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534 z JUNE JOGC JUIN 2015 J Obstet Gynaecol Can 2015;37(6):534–549 1R 0D\ 5HSODFHV 'HFHPEHU 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.

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Page 1: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

534 z JUNE JOGC JUIN 2015

J Obstet Gynaecol Can 2015;37(6):534–549

1R�������0D\�������5HSODFHV�������'HFHPEHU������

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.

Page 2: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

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

Page 3: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

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

Page 4: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

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

5%&�IRODWH�WHVWLQJ�VFUHHQLQJ�IRU�WKH�SUHYHQWLRQ�RI �ELUWK�GHIHFWV� LQ� FHUWDLQ� FR�H[LVWLQJ�PDWHUQDO� KHDOWK� FRQGLWLRQV�requires more investigation to determine the actual HIIHFWLYHQHVV�DQG�XVH�RI �WKLV�WHVWLQJ�

Factors that may affect the ability to achieve adequate maternal folic acid tissue levels2SWLPL]DWLRQ�RI �RUDO�PDWHUQDO�IROLF�DFLG�VXSSOHPHQWDWLRQ�LV� GLIÀFXOW� EHFDXVH� LW� UHOLHV� RQ� IROLF� DFLG� GRVH�� W\SH� RI �IRODWH� VXSSOHPHQW�� ELR�DYDLODELOLW\� RI � WKH� IRODWH� IURP�foods, timing of supplementation initiation, maternal PHWDEROLVP�JHQHWLF�IDFWRUV��DQG�PDQ\�RWKHU�IDFWRUV���²��

Recommendations���� :RPHQ�VKRXOG�EH�DGYLVHG�WR�PDLQWDLQ�D�KHDOWK\�

IRODWH�ULFK�GLHW��KRZHYHU��IROLF�DFLG�PXOWLYLWDPLQ�VXSSOHPHQWDWLRQ�LV�QHHGHG�WR�DFKLHYH�WKH�UHG�EORRG�FHOO�IRODWH�OHYHOV�DVVRFLDWHG�ZLWK�PD[LPDO�SURWHFWLRQ�DJDLQVW�QHXUDO�WXEH�GHIHFW���,,,�$�

���� $OO�ZRPHQ�LQ�WKH�UHSURGXFWLYH�DJH�JURXS� ���²���\HDUV�RI �DJH��ZKR�KDYH�SUHVHUYHG�IHUWLOLW\��D�SUHJQDQF\�LV�SRVVLEOH��VKRXOG�EH�DGYLVHG�DERXW�WKH�EHQHÀWV�RI �IROLF�DFLG�LQ�D�PXOWLYLWDPLQ�supplementation during medical wellness YLVLWV��ELUWK�FRQWURO�UHQHZDO��3DS�WHVWLQJ��\HDUO\�J\QDHFRORJLFDO�H[DPLQDWLRQ��ZKHWKHU�RU�QRW�D�SUHJQDQF\�LV�FRQWHPSODWHG��%HFDXVH�VR�PDQ\�pregnancies are unplanned this applies to all women ZKR�PD\�EHFRPH�SUHJQDQW���,,,�$�

FOlIC ACID FOR CONGENITAl ANOMAlIES PREVENTION AND EVAlUATION

Background for NTD Prevention1HXUDO� WXEH�GHIHFWV� DUH� VHYHUH� FRQJHQLWDO� DQRPDOLHV� WKDW�RFFXU� GXH� WR� D� ODFN� RI � QHXUDO� WXEH� FORVXUH� DW� HLWKHU� WKH�upper, middle, or lower portion of the spine in the third WR� IRXUWK�ZHHN�DIWHU� FRQFHSWLRQ� �GD\���� WR�GD\����SRVW�FRQFHSWLRQ��77

,Q� &DQDGD�� WKH� SUHYDOHQFH� RI � 17'V� LQ� QHZERUQV� KDV�GHFOLQHG�VLQFH������GXH�WR�IRRG�IRUWLÀFDWLRQ�DQG�LQFUHDVHG�

vitamin supplementation,��²�� as well as to an increase of SUHQDWDO�GLDJQRVLV�WHUPLQDWLRQ�45,46

