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JOGC NOVEMBER 2003
Abstract
Objective: To provide information regarding the use of folic acid
for the prevention of neural tube defects (NTDs) and other
congenital anomalies, in order that physicians, midwives, nurses,
and other health-care workers can assist in the education of
women in the preconception phase of their health care.
Option: Folic acid supplementation is problematic, since 50% of
pregnancies are unplanned and the health status of women
may not be optimal.
Outcomes: Folic acid supplementation has been proven to
decrease or minimize specific birth defects.
Evidence: A systematic review of the literature, including review
and peer-reviewed articles, government publications, the pre-
vious Society of Obstetricians and Gynaecologists of Canada
(SOGC) Policy Statement of March 1993, and statements from
the American College of Obstetrics and Gynecology, was used
to develop a new clinical practice guideline for the SOGC.
Values: Peer-review process within the committee structure.
Benefits, harms, and costs: The benefit is reduced lethal and
severe morbidity birth defects and the harm is minimal.The
personal cost is of vitamin supplementation on a daily basis
and eating a healthy diet.
Recommendations:
1. Women in the reproductive age group should be advised
about the benefits of folic acid supplementation during well-
ness visits (birth control renewal, Pap testing, yearly examina-
tion), especially if pregnancy is contemplated. (III-A)
2. Women should be advised to maintain a healthy nutritional
diet, as recommended in Canada’s Food Guide to Healthy Eating
(good or excellent sources of folic acid: broccoli, spinach, peas,
Brussels sprouts, corn, beans, lentils, oranges). (III-A)
3. Women who could become pregnant should be advised to
take a multivitamin containing 0.4 mg to 1.0 mg of folic acid
daily. (II-1A)
4. Women taking a multivitamin with folic acid supplement
should be advised not to take more than 1 daily dose of
vitamin supplement, as indicated on the product label. (II-2A)
5. Women in intermediate- to high-risk categories for NTDs
(NTD-affected previous pregnancy, family history, insulin-
dependent diabetes, epilepsy treatment with valproic acid or
carbamazepine) should be advised that high-dose folic acid
(4.0 mg–5.0 mg daily) supplementation is recommended. This
should be taken as folic acid alone,not in a multivitamin for-
mat, due to risk of excessive intake of other vitamins such as
vitamin A. (I-A)
6. The choice of a 5 mg folic acid daily dose for women consid-
ering a pregnancy should be made under medical supervision
after minimizing the risk of undiagnosed vitamin B12 deficiency
(hypersegmentation of polymorphonuclear cells, macrocystic
indices, large ovalocytes, leukopenia, thrombocytopenia,
markedly elevated lactate dehydrogenase level, confirmed red
blood cell folate level). (II-2A)
7. Signs or symptoms of vitamin B12 deficiency should be con-
sidered before initiating folic acid supplementation of doses
greater than 1.0 mg. (III-A)
8. A three-generation pedigree on the families of both the preg-
nant woman and the biological father should be obtained to
1
THE USE OF FOLIC ACID FOR THE PREVENTION OF NEURAL
TUBE DEFECTS AND OTHER CONGENITAL ANOMALIES
This guideline has been prepared by the Genetics Committee and approved by the
Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.
SOGC CLINICAL PRACTICE GUIDELINES
No. 138, November 2003
These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change.The information should not be construed as
dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions.They should be well doc-
umented if modified at the local level. None of the contents may be reproduced in any form without prior written permission of SOGC.
