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 Clinical Practice Guideline was prepared by the Aideen Moore, MD, Toronto ON Genetics Committee, reviewed by the Family Physician William Mundle, MD, Windsor ON Advisory Committee, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists Deborah O’Connor, PhD RD, Toronto ON of Canada. Joel Ray, MD, Toronto ON
PRINCIPAl AUTHOR Michiel Van den Hof, MD, Halifax NS R. Douglas Wilson, MD, Calgary AB Disclosure statements have been received from all contributors.
GENETICS COMMITTEE R. Douglas Wilson (Chair), MD, Calgary AB Abstract François Audibert, MD, Montreal QC Objective: To provide updated information on the pre- and post- conception use of oral folic acid with or without a multivitamin/ Jo-Ann Brock, MD, Halifax NS micronutrient supplement for the prevention of neural tube June Carroll, MD, Toronto ON defects and other congenital anomalies. This will help physicians, Lola Cartier, MSc, Montreal QC midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic Alain Gagnon, MD, Vancouver BC acid/multivitamin supplementation before and during pregnancy. Jo-Ann Johnson, MD, Calgary AB Evidence: Published literature was retrieved through searches of Sylvie Langlois, MD, Vancouver BC PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., Lynn Murphy-Kaulbeck, MD, Moncton NB folic acid, prenatal multivitamins, folate sensitive birth defects, Nanette Okun, MD, Toronto ON congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control Melanie Pastuck, RN, Calgary AB trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on SPECIAl CONTRIBUTORS a regular basis and incorporated in the guideline to June 2014 Paromita Deb-Rinker, PhD, Ottawa ON Linda Dodds, MD, Halifax NS Juan Andres Leon, MD, Ottawa ON J Obstet Gynaecol Can 2015;37(6):534–549 Hélène Lowell, RD DtP, Ottawa ON Key Words: Folic acid, folate, prenatal multivitamins, Wei Luo, MB MSc, Ottawa ON Amanda MacFarlane, PhD, Ottawa ON congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception Rachel McMillan, BSc, Ottawa ON counseling, birth defects, pregnancy, prevention
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.
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Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies SOGC ClINICAl PRACTICE GUIDElINE
Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*
I: Evidence obtained from at least one properly randomized A. There is good evidence to recommend the clinical preventive action controlled trial
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action randomization
II-2: Evidence from well-designed cohort (prospective or C. retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action; more than one centre or research group
II-3: Evidence obtained from comparisons between times or D. There is fair evidence to recommend against the clinical preventive action places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with E. There is good evidence to recommend against the clinical preventive penicillin in the 1940s) could also be included in this category action
III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees 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 on Preventive Health Care.193
websites of health technology assessment and health technology- supplementation for women with a risk for primary or recurrent related agencies, clinical practice guideline collections, clinical trial neural tube or other folic acid-sensitive congenital anomalies who registries, and national and international medical specialty societies. are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to vitamin supplementation and eating a healthy folate-enriched mitigate even theoretical concerns. (II-2A) diet. The risks are of a reported association of dietary folic acid 4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, increased likelihood of a twin pregnancy. These associations may should be advised to follow the product label and not to take more require consideration before initiating folic acid supplementation. than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired intake combined with a multivitamin/micronutrient supplement is dose. (II-2A) an associated decrease in neural tube defects and perhaps in 5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low Values: The quality of evidence in the document was rated using the risk require a diet of folate-rich foods and a daily oral multivitamin criteria described in the Report of the Canadian Task Force on supplement containing 0.4 mg folic acid for at least 2 to 3 months Preventative Health Care (Table 1). before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) Summary Statement 6. Women with a MODERATE RISK for a neural tube defect or In Canada multivitamin tablets with folic acid are usually available in 3 other folic acid-sensitive congenital anomaly or a male partner formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic with moderate risk require a diet of folate-rich foods and daily oral acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, supplementation with a multivitamin containing 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) beginning at least 3 months before conception. Women should continue this regime until 12 weeks’ gestational age. (1-A) From Recommendations 12 weeks’ gestational age, continuing through the pregnancy, 1. Women should be advised to maintain a healthy folate-rich diet; and for 4 to 6 weeks postpartum or as long as breast-feeding however, folic acid/multivitamin supplementation is needed to continues, continued daily supplementation should consist of a achieve the red blood cell folate levels associated with maximal multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) protection against neural tube defect. (III-A) 7. Women with an increased or HIGH RISK for a neural tube defect, 2. All women in the reproductive age group (12–45 years of age) a male partner with a personal history of neural tube defect, or who