PREGNANCY AND PREGNANCY AND PKU:PKU:

The JourneyThe JourneyKathryn Moseley, M.S., Kathryn Moseley, M.S.,

R.D.R.D.

USC Keck School of USC Keck School of MedicineMedicine

Department of Pediatrics, Department of Pediatrics, GeneticsGenetics

AgendaAgenda• 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

INTRODUCTIONINTRODUCTION

• 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 PKUMaternal PKU

New England Journal of Medicine, Nov. 1980

Lenke RR, Levy HL

Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies.

MATERNAL PKUMATERNAL PKUReport from the Report from the

1984-2002 1984-2002 Collaborative StudyCollaborative Study

Richard Koch, M.D.Richard Koch, M.D.Division of Medical GeneticsDivision of Medical Genetics

Childrens Hospital Los AngelesChildrens Hospital Los Angeles

Supported by the NICHDSupported by the NICHD

Background: MPKUCSBackground: 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 DevelopmentEmbryonic Development

MPKUCS SummaryMPKUCS Summary• Controlled blood Phe levels (120-

360umol/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 Maternal PKU Study RevisitedRevisited

Congenital Heart DefectsCongenital 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) ________ Wilcoxon Adjusted* Variable N Median (IQR) N Median (IQR) P-value P-value Blood Phe weeks 4-8 387 556.27 (326.92,967.07) 28 1227.30 (987.60,1502.05) <0.0001 n/a Protein Intake 206 67.92 (55.70,77.24) 12 38.6 (29.43,56.47) 0.0004 0.0003 Phe Intake 206 543.00 (399,804) 11 802 (597.18,1204) 0.0434 0.0916 Plasma AA Proline 197 140.02 (110.05,176.98) 11 100.76 (87.03,124.99) 0.0028 0.0118 Valine 211 196.31 (165.27,230.89) 11 152.28 (134.71,181.30) 0.0023 0.0537 Methionine 211 20.98 (16.42,26.51) 11 16.76 (14.48,19.97) 0.0183 0.0093 Isoleucine 215 52.00 (43.00,63.01) 11 40.03 (37.97,52.00) 0.0178 0.0185 Leucine 215 99.03 (84.01,119.50) 11 78.49 (69.03,84.01) 0.0030 0.0144 Phenylalanine 218 486.03 (300.52,790.56) 12 825.30 (513.53,1071.00) 0.0285 0.3208 Lysine 210 149.45 (127.20,180.22) 11 113.68 (97.13,151.21) 0.0053 0.0075 Arginine 93 59.01 (46.49,76.00) 7 38.00 (23.99,52.49) 0.0226 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 PKUMaternal PKU

• What you need to know

HOW TO REDUCE NEGATIVE HOW TO REDUCE NEGATIVE OUTCOMESOUTCOMES

• 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 pregnancyPlan for pregnancy

RecommendationsRecommendations

• 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 Recommended Schedule of AssessmentsAssessments

• 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 LevelsPhenylalanine Levels

•2-6mg/dl (120-360umol/l)•Monitor at least weekly

Maintain Optimal Maintain Optimal Nutritional StatusNutritional 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 PlanHealthy 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 GainRecommended Weight Gainin Pregnancyin Pregnancy

Women with a Normal BMI

• 1st Trimester 3-4 lbs• 2nd Trimester 10 lbs• 3rd Trimester 1 lb/wk

BMI Category

BMI (kg/m2 Weight Gain (lb)

Below 18.5 28-40

18.5-24.9 25-35

25.0-29.9 15-25

Over 29.0 15

Institute of Medicine 1990

The importance of fat The importance of fat intakeintake

• Needed for brain growth• DHA supplemention

Function of DHAFunction 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 LCPUFAs in Infant DevelopmentDevelopment

• In utero-preferential 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

0

2000

4000

6000

8000

10000

12000

20 40 60 80 100 120 140

DHA, FA deficienciesDHA, 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 supplementationBenefits of supplementation