5HFXUUHQFH� ULVNV�PD\� UHÁHFW� WKH� JHQHWLF� FRQWULEXWLRQ� LQ�different regional or population incidence and folic acid 17'� VHQVLWLYLW\� �7DEOH� ���� DV� WKHUH� LV� VWLOO� DQ� HVWLPDWHG�1% recurrence rate even with the 4 to 5 mg folic acid SURSK\OD[LV�VXSSOHPHQWDWLRQ�DSSURDFK���������²��

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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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7DEOH����$QHQFHSKDO\�DQG�VSLQD�EL¿GD�DSSUR[LPDWH�UHFXUUHQFH�ULVN�ZLWK�QR�IRRG�IROLF�DFLG�IRUWL¿FDWLRQ�RU�IRODWH�VXSSOHPHQWDWLRQ

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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Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

'HWDLOV� IRU� WKH� JHQHWLF� DQG� HQYLURQPHQWDO� IDFWRUV�considerations with fetal and pediatric outcomes are DYDLODEOH�LQ�WKH�UHIHUHQFHV�19²������²���

POTENTIAl CAUTION FOR MATERNAl, FETAl, CHIlDHOOD, OR GENERAl POPUlATION WITH FOlIC ACID SUPPlEMENTATION

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IURP� RUDO� IROLF� DFLG� LQWDNH� GXH� WR� YLWDPLQ� VXSSOHPHQWV�DQG�RU�IRUWLÀHG�IRRGV�LV�ORZ��)ROLF�DFLG�LV�D�ZDWHU�VROXEOH�YLWDPLQ��VR�DQ\�H[FHVV�LQWDNH�LV�DQWLFLSDWHG�WR�EH�H[FUHWHG�LQ�WKH�XULQH�

)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

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540 z JUNE JOGC JUIN 2015

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(YLGHQFH� KDV� EHHQ� UHSRUWHG� IRU� D� GHFUHDVHG� SUH� valence of preeclampsia with maternal folic acid VXSSOHPHQWDWLRQ��������²���

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Risks and Cautions)ROLF� DFLG�GRVLQJ�DERYH� WKH� UHFRPPHQGHG�VXSSOHPHQW�DWLRQ� DPRXQWV� �VXSUD�SK\VLRORJLF� GRVHV�� KDV� QRW� EHHQ�VKRZQ� WR� KDYH� DQ\� DGGHG� IHWDO�PDWHUQDO� KHDOWK� RU�GHYHORSPHQWDO� EHQHÀWV�� DOWKRXJK� UHFHQW� HSLJHQHWLF�methylation studies in animals and humans have LQGLFDWHG� WKDW� VRPH� FDXWLRQ� DQG� UHVHDUFK� LV� UHTXLUHG��7KH� IROLF� DFLG� GRVHV� RI � ��PJ� KDYH� QRW� EHHQ� UHSRUWHG�WR�KDYH�PDWHUQDO�RU�IHWDO�ULVNV��EXW� ORQJ�WHUP�KLJK�GRVH� ��PJ�IROLF�DFLG�XVH�KDV�QRW�EHHQ�ZHOO�VWXGLHG�LQ�D�SUHQDWDO�SRSXODWLRQ�����²�������������������

Recent summary conclusions from colorectal cancer UHYLHZV�RI � WKH� WRSLF� DUH� VWLOO� FDXWLRQDU\����²��� Two studies show no association of folic acid with colorectal adenoma RU�UHFXUUHQFH�178,179

FETAl AND PEDIATRIC ISSUES

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$�VWXG\�ORRNLQJ�DW�PDWHUQDO�XVH�RI �IROLF�DFLG�VXSSOHPHQWDWLRQ�and the diagnosis of childhood autism found that folic acid supplementation around the time of conception was DVVRFLDWHG�ZLWK�ORZHU�ULVN�RI �DXWLVWLF�GLVRUGHU�LQ�D�1RUZHJLDQ�FRKRUW�� 7KH� DGMXVWHG�25� IRU� DXWLVWLF� GLVRUGHU� LQ� FKLOGUHQ�RI �IROLF�DFLG�XVHUV�ZDV�����������&,������WR��������7KHVH�ÀQGLQJV�FDQQRW�HVWDEOLVK�FDXVDOLW\�EXW�WKH\�GR�VXSSRUW�WKH�XVH�RI �SUHQDWDO�IROLF�DFLG�VXSSOHPHQWDWLRQ�148,149

