LONG TERM IMPACT OF MALNUTRITION IN PREGNANCY Fetal origins of chronic disease Dr Sabby Kant GPSI Cardiology
My Objectives This Evening is to. make you think of your lovely mum & your BW introduce you to an exciting new field of DOHAD A paradigm (evolution, comparative biology, etc) that will shift the way you thinking about pregnancy & chronic diseases compel you to pinch your belly & grope your ankles! But 2 caveats: 1. South Asian context but the principles apply to all 2. Nosey Generalist
1. Relatively undernourished mum 42kg, 1700cal/d mum s physiological adaptation 2. Fetus prioritises glucose for the brain (blood bypass systems) 3. Switches off glucose to muscles/bone (less investment in skeletal growth) 4. Skeletal muscles atrophy (small lean mass) 5. Smaller capillary beds (organs) 6. Extra sugar stored as central fat (anticipating a starving environment) 7. THIN FAT LIGHT baby BW 2.65kg 8. PREDICTIVE ADAPTIVE RESPONSE (PAR) The Story Of Baby Shakti
Shakti
The Evolutionary Imperatives Evolution only cares for Reproductive Fitness There is a need for survival mechanisms to cope with shorter environmental changes (intergenerational) Plenty of examples in the world of biology Environmental influence leads to varying phenotypes within same genotype The Thrifty Genotype hypothesis does not apply here as mutations and genetic drift takes multiple generations (thousands of years) Meadow vole American alligator
The Thrifty Genotype (Neel) 1960s selection of IR genes in certain populations Neel, J.V. (1962). Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am. J. Hum. Genet. 14: 353-362 The Thrifty Phenotype (Barker) David Barker Type 2 diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35:595 601 1992 We only have 35,000 genes Under nutrition at certain stages of pregnancy programmes the fetus's physiology for more efficient utilisation & storage of food energy
Animal Studies Rats and Mice Studies Rat pups undernourished in utero develop central obesity Reduce maternal protein in diet > offspring get IR, stiff arteries, raised BP > feed pups high fat they get even fatter > subsequent generations affected (even if back on normal diet) environment can have multigenerational effects independent of genetic inheritance Add glycine or folate to the protein poor maternal diet and the effect is reversed
Evidence Framework ASSOCIATION PLAUSIBILITY CAUSALITY
Barker s Observational Study 1900s 1970s
Barker s Hertfordshire Longitudinal Study Risk 7 6 5 4 3 2 1 0 Risk of diabetes or glucose intolerance at age 64 according to birth weight <5.5-6.5-7.5-8.5-9.5 >9.5 Birthweight (lb) Birth-Weight is only a crude surrogate for suboptimal Nutritionalso influenced by genetics, infection, etc
SYSTOLIC BP by Birth weight Herts Data n=468 (men aged 59 70 yrs) 170 Systolic blood pressure 165 160 5.5-6.5-7.5-8.5-9.5 >9.5 Birthweight
30 25 20 % 15 10 Birth Weight & metabolic syndrome Other associations with low BW Abnormal lipid profiles Low bone density Less elastic arteries Altered cortisol response to stress Altered autonomic function 5 0 >5.5-6.5-7.5-8.5-9.5 >9.5 Birthweight (lb)
Dutch Winter Hunger [1944] Families Study 2004 malnourised first 6m of preg Daily ration 400-800 C for 7m
The new science of DOHAD Developmental Origins of Health & Disease inactivity + nutrition transition PAR Survival Phenotype Mismatch Phenotype Disease Critical windows of plasticity for programming nutrition Availability of plasma glucose Catch-up growth Low energy requirements Energy sparing physiology Tendency to store fat Small organs (less reserve) Enchanced stress response IMPROVES SURVIVAL UNTIL REPRODUCTION reproduction Metabolic syndrome Raised BP Obesity Inflammatory fat EARLY ANTECEDANTS TO DISEASE Mismatch Diabetes CVD Osteoporosis Cancers Pre conceptn birth early puberty post-reproductive years
