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PREGNANCY AND PKU:
The Journey
Kathryn Moseley, M.S., R.D.
USC Keck School of Medicine
Department of Pediatrics,
Genetics
Agenda
•
•
•
•
•
•
•
•
Background on MPKU and review of MPKUCS
Maternal PKU: what you need to know
Plan for pregnancy
What to monitor
Therapies
Communication and support
Will my baby have PKU?
Questions
INTRODUCTION
• It is well known that women with
untreated PKU have babies affected
with fetal complications that include
congenital heart disease,
microcephaly, mental retardation, and
intrauterine growth retardation.
• Women with PKU under good dietary
control can have a successful
pregnancy with good outcomes.
Maternal PKU
Maternal phenylketonuria and hyperphenylalaninemia.
An international survey of the outcome of untreated and
treated pregnancies.
New England Journal of Medicine, Nov. 1980
Lenke RR, Levy HL
MATERNAL PKU
Report from the 19842002
Collaborative Study
Richard Koch, M.D.
Division of Medical Genetics
Childrens Hospital Los Angeles
Supported by the NICHD
Background: MPKUCS
• Over 400 pregnancies
• 45% of women initiated treatment prior to
pregnancy
• 16% achieved metabolic control before
conception
• 77% of women did not achieve metabolic
control until after 10 weeks gestation
• Offspring: 19% MR range, 17% borderline
range at age 7
Embryonic Development
MPKUCS Summary
• Controlled blood Phe levels (120360umol/L) is recommended for optimal
outcome
• Normal IQ in mothers planning a
pregnancy provide best outcome
• Cooperation with obstetrician and
metabolic team is essential for
optimal outcome
Maternal PKU Study Revisited
Congenital Heart Defects
• 28 pregnancies resulted in babies with CHD
• Low levels of folate and other amino acids
ie low protein intake
• All mothers who gave birth to babies with
CHD had low methonine levels
• Methonine contributes to global DNA
methylation which may affect embryonal organ
development
• Low folate may also contribute to
hypomethylation
Frequency of offspring with CHD in MPKU pregnancies:
classified by blood Phe and protein intake
Blood Phe
Protein Intake N
Phe Intake*
#CHD
Percent
P-value
----------------------------------------------------------------------------------------------------------------------------Low ( 900 umol/L)
High (>50 grams)
134
543(401,845)
1
0.8%
0.006
Low ( 50 grams)
33
662(465,963)
4
12.1%
----------------------------------------------------------------------------------------------------------------------------High (>900 umol/L)
High (>50 grams)
41
523(392,615)
3
7.3%
0.02
Low ( 50 grams)
10
1044(541,1333) 4
40.0%
----------------------------------------------------------------------------------------------------------------------------* median (IQR)
Number and percent of maternal PKU pregnancies with CHD in offspring, classified by
mean blood Phe during 4-8 weeks gestation and mean first trimester protein intake,
compared by Fisher’s exact test within blood Phe strata. Higher protein intake with
lower Phe intake indicates use of PKU formula. CHD=congenital heart defect, not
including patent ductus arteriousus.
Table 1: First trimester variables differing between MPKU pregnancies with and without CHD
No CHD (n=388)
CHD (n=28)
________
Variable
N
Median (IQR)
N
Median (IQR)
Wilcoxon
P-value
Adjusted*
P-value
Blood Phe weeks 4-8
Protein Intake
Phe Intake
387
206
206
556.27
67.92
543.00
(326.92,967.07)
(55.70,77.24)
(399,804)
28
12
11
1227.30 (987.60,1502.05)
38.6
(29.43,56.47)
802
(597.18,1204)
<0.0001
0.0004
0.0434
n/a
0.0003
0.0916
Plasma AA
Proline
Valine
Methionine
Isoleucine
Leucine
Phenylalanine
Lysine
Arginine
197
211
211
215
215
218
210
93
140.02
196.31
20.98
52.00
99.03
486.03
149.45
59.01
(110.05,176.98)
(165.27,230.89)
(16.42,26.51)
(43.00,63.01)
(84.01,119.50)
(300.52,790.56)
(127.20,180.22)
(46.49,76.00)
11
11
11
11
11
12
11
7
100.76
152.28
16.76
40.03
78.49
825.30
113.68
38.00
(87.03,124.99)
(134.71,181.30)
(14.48,19.97)
(37.97,52.00)
(69.03,84.01)
(513.53,1071.00)
(97.13,151.21)
(23.99,52.49)
0.0028
0.0023
0.0183
0.0178
0.0030
0.0285
0.0053
0.0226
0.0118
0.0537
0.0093
0.0185
0.0144
0.3208
0.0075
0.0665