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$�VOLJKWO\�LQFUHDVHG�ULVN�RI �ZKHH]H�DQG�UHVSLUDWRU\�LQIHFWLRQ�ZDV� IRXQG� LQ� WKH�RIIVSULQJ�ZKRVH�PRWKHUV� WRRN� IROLF� DFLG�VXSSOHPHQWV�GXULQJ�SUHJQDQF\�184 It was suggested that methyl GRQRUV�LQ�WKH�PDWHUQDO�GLHW�GXULQJ�SUHJQDQF\�PD\�LQÁXHQFH�respiratory health in children consistent with epigenetic PHFKDQLVPV��=HWVWUD�YDQ�GHU�:RXGH�HW�DO��UHSRUWHG�PDWHUQDO�KLJK�GRVH�IROLF�DFLG����PJ��ZDV�DVVRFLDWHG�ZLWK�DQ�LQFUHDVHG�rate of asthma medication among children (recurrent asthma PHGLFDWLRQ�,55�>LQFLGHQFH�UDWH�UDWLR@� ������������WR������DQG�UHFXUUHQW�LQKDOHG�FRUWLFRVWHURLGV�,55� ������������WR��������,Q� WKH� FRKRUW� RI � ������� SUHJQDQFLHV�� �����ZHUH� H[SRVHG�WR� KLJK�GRVH� IROLF� DFLG�185 Associations were clustered on the mother and adjusted for maternal age, maternal asthma PHGLFDWLRQ�� DQG� GLVSHQVLQJ� RI � EHQ]RGLD]HSLQHV� GXULQJ�SUHJQDQF\�186�9HHUDQNL�HW�DO��XVHG�D�UHWURVSHFWLYH�FRKRUW�RI ���������PRWKHU²LQIDQW�SDLUV� WR� FRPSDUH�QR�SUHQDWDO� IROLF�DFLG�H[SRVXUH�ZLWK�ÀUVW�WULPHVWHU�RQO\�IROLF�DFLG�H[SRVXUH�DQG�UHSRUWHG�KLJKHU�UHODWLYH�RGGV�RI �EURQFKLROLWLV�GLDJQRVLV��D25������� ����� WR������� DQG�JUHDWHU� VHYHULW\� �D25������� ����� WR��������7KH�HIIHFW�ZDV�QRW�VLJQLÀFDQW�LQ�WKH�RWKHU���H[SRVHG�JURXSV�RI �´DIWHU�WKH�ÀUVW�WULPHVWHUµ�RU�´ERWK�ÀUVW�WULPHVWHU�DQG�DIWHU�WKH�ÀUVW�WULPHVWHUµ�186

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YLWDPLQ�%���GHÀFLHQF\��SHUQLFLRXV�DQHPLD���,QYHVWLJDWLRQV��H[DPLQDWLRQ�RU�ODERUDWRU\��DUH�QRW�required prior to initiating folic acid supplementation IRU�ZRPHQ�ZLWK�D�ULVN�IRU�SULPDU\�RU�UHFXUUHQW�QHXUDO�WXEH�RU�RWKHU�IROLF�DFLG�VHQVLWLYH�FRQJHQLWDO�DQRPDOLHV�ZKR�DUH�FRQVLGHULQJ�D�SUHJQDQF\��,W�LV�UHFRPPHQGHG�WKDW�IROLF�DFLG�EH�WDNHQ�LQ�D�PXOWLYLWDPLQ�LQFOXGLQJ���� XJ�GD\�RI �YLWDPLQ�%���WR�PLWLJDWH�HYHQ�WKHRUHWLFDO�FRQFHUQV���,,��$�

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COUNSEllING AND FOlIC ACID SUPPlEMENTATION