The Pune Maternal Nutrition Study 1993+ (prospective data)
PUNE STUDY The Thin Fat Baby DSc =deep subcut tissue, SSc=superficial, TAT=thigh adipose tissue
Fetal Programming Processes whereby IN UTERO ENVIRONMENTAL CHALLENGES (nutritional, endocrine, etc) provokes long term adapative physiological imprinting in the fetus. MISMATCH to the outside environment leads to dysfunctional physiology leading to chronic disease FOETAL PROGRAMMING CRITICAL WINDOW POST-NATAL PROGRAMMING Cardio-metabolic Disease -Maternal undernutrition -Inflammation / infection -Placental health Epigenetic mechanisms Modulation of gene expression Inflammation Cancers
Mechanisms for Thrifty Survival Phenotype FETAL NUTRITION mum s phenotype>>her diet >>nutrient stores >> SUPPLY LINE >> transport systems >> uterine flow>>placenta>> umb cord >> >> fetal circulation >>tissue uptake Inadequate building blocks smaller body less energy needs Adaptation to reduce demand Kidney s Liver Pancrea s Muscle, Fat, Bone Brain HPA axis Reduced nephron numbers Altered zonation IGF-1 IS βcells Insulin Muscle & bone Fat, IS Appetite centres Leptin Resistance Cortisol Early maturation Hyperlipidaemia Hypertension Central obesity Insulin resistance T2DM, CVD OBESOGENIC ENVIRONMENT
Epigenetic mechanisms Methyl donors like folate & vitamin B12 play a pivotal role in epigenetic changes.
A key in utero mechanism? Pune Maternal Nutrition Study Low Maternal B12 at 18 wks = IR in child Maternal folate and low B12 = IR in child Vitamin B12 acts as an methyl donor
What happens to thin fat babies as they get older?
Catch up growth Evolutionary rush to reproductive fitness Looks healthy but is it? But in today s world of nutrition & inactivity transition. against a super sensitive physiology early tipping into dysmetabolic state
BP sensitivity to weight gain in girls
Double trouble Short, Malnourished Mum Thin-Fat Baby Remains malnourished unhealthy HEALTHY Unhealthy life CATCH UP Nutrition transition URBANISATION (energy rich, sedentary) Fat Nourished Short mum Unhealthy life Hyperglycaemia HEALTHY Fat Baby
Diabetes Epidemic super-sensitive physiology? The Fetal Matrix Gluckman Hanson
Diabetes Epidemic Despite screaming at them for the last 25 years, there are no effective public health programs in India. They are facing a catastrophe within the next generation Philip James (WHO)
Does epigenesis last for generations? Conclusion Except for subscapular skinfold thickness & length, all neonatal measurements were intermediate between those from Southampton & Pune. The thin-fat phenotype is preserved in neonates of the 4 th to 5 th generation after migration from India
Thin fat trait into adulthood (UK Asians) Prof Chaturvedi Epidemiologist Imperial College
Newly diagnosed DM ( Indian vs Cauc. UK) Yajnik CS, Nutr Rev 2001
Mismatch: the toxic environment Rapid nutritional & physical inactivity transition
Lifestyle health starts in utero! Proactive Care GP Reactive Care
Lifespan Medicine in Primary Care? but still need to establish whether in humans, maternal under nutrition programmes adult chronic disease what optimal fetal nutrition is what the optimal diet is for women preparing for pregnancy Optimal health = RE-BALANCING PHYSIOLOGY (lifestyle, pharmacology, etc) THE SECRET TO HEALTHY GENERATIONS LIES IN THE HEALTH OF THE FUTURE MUMS Good Nourishment Bad nourishment
If the world doesn t wake up, this thing WILL knock down generations David Barker Bloomberg Markets Magazine Nov 2010 Acknowledgment Prof. David Phillips (Southampton) for some slides