Preparing for the Literature Review: Developing an Annotated Bibliography

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The Assignment (2-3 pages):

  • Select and annotate five articles (attached) from peer-reviewed journals that you would include in your literature review. The annotation for each article should be 6-8 lines, and should include a summary of the purpose, methods and results of the study, and a brief reference to how the articles relate to your dissertation topic.

Hindawi Publishing Corporation Journal of Pregnancy Volume 2013, Article ID 294312, 9 pages http://dx.doi.org/10.1155/2013/294312 Clinical Study Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: The Folic Acid Clinical Trial Study Shi Wu Wen,1,2,3,4 Josee Champagne,1,2 Ruth Rennicks White,1,2 Doug Coyle,4 William Fraser,5 Graeme Smith,6 Dean Fergusson,2,3,7 and Mark C. Walker1,2,4 1 OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, Ottawa Hospital, University of Ottawa, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 2 Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 3 Department of Epidemiology, Biostatistics and Occupational Health and Department of Pediatrics, McGill University Faculty of Medicine, 3175 Cote Ste. Catherine, Montreal, QC, Canada H3T 1C5 4 Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada 5 Department of Obstetrics and Gynecology, Ste. Justine Hospital, 3175 Cote Ste. Catherine, Montreal, QC, Canada H3T 1C5 6 Queen’s Perinatal Research Unit, Department of Obstetrics and Gynecology, Queen’s University, 76 Stuart Street, Connell 4, Kingston, ON, Canada K7L 2V7 7 Department of Medicine, Faculty of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 Correspondence should be addressed to Shi Wu Wen; swwen@ohri.ca Received 26 March 2013; Accepted 8 July 2013 Academic Editor: Fabio Facchinetti Copyright © 2013 Shi Wu Wen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 80/7 and 166/7 weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159. 1. Introduction Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality [1, 2]. It accounts for about one-third of maternal deaths, ranking second amongst causes of pregnancy associated deaths in industrialized countries [3, 4]. A 3- to 25-fold increased risk of abruptio placentae, thrombocytopenia, disseminated intravascular coagulation, pulmonary edema, and aspiration pneumonia [5] is associated with PE. Furthermore, women with a history of PE continue to be at increased risk for future cardiovascular events [6, 7]. Since delivery is the only known cure, PE is a leading cause of indicated preterm delivery [8]. PE accounts for 25% of very low birth weight infants [9], and as many as 60% of these infants suffer from learning disabilities and are associated with a low IQ [10]. PE may also increase the risk of cardiovascular disease in the offspring through “fetal origins of adult diseases” [11, 12]. There is strong evidence from both animal and human studies, including our own large cohort studies [13, 14] to 2 support the hypothesized protective effect of folic acid on PE. We conducted a thorough search of literature in 2008 (MEDLINE (1966—September 2013), EMBASE (1980–2013), and Cochrane Central Register of Controlled Trials (Cochrane Library 2013), using a combination of the following medical subject heading (MeSH) terms: folic acid, folate, multiple vitamin, multivitamin, gestational hypertension or hypertension in pregnancy or pregnancy induced hypertension, and PE. We identified ten relevant studies, including six cohort studies, two case-control studies, and two randomized controlled trials (RCTs). Three earlier cohort studies assessed the effect of folic acid containing multivitamins (including folic acid) and gestational hypertension (including PE) [13, 15, 16], all showed a protective effect of folic acid supplementation on PE. A recent large cohort study from Denmark also showed that regular use of folic acid in pregnancy was related to a reduced risk of PE among normal-weight women [17]. However, two recent studies in China [18] and Holland [19] failed to find an effect of folic acid supplementation on PE or gestational hypertension. A case-control study (𝑛 = 231 patients) in Syria did not report the crude and adjusted odds ratio (OR) [20]. Based on available data we calculated the OR as being 0.14 (95% CI = 0.06–0.31), showing a strong protective effect of folic acid supplementation. In a large casecontrol study in Hungary involving 1,017 pregnant women with medically recorded PE and 37,134 pregnant women without PE, Bánhidy et al. found that there was a lower risk of preterm birth of newborn infants born to pregnant women with early onset PE after folic acid supplementation from early pregnancy [21]. In a reanalysis of randomized controlled trial (𝑛 = 2,928 