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+DQ�HW�DO��UHSRUWHG�WKDW�FHUWDLQ�JURXSV�RI �ZRPHQ��IURP�WKH� &DULEEHDQ�� /DWLQ� $PHULFD�� 1RUWK� $IULFD�� 0LGGOH�(DVW��&KLQD�� DQG� 6RXWK�3DFLÀF��ZKR� DUH� LPPLJUDQWV� WR�&DQDGD�WDNH�IHZHU�IROLF�DFLG�VXSSOHPHQWV�WKDQ�&DQDGLDQ�ERUQ� ZRPHQ�� 7KLV� LPPLJUDQW� JURXS�PD\� EHQHÀW� IURP�enhanced or directed pre-conception education and FRXQVHOOLQJ�66

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2UDO� VXSSOHPHQWDWLRQ� VXFFHVV� PD\� EH� YDULDEOH� EHFDXVH�RI � FRPSOLDQFH� LVVXHV� ZLWK� GDLO\� RUDO� WDEOHW� XVH� �QDXVHD��´IRUJRW�µ�´GRQ·W�OLNH�WR�WDNH�SLOOVµ��EXW�DV�D�UHVXOW�RI �IRRG�IRUWLÀFDWLRQ�ZLWK�IROLF�DFLG��&DQDGD�KDV�DOPRVW�HOLPLQDWHG�IRODWH� GHÀFLHQF\�191� 7KH� EHVW� SUHGLFWRU� RI � SUHQDWDO�multivitamin adherence in pregnant women is related to WKH�ZRPHQ·V�SUHYLRXV�H[SHULHQFHV�ZLWK�PXOWLYLWDPLQ�XVH��7KH� PRVW� LPSRUWDQW� IDFWRUV� LQKLELWLQJ� SUHQDWDO� YLWDPLQ�XVH� DUH� IHDU� RU� WKH� H[SHULHQFH� RI � QDXVHD�� YRPLWLQJ�� DQG�JDJJLQJ��)RU�ZRPHQ�ZKR�WRRN�WKH�VXSSOHPHQWDO�YLWDPLQV��the most important factors were the dosing regimen, health FDUH�SURYLGHU�DGYLFH��DQG�WKH�PRGH�RI �SURGXFW�GLVWULEXWLRQ �SUHVFULSWLRQ��RYHU�WKH�FRXQWHU��FRYHUHG�E\�LQVXUDQFH��191

7KH� OLPLWHG� 5&7� GDWD� IRU� IROLF� DFLG� VXSSOHPHQWDWLRQ� LQ�certain clinical scenarios requires the use of cohort and

FDVH²FRQWURO�HYDOXDWLRQ�DQG�H[SHUW�RSLQLRQ�H[WUDSRODWLRQ��Alternate opinions regarding oral supplemental dosing KDYH�EHHQ�SXEOLVKHG�E\�0RWKHULVN�192

Other long-term uses for folic acid in the other clinical use FRQWH[W� �DOFRKROLFV�� DQHPLD�� OLYHU� GLVHDVH�� NLGQH\� GLVHDVH��PDODEVRUSWLRQ�� FDUGLDF� GLVHDVH�� FDQFHU� WUHDWPHQW�� UHJXODU�PXOWLYLWDPLQ�ZHOOQHVV�XVH��DUH�QRW�FRQVLGHUHG�RU�GLVFXVVHG�LQ�WKLV�JXLGHOLQH�

Summary Statement,Q�&DQDGD�PXOWLYLWDPLQ�WDEOHWV�ZLWK�IROLF�DFLG�DUH�XVXDOO\�DYDLODEOH�LQ���IRUPDWV��UHJXODU�RYHU�WKH�FRXQWHU�PXOWLYLWDPLQV�ZLWK�����WR�����PJ�IROLF�DFLG��SUHQDWDO�RYHU�WKH�FRXQWHU�PXOWLYLWDPLQV�ZLWK�����PJ�IROLF�DFLG��DQG�SUHVFULSWLRQ�PXOWLYLWDPLQV�ZLWK�����PJ�IROLF�DFLG���,,,�

