Low birth weight and brain disorders..

The prevalence of low is greater than in

1953

Michael A. Crawford

Institute of Brain Chemistry and Human Nutrition,

.

michael@macrawf.demon.co.ukhttp://www.londonmet.ac.uk/ibchn

Last century, science and food policy focussed on protein and body growth.

H. Sapiens is about brain growth not body growth.

.

Note the similar sizes of the brain case of the 1 year old and his mother

Note the sizes of the hands.

The brain is the first priority on H. sapiens

Body = proteinBrain = lipids.

Priority for food policy is the brain specific lipid.

Central Nervous System Disorders And Birthweight

0

5

10

15

20

25

1000 2000 3000 4000 5000

% CNS Disorder

Birthweight grams UK OPCS DATA

Key milestones in the Hackney Project

1980 Hackney Baseline Poor Nutrition = LBW

1982 Hackney vs Hampstead Socio-economic diff.

1988 Intervention last trimester Diet at conception

more powerful

1990 12-14 yr school children Girls << Boys

1998 Inter-pregnancy Enter 2nd deficient

folate, iron, omega 3

2005 RCT 450 pregnancies Reduction in small for

gestational age

2008 Ethnicity study Diet-LBW independent

smoking, ethnicity,

socio-econmic status.

Hackney Project.

During the 1st trimester :

• significant correlation between BW and maternal intake of

many micronutrients, notably thiamin, niacin, Mg and Fe

• there was a strong social class gradient with both nutrient intakes

and birthweight.

.W., Wynn, A.H.A., Doyle, W. and Crawford, M.A. (1994) The association of maternal social class with maternal

diet and the dimensions of babies in a population of London Women. Nutr. Health 9: 303-315.

Mothers of LBW (<2.5kg) babies :

• had significantly lower intakes of almost all vitamins and

minerals than mothers of babies weighing 3.5-4.5kg

• had vitamin and mineral intakes well below the RNIs

Doyle et al, (1992) J Nutr. Med. 3:249-56.

Mean daily intakes in 1st trim. of pregnancy in 193

mothers with BWs 2.5 kg & 3.5 - 4.5 kg at birth

2.5 kg 3.5-4.5 kg p=

n = 28 n = 165

Energy kcals 1642 1974 0.001

Magnesium mg 209 283 < 0.001

Iron mg 9.35 12.9 < 0.001

Phosphorus mg 1039 1315 0.001

Copper mg 1.26 1.70 0.001

Zinc mg 8.16 10.2 0.003

Thiamin (B1) mg 0.96 1.21 < 0.001

Niacin (B3) mg 12.3 16.1 0.001

Pyridoxine (B6)mg 1.16 1.50 0.001

Riboflavin (B2) mg 1.48 1.96 0.002

Mean Daily intake of mothers in Hackney and

of non-pregnant, women in the UK

LBW Average UK Opt BW

mothers women mothers

n = 165 n = 1110 n = 128

Energy kcals 1642 1680 1975

Protein g 62.8 62.0 74.4

Fat g 72.4 73.5 88.9

Carbohydrate g 195 193 231

BIRTHWEIGHT RISK BY THIAMINE

INTAKE Mg/day. Wynn et al 1991, Nutr & Health

7: 69-88.

0.0120

0

0.43-0.9 1.1 0.26 1.48 1.49-2.46

0.025

0.06

0.108

Wynn et al 1991, Nutr

& Health 7: 69-88.

There is a greater

than ten fold

increment in low

birthweight risk

with a five fold

reduction in

thiamine intakes.

The Brain is Made of

Fat(60% of its structural material)Just as protein requires essential amino acids so the brain requires

ESSENTAL FATTY ACIDS especially.

Docosahexaenoic acid DHA

Synthesis of Arachidonic (AA) & Docosahexaenoic (DHA)from LINOLEIC & a -LINOLENIC ACIDS

N-6 or OMEGA 6 FamilyAA

18:2w6 18:3w6 20:3w6 20:4w6 22:4w6 22:5w6

Linoleic Gamma-linolenic Arachidonic

prostaglandins & leukotrienes

N-3 or OMEGA 3 FamilyEPA DHA

18:3w 3 18:4w3 20:4w3 20:5w3 22:5w3 22:6 w3

Alpha-linolenicEicosapentaenoic Docosahexaenoic

Peroxisomes

24:5w3 24:6w3

Long-lived Molecules in Long-Lived Cells Record Isotope Ratios – “Molecular Fossils”

Immigrants (European-born Americans) living in the USA (average = 46 yrs) have cerebellar DNA d13C resembling European-born Europeans, not Americans. (You are what your mom ate.)