• Improved visual function• Improved neurodevelopmental

performance• Decreased serum triglycerides• Improve large artery endothelium-

dependent dilation in hypercholesterolemia

• Supplementation in formula reduces blood pressure in later childhood

Food Sources of DHA Food Sources of DHA Amount Food Mg DHA  Fish  

4 oz Salmon (pink)-baked/broiled 8524 oz Bluefish-baked/broiled 7544 oz Bass (fresh water)-baked/broiled 5194 oz Trout (sea,steelhead) fillet 3004 oz Sole/Flounder-fillet 2934 oz Tuna in water, canned and

drained253

4 oz Cod(atlantic) fillet 1754 oz Fish sticks- frozen 145¾ CUP Tuna salad 856 each Shrimp (large) steamed 48  Organ Meats  

4 oz Beef Brains 7604 oz Beef Liver 3294 oz Chicken Liver 91  Poultry  

4 oz Chicken or Turkey Dark Meat 574 oz Chicken or Turkey Breast 34  Eggs  

1 Large whole 191 Large egg yolk 19

Current RecommendationsCurrent Recommendations

• 1999-Expert Panel sponsored by the NIH, Center for Genetics, Nutrition and Health, ISSFAL

Adults: LA=2% ALA=1%DHA=220mg/dEPA=220mg/dPregnant & lactating

need 300mg/d DHAPreterm and term

infants:Adequate intake in

infant formula: 0.35% DHA

0.5% ARA

SupplementsSupplements

• 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) 28 mg

Vitamin E (d-alpha tocopherol, USP) 30 IU

Vitamin B6 (pyridoxine hydrochloride, USP) 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) 750 mg *

Docusate Sodium, USP 55 mg

* Providing 325 mg DHA (docosahexaenoic acid)

What is KuvanWhat 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

KuvanKuvan• 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

0

100

200

300

400

500

600

Trimester

Phe

µmol

/L

1st 2nd 3rd

Recommendations:

120-360umol/L

MK BLOOD PHE CONCENTRATIONS

0

100

200

300

400

500

600

Trimester

Phe

umol

/L

1st 2nd 3rd

Recommendations:

120-360umol/L

Table 1: SUBJECT PROFILE AND PREGNANCY OUTCOME

SubjectVW MK

Age at conception 37yr 32yr

PAH mutation IVS12nt1g>a/R261Q IVS12nt1g>a/P281L

Dietary Phe intake average (mg)

1st trimester 430 430

2nd trimester 1350 770

3rd trimester 1620 1540

BH4 dose (mg)

1st trimester 300 200

2nd trimester 400 400

3rd trimester 600 600

Average Blood Phe (µmol/l)

1st trimester 305 205

2nd trimester 237 122

3rd trimester 272 184

Infant Characteristics

Gender Male Female

Birth weight (g) 3055 (10-25th %ile) 3175 (25-50th %ile)

Length (cm) 48.3 (25th-50th %ile) 48.3 (25-50th %ile)

Head circumference 34.5 (25-50th %ile) 34 (25-50th %ile)

Maintain Close Maintain Close Communication with your Communication with your

metabolic teammetabolic team

We are here to help!!!

Resource Mothers ProgramResource 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 MothersResource 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

SAMSAM

•Social support•Positive Attitudes•Manageability

Will my baby have PKU?Will my baby have PKU?

• If individual with PKU marries a non-carrier– All babies will be

carriers

• If individual with PKU marries a carrier:– 50% chance a having a

PKU baby

Carrier Carrier Carrier Carrier

PKU Individual Non-Carrier

Carrier Carrier PKU PKU

PKU Individual Carrier

Carrier TestingCarrier Testing• Carrier testing is available

• Ask your doctor or a genetic counselor

Can I Breastfeed My Baby??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!!!!!Twins!!!!!• Need

– More calories– More protein– More fat

• You will– Gain more weight– Have an increase in

phe tolerance– Be very busy!!

Thank YouThank You• Questions???