RBC Folate
149
420
(281,605)
9
271
(257,391)
0.0363
0.0437
* association with CHD, adjusted for blood Phe, by multiple logistic regression
Maternal PKU
• What you need to
know
HOW TO REDUCE NEGATIVE OUTCOMES
• Plan pregnancy
• Maintain phe levels within the
recommended ranges
• Maintain optimal nutritional status
• Obtain recommended laboratory
evaluations
• Close clinical follow-up with
metabolic center/dietitian/OB
• Support system
Plan for pregnancy
Recommendations
• Plan at least 6 months in advance
• Take a medical food product
• Obtain dietary guidance from your
dietitian
• Adhere to dietary recommendations
• Obtain pre-pregnancy laboratory
evaluations
• Cultivate a support system
Recommended Schedule of
Assessments
• Pre-pregnancy and per
trimester-labs
– Plasma amino acids
– CBC, CMP
– Albumin, prealbumin
– Ferritin, RBC folate
– Cholesterol
– Zinc, selenium
– Essential fatty acids
– Vitamin B12, Vitamin D
– homocysteine
• Weekly phe/tyr
• Monthly weight
• Monthly plasma
amino acids
• Fetal Ultrasounds
• 6-7 weeks, 20 weeks
Phenylalanine Levels
•2-6mg/dl (120360umol/l)
•Monitor at least
weekly
Maintain Optimal Nutritional
Status
• Healthy meal plan
• Optimal weight gain
• Take all prescribed
medical products
• Vitamins
• Report all medications,
supplements, vitamins
etc, to your metabolic
team
Healthy Meal Plan
• Protein intake at least 75g/d
• Adequate calories
– Low calorie intake results in high blood
phe, low phe tolerance, low weight gain,
low birth weight, microcephaly
• Vitamins, mineral supplement
• DHA supplementation
Recommended Weight Gain
in Pregnancy
• 1st
• 2nd
• 3rd
Women with a Normal BMI
Trimester
3-4 lbs BMI (kg/m2
Trimester 10 lbs
Below 18.5
Trimester 1 lb/wk
18.5-24.9
BMI Category
Weight Gain
(lb)
28-40
25-35
25.0-29.9
15-25
Over 29.0
15
Institute of Medicine 1990
The importance of fat intake
• Needed for brain growth
• DHA supplemention
Function of DHA
• Membrane disorder (membrane fluidity)
• Dopaminergic and serotoninergic
neurotransmission
• Signal transduction via effects of inositol
phosphates, kinases
• Regulation of synthesis of eicosanoids
derived from AA
• Regulation of gene expression
• Regulation of neuron size
•
Sinclair et al, 2002
LCPUFAs in Infant
Development
•
DHA  It (t d pt) 
(t
utero-preferential  up t 2 ys  g
In
transfer of DHA and ARA via
the placenta to the fetus.
• This occurs at an
accelerated rate during the
last trimester and first 18
months of postnatal life
• Cerebral Cortex is 22%
phospholipid and the white
matter of the brains 24%
phospholipid.
• 30-40% of this phospholipid
is DHA.
• The retina is highest in DHA
concentration than any other
organ
12000
10000

8000
6000
4000
2000
0
20 40 60 80 100 120 140
wks  cc
DHA, FA deficiencies
• Early studies on lipids in PKU brains
• Perixosomal disorders (Zellweger)
• Many studies on animals and humans showing
visual and cognitive impairment
• Mitochondrial disorders
• Schizophrenia
• ADHD, dyslexia
• Depression
Benefits of supplementation
• Improved visual function
• Improved neurodevelopmental
performance
• Decreased serum triglycerides
• Improve large artery endotheliumdependent dilation in
hypercholesterolemia
• Supplementation in formula reduces
blood pressure in later childhood
Food Sources of DHA
Amount
4 oz
4 oz
4 oz
4 oz
4 oz
4 oz
4 oz
4 oz
¾ CUP
6 each
4 oz
4 oz
4 oz
4 oz
4 oz
1
1
Food
Fish
Salmon (pink)-baked/broiled
Bluefish-baked/broiled
Bass (fresh water)-baked/broiled
Trout (sea,steelhead) fillet
Sole/Flounder-fillet
Tuna in water, canned and
Cod(atlantic)
fillet
drained
Fish sticks- frozen
Tuna salad
Shrimp (large) steamed
Organ Meats
Beef Brains
Beef Liver
Chicken Liver
Poultry
Chicken or Turkey Dark Meat
Chicken or Turkey Breast
Eggs
Large whole
Large egg yolk
Mg DHA
852
754
519
300
293
253
175
145
85
48
760
329
91
57
34
19
19
Current Recommendations
• 1999-Expert Panel
sponsored by the
NIH, Center for
Genetics, Nutrition
and Health, ISSFAL
Adults: LA=2% ALA=1%
DHA=220mg/d
EPA=220mg/d
Pregnant & lactating need
300mg/d DHA
Preterm and term infants:
Adequate intake in infant
formula: 0.35% DHA
0.5%
ARA
Supplements
• Neuromins® (Martek Biosciences Corp.)
