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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 It (t d pt) (t utero-preferential up t 2 ys 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 wks cc 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???