patients), the adjusted odds ratio (OR) was 0.46 (95% CI = 0.20–1.05) for the 0.2 g/day folic acid supplementation group and 0.59 (95% CI = 0.26–1.32) for the 5.0 g/day folic acid supplementation group [22]. Merchant et al. conducted a randomized trial to evaluate the effect of multivitamin (20 mg thiamine, 20 mg riboflavin, 25 mg B-6, 50 microg B-12, 500 mg C, 30 mg E, and 0.8 mg folic acid) and vitamin A supplements (30 mg beta-carotene plus 5000 IU preformed vitamin A) in relation to hypertension in pregnancy (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg at any time during pregnancy) in 955 HIV-positive pregnant Tanzanian women [23]. They found that women who received multivitamins were 38% less likely to develop hypertension during pregnancy than those who received placebo (relative risk (RR) = 0.62, 95% CI = 0.40–0.94), while no such effect was found in women who received vitamin A (RR = 1.00, 95% CI = 0.66– 1.51). The result of this RCT in HIV-positive patients with folic acid as a cointervention for gestational hypertension (including PE) was quite consistent with findings from observational studies. In a historical cohort study, we compared the occurrence of PE between pregnant women exposed to folic acid antagonists and nonexposed women (matched by year of childbirth, type of institute at birth, and mother’s residence (postal code), using the 1980 to 2000 Canadian province of Saskatchewan databases. The risks of PE (adjusted OR 1.52, 95% confidence interval (95% CI): 1.39, 1.66) and severe PE (OR: 1.77, 95% CI: 1.38, 2.28) were increased in mothers with Journal of Pregnancy folic acid antagonist exposure [14]. Supplementary analyses by tight matching with propensity scores restricting study participants to first and second trimester exposure and to specific categories of folic acid antagonists yielded similar results. Folic acid antagonists include a broad spectrum of drugs with a common mechanism of depleting maternal folate. Findings from the effect of maternal exposure to folic acid antagonists on the increased risk of PE add to the weight of evidence that folic acid supplementation may decrease the risk of PE. As this review suggested, while earlier studies showed protective effect of folic acid on reduced risk of PE, some recent studies failed to find such an effect. The problem in recent studies was that nonsupplementation was rare (less than 5% in most recent studies) so that selection bias/confounding becomes difficult to control. That is why an RCT is needed to sort things out. Another issue from studies by Bodnar et al. [15] and Catov et al. [17] was that they found a beneficial effect of folic acid in lean women or normalweight women only. We believe that this is caused by a dose issue: in the Bodnar and Catov studies most women had supplementation of 0.4 mg per day, and we proposed a dose of 4 mg per day in our FACT trial. Because of the potential genetic and metabolic defects, women with increased risk may need a higher dose. A recent study by Keating et al. found that folate uptake was decreased by amphetamine, atenolol, ethanol, ecstasy, glucose, labetalol, nicotine, and tetrahydrocannabinol [24]. Moreover, many of these drugs/substances were cytotoxic, and they differentially modulated the mRNA expression of folate placental transport systems. In our birth cohort study, we observed a dose-response relationship in high risk women (Table 1). Before initiation of the FACT study, we cautiously assessed the potential risk of daily supplementation with 4.0 mg folic acid during pregnancy (for a duration of about 6 months) from the following four aspects: (1) short-term effects, (2) long-term effects, (3) existing policy on folic acid supplementation, and (4) health care provider support in the obstetrical community through a survey of high risk obstetricians in the country. (1) Short-Term Effects. No adverse outcomes were observed in women who took very high doses of folic acid in suicide attempts [25]. No short-term adverse outcome associated with folic acid supplementation in pregnancy at the recommended dosage has been reported. In the proposed study, most of the study visits for study participants will be integrated with their routine prenatal care services. The physical and emotional burden to the participants in the proposed study is small. (2) Long-Term Effects. A hypothesis found in the literature suggested that because folic acid is an essential coenzyme in purine and thymine nucleotide biosynthesis and hence DNA and RNA metabolism, it may stimulate initiation or promotion of cancers such as colorectal cancer. Findings from animal experiments and human studies of the relationship between folic acid supplementation and colorectal cancer Journal of Pregnancy 3 Table 1: Dose-response relationship