PRINCIPAL AUTHOR
R. Douglas Wilson, MD, FRCSC, Philadelphia PA
GENETICS COMMITTEE
R. Douglas Wilson (Chair), MD, FRCSC, Philadelphia PA
Gregory Davies, MD, FRCSC, Kingston ON
Valérie Désilets, MD, FRCSC, Montreal QC
Gregory J. Reid, MD, FRCSC,Winnipeg MB
Anne Summers, MD, FRCPC, Toronto ON
Philip Wyatt, MD, PhD,Toronto ON
David Young, MD, FRCSC, Halifax NS
Key Words
Folic acid, neural tube defect, prevention, myelomeningocele,
anencephaly, spina bifida, risk reduction
identify increased risk for congenital birth defects (i.e., NTD,
cardiac, chromosomal, genetic). (III-A)
9. Women who become pregnant should be advised of the avail-
ability of noninvasive screening tests and invasive diagnostic
tests for congenital birth defects (including NTDs): maternal
serum “triple marker screen” at 15 to 20 weeks, ultrasound
at 16 to 20 weeks, and amniocentesis after 15 weeks of preg-
nancy if a positive screening test is present. (I-A)
Validation: This is a revision of a previous guideline and infor-
mation from other consensus reviews from medical and gov-
ernment publications has been used.
Sponsor: The Society of Obstetricians and Gynaecologists of
Canada.
J Obstet Gynaecol Can 2003;25(11):959–65.
INTRODUCTION
It is estimated that at least 5% of babies are born with some
serious congenital anomaly.1Of these 5 babies in 100, 2 or 3 will
have anomalies that can be recognized prenatally by a non-
invasive screening test, through invasive diagnostic testing,
or at birth, while the other 2 babies will have developmental or
functional anomalies recognized during the first year of their life.1
The ingestion of folic acid by a woman prior to conception and
during the early stages of pregnancy plays a role in preventing
neural tube defects (NTDs) and has been associated with pre-
venting other congenital anomalies.2Public health initiatives to
increase the awareness and prevention of birth defects have
focused on folic acid intake for the prevention of NTDs, but there
are several studies that have indicated that taking multiple vita-
mins containing folic acid during the periconception period can
reduce the risk of other neonatal conditions such as congenital
heart defects,2-5 urinary tract anomalies,5,6 oral facial clefts,2,7-9
limb defects,2and pyloric stenosis.3It has been estimated that as
many as half of all birth defects can be prevented if women of
childbearing age consume an adequate amount of folic acid, either
by eating sufficient quantities of foods that are fortified with folic
acid or by taking vitamin supplements.10
The objective of this clinical practice guideline update is to
inform women’s health-care providers of new information regard-
ing the use of folic acid for the prevention of neural tube defects
and other congenital anomalies. The quality of evidence reported
in this guideline has been described using the Evaluation of
Evidence criteria outlined in the Report of the Canadian Task
Force on the Periodic Health Examination (Table 1).11
METHODS
A systematic review of the literature, including review and peer-
reviewed articles, government publications, the previous Society
of Obstetricians and Gynaecologists of Canada (SOGC)
Policy Statement The Use of Folic Acid for Prevention of Neural
Tube Defects published in March 1993,12 and statements from
the American College of Obstetrics and Gynecology,13 was used
to develop a new clinical practice guideline for the SOGC.
JOGC NOVEMBER 2003
2
TABLE 1
QUALITY OF EVIDENCE ASSESSMENT11
The quality of evidence reported in these guidelines has been
described using the Evaluation of Evidence criteria outlined in
the Report of the Canadian Task Force on the Periodic Health
Examination.
1: Evidence obtained from at least one properly randomized
controlled trial.
II-1: Evidence from well-designed controlled trials without
randomization.
II-2: Evidence from well-designed cohort (prospective or
retrospective) or case-control studies, preferably from
more than one centre or research group.
II-3: Evidence obtained from comparisons between times or
places with or without the intervention. Dramatic results
in uncontrolled experiments (such as the results of treat-
ment with penicillin in the 1940s) could also be included
in this category.
III: Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
CLASSIFICATION OF RECOMMENDATIONS11
Recommendations included in these guidelines have been
adapted from the ranking method described in the
Classification of Recommendations found in the Canadian
Task Force on the Periodic Health Examination.
A. There is good evidence to support the recommendation
that the condition be specifically considered in a periodic
health examination.
B. There is fair evidence to support the recommendation
that the condition be specifically considered in a periodic
health examination.
C. There is poor evidence regarding the inclusion or
exclusion of the condition in a periodic health examination,
but recommendations may be made on other grounds.
