Periconceptional Folic-Acid Containing

Multivitamin Supplementation for

Prevention of Neural-tube Defects and

Cardiovascural Malformations

Periconceptional Folic-Acid Containing

Multivitamin Supplementation for

Prevention of Neural-tube Defects and

Cardiovascural Malformations

Prof. Andrew E. Czeizel, MD., C.Sc., D.Sc.(Scientific director of the Foundation for

Community Control of Hereditary Diseases,

Budapest, Hungary)

Prof. Andrew E. Czeizel, MD., C.Sc., D.Sc.(Scientific director of the Foundation for

Community Control of Hereditary Diseases,

Budapest, Hungary)

Characteristics of Birth Defects, Structural Birth Defects =

Congenital Abnormalities (CAs)

Very early onset

Defect condition

Optimal solution: prevention

Neural-tube defects (NTD)

anencephalus (1a, b)

encephalocele, occipital (2)

spina bifida aperta (3a), spina bifida cystica (3b), closed spina bifida (3c), spinal dysraphism (3d)

1/a

1/b

2

3/a 3/b

3/c

3/d

1.Polygenic predisposition: recurrence is 10-fold higher than occurrence.

2.Environmental factors: socioeconomicdependence (diet ?)

3. Early critical period: between 15th and 28th postconceptional days, this explains the use of "periconceptional supplementation".

Characteristics of NTD

Data and results of previous intervention studies for the reduction of recurrent NTD

Type Method Location Supplement Risk Reduction

Recurrence Non-randomized Yorkshire

Multivitamin(0.36 mg Folic Acid) 91%

Northern Ireland 83%

Randomized Multicenter MRCFolic Acid(4.0 mg) 71%

Hungarian Periconceptional Care( HPS)

1. Check-up of reproductive health

2. The 3-month preparation for conception

3. Better protection of early pregnancy

Goals 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 firstoccurrence of NTD

The pharmacological dose (> 1 mg, e.g., 4 mg) of folic acid cannot berecommended for the population at large or without medicalsupervision.

Thus, the question is whether a physiological dose (< 1 mg) iseffective

Possible other beneficial or adverse effects of periconceptionalmultivitamin supplementation.

Composition of supplements

"Multivitamin(Elevit Pronatal)"

"Placebo-likeTrace Elements"

VitaminsA 4000 IUB1 1.6 mgB2 1.8 mgNicotinamid 19.0 mgB6 2.6 mgCalcium Panthothenate 10.0 mgBiotin 0.2 mgB12 4.0 mcgC 100.0 mg 7.5 mgD 500.0 IUE 15.0 mgFolic Acid 0.8 mgMineralsCalcium 125.0 mgPhosphorus 125.0 mgMagnesium 100.0 mgIron 60.0 mgTrace ElementsCopper 1.0 mg 1.0 mgManganese 1.0 mg 1.0 mgZinc 7.5 mg 7.5 mg

RCT

50% of participants in HPS were supplied by „multivitamin” while other half were supplied by

placebo-like trace elements.

Result of the RCT: Reduction of the First Occurrence of NTD

Study groups Number of informative offspring

Observed NTD No. per 1000

Expected NTD No. per 1000

Multivitamin 2,471 0 0.00 6.9 2.78

Placebo-like trace element

2,391 6* 2.51 6.6 2.78

Relative risk (with 95% confidence interval) = 0.06 (0.00, 0.63) Fisher test P2= 0.01

* anencephaly 2, spina bifida aperta 2, anencephaly + spina bifida 2

Number and rate (per 1000) of different CA-groups in multivitamin and no multivitamin supplemented group

Categories of CAsGroup of CAs

Multivitamin(N=2,471)

No multivitamin(N=2,391)

RR (with 95% CI)No. Rate No. Rate

Isolated CAsNTDOrofacial cleftsCardiovascular

CAsCAs of urinary

tractLimb

deficienciesCong. pyloric

stenosisOthers

04

10212

22

0.01.624.050.810.400.818.90

65

20958

32

2.512.098.363.762.093.34

13.38

0.07 (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 CAs 10 4.05 12 5.02 0.81 (0.36, 1,26)

Total 51 20.64 97 40.57 0.53 (0.35, 0.70)

Meta-analysis of cohort and RCT for cardiovascular malformations ( Goh et al., 2006)

