pre-conception folic acid and multivitamin supplementation ... · congenital anomalies, fetal...
TRANSCRIPT
534 z JUNE JOGC JUIN 2015
J Obstet Gynaecol Can 2015;37(6):534–549
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SOGC ClINICAl PRACTICE GUIDElINE
Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies
This document reflects emerging clinical and scientific advances on the date issued and is 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 documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.
This Clinical Practice Guideline was prepared by the Genetics Committee, reviewed by the Family Physician Advisory Committee, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada.
PRINCIPAl AUTHOR
R. Douglas Wilson, MD, Calgary AB
GENETICS COMMITTEE
R. Douglas Wilson (Chair), MD, Calgary AB
François Audibert, MD, Montreal QC
Jo-Ann Brock, MD, Halifax NS
June Carroll, MD, Toronto ON
Lola Cartier, MSc, Montreal QC
Alain Gagnon, MD, Vancouver BC
Jo-Ann Johnson, MD, Calgary AB
Sylvie Langlois, MD, Vancouver BC
Lynn Murphy-Kaulbeck, MD, Moncton NB
Nanette Okun, MD, Toronto ON
Melanie Pastuck, RN, Calgary AB
SPECIAl CONTRIBUTORS
Paromita Deb-Rinker, PhD, Ottawa ON
Linda Dodds, MD, Halifax NS
Juan Andres Leon, MD, Ottawa ON
Hélène Lowell, RD DtP, Ottawa ON
Wei Luo, MB MSc, Ottawa ON
Amanda MacFarlane, PhD, Ottawa ON
Rachel McMillan, BSc, Ottawa ON
Key Words: Folic acid, folate, prenatal multivitamins,
PLFURQXWULHQWV��QHXUDO�WXEH�GHIHFW��VSLQD�EL¿GD��P\HORPHQLQJRFHOH��congenital anomalies, fetal anomalies, folate sensitive birth
defects, congenital anomaly risk reduction, preconception
counseling, birth defects, pregnancy, prevention
Abstract
Objective: To provide updated information on the pre- and post-
conception use of oral folic acid with or without a multivitamin/
micronutrient supplement for the prevention of neural tube
defects and other congenital anomalies. This will help physicians,
midwives, nurses, and other health care workers to assist in the
education of women about the proper use and dosage of folic
acid/multivitamin supplementation before and during pregnancy.
Evidence: Published literature was retrieved through searches of
PubMed, Medline, CINAHL, and the Cochrane Library in January
2011 using appropriate controlled vocabulary and key words (e.g.,
folic acid, prenatal multivitamins, folate sensitive birth defects,
congenital anomaly risk reduction, pre-conception counselling).
Results were restricted to systematic reviews, randomized control
trials/controlled clinical trials, and observational studies published
in English from 1985 and June 2014. Searches were updated on
a regular basis and incorporated in the guideline to June 2014
*UH\��XQSXEOLVKHG��OLWHUDWXUH�ZDV�LGHQWL¿HG�WKURXJK�VHDUFKLQJ�WKH�
Aideen Moore, MD, Toronto ON
William Mundle, MD, Windsor ON
Deborah O’Connor, PhD RD, Toronto ON
Joel Ray, MD, Toronto ON
Michiel Van den Hof, MD, Halifax NS
Disclosure statements have been received from all contributors.
JUNE JOGC JUIN 2015 z 535
Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies
SOGC ClINICAl PRACTICE GUIDElINE
websites of health technology assessment and health technology-
related agencies, clinical practice guideline collections, clinical trial
registries, and national and international medical specialty societies.
&RVWV��ULVNV��DQG�EHQH¿WV��7KH�¿QDQFLDO�FRVWV�DUH�WKRVH�RI�GDLO\�vitamin supplementation and eating a healthy folate-enriched
diet. The risks are of a reported association of dietary folic acid
VXSSOHPHQWDWLRQ�ZLWK�IHWDO�HSLJHQHWLF�PRGL¿FDWLRQV�DQG�ZLWK�DQ�increased likelihood of a twin pregnancy. These associations may
require consideration before initiating folic acid supplementation.
7KH�EHQH¿W�RI�IROLF�DFLG�RUDO�VXSSOHPHQWDWLRQ�RU�GLHWDU\�IRODWH�intake combined with a multivitamin/micronutrient supplement is
an associated decrease in neural tube defects and perhaps in
RWKHU�VSHFL¿F�ELUWK�GHIHFWV�DQG�REVWHWULFDO�FRPSOLFDWLRQV�
Values: The quality of evidence in the document was rated using the
criteria described in the Report of the Canadian Task Force on
Preventative Health Care (Table 1).
