrition,
and ischaemic heart disease in England and Wales. Lancet
1986; i : 1077-81.
4.
Barker DJP, Osmond C, Winter PDW, Margetts B, Simmonds
SJ. Weight in infancy and death from ischaemic heart disease.
Lancet 1989; ii : 577-80.
5.
EARLYREAD Collaboration. Birthweight and risk of type
2 diabetes: a quantitative systematic review of published
evidence. JAMA 2008; 300 : 2885-97.
6.
Ramadhani MK, Grobbee DE, Bots ML, Castro Cabezas M,
Vos LE, Oren A, et al. Lower birthweight predicts metabolic
syndrome in young adults: the Atherosclerosis Risk in Young
Adults (ARYA) study. Atherosclerosis 2006; 184 : 21-7.
7.
Barker DJP, Godfrey KM, Fall CHD, Osmond C, Winter
PD, Shaheen S. The relation of birthweight and childhood
respiratory infection to adult lung function and death from
chronic obstructive airways disease. BMJ 1991; 303 : 671-5.
8.
Cooper C, Westlake S, Harvey N, Javaid K, Dennison E,
Hanson M. Developmental origins of osteoporotic fracture.
Osteoporosis Int 2006; 17 : 337-47.
9.
Landon J, Davison M, Breier B. The developmental
environment: influences on subsequent cognitive function and
behaviour. In: Gluckman P, Hanson M, editors. Developmental
origins of health and disease. Cambridge: Cambridge
University Press; 2006. p. 370-8.
10. Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter
L, et al and the Maternal and Child Undernutrition Study
Group. Maternal and child undernutrition: consequences for
adult health and human capital. Lancet 2008; 371 : 340-57.
11. Barker DJP. Mothers, babies and health in later life. London:
Churchill Livingstone; 1998.
12. Lucas A. Programming by early nutrition in man. Ciba
Foundation Symposium No. 156, Chichester, UK: John Woley
and Sons; 1991. p. 38-50.
13. Waterland RA, Garza C. Potential mechanisms of metabolic
imprinting that lead to chronic disease. Am J Clin Nutr 1999;
69 : 179-97.
14. Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KMK.
Epigenetic control of fetal gene expression. Br J Obstet Gyncol
2008; 115 : 158-68.
15. Fall CHD. Fetal and maternal nutrition. In: Stanner S, editor.
Cardiovascular disease: Diet, nutrition and emerging risk
factors. Oxford, UK: British Nutrition Foundation Task Force.
Blackwell Publishing; 2005.
16. Langley SC, Jackson AA. Increased systolic blood pressure in
adult rats induced by fetal exposure to maternal low protein
diets. Clin Sci 1994; 86 : 217-22.
17. Ozanne SE, Hales CN. The long-term consequences of intrauterine protein malnutrition for glucose metabolism. Proc
Nutr Soc 1999; 58 : 615-9.
18. Ozanne SE, Dorling MW, Wang CL, Nave BT. Impaired PI
3-kinase activation in adipocytes from early growth-restricted
rats. Am J Physiol 2001; 280 : E534-9.
19.Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman
PD. Fetal origins of hyperphagia, obesity, and hypertension
and postnatal amplification by hypercaloric nutrition. Am J
Physiol Endocrinol Metab 2000; 279 : E83-7.
20. Hales CN, Desai M, Ozanne SE, Crowther NJ. Fishing in the
stream of diabetes: from measuring insulin to the control of
fetal organogenesis. Biochem Soc Trans 1996; 24 : 341-50.
21. Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R,
Jackson AA, et al. Folate supplementation during pregnancy
improves offspring cardiovascular dysfunction induced by
protein restriction. Hypertension 2006; 47 : 982-7.
22. Bavdekar A, Yajnik CS, Fall CHD, Bapat S, Pandit AN,
Deshpande V, et al. The insulin resistance syndrome (IRS) in
eight-year-old Indian children: small at birth, big at 8 years or
both? Diabetes 2000; 48 : 2422-9.
FALL: DEVELOPMENTAL ORIGINS OF HEALTH & DISEASE
23. Bhargava SK, Sachdev HPS, Fall CHD, Osmond C, Lakshmy
R, Barker DJP, et al. Relation of serial changes in childhood
body mass index to impaired glucose tolerance in young
adulthood. N Engl J Med 2004; 350 : 865-75.
24. McCance RA. Food, growth and time. Lancet 1962; ii :
621-6.
25. Lever AF, Harrap SB. Essential hypertension: a disorder of
growth with origins in childhood? J Hyperten 1992; 10 :
101-20.
26. Rao S, Yajnik CS, Kanade A, Fall CHD, Margetts BM, Jackson
AA, et al. Intake of micronutrient-rich foods in rural Indian
mothers is associated with the size of their babies at birth; the
Pune Maternal Nutrition Study. J Nutr 2001; 131 : 1217-4.
27. Yajnik CS, Fall CHD, Coyaji KJ, Hirve SS, Rao S, Barker
DJP, et al. Neonatal anthropometry: the thin-fat Indian baby;
the Pune Maternal Nutrition Study. Int J Obesity 2003; 27 :
173-80.
