1. Maternal PKU – dietary management Fiona White Chief Metabolic Dietitian Manchester Children’s Hospitals NSPKU Conference 3/3/07

2. look at …….. history of maternal PKU evidence for guidelines for management of maternal PKU dietary management outcome Manchester experience

3. history of maternal PKU 1957 – first description by Prof Charles Dent mother, mentally handicapped, with PKU 3 mentally retarded children, non PKU was PKU the cause?

4. history of maternal PKU 1980 – Lenke & Levy (USA) published survey of 524 pregnancies in 155 women with PKU –34 pregnancies a low phe diet preconception or started after

5. maternal PKU 0 10 20 30 40 50 60 70 80 90 100 1200 1000 850600 phe µmol/l % of offspring mental retardation microcephaly heart disease b wt <2500g Lenke and Levy (1980) normal population

6. maternal PKU - clinical presentation microcephaly (small head,>70%) low birth weight / poor growth (50%) dysmorphic features slow development (>90%) congenital heart disease (15–20%) other malformations behavioural problems ‘maternal PKU syndrome’

7. evidence for dietary management guidelines - from maternal PKU outcome studies 2 major studies International maternal PKU collaborative study (MPKUCS), 1984 – 2002 UK MRC/DHSS PKU registry, 1978-97

8. cognitive outcome

9. maternal PKU outcome - IQ Platt et al, 2000 (MPKUCS) best IQ outcome occurred when maternal blood phenylalanine level <600 µmol/l by 8-10 weeks gestation and maintained throughout pregnancy

10. maternal PKU outcome - IQ R 2 =0.5742 40 60 80 100 120 140 05001000150020002500 mean phe 1 st trimester (µmol/l) IQ (MPKUCS)

11. Drogari et al (1987) birth head circumference 30 31 32 33 34 35 36 50th centileIIIIIIIVV group cm p < 0.001 n = 17 n = 12n = 9n = 8n = 18 UK MRC/DHSS PKU Registry I – strict diet at conception II – relaxed diet at conception III – diet started in 1 st trimester IV - diet started in 2 nd or 3 rd trimester V – no diet

12. heart

13. maternal PKU outcome – congenital heart disease Levy et al 2001 (MPKUCS) –14% risk of heart defect if phe >900 µmol/l at conception & poor control by 8th week Matalon et al 2003 (MPKUCS) –heart disease also increased where <50% recommended protein intake consumed in first trimester

14. growth

15. maternal PKU outcome – effect of maternal nutrition Acosta et al, 2000 (MPKUCS) –highest protein intake (>RDA) & –achieving recommended energy intake associated with best phe control –phe<360µmol/l by 10 weeks –maintained between 120 - 360µmol/l for rest of pregnancy best growth measurements at birth

16. maternal PKU outcome – growth Lee et al,2005 (UK MRC/DHSS PKU Registry) preconception diet – better birth weight & head circumference

17. summary of evidence high maternal phenylalanine levels are toxic preconception diet, good phe control & good nutrition throughout pregnancy produces best outcome if pregnancy unplanned start diet as soon as possible –phe control by 8-10 weeks reduces risk heart defects improves IQ outcome improves growth

18. maternal PKU – management aims control of blood phe within acceptable limits throughout pregnancy MRC 1993: 60 - 250  mol/l our unit currently 100 - 250  mol/l ? 150 - 300  mol/l –preconception control is the ideal 4 weeks of consecutive levels within desired range before stopping contraception –if pregnant with higher levels - to achieve control within 1 st trimester good nutrition

19. dietary requirements in maternal PKU 5 key areas: phenylalanine protein tyrosine energy micronutrients

20. dietary requirements in maternal PKU 1 - phenylalanine phenylalanine requirements - exchanges – based on blood phe level – individual tolerance – use 50mg phe exchange system – initially number of exchanges small distribute evenly throughout day tolerance should increase later –may need to use high protein foods (6g exchanges)

21. phenylalanine tolerance - BE

22. dietary requirements in maternal PKU 2 - protein protein requirements –approx. RNI for pregnancy + 15% (total 60g) –initially all from phe free protein substitute –may give extra to improve phe control

23. 1992 – 3 protein substitutes suitable for maternal PKU XP Maxamum PK Aid 4 Aminogran

24. 2007 – 12 protein substitutes suitable for maternal PKU Powders

25. 2007 – 12 protein substitutes suitable for maternal PKU Liquids

26. 2007 – 12 protein substitutes suitable for maternal PKU tablets

27. improving tolerance of protein substitute disguising smell chilling flavouring alter dilution increase frequency alternative product - tablets

28. Dietary requirements in maternal PKU 3 - tyrosine –essential amino acid in PKU (added to supplements) –may require additional supplement in pregnancy

29. dietary requirements in maternal PKU 4 - energy energy requirements –vary widely (2000 - 3000kcals/day) preconception - sufficient to maintain appropriate weight during pregnancy - sufficient to promote appropriate pregnancy weight gain non protein sources - low protein products, free foods, energy supplements

30. free foods

31. calorie supplements

32. dietary requirements in maternal PKU 5 - micronutrients micronutrients – to provide RNI + monitor at risk nutrients – folic acid provided in protein substitute, if not separate supplement

33. vitamins & minerals + calcium

34. maternal PKU diet - difficulties may have been off diet for many years little awareness of managing the diet –now up to them not their parents accustomed to normal food poor cooking & organisational skills satisfying appetite lack of support

35. maternal PKU diet - difficulties problems during pregnancy nausea & vomiting severe hyperemesis weight loss inadequate protein substitute illness poor compliance (lack of support)

36. maternal PKU - monitoring blood phenylalanaine & tyrosine – twice weekly maternal weight twice weekly / more frequent contact with dietitian monthly clinic review - Dr & dietitian monthly monitoring of Ferritin, B12, folate, FBC foetal monitoring

37. Pregnancy - outcome

38. 1 - planned pregnancy LE Bwt - 25th centile length - 75th centile OFC - 25th centile normal developmental progress DQ 111 age 4 Phe µmol/l

39. 2 - conception on a normal diet TO Bwt - 25th centile OFC - 3rd centile coarctation of the aorta ? normal development Phe  mol/l JV presented 8/40 preconception diet until just prior to conception weight loss affecting phe control

40. 3 – poor compliance LR dob 27/6/62 diagnosed age 35 - maternal screening 3 previous miscarriages pregnancy terminated as unable to control phe levels preconception diet Phe  mol/l weeks SR bwt - 3rd centile length - < 3rd centile OFC - << 3rd centile microcephaly severe learning difficulties

41. Post birth infant feeding advice –breast feeding OK whether mum on or off PKU diet record birth information –gestational age –birth wt, length, head circumference –any medical problems routine newborn screening follow up by metabolic paediatrician –DQ at 2, 4, 8, 14, 18years regular follow up of mother even if not on diet

42. maternal PKU – why be concerned? screened & treated PKU women - good outcome to prevent adverse outcome of pregnancy from high maternal phe levels  number of women of child bearing age - many lost to follow up unplanned pregnancies despite pre -conceptual advice

43. Manchester - size of the problem children (n=66) adults (n=98)

44. maternal PKU births in Manchester 1983 - 2006 = 80 (44 planned - 55%)

45. successful management of maternal PKU commitment from patient, Dr & dietitian family support communication between agencies metabolic team GP maternity services frequent biochemical monitoring reliable, quick laboratory service inpatient facilities

46. conclusions good dietary control in maternal PKU normal outcome encourage female PKU’s to maintain regular contact with metabolic clinic maintain diet? continue protein substitute?