have preserved fertility (a pregnancy is possible) should history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement supplementation during medical wellness visits (birth control with 4.0 mg folic acid for at least 3 months before conception renewal, Pap testing, yearly gynaecological examination) and until 12 weeks’ gestational age. From 12 weeks’ gestational whether or not a pregnancy is contemplated. Because so many age, continuing throughout the pregnancy, and for 4 to 6 weeks pregnancies are unplanned, this applies to all women who may postpartum or as long as breast-feeding continues, continued daily become pregnant. (III-A) supplementation should consist of a multivitamin with 0.4 to 1.0 3. Folic acid supplementation is unlikely to mask vitamin B12 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy or laboratory) are not required prior to initiating folic acid with a neural tube defect. (II-2A)
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INTRODUCTION acid supplementation dosing evidence (from initial 1 Iwith a serious congenital anomaly ; 2% to 3% will have congenital anomalies (malformations, deformations or invasive ultrasound screening or anticipated through invasive diagnostic testing and 2% will have developmental or functional anomalies and minor congenital anomalies 1 Folic stages of pregnancy, plays a role in preventing neural 16 other folic acid-sensitive congenital anomalies such as heart defects, urinary tract anomalies,15,28,31 oral facial clefts, 15 ORAl FOlIC ACID SUPPlEMENTATION PREGNANCY CARE
FOlIC ACID SUPPlEMENTATION AND THE PREVENTION OF BIRTH DEFECTS supplementation is required as it is the primary source folic acid supplementation for recurrence prevention of 2 supplementation daily prior to pregnancy and throughout diet, as recommended in Eating Well with Canada’s Food Guide 42 3 compared with 6 cases in 2391 women not receiving folic studies that had provided evidence that pregnant women using multivitamins containing folic acid or dietary folic Oral Supplementation ABBREVIATIONS aOR adjusted odds ratio BMI body mass index 1,6,16 GI gastrointestinal MTHFR 5,10-methylenetetrahydrofolate reductase NTD neural tube defect 45,46 OR odds ratio data populations may not have included termination of RBC red blood cell RCT randomized controlled trial
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vitamin supplementation, as well as to an increase of pregnant and lactating women at the presently mandated 45,46 conclusion was, at the present mandated levels of food different regional or population incidence and folic acid 1% recurrence rate even with the 4 to 5 mg folic acid from dietary sources alone, however the actual level of 50 requires more investigation to determine the actual 77 Factors that may affect the ability to achieve adequate maternal folic acid tissue levels foods, timing of supplementation initiation, maternal Recommendations 15,30,37,38,40,53 Folic shown to reduce certain other congenital anomalies such as heart defects, urinary tract anomalies,15,28,31 oral facial clefts, 15At present, multifactorial 79,107,108 is supplementation during medical wellness monogenic, chromosomal, and teratogenic etiologies have 109 pregnancies are unplanned this applies to all women FOlIC ACID FOR CONGENITAl ANOMAlIES PREVENTION AND EVAlUATION Background for NTD Prevention epigenetics, and associated chromosomal anomalies, and upper, middle, or lower portion of the spine in the third 77
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Recurrence risk, % based on population NTD incidence Population Population Population Relationship of NTD affected incidence incidence incidence individual to the at-risk fetus 5 per 1000 2 per 1000 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
folate status Personal/family history NTD: maternal or paternal affected, previous affected fetus for or ethnic risk1–5,19–22 either parent, child, sibling, or second /third degree relative MTHFR genotype 677TT carrier homozygous 677CST carrier heterozygous Medical/surgical condition41,77–79,100–103 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 Maternal obesity: BMI > 30 kg/m2 or 80 kg co-morbidities81,92–97 (pre-pregnancy weight) Maternal lifestyle Smoking factors82,98,99,190–192 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 acid 1. Biology reduced folic acid Interference with Chloramphenicol activity erythrocyte maturation 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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Table 5. Summary of congenital anomalies (decreased or increased or no effect) following Case–Control Cohort/RCT Study reference Anomaly (95% CI) (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 0.52 (0.34–0.78) 0.27 (0.14–0.55) Godwin et al. (2008)40 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) 53 Anencephaly 0.84 (0.76–0.94) 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 Trisomy 21 Pyloric stenosis Undescended testis Hypospadias RCT: randomized control trial; OS: ostium secunda; TGA: transposition of the great arteries
considerations with fetal and pediatric outcomes are 19 POTENTIAl CAUTION FOR MATERNAl, FETAl, CHIlDHOOD, OR GENERAl POPUlATION WITH FOlIC ACID SUPPlEMENTATION 156
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Risks and Cautions valence of preeclampsia with maternal folic acid associated with an increased incidence of twins, although
An Australian study found that high serum folate did 161 of folic acid supplementation on pregnancy outcomes 184 It was suggested that methyl 162 respiratory health in children consistent with epigenetic Risks and Cautions rate of asthma medication among children (recurrent asthma methylation studies in animals and humans have 185 Associations were clustered on the mother and adjusted for maternal age, maternal asthma 186 Recent summary conclusions from colorectal cancer Two studies show no association of folic acid with colorectal adenoma 178,179 186 FETAl AND PEDIATRIC ISSUES 187 188 40,128 Maternal use of prenatal multivitamins More population studies are required to understand 40,146,180 40 of using the lowest effective folic acid supplementation 40,147 142 primitive neuroectodermal 145 145 tumours, It was stated that it is Recommendations and the diagnosis of childhood autism found that folic required prior to initiating folic acid supplementation acid supplementation around the time of conception was 148,149
