Presentation on theme: "Periconceptional Folic-Acid Containing Multivitamin Supplementation for Prevention of Neural-tube Defects and Cardiovascural Malformations Prof. Andrew."— Presentation transcript:
1Periconceptional Folic-Acid Containing Multivitamin Supplementation for Prevention of Neural-tube Defects and Cardiovascural MalformationsProf. Andrew E. Czeizel, MD., C.Sc., D.Sc. (Scientific director of the Foundation for Community Control of Hereditary Diseases, Budapest, Hungary)
2Characteristics of Birth Defects, Structural Birth Defects = Congenital Abnormalities (CAs)Very early onsetDefect conditionOptimal solution: prevention
10Characteristics of NTD Polygenic predisposition: recurrence is 10-fold higher than occurrence.Environmental factors: socioeconomicdependence (diet ?)3. Early critical period: between 15th and 28th postconceptional days, this explains the use of "periconceptional supplementation".
11Data and results of previous intervention studies for the reduction of recurrent NTD
12Hungarian Periconceptional Care ( HPS)Check-up of reproductive healthThe 3-month preparation for conceptionBetter protection of early pregnancy
13Goals of the Hungarian randomized double-blind controlled trial (RCT) About 95% of women with NTD offspring have no previous NTD pregnancies.Thus the question is whether the periconceptional folic acid- containing multivitamin supplementation can reduce the first occurrence of NTDThe pharmacological dose (> 1 mg, e.g., 4 mg) of folic acid cannot be recommended for the population at large or without medical supervision.Thus, the question is whether a physiological dose (< 1 mg) iseffectivePossible other beneficial or adverse effects of periconceptional multivitamin supplementation.
15RCT50% of participants in HPS were supplied by „multivitamin” while other half were supplied by placebo-like trace elements.
16Result of the RCT: Reduction of the First Occurrence of NTD
17Categories of CAs Group of CAs Number and rate (per 1000) of different CA-groups in multivitamin and no multivitamin supplemented groupCategories of CAs Group of CAsMultivitamin (N=2,471)No multivitamin (N=2,391)RR (with 95% CI)No.RateIsolated CAs NTD Orofacial clefts Cardiovascular CAs CAs of urinary tract Limb deficiencies Cong. pyloric stenosis Others0.07 (0.04, 0.13) 0.77 (0.22, 2.69) 0.42 (0.19, 0.98) 0.21 (0.05, 0.95) 0.19 (0.03, 1.18) 0.24 (0.05, 1.14) 0.68 (0.37, 1.10)Multiple CAs104.05125.020.81 (0.36, 1,26)Total5120.649740.570.53 (0.35, 0.70)
18Meta-analysis of cohort and RCT for cardiovascular malformations ( Goh et al., 2006) OR: 0.61, 95% CI:
19Birth prevalence of cardiovascular malformations (CVM) and neural-tube defects (NTD) in Hungary per 1000%ReductionAbsolute reduction No.per 100,000CVM10.2406.1408NTD2.8900.3252Conclusion: We recommend the incorporation of primary prevention of CVM into public health action
20Metabolism of Homocysteine and the Effect of Folate-Folic Acid (Vitamin B11), Vitamin B2, Vitamin B6 and Vitamin B12MTHFR-geneVitamin BFolate(polyglutamate)Folic acid(monoglutamate)11Reductase5-methyl-THF5,10-methylene-THFVitamin CTetrahydrofolate =THFDihydrofolateMonoglutamateZincConjugaseMethylene-THF-reductase=MTHFRB2ProteinsMethionineS-adenosylmethionineHomocysteineHomocystinuriaCystathioneCysteineSulphate6Cystathione-betasynthaseSerinCystathionase12Methionine-CH+3
21MTHFR gene Gene location: Chromosome l, short arm 36.3 Mutation: 677 T CFrequency ofmutant homozygosity: % (11%)heterozygosity: % (45%)
22Metabolism of Homocysteine and the Effect of Folate-Folic Acid (Vitamin B11), Vitamin B2, Vitamin B6 and Vitamin B12MTHFR-geneVitamin BFolate(polyglutamate)Folic acid(monoglutamate)11Reductase5-methyl-THF5,10-methylene-THFVitamin CTetrahydrofolate =THFDihydrofolateMonoglutamateZincConjugaseMethylene-THF-reductase=MTHFRB2ProteinsMethionineS-adenosylmethionineHomocysteineHomocystinuriaCystathioneCysteineSulphate6Cystathione-betasynthaseSerinCystathionase12Methionine-CH+3
27Why? Low mean folate intake 0.18 mg/day Optimal dose for prevention of NTD (McPartlin et al., 1993) mg/dayDifference mg/day(15 plates of spinach or broccoli!)Low bioavailability of folate in food (30-80%)There is a threshold in folate absorption fromgastroenteral system
28What is optimal recommendation ? Question 3.:What is optimal recommendation ?Periconceptional folic acid or folic acid-containing supplementation seems to be appropriate
29Question 4.: Whether folic acid alone or folic acid- containing multivitamin is better?
30Folic acid alone or folic acid-containing multivitamin Folic acid alone MultivitaminEfficacy70% of NTD % of NTDOther effects? Prevention of other major CAsOther arguments in hyperhomocysteinemia related NTDKey factor Vitamin B12, B2 and B6 are independent factorsCostLow Moderate (reimbursement)
31Question 5.: What is the optimal dose of folic acid? No scientific evidenceThere are two forms of Vitamin 11 (or 9)dietary polyglutamate folatesynthetic monoglutamate folic acid
32US recommendation0.4 mg (400 microgram) folic acidThe Institute of Medicine, US NationalAcademy (1998) –European Commission Scientific Committee on Food (1998)physiological dose of folic acid (less than 1 mg) for preventive purpose in healthy peoplepharmacological dose of folic acid (more than1 mg) for treatment of patients or under permanent medical control
33However,0.4 mg folic acid needs 8-12 weeks0.8 mg folic acid needs 4.2 ± 3.5 weeksto reach the lowest risk of NTD(red blood cell folate: 906 nmol/L)Thus the recent recommendation: supplementation at least 2-3 months before conception and 3-4 months after conception
34Comparison of different medical approaches for reduction of NTD * incl. termination of pregnancy
35Recent estimation regarding pregnancy outcomes of women who had fetuses affected with NTDin Hungary, 2008Elective termination77%Birth (spina bifida)18%Prevention by FA/MV5%FA = folic acid; MV = multivitamins