Estimated turnover of neuronal DNA: t½ > 71 years.

Drawn from Slatkin, Friedman, Irsa,

Micca, The Stability of Human

Cerebellar Neurons. Science, 1985.

-22

-21

-20

-19

-18

-17

-16

-15

Neuronal DNA White matter

d1

3C

(‰

) American

Immigrant

European

Adapted by J T Brenna

Primate Omega 3 deficiency/ linoleic excess – Capuchins

– hair, skin & behavioural pathology.Fiennes Sinclair & Crawford 1973 J. Med. Prim. 2: 155 169.

Primate Omega 3 deficiency & linoleic

excess – fatty liver & loss of vascular

elastic tissue

Omega 3 Deficiency & Brain Haemorrhage During Growth Spurt.A model of intraventricular haemorrhage, infant stroke and neurodevelopmental disorder.Budowski, P., Hawkey, C.M. and Crawford M.A. (1980) L'effet protecteur de l'acide alpha-linolenique sur

l'encephalomalacie chez le poulet. Ann. Nutr. Alim. 34: 389-400.

Brain Essential Fatty Acid Composition

Ethanolamine Phosphoglycerides

(inner cell membrane lipid)

0

2

4

6

8

10

12

14

16

18

20

Omega 6

Omega 3

18:2 20:3 20:4 22:4 18:3 20:5 22:5 22:6

% Fatty Acids

Zellwegers disease absence of

peroxisomes.

Adrenoleucodystrophy

Floppy, uncontrolled head and

hands - going blind.

Zellwegers disease: same child one

year later with 300Mg DHA/day

Adrenoleucodystrophy: same child a

year later DHA 300mg/day

Able to sit up, walk and read.

BIOMAGNIFICATION ACROSS

THE PLACENTA

0

2

4

6

8

10

12

14

16

18

20

Mid-term Term

AA Maternal

AA cord

DHA Maternal

DHA cord

0

2

4

6

8

10

12

14

16

18

20

Maternal Fetal Plasma Fetal Liver Fetal Brain

Biomagnification of DHA for the Fetal Brain

during Human ReproductionCrawford et al Lancet 1976

DHA deficiency (of marine fat) in the

developing brain restricts migration of cortical

neurones.Diet 59 with marine fat Diet 61 (Deficient)

x4

Data from Ephraim Yavin

Adequate ALA deficient

iv

SVZ

Hip

Nissl stain

DCP

v

vi

s

p

c

c

MZ

CA1

CA3

DG

sc

CA1

CA3DG

sc

Distribution of BrdU labeling in the neonatal Cortex and Hippocampus after n-3 ALA

deficiency

Yavin et al Neuroscience 20091 day old

Photo-receptor Omega 3 requirement as DHA.

Ethanolamine Phosphoglycerides –

Gene Anderson & Nicholas Bazan 1968-74

0

10

20

30

40

50

60

N-6

N-3

18:2 20:3 20:4 22:4 18:3 20:5 22:5 22:6

% Fatty Acids

Cod Muscle compared to meat.

0

5

10

15

20

25

30

35

40

45

50

COD

MEAT

18:2 20:3 20:4 22:4 18:3 20:5 22:5 22:6

% Fatty Acids

5,2

From the eye spot of the dynoflagelate to

mammals, the chemistry is the same over 600 M

Years of evolution

0

10

20

30

40

50

60 % Fatty Acids

DHA

1. Dynoflagelate

2. Cephalo[ods

3. Fish

4. Amphibia

5. Reptiles

6. Birds

7. Mammals

8. Humans

DHA

1 2 3 4 5 6 7

The most compelling

evidence for

essentiality of DHA

600 mya 450mya 400mya 300mya 200mya 150myaa -

> todayya

Liver Essential Fatty Acid Composition

Ethanolamine Phosphoglycerides

0

5

10

15

20

25

30

35

40

45

18:2 20:3 20:4 22:4 18:3 20:5 22:5 22:6

% Fatty Acids*

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Crawford M, Casperd N. Sinclair AJ (1976) The long chain metabolites of linoleic and linolenic

acids in liver and brain in herbivores and carnivores. Comp. Biochem. Physiol. 54B: 395-401.

Brain Essential Fatty Acid Composition

Ethanolamine Phosphoglycerides

0

5

10

15

20

25

18:2 20:3 20:4 22:4 18:3 20:5 22:5 22:6

% Fatty Acids

*

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Crawford M, Casperd N. Sinclair AJ (1976) The long chain metabolites of linoleic and linolenic

acids in liver and brain in herbivores and carnivores. Comp. Biochem. Physiol. 54B: 395-401.