D. There is fair evidence to support the recommendation
that the condition not be considered in a periodic health
examination.
E. There is good evidence to support the recommendation
that the condition be excluded from consideration in a
periodic health examination.
JOGC NOVEMBER 2003
3
RESULTS
NEURAL TUBE DEFECTS
INCIDENCES AND INHERITANCE
Neural tube defects are severe birth anomalies, due to the lack
of neural tube closure at either the upper or lower end in the
third to fourth week after conception (day 26 to day 28 post-
conception).14 The incidence and the empiric recurrence risk for
NTDs vary across North American regions (Table 2).10,14-22
In Canada, the birth prevalence of NTDs has declined
from a rate of 11.6 per 10 000 live births in 1989 to 7.5 per
10 000 total births (live births and stillbirths) in 1997.23 Reasons
given for this decrease in the rate of NTDs include an increased
usage of prenatal diagnoses (ultrasound, maternal serum screen-
ing) with subsequent pregnancy termination and, possibly,
increased vitamin supplementation.23 The rate of NTDs tends
to be higher in Eastern Canada than in Western Canada.24,25
Women of certain ethnic groups including Celtic26 and Sikh,27
as well as women from Northern China,28 are at higher risks of
having children with NTDs.24-28 It remains unclear whether these
risks vary due to genetic predisposition, culture dietary prefer-
ences, or a combination of these factors.
Multifactorial inheritance24,29,30 is the most common cause of
NTDs, but monogenic, chromosomal, and teratogenic causes
have specific risks and have not been studied in association with
folic acid deprivation or supplementation (Table 3).14 The prev-
alence of aneuploidy and additional anatomical abnormalities in
fetuses with open spina bifida was reviewed using Utah birth defect
network data.31 Chromosome results were known in 45 of 51 cases
of open spina bifida, with 6 cases (13%) having aneuploidy.
Additional major anatomic abnormalities were present in 4 of the
6 cases and included cardiac, renal, omphalocele, brain, and bi-
lateral oral clefting. There was a 4% risk of aneuploidy in sono-
graphically isolated spina bifida cases within this population.31
PRENATAL DIAGNOSIS
Prenatal diagnosis should be specifically and appropriately timed
to women with an increased risk of having a child with an
NTD.32-38 Folic acid supplementation will not eliminate but
TABLE 2
INCIDENCE AND RECURRENCE RISK FOR NTD
IN DIFFERENT REGIONS OF
CANADA AND THE UNITED STATES1,10,19-22
Region Incidence Recurrence Risks
(per 1000 total births)
(%)
British Columbia 1.6 2.1
Ontario 1.2 (1986) 2.4
1.6 (1995)
0.9 (1999)
Quebec 4.0 4.5
Nova Scotia 2.6 (1991–1997)
1.2 (1998–2000)
Newfoundland 4.0 5.0
United States 1.4–1.6 1.5–3.0
Canada 0.75 (1997)
TABLE 3
RECOGNIZED CONDITIONS ASSOCIATED WITH
NEURAL TUBE DEFECTS14*
1. Multifactorial: Homocysteine metabolism variants
(MTHFR)
2. Monogenic: AR Acrocallosal syndrome
Cerebro-costo-mandibular syndrome
Fanconi’s pancytopenia syndrome
Fraser’s syndrome
Hydrolethalus syndrome
Jarcho-Levin syndrome
Meckel-Gruber syndrome
AD Waardenburg’s syndrome
3. Chromosomal: Miller-Dieker syndrome (deletion 17p13.3)
Triploidy
Trisomy 9 (mosaic)
Trisomy 13
Trisomy 18
4. Teratogen: Fetal hyperthermia spectrum
Fetal alcohol syndrome
Fetal amniopterin/methotrexate
syndrome
Fetal rubella
Fetal valproate/carbamazepine/maternal
epilepsy syndrome
Maternal insulin-dependent diabetes
(preconception)
5. Unknown: Caudal dysplasia sequence
Child syndrome
Extrophy of cloacae sequence
Laterality sequences
Limb-body Wall complex
Monozygotic twinning
*NTD: neural tube defect; MTHFR: 5,10-methylenetetra-
hydrofolate reductase;AR: autosomal recessive inheritance;
AD: autosomal dominant inheritance.