– Extracts DHA from Algae (toxin free)
• EFA Complete (GNC)
– Marine microalgae oil (toxin free)
• Some prenatal vitamins have DHA
Each softgel capsule contains:
Vitamin C (ascorbic acid, USP)
Vitamin E (d-alpha tocopherol, USP)
Vitamin B6 (pyridoxine hydrochloride, USP)
28 mg
30 IU
25 mg
Folic Acid, USP
1.25 mg
Calcium (tricalcium phosphate, NF)
160 mg
Iron (ferrous fumarate, USP)
29 mg
Vitamin D3 (cholecalciferol, USP)
800 IU
Algal oil blend (derived from Crypthecodinium cohnii)
Docusate Sodium, USP
* Providing 325 mg DHA (docosahexaenoic acid)
750 mg *
55 mg
What is Kuvan™?
• Kuvan is the first and
only FDA-approved
medication for PKU
• Kuvan functions like BH4,
a substance that occurs
naturally in the body
Kuvan
• Classified as “Pregnancy Category C”
by the FDA, indicated by animal
reproduction studies showing an
adverse effect on the fetus at
600mg/kg. 10 times the recommended
dose
• There are no adequate controlled
studies in humans
• Women exposed to Kuvan are encouraged
to enroll in the patient registry
VW BLOOD PHE CONCENTRATIONS
Recommendations:
600
120-360umol/L
Phe µmol/L
500
400
300
200
100
1st
2nd
3rd
0
Trimester
MK BLOOD PHE CONCENTRATIONS
600
Recommendations:
Phe umol/L
500
120-360umol/L
400
300
200
100
1st
2nd
3rd
0
Trimester
Table 1: SUBJECT PROFILE AND PREGNANCY OUTCOME
VW
MK
Age at conception
37yr
32yr
PAH mutation
IVS12nt1g>a/R261Q
IVS12nt1g>a/P281L
1st trimester
430
430
2nd trimester
1350
770
3rd trimester
1620
1540
1st trimester
300
200
2nd trimester
400
400
3rd trimester
600
600
1st trimester
305
205
2nd trimester
237
122
3rd trimester
272
184
Gender
Male
Female
Birth weight (g)
3055 (10-25th %ile)
3175 (25-50th %ile)
Length (cm)
48.3
Subject
Dietary Phe intake average (mg)
BH4 dose (mg)
Average Blood Phe (µmol/l)
Infant Characteristics
(25th-50th %ile)
th
48.3 (25-50th %ile)
th
Maintain Close Communication
with your metabolic team
We are here to help!!!
Resource Mothers Program
• The Resource Mothers Program was designed to
help women with PKU gain metabolic control
before or during a pregnancy by providing
social support and promoting a positive
attitude about treatment through home
visitation. The Resource Mothers are women who
have children with PKU, and thus understand the
diet and hardships associated with the
disorder. They provide social support, and act
as role models for women with PKU, teaching
them confidence in their ability to follow the
strict diet while maintaining a relatively
"normal" life.
Resource Mothers
• Mothers of PKU individuals
• Cook, shop, give advice, keep
records, accompany Daughter to
appts., provide support and act as a
role model
• Up to 20 home visits
• Supervise ongoing treatment
• Become a reliable friend and mentor
• Respect confidentiality
SAM
• Social support
• Positive Attitudes
• Manageability
Will my baby have PKU?
• If individual with
PKU marries a noncarrier
– All babies will be
carriers
• If individual with
PKU marries a
carrier:
– 50% chance a having
a PKU baby
PKU Individual
Carrier
Non-Carrier
Carrier
Carrier
Carrier
PKU Individual
Carrier
Carrier
Carrier
PKU
PKU
Carrier Testing
• Carrier testing is available
• Ask your doctor or a genetic
counselor
Can I Breastfeed My Baby??
• Yes
– Continuing with the
medical food
products will
provide more
calories protein and
nutrients
– May be better able
to cope with
motherhood
– More phe tolerance
Twins!!!!!
• Need
– More calories
– More protein
– More fat
• You will
– Gain more weight
– Have an increase in
phe tolerance
– Be very busy!!
Thank You
• Questions???