Summary Statement
In Canada multivitamin tablets with folic acid are usually available in 3
formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic
acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid,
and prescription multivitamins with 5.0 mg folic acid. (III)
Recommendations
1. Women should be advised to maintain a healthy folate-rich diet;
however, folic acid/multivitamin supplementation is needed to
achieve the red blood cell folate levels associated with maximal
protection against neural tube defect. (III-A)
2. All women in the reproductive age group (12–45 years of age)
who have preserved fertility (a pregnancy is possible) should
EH�DGYLVHG�DERXW�WKH�EHQH¿WV�RI�IROLF�DFLG�LQ�D�PXOWLYLWDPLQ�supplementation during medical wellness visits (birth control
renewal, Pap testing, yearly gynaecological examination)
whether or not a pregnancy is contemplated. Because so many
pregnancies are unplanned, this applies to all women who may
become pregnant. (III-A)
3. Folic acid supplementation is unlikely to mask vitamin B12
GH¿FLHQF\��SHUQLFLRXV�DQHPLD���,QYHVWLJDWLRQV��H[DPLQDWLRQ�or laboratory) are not required prior to initiating folic acid
supplementation for women with a risk for primary or recurrent
neural tube or other folic acid-sensitive congenital anomalies who
are considering a pregnancy. It is recommended that folic acid
be taken in a multivitamin including 2.6 ug/day of vitamin B12 to
mitigate even theoretical concerns. (II-2A)
4. Women at HIGH RISK, for whom a folic acid dose greater than 1
mg is indicated, taking a multivitamin tablet containing folic acid,
should be advised to follow the product label and not to take more
than 1 daily dose of the multivitamin supplement. Additional tablets
containing only folic acid should be taken to achieve the desired
dose. (II-2A)
5. Women with a LOW RISK for a neural tube defect or other folic
acid-sensitive congenital anomaly and a male partner with low
risk require a diet of folate-rich foods and a daily oral multivitamin
supplement containing 0.4 mg folic acid for at least 2 to 3 months
before conception, throughout the pregnancy, and for 4 to 6 weeks
postpartum or as long as breast-feeding continues. (II-2A)
6. Women with a MODERATE RISK for a neural tube defect or
other folic acid-sensitive congenital anomaly or a male partner
with moderate risk require a diet of folate-rich foods and daily oral
supplementation with a multivitamin containing 1.0 mg folic acid,
beginning at least 3 months before conception. Women should
continue this regime until 12 weeks’ gestational age. (1-A) From
12 weeks’ gestational age, continuing through the pregnancy,
and for 4 to 6 weeks postpartum or as long as breast-feeding
continues, continued daily supplementation should consist of a
multivitamin with 0.4 to 1.0 mg folic acid. (II-2A)
7. Women with an increased or HIGH RISK for a neural tube defect,
a male partner with a personal history of neural tube defect, or
history of a previous neural tube defect pregnancy in either partner
require a diet of folate-rich foods and a daily oral supplement
with 4.0 mg folic acid for at least 3 months before conception
and until 12 weeks’ gestational age. From 12 weeks’ gestational
age, continuing throughout the pregnancy, and for 4 to 6 weeks
postpartum or as long as breast-feeding continues, continued daily
supplementation should consist of a multivitamin with 0.4 to 1.0
mg folic acid. (I-A). The same dietary and supplementation regime
should be followed if either partner has had a previous pregnancy
with a neural tube defect. (II-2A)
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health CareQuality of evidence assessment* &ODVVL¿FDWLRQ�RI�UHFRPPHQGDWLRQV�
I: Evidence obtained from at least one properly randomized
controlled trial
A. There is good evidence to recommend the clinical preventive action
II-1: Evidence from well-designed controlled trials without
randomization
B. There is fair evidence to recommend the clinical preventive action
II-2: Evidence from well-designed cohort (prospective or
retrospective) or case–control studies, preferably from
more than one centre or research group
C. 7KH�H[LVWLQJ�HYLGHQFH�LV�FRQÀLFWLQJ�DQG�GRHV�QRW�DOORZ�WR�PDNH�D�recommendation for or against use of the clinical preventive action;
KRZHYHU��RWKHU�IDFWRUV�PD\�LQÀXHQFH�GHFLVLRQ�PDNLQJ
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 treatment with
penicillin in the 1940s) could also be included in this category
D. There is fair evidence to recommend against the clinical preventive action
E. There is good evidence to recommend against the clinical preventive
action
III: Opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert committees
/����7KHUH�LV�LQVXI¿FLHQW�HYLGHQFH��LQ�TXDQWLW\�RU�TXDOLW\��WR�PDNH�D�UHFRPPHQGDWLRQ��KRZHYHU��RWKHU�IDFWRUV�PD\�LQÀXHQFH�decision-making
*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health
Care.193
�5HFRPPHQGDWLRQV�LQFOXGHG�LQ�WKHVH�JXLGHOLQHV�KDYH�EHHQ�DGDSWHG�IURP�WKH�&ODVVL¿FDWLRQ�RI�5HFRPPHQGDWLRQV�FULWHULD�GHVFULEHG�LQ�WKH�&DQDGLDQ�7DVN�)RUFH�on Preventive Health Care.193
536 z JUNE JOGC JUIN 2015
SOGC ClINICAl PRACTICE GUIDElINE
INTRODUCTION
IW�KDV�EHHQ�HVWLPDWHG�WKDW����WR����RI �EDELHV�DUH�ERUQ�with a serious congenital anomaly1; 2% to 3% will have
congenital anomalies (malformations, deformations or GLVUXSWLRQV�� WKDW� FDQ� EH� UHFRJQL]HG� SUHQDWDOO\� E\� QRQ�invasive ultrasound screening or anticipated through invasive diagnostic testing and 2% will have developmental or functional anomalies and minor congenital anomalies UHFRJQL]HG�DW�ELUWK�RU�GXULQJ� WKH�ÀUVW�\HDU�RI � OLIH�1 Folic DFLG��WDNHQ�RUDOO\�SULRU�WR�FRQFHSWLRQ�DQG�GXULQJ�WKH�HDUO\�stages of pregnancy, plays a role in preventing neural WXEH� GHIHFWV�²��� DQG� KDV� EHHQ� DVVRFLDWHG�ZLWK� SUHYHQWLQJ�other folic acid-sensitive congenital anomalies such as heart defects,�����²�� urinary tract anomalies,15,28,31 oral facial clefts,�����²���DQG�OLPE�GHIHFWV�15
FOlIC ACID SUPPlEMENTATION AND THE PREVENTION OF BIRTH DEFECTS
7KH� LQLWLDO�17'�WUDQVODWLRQDO� UHVHDUFK�VWXG\� LQYHVWLJDWHG�folic acid supplementation for recurrence prevention of 17'V�LQ�D�UDQGRPL]HG�GRXEOH�EOLQG�FOLQLFDO�WULDO�LQYROYLQJ������ FRPSOHWHG� KLJK� ULVN� SUHJQDQFLHV� LQ� ZRPHQ� IURP���� FHQWUHV�2� 7KH� 17'� UHFXUUHQFH� UDWH� GHFUHDVHG� IURP������ LQ� D� QRQ�VXSSOHPHQWHG� JURXS� WR� ��� IRU� ZRPHQ�UDQGRPL]HG�WR�WKH�JURXS�UHFHLYLQJ�DQ�RUDO���PJ�IROLF�DFLG�supplementation daily prior to pregnancy and throughout WKH�ÀUVW���ZHHNV�RI �SUHJQDQF\�
7KH� VHFRQG� 17'� WUDQVODWLRQDO� UHVHDUFK� VWXG\� ZDV� D�UDQGRPL]HG� FRQWUROOHG� WULDO� IRU� WKH� SULPDU\� SUHYHQWLRQ�RI �17'�RFFXUUHQFH�3�7KH�IUHTXHQF\�RI �17'V�ZDV�]HUR�LQ� ����� ZRPHQ� UHFHLYLQJ� ����PJ� SHU� GD\� RI � IROLF� DFLG�compared with 6 cases in 2391 women not receiving folic DFLG�� 7KLV� 5&7� VWXG\� VXSSRUWHG� SUHYLRXV� FDVH²FRQWURO�studies that had provided evidence that pregnant women using multivitamins containing folic acid or dietary folic DFLG�KDG�D� ORZHU� ULVN�RI �RFFXUUHQFH�17'V� WKDQ�ZRPHQ�QRW�WDNLQJ�VXSSOHPHQWV���²��
7KHVH� �� ODQGPDUN� 5&7� VWXGLHV� KDYH� SURYLGHG� WKH� IROLF�acid supplementation dosing evidence (from initial H[SHULPHQWDO�H[SHUW�RSLQLRQ��IRU�17'�SULPDU\�SUHYHQWLRQ�DQG� UHFXUUHQFH�� EXW� WKH\� ZHUH� FRPSOHWHG� LQ� IHPDOH�SRSXODWLRQV�ZLWKRXW�WKH�DGGLWLRQDO�H[SRVXUH�RU�EHQHÀW�RI �IROLF�DFLG�IRRG�IRUWLÀFDWLRQ�WKDW�LV�DW�SUHVHQW�LQ�WKH�1RUWK�$PHULFDQ� IRRG�HQYLURQPHQW��7KHVH�5&7�IROLF�DFLG�GRVH�UHVXOWV�PD\�QHHG� WR�EH�DGMXVWHG�GXH� WR� WKH�SUHVHQW� IRRG�HQYLURQPHQW�´ZLWK�IROLF�DFLG�IRUWLÀHG�ZKLWH�ÁRXU�SURGXFWV�EXW� PRUH� UHVHDUFK� LV� UHTXLUHG� IRU� RSWLPL]DWLRQ� RI � RUDO�VXSSOHPHQWDWLRQ� GRVH� �PD[LPXP� EHQHÀW�� PLQLPXP� RU�QR� ULVN�� ZLWK� QRQ�SUHJQDQW� SUH�FRQFHSWLRQ� H[SRVXUH� WR�IRUWLÀHG�IRRG�SURGXFWV�16
ORAl FOlIC ACID SUPPlEMENTATION PREGNANCY CARE
2UDO� SUH�FRQFHSWLRQ� IROLF� DFLG� GLHWDU\� LQWDNH� RU�supplementation is required as it is the primary source IRU�WKH�WUDQV�SODFHQWDO�WUDQVIHU�RI �IRODWH�IROLF�DFLG�WR�WKH�HPEU\R�IHWXV��1R� VSHFLÀF� VWXGLHV� KDYH� EHHQ� SXEOLVKHG�ORRNLQJ� DW� WKH� HPEU\RQLF� FHOO� IRODWH� DYDLODELOLW\� LQ�KXPDQV� GXULQJ� WKLV� HPEU\RQLF� WDUJHW� SHULRG� RI � �� WR� ��ZHHNV� �FRQFHSWLRQ� WR� ��� JHVWDWLRQDO� ZHHNV��� &DQDGLDQ�UHVHDUFKHUV�KDYH�PDGH� VWURQJ�FRQWULEXWLRQV� LQ� WKLV� DUHD�RI �SUHYHQWLRQ���²��
:RPHQ�VKRXOG�EH�DGYLVHG�WR�PDLQWDLQ�D�QXWULWLRQDOO\�KHDOWK\�diet, as recommended in Eating Well with Canada’s Food Guide�42�*RRG�RU�H[FHOOHQW�VRXUFHV�RI �QDWXUDO�IRODWH�LQFOXGH�EURFFROL�� VSLQDFK��SHDV��%UXVVHOV� VSURXWV��FRUQ�� OHQWLOV�� DQG�RUDQJHV�
&RXQVHOOLQJ� VKRXOG� HPSKDVL]H� WKDW� WKH� UHFXUUHQFH� ULVN�IRU�D�IHWXV�ZLWK�DQ�17'�LV�VKDUHG�E\�ERWK�PRWKHU·V�DQG�IDWKHU·V�SHUVRQDO�UHSURGXFWLYH�KLVWRU\��EXW�RQO\�WKH�PRWKHU�LV�WUHDWHG�ZLWK�WKH�VXSSOHPHQWDO�GRVH�RI �SUH�FRQFHSWLRQ�ÀUVW�WULPHVWHU�IROLF�DFLG�
)ROLF�$FLG�)RRG�)RUWL¿FDWLRQ�DQG� Oral Supplementation,Q�&DQDGD��VLQFH�������LQ�DQ�HIIRUW�WR�UHGXFH�WKH�UDWH�RI �17'V��WKHUH�KDV�EHHQ�PDQGDWRU\�IROLF�DFLG�IRUWLÀFDWLRQ�RI � ZKLWH� ÁRXU�� HQULFKHG� SDVWD�� DQG� FRUQPHDO�� )RRG�IRUWLÀFDWLRQ� FRLQFLGHG� ZLWK� DQ� REVHUYHG� GHFUHDVH� LQ�17'V� LQ� OLYH�ERUQ� LQIDQWV�1,6,16� EXW� D�SURSRUWLRQ�RI � WKH�GRFXPHQWHG� 17'� GHFUHDVH� PD\� DOVR� EH� UHODWHG� WR� DQ�LQFUHDVHG�XVH�RI �SUHQDWDO�WHVWV�DQG�VXEVHTXHQW�SUHJQDQF\�WHUPLQDWLRQ� �VHFRQGDU\� SUHYHQWLRQ�� UDWKHU� WKDQ� WR�IRUWLÀFDWLRQ�DORQH�45,46�,W�LV�SRVVLEOH�WKDW�FHUWDLQ�SUHYDOHQFH�data populations may not have included termination of SUHJQDQF\�SULRU� WR� WKH����ZHHNV·�JHVWDWLRQ� LQIRUPDWLRQ�LQ�WKHLU�UHSRUWHG�UDWH�
ABBREVIATIONSaOR adjusted odds ratio
BMI body mass index
&,�� FRQ¿GHQFH�LQWHUYDO
GI gastrointestinal
MTHFR 5,10-methylenetetrahydrofolate reductase
NTD neural tube defect
OR odds ratio
RBC red blood cell
RCT randomized controlled trial
JUNE JOGC JUIN 2015 z 537
Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies
6KHUZRRG� HW� DO�� DVVHVVHG� WKH� GLHWDU\� IRODWH� LQWDNH� RI �pregnant and lactating women at the presently mandated DQG� SUHGLFWHG� IROLF� DFLG� IRUWLÀFDWLRQ� OHYHOV� WR� GHWHUPLQH�WKH� SUHYDOHQFH� RI � LQDGHTXDWH� DQG� H[FHVVLYH� LQWDNHV�� 7KH�conclusion was, at the present mandated levels of food IRUWLÀFDWLRQ��PDQ\�SUHJQDQW�DQG�ODFWDWLQJ�ZRPHQ�DUH�VWLOO�XQOLNHO\� WR� PHHW� WKHLU� DSSURSULDWH� IRODWH� UHTXLUHPHQWV�from dietary sources alone, however the actual level of LQDGHTXDF\�FDQQRW�EH�GHWHUPLQHG�XQWLO� WKH� OHYHO�RI � IROLF�DFLG�LQ�WKH�IRRG�VXSSO\�LV�NQRZQ�ZLWK�JUHDWHU�SUHFLVLRQ�50
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FOlIC ACID FOR CONGENITAl ANOMAlIES PREVENTION AND EVAlUATION
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vitamin supplementation,��²�� as well as to an increase of SUHQDWDO�GLDJQRVLV�WHUPLQDWLRQ�45,46