only reduce the risk of NTDs.39 Women at increased risk for a
pregnancy complicated by NTDs often have a history of:
• a previous fetus or child with an NTD12,13,37,40
• a first-, second-, or third-degree relation with an
NTD12,37,40
• insulin-dependent (type 1) diabetes12,37,40
• epilepsy and the ingestion of valproic acid or carba-
mazepine for seizure control12,37,40
• use of folic acid antagonists (amniopterin, methotrex-
ate)12,37,40
Noninvasive prenatal diagnoses by ultrasound and maternal
serum screening38 should be offered at 16 to 20 weeks’ and
15 to 20 weeks’ gestation, respectively, and will identify 95% to
100% of NTDs (anencephaly, 100%; spina bifida, 95%). Ultra-
sound imaging41,42 of the cranium and the identification of
cranial scalloping (lemon sign) and cerebellar crowding (banana
sign) in association with mild ventriculomegaly is diagnostic of
an open myelomeningocele, even if a defect is not easily identifi-
able in the spine due to the level of the spinal defect, fetal
position, or maternal habitus. After 15 weeks of pregnancy,
invasive prenatal diagnosis with ultrasound-guided amniocentesis,
with confirmation by increased levels of amniotic fluid alphafeto-
protein and acetylcholinesterase, can be diagnostic of open or
closed lesions, and used to evaluate fetal karyotype.38
FOLIC ACID AND PREVENTION
A recent Health Canada document40 entitled Preconception
Health: Folic Acid for Primary Prevention of Neural Tube Defects –
a Resource Document for Health Professionals 2002, states that, from
the human data, it is clear that periconceptional use of supple-
ments containing folic acid substantially reduces the risks of
occurrence (first affected pregnancy) and recurrence (additional
affected pregnancies) of neural tube defects.
Women should be advised to maintain a healthy nutri-
tional diet as recommended in Canada’s Food Guide to Healthy
Eating.43 Good or excellent sources of folic acid are found in
broccoli, spinach, peas, Brussels sprouts, corn, lentils, and
oranges.
A randomized trial44 for the prevention of primary occurrence
found periconceptional vitamin supplementation (12 vitamins
including 0.8 mg of folic acid, 4 minerals, 3 trace elements)
decreased the incidence of a first occurrence of an NTD. Previous
case control studies had provided supportive and equivocal
evidence that pregnant women using multivitamins containing
folic acid or dietary folic acid had a lower risk of occurrence of
NTDs than women not taking supplements.45-49
For prevention of recurrence of NTDs, a randomized
double-blind clinical trial,39 involving 1195 completed
pregnancies in high-risk women from 33 centres, reported
72% fewer cases of NTDs among the children of the folic acid
supplementation group than among the offspring of controls
who did not take folic acid supplementation.39 The recurrence
rate decreased from 3.5% to 1% for women randomized to
receive 4 mg folic acid supplementation prior to pregnancy and
throughout the first 6 weeks of pregnancy. The results in the
group taking vitamins without folic acid were similar to the
results in the group not taking vitamin supplementation, with
recurrence risks of 3.5%.
Wald et al.50 looked at the dose of folic acid to maximize the
already known benefit of folic acid in preventing NTDs. The study
analyzed published data from 13 other studies of folic acid
supplementation on serum folate concentrations, as well as results
from a large cohort study of the risk of NTDs according to serum
folate. The results of the analysis indicated that the folic acid
preventive effect is greater in women with an initial low serum
folate concentration than in women with higher serum folate con-
centrations. The results of serum folate levels have also been used
to predict direct observations from large randomized trials on
the effect of food fortification in preventing NTDs. For Caucasian
women, a serum folate of 5 ng/mL, about 0.2 mg per day (the
United States’ level of folic acid fortification) would be expected
to reduce NTDs by about 20%.50 A similar effect can be expect-
ed from the current British fortification recommendation of
0.24 mg per day. An increase of 0.4 mg/day would reduce the risk
by about 36%, 1 mg per day by 57%, and the use of a 5 mg tablet
daily would reduce risk by about 85%. Wald et al.50 concluded
that folic acid fortification levels should be increased accordingly,
and that women planning a pregnancy should take 5 mg folic acid
tablets daily instead of the 0.4 mg dose presently recommended.
