Folic Acid And The Prevention of Neural Tube Defects We Can Make A Difference!
Jordan H. Perlow M.D.
Director; Folic Acid Education Campaign March of Dimes, State of Arizona Associate Director: Maternal-Fetal Medicine Good Samaritan Regional Medical Center Phoenix, Arizona Partner; Phoenix Perinatal Associates Obstetrix Medical Group of Phoenix PerlowMFM@aol.com
Neural Tube Defects (NTDs)
Anencephaly
Uniformly Lethal Incomplete Forebrain Development
Meningomyelocele
Spina Bifida Thoracic-Lumbar-Sacral Defects of Neural Tube
Rare Protrusion of brain or membranes through an occipital defect of the Neural Tube
Encephalocele
Anencephaly: 18 week Fetus
A Rare Occurrence: Spina Bifida and Encephalocele
Craniorachischisis: A rare and lethal NTD
Embryo: Prior to Neural Tube Closure
Neural Tube Defects: Embryology
First Fetal System to Develop Closure of Neural Tube
Somite Fusion initiates “mid-embryo” Cephalad and Caudad Rostral complete by 23-26 days Caudal complete by 26-30 days
Process of Neuralation
Post-conception dating
Complete “Formation or Malformation” by 6 weeks Menstrual (Obstetrical) Dating
Neural Tube Defects: Incidence and Risk Factors
Population Incidence / 1000 livebirths
Overall USA Pre-Gestational Diabetes Valproic Acid 1st Trimester 1 Prior Fetus / Child w/ NTD 2 Prior Fetus’s / Children w/ NTDs Gravida w/ Spina Bifida
1 20 10 15-30 50-60 10
Neural Tube Defects: Etiology
Multifactorial Inheritance Single Gene Mutation
Meckel-Gruber Syndrome Trisomy 16, 18 Triploidy Accutane, Valproic Acid, Carbamazepine
Aneuploidy
Teratogenic Drugs
Hyperglycemia Aberrations of Folic Acid Intake/Metabolism
Incidence of Neural Tube Defects:
Worldwide Differences
NTD Incidence: Recent Geographic Variance
a h in S.C in a h N.C n nd pa Ja zerla it Sw mark n D e er th Ne ly Ita iu m p lg Be h Re ec Cz n d la Ire ce n Fra ay rw No n ai Sp U K u ay ag Ur i l az Br ile a Ch n ti n ge la Ar z u e ne Ve co xi Me ralia st Au A US
60
50
40
30
20
10
0
Neural Tube Defects: Yearly Incidence
400,000
100,000
4,000
USA
CHINA
WORLD
Neural Tube Defects: Morbidity and Mortality
Death Paralysis Incontinence Neurodevelopmental Delay Hydrocephalus Surgical / Shunt Complications Psycho-Social-Economic Impact
Folic Acid and the prevention of Neural Tube Defects
The Clinical Evidence
Folic Acid and NTD Prevention: Clinical Evidence
Prevention of Neural Tube Defects: Results of the MRC Vitamin Study Lancet; Vol. 338, July, 1991 Prospective Randomized Blinded Clinical Trial Evaluate PRECONCEPTION Folic Acid and the Prevention of RECURRENT NTDs >1000 Pregnancy Outcomes
Women with prior fetus/child with NTD
Study halted due to ethical concerns regarding continued randomization
Folic Acid and NTD Prevention: Clinical Evidence
Folic Acid Exposed Group 4.0 mg. / day Other Vitamins or Placebo Group
n=6 1%
Recurrent NTDs RR=0.28 CI=0.12-0.71
n=21 3.5%
MRC Vitamin Study: Conclusion
4.0 mg. Folic Acid taken daily beginning preconceptionally and continuing through the first trimester REDUCES the risk of Recurrent Neural Tube Defects by 72%
Excellent data supporting Folic Acid in the prevention of RECURRENT Neural Tube Defects, However……………
at least 90% of NTDs are FIRST OCCURRENCES
Folic Acid and NTD Prevention: Clinical Evidence
Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation Czeizel and Dudas; New Engl J Med 1992
Multivitamin w/ 0.8 mg. Folic Acid vs. No Folic Acid / Trace Element Supplement
Folic Acid and NTD Prevention: Clinical Evidence
7,540 Patients Randomized 4,156 Known Outcomes
Malformations
n=2,104 Folic Acid
13.3/1000
n=2,052 No Folic Acid
22.9/1000
p=0.02
NTDs
0
Czeizel and Dudas; New Engl J Med 1992
6
p=0.03
Morbidity and Mortality Weekly Report; Sept. 1992: CDC Recommendations
Acting on the study by Czeizel and Dudas and given that >50% of pregnancies are Unplanned…….