between folic acid supplementation and PE in high risk∗ women, OaK birth cohort study, October 2002 to December 2005. Dose of folic acid (mg) 0 0.1–0.9 1.0 1.1–1.9 ≥2.0 No. of subjects No. (%) PE ORs and 95% CIs∗∗ 33 11 186 18 34 9 (27.27) 1 (9.09) 17 (9.14) 2 (11.11) 1 (2.94) Reference 0.74 (0.06, 8.88) 0.32 (0.10, 1.02) 0.24 (0.03, 1.90) 0.08 (0.01, 0.80) ∗ High risk in this analysis included chronic hypertension, type 1 and type 2 diabetes, history of PE, and multiple gestation; ∗∗ 𝑃 < 0.05 for trend test. were controversial, with some studies showing a protective effect while other studies showing a potential causative effect [26–28]. A recent meta-analysis of 10 RCTs reporting overall cancer incidence (𝑁 = 38, 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI = 1.00–1.14) compared to controls [29]. Metaanalyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI = 1.03– 1.49) for the men receiving folic acid compared to controls, while no significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type [29]. Charles et al. followed up participants from a clinical trial of folic acid supplementation in pregnancy and found a nonsignificant increase in the risk of breast cancer deaths in the two supplementation groups (0.2 and 5.0 mg folic acid/d) as compared with placebo group [30]. This report is short and carries little description of the study population and research methodology. The number of deaths was small, the confidence intervals were wide, and the authors had no prespecified hypothesis that taking folic acid supplementation in pregnancy would increase the risk of cancer [30]. In the accompanying commentary, Oakley and Mandel suggested that the most likely explanation for the reported association was chance [31]. On the contrary, a number of other studies found that folic acid supplementation was associated with lower risk of breast cancer [31, 32]. Several more recent studies generated even more controversial results. Ebbing et al. [33] conducted a combined analysis and extended followup of participants from 2 randomized, double-blind, placebo-controlled clinical trials (a total of 6837 patients with ischemic heart disease). After a median of 39 months of treatment and an additional 38 months of posttrial observational followup, 341 participants (10.0%) who received folic acid plus vitamin B(12) versus 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio (HR) = 1.21; 95% confidence interval (CI) = 1.03–1.41; 𝑃 = .02) [33]. On the other hand, in a large double-blind randomized controlled trial of 12064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008, the SEARCH Collaborative Group failed to find such an association: 678 incident cancers (11.2%) were detected in the trial arm versus 639 cases (10.6%) in the placebo arm [34]. The dose (2 mg folic acid plus 1 mg vitamin B(12) daily) was higher and the intervention was longer (6.7 years) in the SEARCH Collaborative Group study [34] versus 0.8 mg folic acid plus 0.4 mg vitamin B(12) daily and 3.2 years in the Ebbing study [33] matching placebo. Interventions in the Ebbing study were also complicated, with oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (𝑛 = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (𝑛 = 1703); vitamin B(6) alone (40 mg/d) (𝑛 = 1705); or placebo (𝑛 = 1721) [33]. Baggott et al. conducted a meta-analysis involving 6 trials (26385 patients) and found an increased cancer incidence in the folic acid-supplemented groups than the nonfolic acidsupplemented groups (relative risk = 1.21 [95% confidence interval: 1.05–1.39]) [35]. On the other hand, Clarke et al. conducted a meta-analysis of 8 large, randomized, placebocontrolled trials of folic acid supplementation involving 37485 individuals at increased risk of cardiovascular disease but did not find an increased risk of cancer: rate ratios (95% confidence intervals) were 1.05 (0.98–1.13) for overall cancer incidence, 1.00 (0.85–1.18) for cancer mortality, and 1.02 (0.97–1.08) for all-cause mortality [36]. One of the major differences between the Baggott study and the Clarke study was that Clarke et al. [36] excluded two small trials on 1955 patients with a history of colorectal adenoma while Baggott et al. included them [35]. The effect of long-term folic acid supplementation for cancer prevention (usually multiyears) may be quite different from the effect of short-term folic acid supplementation for PE prevention (usually a few months). (3) Existing Policies. The proposed 4.0 mg folic acid supplementation in the trial arm has been recommended for women with a previous pregnancy complicated by NTDs by the federal government of Canada [37]. The recent recommendations by the Society for Obstetricians and Gynecologists of Canada (SOGC) are even more liberal in terms of dosage (5.0 mg instead