Long-term consequences of low birth weight and the role of neha - - PowerPoint PPT Presentation

Caroline Fall

Long-term consequences of low birth weight

and the role of maternal nutrition

neha

Coronary Heart Disease Mortality

Men and women born in Hertfordshire 1911-1930

Birthweight (pounds)

20 40 60 80 100 ≤5.5 -6.5 -7.5 -8.5 -9.5 >9.5 20 40 60 80 100 ≤5.5 -6.5 -7.5 -8.5 -9.5 >9.5

WOMEN n=5,585 MEN n=10,141

Barker D et al. Lancet 1989; ii: 577-80; Osmond C et al. BMJ 1993; 307: 1519-24

Type 2 diabetes and IGT (pre-diabetes)

Men and women aged 60-71 years, Hertfordshire (n=667)

5 10 15 20 25 30 35 40 45 ≤5.5 -6.5 -7.5 -8.5 -9.5 >9.5 5 10 15 20 25 30 35 40 45 ≤5.5 -6.5 -7.5 -8.5 -9.5 >9.5

IGT + DM DM Birthweight (pounds) Weight at one year (pounds)

BMJ 1991;303:1019-22, BMJ 1995;310:428-32

% %

Type 2 diabetes or pre-diabetes

Men and women aged 60-71 years, Hertfordshire (n=667)

BMJ 1991;303:1019-22, BMJ 1995;310:428-32

Normal (BMI <25) Overweight (BMI <28) Obese (BMI >28) 5 10 15 20 ≤6.5

• 8.5

>8.5 % Birthweight (lbs)

Small babies and infants….

• Coronary heart disease
• Hypertension
• Type 2 diabetes
• COPD
• Chronic kidney disease
• Osteopenia
• Poor mental health

Small babies and infants….

• Central adiposity
• Low muscle mass
• Altered endocrine

responses eg insulin, cortisol and growth hormone

• Inflammation
• Hyperlipidaemia

Mother unable to supply nutrients to satisfy fetal demand FETAL UNDERNUTRITION

Reduced nephron numbers

Central

• besity

Insulin resistance Type 2 diabetes Coronary heart disease

Inadequate ‘building blocks’ Adaptation to reduce demand

Hyperlipidaemia Hypertension

Mother’s diet and nutrient stores Mother’s ability to mobilise and transport nutrients ‘Supply-line’ to the fetus Uterine blood flow Placental structure and function

Kidneys Liver Pancreas Muscle, Fat, Bone Brain HPA axis

Altered zonation ↓ Insulin sensitivity ↓ IGF-1 ↓ β cells ↓ Insulin secretion ↓ Muscle and bone ↑ Fat ↓ Insulin sensitivity Appetite centres Leptin resistance ↑ Cortisol Early maturation

Mother unable to supply nutrients to satisfy fetal demand FETAL UNDERNUTRITION

Reduced nephron numbers

Central

• besity

Insulin resistance Type 2 diabetes Coronary heart disease

Inadequate ‘building blocks’ Adaptation to reduce demand

Hyperlipidaemia Hypertension

Mother’s diet and nutrient stores Mother’s ability to mobilise and transport nutrients ‘Supply-line’ to the fetus Uterine blood flow Placental structure and function

Kidneys Liver Pancreas Muscle, Fat, Bone Brain HPA axis

Altered zonation ↓ Insulin sensitivity ↓ IGF-1 ↓ β cells ↓ Insulin secretion ↓ Muscle and bone ↑ Fat ↓ Insulin sensitivity Appetite centres Leptin resistance ↑ Cortisol Early maturation

Obesity and Inactivity

5 10 15 20 25 30 35 40 10 20 30 40 50 60 70 80 90

Low protein

Control

Time

Plasma glucose in adult

• ffspring

(mmol/l)

Hales & Ozanne. Biochem Soc Transac 1996;24:341-50

Maternal protein restriction

In rats, maternal protein restriction in pregnancy:

• Raised blood pressure,
• Increased adiposity
• Insulin resistance
• Glucose intolerance

In the adult offspring

Maternal global diet restriction

Vickers MH et al. Current Drug Targets 2007; 8: 923-34.

Birthweight and type 2 diabetes

Overall Nurses Health Study Pima Indians

2 2.5 3 3.5 4 4.5

Odds Ratio for Type 2 Diabetes

.75 1.25 1.75 2.25

Birth Weight (kg)

Whincup P et al. JAMA 2009

Low birth weight Diabetes

Insulin resistance (HOMA)

8-year-old children, Pune, India (n=477)

0.5 0.8 1.1 1.4 1.7 2.5

• 3.0

>3.0 <20 <22.8 22.8 

Birthweight (kg)

Bavdekar A et al. Diabetes 2000;48:2422-9



*** ** **

ns ns

**

Birthweight p=0.7 Current weight p<0.001 Birthweight p=0.03 Current weight p<0.001 Birthweight x current weight p=0.004