All women of childbearing age in the United States capable of becoming pregnant should consume 0.4 mg of folic acid each day to reduce their neural tube defect affected pregnancy risk.
Prevention on Neural Tube Defects in China: Validation of the 0.4 mg Dosing Recommendation
Chinese Public Health Campaign; 1993-1995 Compares Northern (high-incidence) Region vs. Southern (lower-incidence) Region 0.4 mg. Folic Acid initiated at required premarital examination through 1st Trimester 247,831 Pregnancy Outcomes Analyzed
Prevention of NTDs in China:
New Engl J Med; Nov. 1999
5 NTDs per 1000 births 4 3 2 1 0
Southern China
Northern China
41% Risk Reduction
85% Risk Reduction
Avoiding Dosage Confusion
General Recommendation
0.4 mg. = 400 micrograms/ mcg.
Recurrent NTD Prevention
4.0 mg.
Folic Acid Intervention for Women with Prior NTD Affected Pregnancy
Not Planning Pregnancy Using Contraception 0.4 mg daily w/in a Multivitamin
Now Desiring Pregnancy Counsel and Initiate 4.0 mg daily 1.0 mg from PNV and 3.0 mg from “pure” FA Supplement CONTINUE BIRTH CONTROL X 1 MONTH
After the first trimester Continue Daily PNV DISCONTINUE additional 3 mg of Folic Acid
After 1 month Discontinue Birth Control Continue 4.0 mg Folic Acid
First trimester dating u/s, Second trimester MSAFP screen and targeted u/s
Folic Acid Intervention for Women with Prior NTD Affected Pregnancy
Not Planning Pregnancy Using Contraception 0.4 mg daily w/in a Multivitamin
Now Desiring Pregnancy Counsel and Initiate 4.0 mg daily 1.0 mg from PNV and 3.0 mg from “pure” FA Supplement CONTINUE BIRTH CONTROL X 1 MONTH
After the first trimester Continue Daily PNV DISCONTINUE additional 3 mg of Folic Acid
After 1 month Discontinue Birth Control Continue 4.0 mg Folic Acid
First trimester dating u/s, Second trimester MSAFP screen and targeted u/s
Folic Acid Intervention for Women with Prior NTD Affected Pregnancy
Not Planning Pregnancy Using Contraception 0.4 mg daily w/in a Multivitamin
Now Desiring Pregnancy Counsel and Initiate 4.0 mg daily 1.0 mg from PNV and 3.0 mg from “pure” FA Supplement CONTINUE BIRTH CONTROL X 1 MONTH
After the first trimester Continue Daily PNV DISCONTINUE additional 3 mg of Folic Acid
After 1 month Discontinue Birth Control Continue 4.0 mg Folic Acid
First trimester dating u/s, Second trimester MSAFP screen and targeted u/s
Folic Acid Intervention for Women with Prior NTD Affected Pregnancy
Not Planning Pregnancy Using Contraception 0.4 mg daily w/in a Multivitamin
Now Desiring Pregnancy Counsel and Initiate 4.0 mg daily 1.0 mg from PNV and 3.0 mg from “pure” FA Supplement CONTINUE BIRTH CONTROL X 1 MONTH
After the first trimester Continue Daily PNV DISCONTINUE additional 3 mg of Folic Acid
After 1 month Discontinue Birth Control Continue 4.0 mg Folic Acid
First trimester dating u/s, Second trimester MSAFP screen and targeted u/s
The Otero-Orta Family !
Neural Tube Defect Prevention: Folic Acid Options
Natural Foods Fortified Foods Vitamin Supplementation
Multivitamin vs. Folic Acid alone
Folic Acid and Diet Sources and Absorption
Yeast Organ Meats / Liver Egg Yolks Crystalline Folic Acid Supplement Spinach Oranges
Excellent Excellent Excellent Excellent
Poor Poor
50% Destruction via Cooking / Processing
Folic Acid and NTD Prevention: FOOD OR VITAMINS?