of 4.0 mg) and target population (including women with other risk profiles such as epilepsy or family history or high risk ethnic group or women without obvious increased risk but with poor compliance to life-style changes for healthy pregnancy) for high dose supplementation [38]. (4) Health Care Provider Support. We surveyed 16 perinatologists (high risk obstetricians) in the country, and 15 of them expressed no concern of safety issue related to the trial dosage of folic acid supplementation. In summary, our careful and thorough assessment concludes that the current data does not justify major concern of the risk of folic acid supplementation during pregnancy, and overall, the risk to benefit ratio favors conducting the trial. 2. Methods This trial has been registered at http://www.controlledtrials.com/ Registration #: ISRCTN23781770 and http://www .clinicaltrials.gov/ Registration #: NCT01355159. This trial has been approved by The Ottawa Hospital Research Ethics Board, protocol number 2009-107-01H. 4 Journal of Pregnancy 3. The Intervention The intervention of the FACT study is daily supplementation of 4.0 mg of folic acid from randomization until delivery of the infant. Our previous study found that about 90% pregnant women took 1.0 mg folic acid or multivitamins containing 1.0 mg folic acid on daily basis [13]. This dose of folic acid was associated with reduced risk of PE in the general population [13]. The preliminary analysis of our OaK birth cohort data demonstrated a clear dose-response relationship between folic acid supplementation and PE risk in women with additional identified risk factors (Table 1). Due to the placental, endothelial, and metabolic defects (including those of folate metabolism) leading to increased risk of developing PE, a high dose of folic acid supplementation may be required. In our birth cohort data, the limited number of women with a supplementation of >2.0 mg prevented us from further grouping them into higher dose groups; however, there is likely a continued linear relationship between folic acid dose and reduced PE risk at doses >2.0 mg. We thus propose a 4.0 mg folic acid for the trial. Women who are taking up to 1.1 mg folic acid are eligible for the trial, and since we will not ask the women to change their practice; the total dose of folic acid maybe up to 5.1 mg in the trial arm (4.0 mg from trial medication and 1.1 mg from routine supplementation) and up to1.1 mg in the placebo arm (from routine supplementation), which is consistent with SOGC’s recommendation for high risk pregnancy [38]. 3.1. Inclusion Criteria. Nulliparous and multiparous women: (1) ≥18 years of age at time of consent. (2) Taking ≤1.1 mg of folic acid supplementation daily at the time of randomization. (3) Live fetus. (4) Gestational age between 80/7 and 166/7 weeks of pregnancy (gestational age is based on the first day of the last menstrual period or ultrasound performed before 126/7 ). (5) Planning to give birth in a participating hospital site. (6) Presenting with at least one of the following identified risk factors for PE: (a) prepregnancy chronic hypertension (or diastolic blood pressure ≥90 mm Hg on two separate occasions of at least 4 hours apart or use of antihypertensive medication for the treatment of hypertension); (b) pre-pregnancy diabetes (type I or type II); (c) twin pregnancy; (d) history of PE in the previous pregnancy; (e) BMI ≥35 kg/m2 within 3 months prior or during the first trimester of current pregnancy. 3.2. Exclusion Criteria (1) Women with known history or presence of clinically significant disease or condition which would be a contraindication to folic acid supplementation of up to 5.1 mg daily for the duration of pregnancy. (2) Women who have known major fetal anomaly or fetal demise. (3) Women who have a history of medical complications, including renal disease with altered renal function, epilepsy, cancer, or use of folic acid antagonists such as valproic acid. (4) Women who are using illicit drug or alcohol abuse (≥2 drinks per day) during current pregnancy. (5) Women with a known hypersensitivity to folic acid. (6) Women with a triplet or higher order of multiple pregnancy. (7) Women who have previously participated in this study in a previous pregnancy. We will not exclude women who are affected by a previous NTD. These women will have a supplementation of folic acid at 5 mg daily as well. But for this indication, the supplementation will be discontinued at 12 weeks of gestation, while for the prevention of PE we propose to supplement for the whole pregnancy. 