Subsequent letters to the editor showed support51,52 for the con-
cept while others recommended caution.53 The choice of a 5 mg
folic acid daily dose for Canadian women considering a preg-
nancy should be made under medical supervision after minimiz-
ing the risk of undiagnosed vitamin B12 deficiency.
FOLIC ACID SUPPLEMENTATION AND BIRTH
DEFECTS OTHER THAN NEURAL TUBE DEFECTS
Folic acid supplementation has been shown to benefit other con-
genital anomalies, such as congenital heart defects,2-5 urinary
tract anomalies,5,6 oral facial clefts,2,7-9 limb defects,2and pyloric
stenosis.3A recent review54 summarizes the recent literature
regarding prevention of congenital anomalies with periconcep-
tional folic acid supplementation.
POTENTIAL HARM OF EXCESS FOLIC ACID INTAKE
Folic acid, in the recommended dosage of 0.4 to 1.0 mg,12,13,40 is
not known to cause demonstrable harm to the developing fetus
or the pregnant woman.16-21 Folic acid is water soluble and its
excess is excreted through the urinary tract. The effects of
higher intake of folic acid (i.e., >1 mg) are not well known, but
they include masking the diagnosis of vitamin B12 deficiency. This
concern has led to a recommendation that, for healthy women,
JOGC NOVEMBER 2003
4
JOGC NOVEMBER 2003
5
1 mg of folic acid daily (from either folic acid supplements or
fortified foods) be considered the maximum dose.12,13
Folic acid can mask vitamin B12 deficiency by correcting the
mesoblastic anemia changes normally identifiable, but it does not
prevent the neurological complications of vitamin B12 deficiency.
In fact, there has been some concern that high doses of folic acid
may precipitate or exacerbate neurological symptoms of vitamin
B12 deficiency.50-53 Clinical symptoms of vitamin B12 deficiency
include tiredness, fatigability, chronic malaise, sore tongue, ataxic
gait, and numbness of the fingers.55 Women with signs of red
cracked tongue, peripheral neuropathy, ataxia, pallor, and other
signs of anemia, and those given a dose of folic acid greater than
1 mg per day, should be investigated for possible vitamin B12
deficiency.55 Other hematological characteristics55 of vitamin B12
deficiency include hypersegmentation of polymorphonuclear cells,
macrocystic indices, large ovalocytes, leukopenia, and thrombo-
cytopenia. A markedly elevated lactate dehydrogenase level and
red blood cell folate level are also usually observed.55
Folic acid rarely has allergic responses but these may include
erythema, rash, itching, general malaise, and bronchospasm.56
INTERACTION OF DRUGS WITH FOLIC ACID
Serum folic acid levels may be affected by the metabolism of
other medications, including antineoplastic agents, epileptic
medications, oral contraceptives, and other medications
(Table 4).12,13,40 Folic acid has recognized drug interactions57
with other commonly used medications such as hyperten-
sive/thiazide combinations, digoxin, thyroid hormones, tetra-
cycline, and thiazide diuretics.
VITAMINS AND MINERALS
There is strong evidence that the use of a multivitamin–
multimineral supplement containing folic acid at 0.4 mg per
daily dose reduces the risk of a first-occurrence NTD.40 The
combination of ingredients varies greatly in over-the-counter
preparations. It is suggested that multivitamin–multimineral
preparations with 0.4 mg–1.0 mg of folic acid per daily dose
be taken,40 but that mineral supplementation may not be
necessary, due to the low risk of deficiency in Canada.40
Supplements containing herbs and other “nonmedicinal
ingredients” should be avoided, as they have neither been proven
to have any benefit nor been studied regarding harm.