3 Groups Provided 0.4 mg Folic Acid/Day Natural Food Group
No Significant Change
Fortified Food Group
Significant Increase
Significant Increase
Folic Acid Supplement Group
Measured RBC Folate Levels
Cuskelly GJ et al. Lancet 1996
Dietary Folic Acid Intake Women - USA
Baseline Intake:
FDA Fortification-1998:
0.1 – 0.15 mg/day 0.1 mg / day
Approx. 0.2 mg/day
Total Daily Intake:
50% Less Folic Acid Intake Than The Amount Recommended
FOLIC ACID & NTD PREVENTION
The Cost:
Least expensive Multivitamin w/ 0.4 mg Folic Acid
$4.50 / 365 tabs
Only 1.2 cents per day!
Total Cereal - General Mills 29 cents per serving 0.4 mg Folic Acid
Homocysteine
The NTD - Folic Acid Link ?
METHIONINE
B6, B12 FOLIC ACID
MTHFR
677C-->T MTHFR MUTATION
HOMOCYSTEINE
Elevated Homocysteine: Health Consequences
Methionine
Folic Acid Vitamins B6, B12 Methylenetetrahydrafolate Reductase (MTHFR)
Homocysteine
Thrombosis Cardiac Malformations
Wenstrom et al AJOG 2001
Preeclampsia IUGR Recurrent Pregnancy Loss
Coronary Artery Disease
Cancer
Stroke
NTDs
Lowering Homocysteine: Nutritional Strategies
%
30 20 10 0 -10 -20 -30
Folate Level Increase
Homocysteine
Reduction
Folate Rich Foods
FA FORTIFIED FA Supplement FOODS
Riddell et al Am J Clin Nutr June 2000
Healthy People 2010:
Goal 16-16
“Increase the proportion of pregnancies begun with an optimum folic acid level”
Consumption of at least 0.4 mg Folic Acid each day from fortified foods or dietary supplement by non-pregnant women ages 15-44 1990s estimate 20%
2010 Goal: 80%
Comparative use and knowledge of preconceptional folic acid among Spanish- and English-speaking patient populations in Phoenix and Yuma, Arizona
Perlow JH. Am J Obstet Gynecol 2001;184:1263-6
Knowledge and Use of Preconceptional Folic Acid
Phoenix and Yuma, Arizona
6 Month Survey 315 patients Spanish-speaking 132 English-speaking 183
Knowledge and Use of Preconceptional Folic Acid: Response to statement……… “Taking vitamins helps prevent birth defects”
%
40 35 30 25 20 15 10 5 0 DEFINITELY SOMETIMES NOT REALLY I'M NOT SURE
Knowledge and Use of Preconceptional Folic Acid: Response to Statement………
“Taking vitamins helps prevent birth defects”
%
50 45 40 35 30 25 20 15 10 5 0
DEFINITELY
Spanish
English
SOMETIMES
NOT REALLY
NOT SURE
Knowledge and Use of Preconceptional Folic Acid
Phoenix and Yuma, Arizona
Among Patients Aware of a Vitamin - Birth Defect Prevention Link
16.7%
Identify Critical Vitamin as FOLIC ACID
Knowledge and Use of Preconceptional Folic Acid
Phoenix and Yuma, Arizona
Knowledge of of Folic Acid - NTD Link
“Less than 1 in 12 patients surveyed (7.9%) were aware of a specific association between folic acid intake and the prevention of NTDs”
Knowledge and Use of Preconceptional Folic Acid
Phoenix and Yuma, Arizona
%
100 80 60 40 20 0
Of Patients Knowing of NTD Prevention Benefits of FOLIC ACID
92
Total n = 25/315
8
SPANISH
ENGLISH
Risk of Neural Tube Defects: Mexican and White Women in California
Nearly twice the risk for NTDs among women of Mexican ancestry vs. White women Odds Ratio 1.9 Shaw et al. Am J Public Health 1997 Educational endeavors within the Spanish-speaking community is critical