4. Randomization and Blinding A permuted blocked randomization method stratified by centre is used to allocate eligible participants. The randomization scheme is generated by an independent statistician based upon instructions from the study statistician. The randomization process consists of a computer-generated random listing of the treatment allocations stratified by centre and in variable permuted blocks of 4 and 6, due to the two groups assignment. The Method Centre at the Ottawa Hospital Research Institute has implemented randomization via the web. To ensure compliance, the trial participants are provided instruction for the appropriate use of study medication and a study treatment diary. Pill counts and review of the study treatment diary will provide data for teaching regarding compliance at each study visit to optimize results. Participants are being randomized in a 1 : 1 ratio to 4.0 mg folic acid and placebo. For the purposes of endpoint collection, the Trial Coordinating Center, data management team, investigators, site personnel, and participants will remain blinded to whether women received the folic acid or placebo throughout the entire study. Folic acid 4.0 mg or placebo will be taken daily by oral administration from randomization (80/7 –166/7 weeks) until delivery by the trial participant. We have a balanced consideration on the starting date of the intervention. Ideally, according to our hypothesis, an earlier intervention should have a better effect. However, it would not be realistic to recruit patients from participating centers earlier than 8 weeks of gestation. Both the folic acid and placebo have identical external appearances to maintain masking, and folic acid has no taste so the participants are not able to determine if they have been allocated to the treatment or placebo group. We expect that the folic acid from Journal of Pregnancy food intake and routine supplementation between trial arm and placebo arm will be balanced through randomization. However, we will collect information on additional sources of folic acid in concomitant medications and a food frequency questionnaire (Block Dietary Folate Equivalents (DFE) Screener, http://www.nutritionquest.com/) and will analyze these impacts on study results. 5. Followups The study participants will have 5 study visits. First visit is at recruitment between 80/7 –166/7 weeks of gestation, second visit at 240/7 –266/7 weeks of gestation, third visit at 340/7 – 366/7 weeks of gestation, fourth visit postpartum just after delivery, and fifth visit as a telephone interview 42 ± 3 days postpartum. If prenatal records are not included in the hospital records, the research team will contact the office of the treating physician to obtain prenatal records. Data on delivery and neonatal status will be abstracted from hospital charts after discharge. For participants who deliver in a centre other than the one initially planned, the research team will contact the medical center and obtain the delivery record to complete data collection. 6. Primary and Secondary Outcome Measures PE is the primary outcome measure. PE is defined as blood pressure ≥90 mm Hg diastolic on two occasions ≥4 hours apart and proteinuria greater than 2+ on dipstick or greater than 300 mg in 24-hour urine collection or random proteincreatinine ratio ≥30 mg protein/mmol, developed in women greater than 20 weeks of gestation; or HELLP syndrome (hemolysis, serum LDH ≥600 U/L, serum AST ≥70 U/L, platelet count <100 × 109/L); or superimposed PE, defined as history of preexisting hypertension (diagnosed prepregnancy or before 20 weeks gestation) with new proteinuria. An adjudication committee comprised of experts in perinatology will blindly adjudicate for the primary outcome. Secondary outcomes include maternal death, severe PE (PE with convulsion(s) or HELLP or delivery <34 weeks), abruptio placenta, preterm delivery, premature rupture of membranes, antenatal inpatient days, intrauterine growth restriction, perinatal mortality, spontaneous abortion, stillbirth, neonatal death, and neonatal morbidity including retinopathy of prematurity, periventricular leukomalacia, early onset sepsis, necrotising enterocolitis, intraventricular hemorrhage, ventilation, need for O2 at 28 days, and length of stay in neonatal intensive care unit (NICU). 7. Blood Pressure and Proteinuria Measurements On visits 1, 2, and 3, systolic and diastolic blood pressure measurements will be measured in a standardized fashion by trained members of the study team, the participants’ weight will be obtained on a calibrated scale, and urine for proteinuria will be evaluated by dipstick. 