Which mammal has a greater requirement for

components to support its brain?

From: http://www.ruf.rice.edu/~pomeran/EyeBrainWorldAlumniCollege2003.htm

MA Crawford graphic adapted by J T Brenna

Low Birthweight, Prematurity and Severe

Brain Injury (CP): Essential Fatty Acid Status

• Lower the weight, the lower the plasma choline phosphoglyceride AA.

• Lower the gestational age the lower the DHA

• Both correlate with head circumference.

• The greatest risk is associated with those of the lowest weight and lowest gestational age.

Leaf A, et al (1992) Factors affecting long-chain polyunsaturated fatty acid composition of plasma choline phosphoglycerides in preterm infants. J. Pediatr. Gastroenterol. Nutr. 14: 300-308.

Leaf, A, Leighfield MJ, Costeloe KL, Crawford MA. (1992) Long chain polyunsaturated fatty acids in fetal growth. Early Hum. Dev. 30: 183 - 191

PRETERM INFANT

RAPID LOSS OF PLACENTAL AAPOSTNATALLY

AA DROPS TO THIRD OF INTRAUTERINE LEVEL DESPITEDESPITEPRECURSOR LA RISING THREE TO FOUR FOLD.N = 63 - After Leaf AA, Leighfield MJ, Costeloe KL Crawford MA. (1992) J. Pediatr. Gastroenterol. Nutr. 14: 300-308.

0

5

10

15

20

25

30

35

12 10 8 6 4 2 0

LA

AA

WEEK

% FA

PRETERM INFANT

RAPID LOSS OF PLACENTAL AAPOSTNATALLY

AA DROPS TO THIRD OF INTRAUTERINE LEVEL DESPITEDESPITEPRECURSOR LA RISING THREE TO FOUR FOLD.N = 63 - After Leaf AA, Leighfield MJ, Costeloe KL Crawford MA. (1992) J. Pediatr. Gastroenterol. Nutr. 14: 300-308.

0

5

10

15

20

25

30

35

12 10 8 6 4 2 0

LA

AA

WEEK

% FA

In utero AA

Very Preterm Infant:

The Rapid, Post-natal Loss of Placental LNF.

Postnatal evidence of LNF (in

this case Arachidonic Acid -AA)

dropping to third of intrauterine

level despitedespite feeding thefeeding the

precursor (LA, linoleic acid) the

blood levels of which rise three

to four fold.After Leaf AA, Leighfield MJ, Costeloe KL

Crawford MA. (1992) J. Pediatr.

Gastroenterol. Nutr. 14: 300-308. 0

5

10

15

20

25

30

35

12 10 8 6 4 2 0

LA

AA

WEEK

% FA

Placenta supplies AA

- . -In utero LA

Observed post-natal LA rise

Postnatal decline in AA

COMPARISON OF TERM MILK & FETAL NUTRITION FOR AA & DHA APPROPRIATE FOR PRETERM INFANTS

Crawford et al (1998),The inadequacy of the essential fatty acid content of present preterm feeds Eur. J. Pediatr. 157: S1: S23-S27.

0

2

4

6

8

10

12

14

16

18

LA AA ALNA DHA LA AA ALNA DHA

Term Milk

Placenta

PLACENTA SUPER PUMP: IMPLICATIONS FOR PRETERMS

VASCULAR COMPLICATIONS :

IVH - HEMORRHAGE EVEN BEFORE BIRTH

PVL - ISCHEMIA

BPD - LEAKAGE IN PULMONARY BLOOD

VESSELS FORMS HYALINE LAYER

ROP - OBLITERATION OF THE RETINAL

BLOOD VESSELS.

NEC - VASCULAR/IMMUNE INVOLVEMENT

24 weeks GA 28 weeks GA 40 weeks GA

Normal Cranial USS

Periventricular leucomalacia

Conclusion I

• The Bax – Little Foundation - European

Cerebral Palsy study using MRI at 4 years of

age showed the lesions were all prior to the

expected date of birth.

• Therefore they were not due to obstetric

mishap.

• 2o% had no MRI evidence of lesions and were

therefore due to connectivity as seen in the

neurogenesis study of DHA deficiency.