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Alternate opinions regarding oral supplemental dosing 192 Other long-term uses for folic acid in the other clinical use COUNSEllING AND FOlIC ACID SUPPlEMENTATION Summary Statement of folic acid supplementation, greater than 33% did not and less than 50% supplemented according to national improve folic acid use in younger women and women with 189 enhanced or directed pre-conception education and 66 2 2 190 191 positive or family history of other folate multivitamin adherence in pregnant women is related to Family history relative the most important factors were the dosing regimen, health with secondary fetal 191 evaluation to determine the multivitamin and folic acid certain clinical scenarios requires the use of cohort and
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Teratogenic medications with secondary fetal secondary to (prescription, over-the- 188 Recommendations defect or other folic acid-sensitive congenital supplementation with an over-the-counter daily prenatal a diet of folate-rich foods and a daily oral conception, throughout the pregnancy, and for 4 supplementation with a prescription daily multivitamin require a diet of folate-rich foods and daily oral SUMMARY supplementation with a multivitamin containing hydrocephalus, oral facial clefts with or without cleft palate, supplementation should consist of a multivitamin partner require a diet of folate-rich foods and a daily reductions in the incidence of other congenital anomalies continuing throughout the pregnancy, and for 4 to continues, continued daily supplementation should
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Decision tree for folic acid supplementation
Woman who may or plans to become pregnant
No known NTD risk factor and no prior pregnancy affected with folate sensitive NTD risk factor† or prior pregnancy congenital anomaly affected with other folate sensitive daily multivitamin containing 0.4 mg/day folic congenital anomaly (Box 1)‡ acid* 3 months prior to pregnancy and continuing throughout pregnancy
If pregnancy does not occur after 1 year, consider referral to fertility services
Other risk factors for NTD Pre- Antiepileptic or folate inhibiting medication (Box 2) •1st or 2nd degree relative of woman or her partner with a history of NTD Previous pregnancy affected with NTD or •GI malabsorptive conditions, such as Celiac personal history of NTD disease, inflammatory bowel disease, or gastric daily multivitamin and a total intake of 4 bypass surgery mg/day folic acid§ 3 months prior to •Advanced liver disease pregnancy and through the first trimester, •Kidney dialysis then a multivitamin containing 0.4 mg/day •Alcohol over-use folic acid* for the remainder of pregnancy. OR OR Prior pregnancy affected with a folate sensitive 5 mg¶ 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.
BOX 1 BOX 2 Congenital anomalies which may be sensitive Practical list of folate-inhibiting medications: to folate (see text for anomaly detail): – Anticonvulsant medications: phenytoin, primidone, phenobarbital, – Oral facial cleft (and palate) carbamazepine, valproic acid – Certain cardiac defects – Metformin – Certain urinary tract anomalies – Methotrexate (a medication that is highly teratogenic to the fetus). – Limb reduction defects – Sulfasalazine – Triamterene – Trimethoprim (as found in cotrimoxazole)
*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. §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.
woman with pre-pregnancy diabetes. recommendations for 4 mg folic acid daily because of the mode of product distribution or compliance issues with taking daily NTD: neural tube defect; GI: gastrointestinal
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ACKNOWlEDGEMENTS REFERENCES periconceptional supplementation with high-dose folic acid and
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acid supplementation depends on methylenetetrahydrofolate reductase
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of folic acid supplementation during pregnancy with reduction of
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concentration and mean red cell volume at varying concentrations of
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in pregnancy and the development of atopy, asthma, and lung function in
APPENDIX FOlIC ACID SUPPlEMENTATION
Risk Folic acid dosing: status Female partner Male partner A healthy folate-rich diet AND: Low No personal or family risk for NTD No personal or family risk for NTD Multivitamin with 0.4 to 1.0 mg folic acid for or folic acid-sensitive birth defects or folic acid-sensitive birth defects 2 to 3 months before conception, throughout pregnancy and for 6 weeks postpartum or to completion of lactation Moderate Personal history positive for folate Personal history positive for folate Multivitamin including 1. 0 mg folic acid for at sensitive anomalies. sensitive anomalies least 3 months before conception to 12 weeks and then for remainder of pregnancy and 6 second-degree relative. second-degree relative weeks postpartum or to completion of lactation Diabetes type I or II Teratogenic medications by folate inhibition GI malabsorption that decreases RBC folate High Personal NTD history. Personal NTD history. Multivitamin including 1.0 mg folic acid plus Previous NTD pregnancy Previous NTD pregnancy 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 in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell
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