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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,
.
[email protected]://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.
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
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
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