5 8. Sample Size and Power Estimation Two-sided test is assumed in the sample size calculation. Based on the literature [39], the best estimation of incidence of PE in the high risk population is 12%. With an alpha error of 5% and a power of >90%, 3,064 women (1,532 in each group) are required to demonstrate a decrease of 30% in the incidence of PE (from 12% to 8.4%) in the trial group (4.0 mg of folic acid) as compared with the placebo group [40]. We will recruit 3,656 high risk women within the study period. This will allow for noncompliance, withdrawn, loss to follow up, and other unanticipated events. The power in our study to detect 30% reduction of PE is 90%. Based on findings from observational studies, all showed unanimously a 30% or more reduction in PE in the supplementation group, suggesting that a 30% reduction in the trial arm as compared with placebo arm is achievable. Moreover, a 30% reduction would be considered clinically important. We anticipate a rate of loss to follow up of <10%. This estimate is a realistic estimate based on other trials that have recruited high risk pregnant women in their first trimester and followed to birth which had the same patient population, outcome ascertainment, treatment mediation, and duration and frequency of visits as the FACT study. Furthermore, these women have existing medical complications of pregnancy that require close management and allows for study visits to be combined with antepartum visits with the high risk care provider. 9. Data Analyses The analysis will be carried out on an “intention to treat” basis. We will first compare the difference in prognostic variables, compliance, and folic acid intake from other sources between intervention and placebo groups. We will then compare the outcomes between the intervention and placebo groups and make adjustment for prognostic and other factors that might confound the comparison. Chi-square test will be used in the comparison of incidence of PE between the intervention and placebo groups. Multiple logistic regression analysis will be used to adjust for potential confounding by parity (0, ≥1, 0 as the reference), age (<20, 20–34, ≥35, 20–34 as the reference), cigarette smoking (yes, no, no as the reference), and other important prognostic factors identified at the description stage. Chi-square test will be used in the comparison of the occurrences of secondary outcome measures, and t-test will be used in the comparison of means of birth weight and gestational age, between the intervention and placebo groups. Multiple logistic regression will be used for binary outcomes, and multiple linear regression analysis will be used for continuously distributed outcomes to adjust for confounding by parity, age, cigarette smoking, and other important prognostic factors. Interim analysis will be performed by the independent DSMB when one-half or 1,828 participants have been randomized and visit 5 (postpartum telephone interview at 42 ± 3 days) has been completed to verify the study trial assumptions. All adverse events will be collected from the 6 Journal of Pregnancy time of randomization to visit 5 (postpartum telephone interview at 42 ± 3 days), the last completed study visit. An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment in accordance with GCP. 10. Results The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. We have worked diligently to implement the FACT study in Canada and internationally. A summary of the progress is presented below. (1) Development and finalization of all FACT related documents including the study protocol, monitoring plan, standard operating procedures, procedure manual, and case report forms (CRFs). (2) Receipt and PK testing of study treatment. (3) Creation and implementation of an electronic web randomization and EDCS. (4) Identification and recruitment of clinical sites (21 Canadian sites, with 18 active sites up to June 15, 2013). (5) Identification and recruitment of international collaborators (7 international collaborators in Australia, Argentina, UK, Netherlands, West Indies, Brazil, and the United States). As of June 15, 2013, 450 participants have been randomized. Additional centers from Canada, Australia, Argentina, UK, Netherlands, West Indies, Brazil, and the United States will join our recruitment efforts soon. 11. Discussion The health benefit of folic acid has so far been focused on its effect on NTDs. Several observations on the association between folic acid and NTDs have been made. Examples include low folate intake levels and risk of NTDs was high in pregnancies from low socio-economic families [41, 42], mean RBC folate concentrations in women with a NTD was lower [43], folic acid metabolism in pregnant women affected by NTD was impaired [44], and the use of aminopterin, a powerful folic acid antagonist, was associated with anencephaly [45]. These observations have led to large scale randomized controlled trials of the effect of periconceptional folic acid supplementation on preventing NTDs. The trials demonstrated a dramatic effect of folic acid on NTDs, at least 70% reduction in the recurrence or first occurrence of NTDs [46, 47]. Based on evidence from