28. Krishnaveni GV, Hill JC, Veena SR, Leary SD, Saperia J,
Chachyamma KJ, et al. Truncal adiposity is present at birth
and in early childhood in South Indian children. Indian Pediatr
2005; 42 : 527-38.
29. Yajnik CS. Obesity epidemic in India: intra-utrine origins?
Proc Nutr Soc 2004; 63 : 1-10.
30. Krishnaveni GV, Hill JC, Leary S, Veena SR, Saperia J,
Saroja A, et al. Anthropometry, glucose tolerance and insulin
concentrations in Indian children: relationships to maternal
glucose and insulin concentrations during pregnancy. Diabetes
Care 2005; 28 : 2919-25.
31. Harding JE. The nutritional basis of the fetal origins of adult
disease. Int J Epidemiol 2001; 30 : 15-25.
32. Leary S, Fall CHD, Osmond C, Lovel H, Campbell D,
Eriksson J, et al. Geographical variation in relationships
between parental body size and offspring phenotype at birth.
Acta Obstet Scand 2006; 85 : 1066-79.
33. Susser M, Stein Z. Timing in prenatal nutrition: a reprise of
the Dutch Famine Study. Nutr Rev 1994; 52 : 84-94.
34. Kramer MS. Balanced protein/energy supplementation in
pregnancy. In: The Cochrane Library, Issue 3. 2001 Oxford:
Update software.
35. Haider BA, Bhutta ZA. Multiple-micronutrient supplementation
for women during pregnancy. Cochrane Database Syst Rev(4),
CD004905, 2006.
36. Bhutta Z, Ahmad T, Black RE, Cousens S, Dewey K,
Giugliani E, et al and the Maternal and Child Undernutrition
Study Group. What works? Interventions to affect maternal
and child undernutrition and survival globally. Lancet 2008;
371 : 417-40.
37. Lumley J, Watson L, Watson M, Bower C. Periconceptional
supplementation with folate and/or multivitamins for
preventing neural tube defects. Cochrane Database Syst Rev
2001; 3 : CD001056.
599
38. Bloomfield F, Oliver M, Harding JE.The late effect of fetal
growth patterns. Arch Dis Child Fetal Neonatal Ed 2006; 91 :
299-304.
39. Watkins AJ, Wilkins A, Cunningham C, Perry VH, Seet MJ,
Osmond C, et al. Low protein diet fed exclusively during mouse
oocyte maturation leads to behavioural and cardiovascular
abnormalities in the offspring. J Physiol 2008; 586 : 2231-44.
40. Godfrey KM, Lillycrop KA. Epigenetic mechanisms and the
mismatch concept of the developmental origins of health and
disease. Ped Res 2007; 61 : 5R-9R.
41. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge
GC. Dietary protein restriction of pregnant rats induces, and
folic acid supplementation prevents, epigenetic modification
of hepatic gene expression in the offspring. Br J Nutr 2005;
135 : 1382-6.
42. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C,
Barker DJP, Hales CN, et al. Glucose tolerance in adults after
prenatal exposure to famine. Lancet 1998; 351 : 173-7.
43. Ganpule A, Yajnik CS, Fall CHD, Rao S, Fisher DJ, Kanade A,
et al. Bone mass in Indian children; relationships to maternal
nutritional status and diet during pregnancy; the Pune Maternal
Nutrition Study. J Clin Endocrinol Metab 2006; 91 : 29943001.
44. Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S,
Fisher DJ, et al. Vitamin B12 and folate concentrations during
pregnancy and insulin resistance in the offspring: The Pune
Maternal Nutrition Study. Diabetologia 2008; 51 : 29-38.
45. Stein AD, Wang M, Ramirez-Zea M, Flores R, Grajeda R,
Melgar P, et al. Exposure to a nutrition supplementation
intervention in early childhood and risk factors for
cardiovascular disease in adulthood: evidence from Guatemala.
Am J Epidemiol 2006; 164 : 1160-70.
46. Kinra S, Sarma KVR, Ghafoorunissa, Mendu VVR, Ravikumar
R, Mohan V, et al. Effect of integration of supplemental
nutrition with public health programmes in pregnancy
and early childhood on cardiovascular risk in rural Indian
adolescents: long term follow-up of Hyderabad nutrition trial.
BMJ 2008; 337 : 1-10.
47. Vaidya A, Saville N, Shrestha BP, Costello AM, Manandhar
DS, Osrin D. Effects of a maternal multiple micronutrient
supplement on children’s weight and size at 2 years of age
in Nepal; follow-up of a double blind randomised controlled
trial. Lancet 2008; 371 : 452-4.
48. Hawkesworth S, Prentice A, Fulford A, Moore S. Maternal
protein-energy supplementation does not affect adolescent
blood pressure in the Gambia. Int J Epidemiol 2009; 38 :
119-27.
49. Hoddinot J, Maluccia JA, Behrman JR, Flores R, Martorell
R. Effect of a nutrition intervention in early childhood on
economic productivity in Guatemalan adults. Lancet 2008;
371 : 411-6.
Reprint requests: Prof. Caroline HD, MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital
Tremona Road, Southampton, UK SO16 6YD
e-mail: chdf@mrc.soton.ac.uk