7KH���FOLQLFDOO\�DW�ULVN�JURXSV�WKDW�ZLOO�EHQHÀW�IURP�IROLF�DFLG� VXSSOHPHQWDWLRQ� DUH� GHULYHG� IURP� HYLGHQFH�EDVHG�UHYLHZ�DQG�H[SHUW�RSLQLRQ��DQG�DUH�EDVHG�RQ�WKH�IROLF�DFLG�VHQVLWLYH�ULVN�RI �WHUDWRJHQLF�RU�JHQHWLF�FRQJHQLWDO�DQRPDO\��RU�WKH�HVWLPDWHG�ULVN�RI �PDWHUQDO�IROLF�DFLG�GHÀFLHQF\��7KH�VXSSOHPHQWDO�IROLF�DFLG�UHTXLUHPHQWV�IRU�WKH�EHVW�EHQHÀW�WR�ULVN�RXWFRPH�KDYH�XVHG�WKH�SXEOLVKHG�&DQDGLDQ�IHPDOH�SRSXODWLRQ��SRVW�IRUWLÀFDWLRQ��5%&�IRODWH�YDOXHV�

,W�LV�LPSRUWDQW�WR�HPSKDVL]H�WKDW�DOO���ULVN�UHFRPPHQGDWLRQV�IRU� WKH� FOLQLFDOO\� ´DW�ULVNµ� JURXSV� KDYH� SUHJQDQW�ZRPHQ�UHWXUQLQJ�WR�RU�FRQWLQXLQJ�WKH�RUDO�ORZ�GRVH�����PJ�IROLF�DFLG�PXOWLYLWDPLQ�VXSSOHPHQWDWLRQ�DW����ZHHNV·�JHVWDWLRQDO�DJH�DQG�FRQWLQXLQJ�WR�PLQLPL]H�DQ\�XQNQRZQ�RU�SRWHQWLDO�ULVN�IRU�IROLF�DFLG�VXSSOHPHQWDWLRQ�DQG�WKH�H[SRVHG�PRWKHU�RU�IHWXV�QHZERUQ�

/2:�ULVN�JURXS��:RPHQ�RU�WKHLU�PDOH�SDUWQHUV�ZLWK�QR�SHUVRQDO� RU� IDPLO\� KLVWRU\� RI � KHDOWK� ULVNV� IRU� IROLF� DFLG�VHQVLWLYH�ELUWK�GHIHFWV�

02'(5$7(� ULVN� JURXS�� :RPHQ� ZLWK� WKH� IROORZLQJ�SHUVRQDO�RU�FR�PRUELGLW\�VFHQDULRV����WR����RU�WKHLU�PDOH�SDUWQHU�ZLWK�D�SHUVRQDO�VFHQDULR����DQG����

����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

����0DWHUQDO�GLDEHWHV��W\SH�,�RU�,,� with secondary fetal WHUDWRJHQLF�ULVN��0HDVXUHPHQW�RI �UHG�EORRG�FHOO�IRODWH�OHYHOV�FRXOG�EH�SDUW�RI �WKH�SUH�FRQFHSWLRQ�evaluation to determine the multivitamin and folic acid VXSSOHPHQWDWLRQ�GRVH�VWUDWHJ\������PJ�ZLWK�5%&�IRODWH�

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542 z JUNE JOGC JUIN 2015

SOGC ClINICAl PRACTICE GUIDElINE

������DQG�����WR�����PJ�ZLWK�5%&�IRODWH�!������ZLWK�D�PXOWLYLWDPLQ�

����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�

6HH�WKH�)LJXUH�IRU�D�GHWDLOHG�GHFLVLRQ�WUHH�

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�

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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)஠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

Page 11: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

544 z JUNE JOGC JUIN 2015

SOGC ClINICAl PRACTICE GUIDElINE

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ACKNOWlEDGEMENTS

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REFERENCES

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Page 12: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

JUNE JOGC JUIN 2015 z 545

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

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Page 13: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

546 z JUNE JOGC JUIN 2015

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Page 14: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

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Page 15: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

548 z JUNE JOGC JUIN 2015

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Page 16: Pre-conception Folic Acid and Multivitamin Supplementation ... · congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception

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

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NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell

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