the randomized controlled trials, policies and guidelines on periconceptional folic acid supplementation have been implemented since the 1990s in many countries including Canada [37, 38, 48], with high dose folic acid (4.0–5.0 mg) recommended for high risk women and low dose folic acid (0.4–1.1 mg) for low risk women in the prevention of NTDs. High dose folic acid (5 mg per day) during pregnancy to treat anaemia in earlier clinical trials [48, 49] did not show any effect on pregnancy complications, a reassurance of its safety. The hypothesis behind the effect of periconceptional folic acid supplementation on NTDs states that once the chorioallantoic placenta is formed and the fetal heart starts to perfuse it, the requirements for folic acid by the conceptus increase steeply. Based on the fact that folate is required for nucleotide synthesis and cellular methylation potential and therefore modifies DNA synthesis, cell proliferation, and gene regulation, a shortage of folate at this stage might interfere with the orderly closure of the neural tube [50]. While this mechanism may explain the observed effects of folic acid on pregnancy outcomes other than NTDs, a number of other mechanisms have been proposed to explain the observed beneficial effect of folic acid supplementation on PE (Figure 1). The first is related to placental implantation and development. A well implanted and developed placenta is essential for the health and wellbeing of the mother and the fetus. Placental growth/development is a period of increased cell proliferation and differentiation. Therefore, higher folate intakes may be required to support appropriate placental implantation and growth and development in early pregnancy. The second is related to the effect of folic acid on lowering blood homocysteine levels [51, 52], as hyperhomocysteinemia is a risk factor for a number of pregnancy complications including PE [53–55]. The third is related to the effect of folate on improving systemic endothelial function and therefore reducing the risk of such complications as PE [55–58]. The potential impacts of folic acid on maternal and child health beyond its effect on NTDs, combined with the lack of solid scientific evidence on the association between folic acid supplementation and adverse outcomes in mothers and offspring, have created a dilemma in folic acid supplementation during pregnancy. The proposed 4.0 mg folic acid supplementation in the FACT study has been recommended for women with a previous pregnancy complicated by an NTD by the federal government of Canada [37]. The recommendation by SOGC [38] is even more liberal in terms of dosage (5.0 mg instead of 4.0 mg) and of the targeted population (including women with epilepsy or family history or high risk ethnic group or women without obvious increased risk but with poor supplementation compliance) for high dose supplementation. The SOGC has recently changed their recommendation, partly because of the lack of evidence; however, many centers and physicians maintain their position on liberal use of high dose folic acid supplementation for such indications as diabetes and obesity throughout pregnancy (Dr. Mark Walker, SIOGC Chair, personal communication). If high dose folic acid is truly beneficial and more conclusive evidence of the benefit is not forthcoming, this treatment may not be offered to women at increased risk of NTDs and other adverse outcomes such as PE, thus denying future generations of women and their offspring this potentially beneficial therapy. On the other hand, if high dose folic acid supplementation is not truly beneficial and more evidence concerning lack of benefit is not forthcoming, practice may gradually change to increase the dose of folic acid supplementation, particularly because there are presently no other effective therapies to offer. Should high dose of folic acid supplementation found to Journal of Pregnancy 7 Folic acid Placental implantation and development Endothelial function Homocysteine Maternal endothelial injury Preeclampsia Figure 1: Schematic of different proposed mechanisms of action by which folic acid decreases the risk of developing preeclampsia. be harmful, future generations of women and their offspring may suffer needlessly. Studies that can offer definitive answers to this important question are thus urgently needed. Given the disease burden of PE, novel preventions, such as folic acid, need to undergo proper scientific investigation. The results obtained in the FACT trial will inform clinical decision making by indicating whether daily supplementation with 4.0 mg folic acid starting in early pregnancy (8 to 16 weeks of gestation) until delivery is effective in preventing PE and its associated adverse outcomes in women with increased risk of developing PE. Follow-up studies for study participants in this large trial can provide answer to the question whether folic acid supplementation during pregnancy has impact on long-term outcomes in the mothers and their offspring. Acknowledgments The authors wish to acknowledge the Canadian Institutes of Health for funding this study. They also thank the principal investigators and study coordinators for their continued contributions in participant recruitment, data collection, and management of participants. 