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7DEOH���VXPPDUL]HV�WKH�VWXGLHV�ZLWK�FDVH²FRQWURO��FRKRUW��RU�5&7�FRPSDULVRQV��RGGV�UDWLR��DQG�GHFUHDVHG��LQFUHDVHG��RU�QR�HIIHFWV�RQ�VSHFLÀF�FRQJHQLWDO�DQRPDOLHV�15,30,37,38,40,53 Folic DFLG�LQ�FRPELQDWLRQ�ZLWK�PXOWLYLWDPLQ�VXSSOHPHQWV�KDV�EHHQ�shown to reduce certain other congenital anomalies such as heart defects,�����²�� urinary tract anomalies,15,28,31 oral facial clefts,�����²��� DQG� OLPE� GHIHFWV�15At present, multifactorial LQKHULWDQFH� �JHQHWLF� DQG� HQYLURQPHQWDO� IDFWRUV�79,107,108 is WKH� PRVW� FRPPRQO\� UHSRUWHG� HWLRORJ\� IRU� 17'V�� EXW�monogenic, chromosomal, and teratogenic etiologies have VSHFLÀF� HIIHFWV� DQG� KDYH� QRW� EHHQ� ZHOO� VWXGLHG� LQ� WKHLU�DVVRFLDWLRQ�ZLWK�IROLF�DFLG�GHSULYDWLRQ�RU�VXSSOHPHQWDWLRQ�109
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Recurrence risk, % based on population NTD incidence
Relationship of NTD affected
individual to the at-risk fetus
Population
incidence
5 per 1000
Population
incidence
2 per 1000
Population
incidence
1 per 1000
One sibling 5 2 2
Two siblings 12 10 10
One parent 4 4 4
One second-degree relative 2 1 1
One third degree relative 1 0.75 0.5
Adapted from Firth HV, Hurst JA, Hall JG. Oxford desk reference. Clinical genetics. Oxford: Oxford University
Press; 2006.77
NTD: neural tube defect
7DEOH����,GHQWL¿HG�LQFUHDVHG�ULVN�IDFWRUV�IRU�IHWDO�17'�RU�ORZ�PDWHUQDO�5%&�folate status Personal/family history
or ethnic risk1–5,19–22
NTD: maternal or paternal affected, previous affected fetus for
either parent, child, sibling, or second /third degree relative
MTHFR genotype 677TT carrier homozygous
677CST carrier heterozygous
Medical/surgical
condition41,77–79,100–103
*,��PDODEVRUSWLRQ�LQÀDPPDWRU\�ERZHO��&URKQ¶V��DFWLYH�&HOLDF� disease, gastric bypass surgery, advanced liver disease
Renal: kidney dialysis
Pre-gestational diabetes (type I or II)
Anti-epilepsy or folate-inhibiting medications (see Table 4)
Maternal
co-morbidities81,92–97
Maternal obesity: BMI > 30 kg/m2 or 80 kg
(pre-pregnancy weight)
Maternal lifestyle
factors82,98,99,190–192
Smoking
Alcohol overuse
Non-prescription drug use/abuse
Low socio-economic status
Poor/restricted diet
NTD: neural tube defect; RBC: red blood cell; MTHFR: methylenete trahydrofolate reductase; GI: gastrointestinal
Table 4. Interactions between drugs or medications and folic acid1. Biology reduced folic acid
activity
Interference with
erythrocyte maturation
Chloramphenicol
Methotrexate
Other Metformin
2. Reduced folic acid levels Impaired absorption Sulfasalazine
Increased metabolism Phenobarbital
Phenytoin
3. Other interactions Not reported Primidone
Triamterene
Barbiturates
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POTENTIAl CAUTION FOR MATERNAl, FETAl, CHIlDHOOD, OR GENERAl POPUlATION WITH FOlIC ACID SUPPlEMENTATION
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)ROLF�DFLG�KDV�QRW�EHHQ�VKRZQ�WR�SURPRWH�RU�WR�SUHYHQW�EUHDVW�FDQFHU����²���
2YDULDQ� FDQFHU� VWXGLHV� VXJJHVW� �EXW� QRW� ZLWK� VWDWLVWLFDO�VLJQLÀFDQFH�� WKDW� UHODWLYHO\�KLJK�GLHWDU\� IRODWH� LQWDNH�PD\�EH�DVVRFLDWHG�ZLWK�D�UHGXFWLRQ�LQ�RYDULDQ�FDQFHU�ULVN�DPRQJ�ZRPDQ�ZLWK�KLJK�DOFRKRO�DQG�PHWKLRQLQH�LQWDNH�156
Table 5. Summary of congenital anomalies (decreased or increased or no effect) following IROLF�DFLG�IRRG�IRUWL¿FDWLRQ
Study reference
Anomaly
Case–Control
(95% CI)
Cohort/RCT
(95% CI)
Meta-analysis
Goh et al. (2006)15 Neural tube defect 0.67 (0.58–0.77) 0.52 (0.39–0.69)
Oral facial cleft 0.63 (0.54–0.73) 0.58 (0.28–1.19)
Cardiovascular defects 0.78 (0.67–0.92) 0.61 (0.40–0.92)
Limb reduction defects 0.48 (0.30–0.76) 0.57 (0.38–0.85)
Cleft palate 0.76 (0.62–0.93) 0.42 (0.06–2.84)
Urinary tract defects 0.48 (0.30–0.76) 0.68 (0.35–1.31)
Congenital hydrocephalus 0.37 (0.24–0.56) 1.54 (0.53–4.50)
Johnson and Little (2008)38 Cleft lip and palate 0.75 (0.65–0.88)
Cleft palate only 0.88 (0.76–1.01)
Single Population
Li et al. (2013)30 +HDUW�GHIHFWV�LVRODWHG� DQG�FRPSOH[
0.52 (0.34–0.78)
0.27 (0.14–0.55)
Godwin et al. (2008)40 6SLQD�EL¿GD 0.51 (0.36–0.73)
OS atrial septal defects 0.80 (0.69–0.93)