New Delhi: Childhood BMI of men and women who developed diabetes or pre-diabetes 230 out of 1518, aged 30 years

Bhargava et al New Eng J Med 2004;350:865-75

5 10 15 20 25 30

Age (years)

• 0.3

0.5

BMI SD score

Cohort mean

IGT/DM

Pune Maternal Nutrition Study

Women aged 15-40 yr in 6 rural villages N=2,466 Body measurements LMP dates 814 Pregnancies Maternal diet

Body composition

Blood nutrients

(Fe, Fol, B12, C, D)

Workload Fetal growth 770 Newborns Detailed anthropometry Children now aged 15 years Risk factors for diabetes and CHD

The ‘thin-fat’ newborn

Yajnik CS et al. Int J Obesity 2003 Modi N et al. Ped Res 2009 van Steijn L et al. Int J Obesity 2009 Fall CHD. Ann Hum Biol 2011

Pune Maternal Nutrition Study

Maternal nutrition and newborn size

Green leafy vegetables @ 28 wks

p<0.001

Factors linked to small newborn size and/or the ‘thin-fat’ baby Maternal stunting + adiposity Foods: Green leafy vegetables Fruit Milk Blood nutrients: Folic acid Vitamin B12 Homocysteine

Rao S et al. J Nutr 2001;131:1217-24

1.5 2.0 2.5 3.0 Never <1 per wk >1 per wk every

• ther

day

Birthweight (kg) Birthweight (kg)

1.5 2.0 2.5 3.0 <357 <505 505

p<0.001

Blood folate (nmol/l) @ 28 wks

≥

0.4 0.5 0.6 0.7 0.8 0.9 <113.6 <160.0 160.0 <357 <505 505 Vitamin B12 @ 18 wks p=0.04 Red cell folate @ 28 wks p<0.001

Pune Maternal Nutrition Study

Maternal nutrition and diabetes risk in the children

18-week Vitamin B12 (pmol/l)

70% of women had low B12 Only 1 had low folate

Insulin resistance (HOMA) in the child @ 6 years

Yajnik CS et al. Diabetologia 2008; 51: 29-38

Dutch Hunger Winter 1944-1945

II III IV II III IV I II III IV I II III IV I II III IV I

1941 1942 1943 1944 1945 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000

Carbohydrates Fats Protein Total number of calories

Average monthly rations 1941-1945

Dutch Hunger Winter

FAMINE EXPOSURE BORN BEFORE LATE GESTN MID GESTN EARLY GESTN CONCEIVED AFTER Maternal weight (kg) 66.7 61.8 63.5 67.9 69.1 Birthweight (g) 3372 3133 3217 3470 3413 Age 50 years SBP (mmHg) 126 127 125 123 125 LDL/HDL 2.9 2.8 2.7 3.3 2.9 120-min glucose (mmol/l) 5.7 6.3 6.1 6.1 5.9 Coronary heart disease % 4 3 1 9 3 IGT/diabetes % 15 21 14 16 15 Chronic airways dis % 16 15 25 23 17 ‘Poor health’ 5 6 4 10 5

Roseboom TJ Mol Cell Endocrinol 2001;185:93-98

Stein AD et al. Am J Epidemiol 2006 164:1160-1170

INCAP trial, Guatemala

1969-1977 Cluster randomised by village; Pregnant/lactating women and children <7 years

ATOLE Protein 6.4 g/100ml Energy 900 kcal/l FRESCO Energy 330 kcal/l Both supplements contained multiple micronutrients

INCAP trial

Effects on risk factors at 25-42 years. Atole compared with Fresco

• 15

15

FASTING GLUCOSE (mg/dl) mg/dl SYSTOLIC BLOOD PRESSURE (mm Hg) mm Hg HDL CHOL (mg/dl) mg/dl TRIGLYCERIDES (mg/dl) mg/dl

Conception to 24 months (N= 257-332) Birth to 36 months (N=234-305) 24 to 48 months (N=263-359) 24 to 60 months (N=263-359) 36-72 months (N=198-277)

Stein AD et al. AM J Epidemiol 2006;164:1160-1170

• 50

50

• 5

5

• 10

10

ICDS supplements for mothers and children

Hyderabad, adolescents aged 13-18 years (N=1165) Intervention Control

Height (cm) 155.9 154.9 * BMI (kg/m2) 17.1 17.3 SBP (mmHg) 108.7 109.6 Arterial stiffness (%) 2.5 5.6 * LDL (mmol/l) 2.05 2.04 HDL (mmol/l) 0.99 1.00 Triglycerides (mmol/l) 0.82 0.83 Glucose (mmol/l) 4.68 4.72 HOMA 3.16 3.79

* Kinra S et al. BMJ 2008;337:a605

“Minimat” trial, Bangladesh

Nutritional supplementation for mothers in pregnancy Children (N=1,335) studied at 4 years