OR: 0.61, 95% CI: 0.40-0.92

Birth prevalence of cardiovascular malformations (CVM) and neural-tube

defects (NTD) in Hungary

Birth prevalenceper 1000

%Reductionper 1000

Absolute reduction No.per 100,000

CVM10.2 40 6.1 408

NTD2.8 90 0.3 252

Conclusion: We recommend the incorporation of primary prevention of CVM into public health action

Metabolism of Homocysteine and the Effect of Folate-Folic Acid (Vitamin B11), Vitamin B2, Vitamin B6

and Vitamin B12

MTHFR-gene

Vitamin B

Folate(polyglutamate)

Folic acid(monoglutamate)

11

Reductase

5-methyl-THF

5,10-methylene-THF

Vitamin C

Tetrahydrofolate =THF

ReductaseDihydrofolate

Monoglutamate

Zinc

Conjugase

Methylene-THF-reductase=MTHFR

B2

Proteins

Methionine

S-adenosylmethionine

Homocysteine

Homocysteine

Homocystinuria

Cystathione

Cysteine

Sulphate

B 6

Cystathione-betasynthase

Serin

B 6

Cystathionase

B12

Methionine-synthase

CH+

3

CH3

MTHFR gene

• Gene location: Chromosome l, short arm 36.3

• Mutation: 677 T C• Frequency of

• mutant homozygosity: 5-15 % (11%)

• heterozygosity: 25-65% (45%)

Metabolism of Homocysteine and the Effect of Folate-Folic Acid (Vitamin B11), Vitamin B2, Vitamin B6

and Vitamin B12

MTHFR-gene

Vitamin B

Folate(polyglutamate)

Folic acid(monoglutamate)

11

Reductase

5-methyl-THF

5,10-methylene-THF

Vitamin C

Tetrahydrofolate =THF

ReductaseDihydrofolate

Monoglutamate

Zinc

Conjugase

Methylene-THF-reductase=MTHFR

B2

Proteins

Methionine

S-adenosylmethionine

Homocysteine

Homocysteine

Homocystinuria

Cystathione

Cysteine

Sulphate

B 6

Cystathione-betasynthase

Serin

B 6

Cystathionase

B12

Methionine-synthase

CH+

3

CH3

Question 1.:

Can folic acid-containing multivitamin prevent other defects beyond neural-tube defects?

WHO Expert Committee (2004)

Folic acid-containing multivitamins can reduce the incidence of congenital defects by about one third

Question 2.:

Is dietary strategy to increase folate intake can neutralise the genetic predisposition for these CAs?

Reply: unlikely

Why?

Low mean folate intake 0.18 mg/dayOptimal dose for prevention of NTD (McPartlin et al., 1993) 0.66 mg/dayDifference 0.50 mg/day (15 plates of spinach or broccoli!)Low bioavailability of folate in food (30-80%)There is a threshold in folate absorption from gastroenteral system

Question 3.:

What is optimal recommendation ?

Periconceptional folic acid or folic acid-containing supplementation seems to be

appropriate

Whether folic acid alone or folic acid-containing multivitamin is better?

Question 4.:

Folic acid alone or folic acid-containing multivitaminFolic acid aloneMultivitamin

Efficacy

70% of NTD 90% of NTD

Other effects

? Prevention of other major CAs

Other arguments in hyperhomocysteinemia related NTD

Key factor Vitamin B12, B2 and B6 are independent factors

Cost

Low Moderate (reimbursement)

Question 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

US recommendation0.4 mg (400 microgram) folic acid

The Institute of Medicine, US National Academy (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 than 1 mg) for treatment of patients or under permanent medical control

However,

0.4 mg folic acid needs 8-12 weeks0.8 mg folic acid needs 4.2 ± 3.5 weeks to 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

Comparison of different medical approaches for reduction of NTD

Comparison of different medical approaches for reduction of NTD

Prevention Method Efficacy(%)

Cost(US $)

Consequence

PrimaryPericonceptional multivitamin or folic acid supplementation

9070

505

True prevention

"Secondary"Prenatal screening of MS-AFP + ultrasound scannings of fetus

85 500*Termination of pregnancy

"Tertiary" In utero surgery ? Very high Correction (?)

* incl. termination of pregnancy* incl. termination of pregnancy

Recent estimation regarding pregnancy outcomes of women who

had fetuses affected with NTDin Hungary, 2008

Elective termination 77%

Birth (spina bifida) 18%

Prevention by FA/MV 5%

FA = folic acid; MV = multivitamins

ConclusionInertia on the use of folic acid or folic acid containing multivitamins for the primary prevention of CAs is medical malpractice