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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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.
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;
*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��
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�
)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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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��
���� $OO�ZRPHQ�LQ�WKH�UHSURGXFWLYH�DJH�JURXS� ���²���\HDUV�RI �DJH��ZKR�KDYH�SUHVHUYHG�IHUWLOLW\��D�SUHJQDQF\�LV�SRVVLEOH��VKRXOG�EH�DGYLVHG�DERXW�WKH�EHQHÀWV�RI �IROLF�DFLG�LQ�D�PXOWLYLWDPLQ�supplementation during medical wellness YLVLWV��ELUWK�FRQWURO�UHQHZDO��3DS�WHVWLQJ��\HDUO\�J\QDHFRORJLFDO�H[DPLQDWLRQ��ZKHWKHU�RU�QRW�D�SUHJQDQF\�LV�FRQWHPSODWHG��%HFDXVH�VR�PDQ\�pregnancies are unplanned this applies to all women ZKR�PD\�EHFRPH�SUHJQDQW���,,,�$�
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��
��� *HQHWLF�IDFWRUV�LQFOXGLQJ�JHQH�SRO\PRUSKLVPV�WKDW�DIIHFW�WKH�HIÀFLHQF\�RI �IRODWH�PHWDEROLVP��JHQH�PXWDWLRQV��DIIHFWV�UHODWHG�WR�'1$�PHWK\ODWLRQ�epigenetics, and associated chromosomal anomalies, and
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
%HQH¿W3HGLDWULF� RQJRLQJ� KHDOWK� EHQHÀWV� KDYH� EHHQ� LGHQWLÀHG�IROORZLQJ�SUHQDWDO�PXOWLYLWDPLQ�VXSSOHPHQWDWLRQ�EHIRUH�DQG�LQ�HDUO\�SUHJQDQF\�40,128 Maternal use of prenatal multivitamins LV�DVVRFLDWHG�ZLWK�D�GHFUHDVHG�ULVN�IRU�SHGLDWULF�EUDLQ�WXPRXUV��25�����������&,������WR�������40,146,180�QHXUREODVWRPD��25�����������&,������WR�������40�OHXNHPLD��25�����������&,������WR� ������40,147�:LOPV·� WXPRXU�142 primitive neuroectodermal tumours,145� DQG� HSHQG\PRPDV�145 It was stated that it is QRW� NQRZQ�ZKLFK� FRQVWLWXHQW�V�� DPRQJ� WKH�PXOWLYLWDPLQV�FRQIHUV�WKLV�SURWHFWLYH�HIIHFW�
$�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
Risks and Cautions)ROLF� DFLG� DQG� PXOWLYLWDPLQ� VXSSOHPHQWDWLRQ� LV� SRVVLEO\�associated with an increased incidence of twins, although SRVLWLYH�DQG�QHJDWLYH�WZLQQLQJ�ÀQGLQJV�KDYH�EHHQ�UHSRUWHG�ZLWK�WKH�SRVVLEOH�FRQIRXQGHUV�RI � LQ�YLWUR�IHUWLOL]DWLRQ�DQG�RYDULDQ� VWLPXODWLRQ� RU� RWKHU� HQYLURQPHQWDO� KRUPRQHV�� $�FOHDU� UHODWLRQVKLS� EHWZHHQ� IROLF� DFLG� VXSSOHPHQWDWLRQ� DQG�WZLQQLQJ�KDV�QRW�EHHQ�FRQÀUPHG�������²���
$�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
More population studies are required to understand ZKHWKHU� WKHUH� LV� DQ� H[SRVXUH� DQG� DQ� HIIHFW� ULVN� IRU�SHGLDWULF�RXWFRPHV��EXW�IRU�QRZ�VRPH�FDXWLRQ�LQ�IDYRXU�of using the lowest effective folic acid supplementation GRVH�LV�UHTXLUHG�
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