Food supplements from early pregnancy (8-10 wks) Multiple micronutrients Fe 30mg + Folic acid Fe 60mg + Folic acid Food supplements from mid-pregnancy (17 wks) Multiple micronutrients Fe 30mg + Folic acid Fe 60mg + Folic acid

Early food supplementation: ↓glucose ↓ LDL cholesterol Multiple micronutrients: : ↓glucose ↓ insulin

Lindstrom E et al. J DOHaD 2009;1 Suppl 1: S163

Multiple Micronutrient trial, Nepal

Cluster randomised in early pregnancy, 1999-2001, N=4926

1. Vitamin A alone 2. Vit A + folate 3. Vit A + iron + folate 4. Vit A + iron + folate + zinc 5. Vit A + multiple micronutrients

Children followed up at 6-8 years, N=3524 No differences in BP, glucose, insulin, lipids Iron+Folate+Zinc group had lower adiposity (skinfolds) Folate group had less Metabolic Syndrome

Stewart CP et al. J Nutr 2009; 139: 1575-81

High-energy biscuit trial, Gambia

Cluster randomised trial for 1460 women, 28 villages, 1989-1994 1015 kcal energy, 22g protein + micronutrients daily from ~20 wks gestation (during lactation in controls) Increased birth weight by 136 g (200 g hungry season) Reduced perinatal mortality

Children followed up at 11-17 years, N=1267 Fasting glucose lower in intervention group

• 0.05 mmol/l ((5% CI -0.10 to -0.001) p=0.05

No differences in BP, body composition, lipids, insulin

Hawkesworth S et al. AJCN 2011 (e-pub)

Maternal folic acid alters pups gene expression by epigenetic effects

Maternal folic acid, B6, choline & betain partially silences the agouti gene Heritable DNA methylation

Waterland RA Mol Cell Biol 2003;23:5295-300

Effects of maternal low protein diet ‘rescued’ by folic acid

Lillycrop KA J Nutr 2005;135:1382-6 Maternal low protein rat model  BP  methylation of specific genes (PPAR and GR) Prevented by supplementing mothers with folic acid

RCT of a daily micronutrient-rich snack for women before and during pregnancy (N=6000) Outcomes: Fetal growth, infant survival Jan 2006-Feb 2012

Mumbai Maternal Nutrition Project

Mumbai Maternal Nutrition Project

Randomised controlled trial of a micronutrient-rich food supplement Preconceptionally and during pregnancy; 6000 women

Multiple Micronutrient supplementation

Meta analysis of 12 trials in low-income countries

NOTE: Weights are from random effects analysis Overall (I-squared = 0.0%, p = 0.722) Guinea Bissau Pakistan Zimbabwe Niger Indonesia (Lombok) Mexico Nepal (Janakpur) Bangladesh Nepal (Sarlahi) Indonesia (Indramayu) Burkina Faso China Study ID

22.36 (8.30, 36.42) 48.88 (-29.95, 127.71) 73.14 (-11.32, 157.61) 31.84 (-31.78, 95.46) 53.98 (-42.53, 150.50) 15.27 (-15.09, 45.63) 9.49 (-54.13, 73.10) 75.50 (21.34, 129.65) 11.25 (-26.75, 49.25) 4.89 (-48.56, 58.34) 5.27 (-38.81, 49.34) 30.87 (-22.84, 84.58) 16.65 (-18.14, 51.45) ES (95% CI) 100.00 3.18 % 2.77 4.88 2.12 21.45 4.89 6.74 13.69 6.92 10.18 6.85 16.33 Weight 22.36 (8.30, 36.42) 48.88 (-29.95, 127.71) 73.14 (-11.32, 157.61) 31.84 (-31.78, 95.46) 53.98 (-42.53, 150.50) 15.27 (-15.09, 45.63) 9.49 (-54.13, 73.10) 75.50 (21.34, 129.65) 11.25 (-26.75, 49.25) 4.89 (-48.56, 58.34) 5.27 (-38.81, 49.34) 30.87 (-22.84, 84.58) 16.65 (-18.14, 51.45) ES (95% CI) 100.00 3.18 % 2.77 4.88 2.12 21.45 4.89 6.74 13.69 6.92 10.18 6.85 16.33 Weight

• 158

158

• 100
• 50

50 100 150 15 20 25 30

Mother’s body mass index (kg/m²)

The lines are truncated to the 5th and 95th percentiles for BMI for each dataset

Effect on birthweight (g) relative to control group

Fall CH et al. Food & Nutr Bulletin 2009;30:533-46

Effect on birth weight (g)

• Lower birthweight is a risk factor for type 2

diabetes, cardiovascular disease and other NCDs

• Maternal undernutrition is a risk factor for low

birthweight

• In experimental animals, maternal undernutrition

programmes cardio-metabolic disease; evidence for epigenetic effects

• Adds weight to the concept of better nutrition in

the ‘first 1000 days’ of life (gestation and first 2 post-natal years)

• Growing evidence that nutritional interventions

improve fetal growth and later cardio-metabolic risk