Ureteric obstruction 1.45 (1.24–1.70)
Abdominal wall defect 1.40 (1.04–1.88)
Pyloric stenosis 1.49 (1.18–1.89)
&DQ¿HOG�HW�DO��������53 Anencephaly 0.84 (0.76–0.94)
6SLQD�EL¿GD 0.66 (0.61–0.71)
TGA 0.88 (0.81–0.96)
Cleft palate only 0.88 (0.82–0.95)
Pyloric stenosis 0.95 (0.90–0.99)
Omphalocele 0.79 (0.66–0.95)
Upper limb reduction 0.89 (0.80–0.99)
O’Neill (2007)37 Cleft lip ± palate 0.61 (0.39–0.96) Folic acid 0.4 mg daily
0.75 (0.50–1.11) Folate diet only
0.36 (0.17–0.77) Supplement + diet
Cleft palate only 1.07 (0.56–2.03)
Goh et al (2006)15 1R�HIIHFW�LGHQWL¿HG�IRU Trisomy 21
Pyloric stenosis
Undescended testis
Hypospadias
RCT: randomized control trial; OS: ostium secunda; TGA: transposition of the great arteries
540 z JUNE JOGC JUIN 2015
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COUNSEllING AND FOlIC ACID SUPPlEMENTATION
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����3HUVRQDO positive or family history of other folate VHQVLWLYH�FRQJHQLWDO�DQRPDOLHV��OLPLWHG�WR�VSHFLÀF�DQRPDOLHV�IRU�FDUGLDF��OLPE��FOHIW�SDODWH��XULQDU\�WUDFW��FRQJHQLWDO�K\GURFHSKDO\�
����Family history�RI �17'�LQ�D�ÀUVW�RU�VHFRQG�GHJUHH�relative
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542 z JUNE JOGC JUIN 2015
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����Teratogenic medications with secondary fetal WHUDWRJHQLF�HIIHFWV�E\�IRODWH�LQKLELWLRQ�YLD�DQWLFRQYXOVDQW�PHGLFDWLRQV��FDUEDPD]HSLQH��YDOSURLF�DFLG��SKHQ\WRLQ��SULPLGRQH��SKHQREDUELWDO���PHWIRUPLQ��PHWKRWUH[DWH��VXOIDVDOD]LQH��WULDPWHUHQH��WULPHWKRSULP��DV�LQ�FRWULPR[D]ROH���DQG�FKROHVW\UDPLQH
����0DWHUQDO�*,�PDODEVRUSWLRQ�FRQGLWLRQV secondary to FR�H[LVWLQJ�PHGLFDO�RU�VXUJLFDO�FRQGLWLRQV�WKDW�KDYH�EHHQ�VKRZQ�WR�UHVXOW�LQ�GHFUHDVHG�5%&�IRODWH�OHYHOV��&URKQ·V�RU�DFWLYH�&HOLDF�GLVHDVH��JDVWULF�E\SDVV�VXUJHU\��DGYDQFHG�OLYHU�GLVHDVH��NLGQH\�GLDO\VLV��DOFRKRO�RYHUXVH�
,1&5($6('�+,*+� ULVN� JURXS��:RPHQ� RU� WKHLU�PDOH�SDUWQHUV�ZLWK�D�SHUVRQDO�17'�KLVWRU\�RU�D�SUHYLRXV�QHXUDO�WXEH�GHIHFW�SUHJQDQF\
Recommendations���� :RPHQ�ZLWK�D�/2:�5,6.�IRU�D�QHXUDO�WXEH�
defect or other folic acid-sensitive congenital DQRPDO\�DQG�D�PDOH�SDUWQHU�ZLWK�ORZ�ULVN�UHTXLUH�a diet of folate-rich foods and a daily oral PXOWLYLWDPLQ�VXSSOHPHQW�FRQWDLQLQJ�����PJ� IROLF�DFLG�IRU�DW�OHDVW���WR���PRQWKV�EHIRUH�conception, throughout the pregnancy, and for 4 WR���ZHHNV�SRVWSDUWXP�RU�DV�ORQJ�DV�EUHDVW�IHHGLQJ�FRQWLQXHV���,,��$�
���� :RPHQ�ZLWK�D�02'(5$7(�5,6.�IRU�D�QHXUDO�WXEH�GHIHFW�RU�RWKHU�IROLF�DFLG�VHQVLWLYH�FRQJHQLWDO�DQRPDO\�RU�D�PDOH�SDUWQHU�ZLWK�PRGHUDWH�ULVN�require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing ����PJ�IROLF�DFLG��EHJLQQLQJ�DW�OHDVW���PRQWKV�EHIRUH�FRQFHSWLRQ��:RPHQ�VKRXOG�FRQWLQXH�WKLV�UHJLPH�XQWLO����ZHHNV·�JHVWDWLRQDO�DJH�����$��)URP����ZHHNV·�JHVWDWLRQDO�DJH��FRQWLQXLQJ�WKURXJK�WKH�SUHJQDQF\��DQG�IRU���WR���ZHHNV�SRVWSDUWXP�RU�DV�ORQJ�DV�EUHDVW�IHHGLQJ�FRQWLQXHV��FRQWLQXHG�GDLO\�supplementation should consist of a multivitamin ZLWK�����WR�����PJ�IROLF�DFLG���,,��$�
���� :RPHQ�ZLWK�DQ�LQFUHDVHG�RU�+,*+�5,6.�IRU�D�QHXUDO�WXEH�GHIHFW��D�PDOH�SDUWQHU�ZLWK�D�SHUVRQDO�KLVWRU\�RI �QHXUDO�WXEH�GHIHFW��RU�KLVWRU\�RI �D�SUHYLRXV�QHXUDO�WXEH�GHIHFW�SUHJQDQF\�LQ�HLWKHU�partner require a diet of folate-rich foods and a daily RUDO�VXSSOHPHQW�ZLWK�����PJ�IROLF�DFLG�IRU�DW�OHDVW���PRQWKV�EHIRUH�FRQFHSWLRQ�DQG�XQWLO����ZHHNV·�JHVWDWLRQDO�DJH��)URP����ZHHNV·�JHVWDWLRQDO�DJH��continuing throughout the pregnancy, and for 4 to ��ZHHNV�SRVWSDUWXP�RU�DV�ORQJ�DV�EUHDVW�IHHGLQJ�continues, continued daily supplementation should
FRQVLVW�RI �D�PXOWLYLWDPLQ�ZLWK�����WR�����PJ�IROLF�DFLG���,�$���7KH�VDPH�GLHWDU\�DQG�VXSSOHPHQWDWLRQ�UHJLPH�VKRXOG�EH�IROORZHG�LI �HLWKHU�SDUWQHU�KDV�KDG�D�SUHYLRXV�SUHJQDQF\�ZLWK�D�QHXUDO�WXEH�GHIHFW���,,��$�
7R�DFKLHYH�D�GRVH�RI �����PJ�GD\�IROLF�DFLG��ZRPHQ�VKRXOG�FRQVXPH�D�PXOWLYLWDPLQ�FRQWDLQLQJ�����PJ�IROLF�DFLG�DQG�DGG���VLQJOH�����PJ�IROLF�DFLG�WDEOHWV���6HH�WKH�DSSHQGL[�IRU�D�VXPPDU\�RI �WKH�ULVN�VWDWXVHV��ULVN�JURXSV��DQG�DSSURSULDWH�IROLF�DFLG�GRVLQJ��
5HFRJQL]LQJ�WKH�FKDOOHQJH�VRPH�FOLQLFDO�RIÀFHV�PLJKW�IDFH�LPSOHPHQWLQJ� WKH� DERYH� UHFRPPHQGDWLRQV� EDVHG�RQ� WKH�PRGH� RI � SURGXFW� GLVWULEXWLRQ (prescription, over-the-FRXQWHU��FRYHUHG�E\�LQVXUDQFH��DQG�FRPSOLDQFH�LVVXHV�ZLWK�WDNLQJ�GDLO\�PXOWLSOH�RUDO�WDEOHWV�188�WKH�IROORZLQJ�VLPSOLÀHG�UHJLPHQ�FRXOG�EH�FRQVLGHUHG��+RZHYHU��LW�LV�LPSRUWDQW�WR�NHHS� LQ�PLQG� WKDW� WKH� IROLF� DFLG� LQWDNH� VKRXOG� EH� DW� WKH�ORZHVW�HIIHFWLYH�DQG�VDIHVW�GRVH�
/RZ�RU�PRGHUDWH� ULVN� JURXS�� D� GLHW� RI � IRODWH�ULFK� IRRGV�LQ�DGGLWLRQ�WR�SUH�FRQFHSWLRQ�DQG�ÀUVW�WULPHVWHU�IROLF�DFLG�supplementation with an over-the-counter daily prenatal PXOWLYLWDPLQ�FRQWDLQLQJ�����PJ�RI �IROLF�DFLG�
,QFUHDVHG�KLJK� ULVN� JURXS�� D�GLHW�RI � IRODWH�ULFK� IRRGV� LQ�DGGLWLRQ� WR� SUHFRQFHSWLRQ� DQG� ÀUVW� WULPHVWHU� IROLF� DFLG�supplementation with a prescription daily multivitamin FRQWDLQLQJ�����PJ�RI �IROLF�DFLG�
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SUMMARY
)ROLF� DFLG� �LQ� WKH� GLHW� DQG�RU� DV� D� SUHQDWDO� RUDO�VXSSOHPHQW�� ZLWK� D� PXOWLYLWDPLQ�PLFURQXWULHQW� KDV�EHHQ� VKRZQ� WR� GHFUHDVH� RU�PLQLPL]H� VSHFLÀF� FRQJHQLWDO�DQRPDOLHV� LQFOXGLQJ� QHXUDO� WXEH� GHIHFWV� ZLWK� DVVRFLDWHG�hydrocephalus, oral facial clefts with or without cleft palate, FRQJHQLWDO�KHDUW�GLVHDVH��XULQDU\�WUDFW�DQRPDOLHV��DQG�OLPE�GHIHFWV��DV�ZHOO�DV�VRPH�SHGLDWULF�FDQFHUV��7KH������SXEOLF�KHDOWK� LQLWLDWLYH� IRU� IRUWLÀFDWLRQ� RI � ÁRXU� KDV� EHHQ� YHU\�EHQHÀFLDO� ZLWK� UHVSHFW� WR� SULPDU\� SUHYHQWLRQ� RI � FHUWDLQ�IROLF� DFLG�VHQVLWLYH� ELUWK� GHIHFWV�� 7KH� FRPSUHKHQVLYH�&DQDGLDQ� DQDO\VLV� RI � QHXUDO� WXEH� UHGXFWLRQ� DIWHU� IROLF�DFLG�ÁRXU�IRUWLÀFDWLRQ�KDV�UHSRUWHG�D�����UHGXFWLRQ��7KH�REVHUYHG�UHGXFWLRQ�ZDV�JUHDWHU�IRU�VSLQD�ELÀGD�������WKDQ�IRU�DQHQFHSKDO\�������DQG�HQFHSKDORFHOH��������)XUWKHU�reductions in the incidence of other congenital anomalies VHQVLWLYH�WR�IROLF�DFLG�DQG�PXOWLYLWDPLQV�VKRXOG�EH�SRVVLEOH�ZLWK� WKH� SDUWLFLSDWLRQ� RI � NH\� VWDNHKROGHUV�� 3XEOLF� KHDOWK�VXUYHLOODQFH�VWUDWHJLHV�VKRXOG�EH�LPSOHPHQWHG�WR�ORRN�IRU�DQ\� DGYHUVH� KHDOWK� RXWFRPHV� �PDWHUQDO�� SHGLDWULF�� WKDW�
JUNE JOGC JUIN 2015 z 543
Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies
NTD risk factor† or prior pregnancy
affected with other folate sensitive
congenital anomaly (Box 1)‡
Previous pregnancy affected with NTD or personal history of NTD
Ædaily multivitamin and a total intake of 4
mg/day folic acid§ 3 months prior to
pregnancy and through the first trimester,
then a multivitamin containing 0.4 mg/day
folic acid* for the remainder of pregnancy.
ORÆ5 mg¶
Other risk factors for NTD Pre-H[LVWLQJ�GLDEHWHVۅ
Antiepileptic or folate inhibiting medication (Box 2)
•1st or 2nd degree relative of woman or her partner
with a history of NTD
•GI malabsorptive conditions, such as Celiac
disease, inflammatory bowel disease, or gastric
bypass surgery
•Advanced liver disease
•Kidney dialysis
•Alcohol over-use
OR Prior pregnancy affected with a folate sensitive
congenital anomaly (Box 1)‡Æ daily multivitamin containing 1 mg/day folic
acid* 3 months prior to pregnancy and through the
first trimester, then a multivitamin containing 0.4
mg/day folic acid* for the remainder of pregnancy
If pregnancy does not occur after 6 to 8 months, change to 0.4 mg/day* for 6 months; if
pregnancy is not achieved in the following 6 months, consider referral to fertility services
and RBC folate testing to ensure level >900 nmol/L.