0

1

2

3

4

5

6

20 40 60 80 100 120 140 160

Apparent Fish Consumption (lbs./ person/year)

r= -0.84

p< 0.005

Maj

or D

epre

ssio

n,

Ann

ual pr

eval

enc

e, (r

ate /

100

pers

ons)

Japan (0.12%)

New Zealand (5.8%)

United States

(3.0%)Puerto

Rico (3.0%)

Taiwan (0.8%)

Korea (2.3%)

Canada (5.2%)

France (4.5%)

W. Germany(5.0%)

Fish Consumption and the Annual Prevalence

Of Mental Ill health & Major Depression.-

Hibbeln, The Lancet, 1998

NB The island that does not eat fish

0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

22.5

25.0

Po

stp

art

um

dep

reesse

d %

Ed

inb

urg

h P

ostn

ata

l D

ep

ress

ion

Sca

le

0 20 40 60 80 100 120 140 160

Fish Consumption (lbs/ person/year)

Japan

Hong Kong

Singapore

Malaysia

Sweden

Chile

France

Postpartum depression and fish consumption

Israel

Canada

Ireland

Switzerland

Netherlands

Italy

UK

United States

Australia

New Zealand

W. Germany

South Africa

Saudi

Arabia

Brazil

r = - 0.76

p < 0.0001

Child thinks before acting (8 y ) and Omega-3 intake by mother in pregnancy (32 w)

164416101598155015221075N =

Ch

ild

Th

inks B

efo

re A

cti

ng

1.95

1.90

1.80

1.7

1.85

1.75

Maternal omega-3 intake from seafood at 32 wks gestation

<2.3%

0.8-5.1g/d

<0.4%

<800 mg/d

<0.15%

<320 mg/d

<0.1%

<200 mg/d<0.03%

<60 mg/d

None

None(energy %)

mg/d 2,000 K

Adverse prosocial score - SDQ, 6 y

n=1593n=4203n= 724

% i

n l

ow

es

t q

ua

rtil

e

40

30

20

>340 g/w1-340 g/wNone

Adverse verbal IQ, 8 y

25

35

Mother

conforms

exceeds

Adverse social development-DDST, 42 m

Figure 2

Maternal seafood consumption

% p

ath

olo

gic

al

n=1618n=4337n=753

16

14

12

10

8

6

>340 g/w1-340 g/wNone

Mother

conforms

exceeds

Maternal seafood consumption

28

26

24

22

20

18n=2178n=6018n=1140

None

% i

n l

ow

es

t q

ua

rtil

e

Mother

conforms

exceeds

Maternal seafood consumption

1-340 g/w >340 g/w

n=1897n=5197n=938

34

32

30

28

26

24

22

20

18

16

Adverse fine motor- DDST, 42 m

Mother

conforms

exceeds

>340g/w 1- 340 g/wNone

Maternal seafood consumption

HIBBELN J et al ALSPAC Lancet

2007

Conclusion IICP is the tip of an iceberg

Brain disorders have now overtaken all others

25 EU member states

cost = €386 billion at 2004 prices.

(European Journal of Neurology June issue, 2005.)

(now half a trillion)

Implications UK

Brain disorders in the UK

Mental ill health cost =

£77 Billion

Greater than heart disease and cancer combined,

www.globalforumhealth.org

Global Forum For Health

First Seven In Order Predicted for 2020.

BURDEN OF DISEASE --------- 1990 2020

• Coronary Heart Disease 3.4 5.9

• Perinatal Conditions 6.7 5.7

• Mental ill health 3.7 5.7*

• Cerebrovascular disease 2.8 4.4

• Tuberculosis 2.8 3.1

• Lower respiratory infections 8.2 3.1

• Diarrhorheal disease 7.2 2.7

The Collapse of Capture

Fisheries

Threatens the

sustainability of Human

mental health and

intelligence.

Herto Skull 160,000

YAgo, Brain = 1.5L

2/3rds Oceans The brain

evolved with

DHA in the sea

500 million ya

The Blue Revolution - Fish is brain food

AGRICULTURALISE

THE OCEANS

Collaborators

• Myer Bloom - Physics Vancouver

• Stephen Cunnane - NMR Toronto

• Kate Costeloe – Neonatology, Royal London

• Keb Gebremeskel – Lipids, ,IBCHN, London

• Laurance Harbige - Immunology Greenwich

• Holm Holmsen – Membrane signalling Bergen, Norway

• Ivan Golfetto, Vascular myography, Venezuela.

• Douglas Kuhn, Placental perfusion, Royal Free, London.

• Alison Leaf - Pediatrics - Bristol.

• Trish Moodley, immunology, IBCHN, London.

• Lucilla Poston, Vascular myography, St Thomas’, London.

• Walt Schmidt, MD, USDA, Beltsville.

• Hiramitsu Suzuki – Synaptic uptake of DHA, NFRI, Japan

• Ephraim Yavin & Ram Reifen – Gene expression – Israel