Multivitamins should have vitamin A as beta-carotene rather
than as retinol. Excess retinol (10 000 IU; 3300 RE) on a daily
basis may cause birth defects.58 For this reason, women should not
take more than 1 daily dose, as indicated on the product label.
FOLIC ACID FOOD FORTIFICATION
In Canada since 1998, in an effort to reduce the rate of NTDs,
there has been mandatory fortification of white flour, enriched
pasta, and cornmeal with folic acid. The overall benefit of for-
tification in reducing NTDs is yet to be determined.40,59 The
minimal effective dose is also unknown.40,59
CONCLUSION
Folic acid (through diet and supplementation) has been proven
to decrease or minimize specific birth defects including neural
tube defects, congenital heart disease, urinary tract anomalies,
oral facial clefts, limb defects, and pyloric stenosis.2-9 Precon-
ceptional folic acid supplementation should be recommended
to women who may become pregnant. The dose of folic acid
supplementation should be adjusted according to the patient’s
history and needs.
RECOMMENDATIONS
1. Women in the reproductive age group should be advised
about the benefits of folic acid supplementation during
wellness visits (birth control renewal, Pap testing, yearly
examination), especially if pregnancy is contemplated.
(III-A)
2. Women should be advised to maintain a healthy nutri-
tional diet, as recommended in Canada’s Food Guide to
Healthy Eating (good or excellent sources of folic acid:
broccoli, spinach, peas, Brussels sprouts, corn, beans,
lentils, oranges). (III-A)
TABLE 4
INTERACTIONS: DRUGS AND FOLIC ACID12,13,40,57
Drugs Effect Mechanism Importance
Chloramphenicol Reduced folic acid effect Interference with erythrocyte Caution
maturation
Phenobarbital, phenytoin, Reduced folic acid levels Increased folic acid metabolism Caution
primidone
Phenytoin Loss of seizure control; Increased phenytoin metabolism Monitor phenytoin levels
decreased phenytoin levels
Sulfasalazine Decreased folic acid levels Impaired absorption Caution
3. Women who could become pregnant should be advised
to take a multivitamin containing 0.4 mg to 1.0 mg of
folic acid daily. (II-1A)
4. Women taking a multivitamin with folic acid supplement
should be advised not to take more than 1 daily dose of
vitamin supplement, as indicated on the product label.
(II-2A)
5. Women in intermediate- to high-risk categories for NTDs
(NTD-affected previous pregnancy, family history,
insulin-dependent diabetes, epilepsy treatment with val-
proic acid or carbamazepine) should be advised that
high-dose folic acid (4.0 mg–5.0 mg daily) supplemen-
tation is recommended. This should be taken as folic acid
alone, not in a multivitamin format, due to risk of exces-
sive intake of other vitamins such as vitamin A. (I-A)
6. The choice of a 5 mg folic acid daily dose for women con-
sidering a pregnancy should be made under medical
supervision after minimizing the risk of undiagnosed
vitamin B12 deficiency (hypersegmentation of polymor-
phonuclear cells, macrocystic indices, large ovalocytes,
leukopenia, thrombocytopenia, markedly elevated lac-
tate dehydrogenase level, confirmed red blood cell folate
level). (II-2A)
7. Signs or symptoms of vitamin B12 deficiency should be
considered before initiating folic acid supplementation
of doses greater than 1.0 mg. (III-A)
8. A three-generation pedigree on the families of both the
pregnant woman and the biological father should be
obtained to identify increased risk for congenital birth
defects (i.e., NTD, cardiac, chromosomal, genetic).
(III-A)
9. Women who become pregnant should be advised of the
availability of noninvasive screening tests and invasive
diagnostic tests for congenital birth defects (including
NTDs): maternal serum “triple marker screen” at 15 to
20 weeks, ultrasound at 16 to 20 weeks, and amnio-
centesis after 15 weeks of pregnancy if a positive screen-
ing test is present. (I-A)
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