No known NTD risk factor and no prior pregnancy affected with folate sensitive
congenital anomalyÆ daily multivitamin containing 0.4 mg/day folic
acid* 3 months prior to pregnancy and continuing
throughout pregnancy
Woman who may or plans
to become pregnant
If pregnancy does not occur after 1 year,
consider referral to fertility services
*Folic acid should be taken in the form of a multivitamin containing vitamin B12. Women should not take more than one
multivitamin supplement each day. In large doses, some substances in multivitamins could be harmful.
�'RHV�127�LQFOXGH�VSLQD�EL¿GD�RFFXOWD�DV�WKLV�LV�QRW�D�ULVN�IRU�17'�
Á7KHUH�DUH�DGGLWLRQDO�IRODWH�VHQVLWLYH�FRQJHQLWDO�DQRPDOLHV�WKDW�ZRXOG�EHQH¿W�IURP�WKH�IROLF�DFLG�OHYHOV�GHVFULEHG�
§To provide a dose of 4 mg/day folic acid, a multivitamin containing 1 mg folic acid should be consumed, with single folic acid
tablets added to achieve the desired folic acid dose.
�3HUL�FRQFHSWLRQDO�JO\FHPLF�FRQWURO�LV�VWURQJO\�UHFRPPHQGHG�WR�UHGXFH�WKH�ULVN�RI�D�FRQJHQLWDO�DQRPDO\�LQ�WKH�RIIVSULQJ�RI�Dۅ woman with pre-pregnancy diabetes.
�)ROLF�DFLG�LQWDNH�VKRXOG�EH�DW�WKH�VDIHVW�DQG�ORZHVW�HIIHFWLYH�GRVH��KRZHYHU��FOLQLFDO�RI¿FHV�WKDW�IDFH�FKDOOHQJHV�LPSOHPHQWLQJ�recommendations for 4 mg folic acid daily because of the mode of product distribution or compliance issues with taking daily
PXOWLSOH�RUDO�WDEOHWV�PD\�FRQVLGHU�WKH�VLPSOL¿HG�UHJLPHQ�RI�RQH���PJ�IROLF�DFLG�PXOWLYLWDPLQ�WDEOHW�GDLO\�
NTD: neural tube defect; GI: gastrointestinal
Decision tree for folic acid supplementation
BOX 2 Practical list of folate-inhibiting medications:
– Anticonvulsant medications: phenytoin, primidone, phenobarbital,
carbamazepine, valproic acid
– Metformin
– Methotrexate (a medication that is highly teratogenic to the fetus).
– Sulfasalazine
– Triamterene
– Trimethoprim (as found in cotrimoxazole)
BOX 1 Congenital anomalies which may be sensitive
to folate (see text for anomaly detail):
– Oral facial cleft (and palate)
– Certain cardiac defects
– Certain urinary tract anomalies
– Limb reduction defects
544 z JUNE JOGC JUIN 2015
SOGC ClINICAl PRACTICE GUIDElINE
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ACKNOWlEDGEMENTS
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JUNE JOGC JUIN 2015 z 549
Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies
Risk
status
Female partner
Male partner
Folic acid dosing:
A healthy folate-rich diet AND:
Low No personal or family risk for NTD
or folic acid-sensitive birth defects
No personal or family risk for NTD
or folic acid-sensitive birth defects
Multivitamin with 0.4 to 1.0 mg folic acid for
2 to 3 months before conception, throughout
pregnancy and for 6 weeks postpartum or to
completion of lactation
Moderate Personal history positive for folate
sensitive anomalies.
)DPLO\�KLVWRU\�IRU�17'�LQ�¿UVW��RU�second-degree relative.
Diabetes type I or II
Teratogenic medications by folate
inhibition
GI malabsorption that decreases
RBC folate
Personal history positive for folate
sensitive anomalies
)DPLO\�KLVWRU\�IRU�17'�LQ�¿UVW��RU�second-degree relative
Multivitamin including 1. 0 mg folic acid for at
least 3 months before conception to 12 weeks
and then for remainder of pregnancy and 6
weeks postpartum or to completion of lactation
High Personal NTD history.
Previous NTD pregnancy
Personal NTD history.
Previous NTD pregnancy
Multivitamin including 1.0 mg folic acid plus
3 × 1.0 mg folic acid (for total of 4.0 mg) OR
prescription multivitamin including 5.0 mg folic
acid* at least 3 months before conception
until 12 weeks’ gestation, then a multivitamin
including 0.4 to 1.0 mg folic acid for remainder
of pregnancy and 6 weeks postpartum or to
completion of lactation
,W�LV�LPSRUWDQW�WR�NHHS�LQ�PLQG�WKDW�IROLF�DFLG�LQWDNH�VKRXOG�EH�DW�WKH�VDIHVW�DQG�ORZHVW�HIIHFWLYH�GRVH����PJ�GDLO\���+RZHYHU��FOLQLFDO�RI¿FHV�WKDW�IDFH�D�FKDOOHQJH�in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and
FRPSOLDQFH�LVVXHV�ZLWK�WDNLQJ�PXOWLSOH�RUDO�WDEOHWV�GDLO\�FRXOG�FRQVLGHU�WKH�VLPSOL¿HG�UHJLPHQ�RI�WKH�����PJ�IROLF�DFLG�SUHVFULSWLRQ�PXOWLYLWDPLQ�
NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell
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������0DJGHOLMQV�)-+��0RPPHUV�0��3HQGHUV�-��6PLWV�/��7KLMV�&��)ROLF�DFLG�XVH�in pregnancy and the development of atopy, asthma, and lung function in FKLOGKRRG��3HGLDWULFV����������H����H����
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APPENDIX FOlIC ACID SUPPlEMENTATION
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