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NIH Public Access Author Manuscript Prev Med. Author manuscript; available in PMC 2012 July 1. NIH-PA Author Manuscript Published in final edited form as: Prev Med. 2011 ; 53(1-2): 85–88. doi:10.1016/j.ypmed.2011.04.009. The Relationship between Pregnancy Intention and Preconception Health Behaviors Cynthia H. Chuang, MD MSca,b, Marianne M. Hillemeier, PhDb,c, Anne-Marie Dyer, MSb, and Carol S. Weisman, PhDb,d aDivision of General Internal Medicine, Penn State College of Medicine, Hershey, PA, 17033, USA bDepartment of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA cDepartment of Health Policy and Administration, Penn State University, University Park, PA, 16802, USA NIH-PA Author Manuscript dDepartment of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA, 17033, USA Abstract Objective—To describe smoking, heavy drinking, and folic acid supplementation in preconception women and determine if the likelihood of healthy preconception behaviors differs by whether and when women intend future pregnancy. Methods—Analysis was based on 35,351 nonpregnant women who participated in the 2004 Behavioral Risk Factor Surveillance System (BRFSS) who were of reproductive age (18–44 years), sexually active, and capable of future pregnancy. The association between future pregnancy intention and preconception behaviors was determined adjusting for diabetes, weight category, age group, race/ethnicity, marital status, education, income, and children living in household. NIH-PA Author Manuscript Results—Eighty-percent of women were non-smokers, 94.3% non-heavy drinkers, and 42.6% daily folic acid users. In adjusted analysis, only the odds of folic acid supplementation remained higher in women intending pregnancy in the next 12 months (adjusted odds ratio 1.57, 95% confidence interval 1.21–2.04) compared with women not intending future pregnancy. Women intending pregnancy later or ambivalent about future pregnancy were no more likely to be engaging in healthy preconception behaviors than women not intending future pregnancy. Conclusion—Women intending pregnancy within 12 months were more likely to use folic acid, but pregnancy intention was not associated with preconception smoking or heavy drinking. © 2011 Elsevier Inc. All rights reserved. Corresponding Author: Cynthia H. Chuang, MD MSc; 600 Centerview Drive, A210; Penn State College of Medicine;, Hershey, PA 17033; cchuang@hmc.psu.edu; phone: 717-531-8161; fax: 717-531-0839. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The authors have no financial disclosures or conflict of interests to report. Chuang et al. Page 2 INTRODUCTION NIH-PA Author Manuscript While the causes of adverse pregnancy outcomes are only partially understood, it is known that predictors include unintended pregnancy and suboptimal preconception health behaviors, such as smoking, alcohol use, and inadequate folic acid supplementation (Institute of Medicine, 1995, Visscher et al., 2003, Kesmodel et al., 2002, March of Dimes, 2006). While current evidence suggests that women with intended pregnancies have healthier prenatal behaviors than women with unintended pregnancies (Kost et al., 1998, Than et al., 2005), it is not well understood whether intention for future pregnancy impacts health behaviors during the preconception period. NIH-PA Author Manuscript In studies of pregnant women who are asked to recall pregnancy intention and preconception behaviors, women with intended pregnancies are more likely to report healthier preconception behaviors (e.g. drug use, smoking, and folic acid use)(Dott et al., 2010, Hellerstedt et al., 1998, Morin et al., 2002). Other studies report healthier behaviors among pregnant women compared with preconception women (Xaverius et al., 2009, Anderson et al., 2006), suggesting that behavior modification occurs, but not until after recognition of pregnancy. However, there is potential for recall and social desirability bias in studies of these types. Studies describing health behaviors in preconception women in regional samples have had conflicting results—one cross-sectional study of non-pregnant women reported women planning pregnancy in the next year were less likely to smoke and more likely to take multivitamins than women not planning pregnancy (Green-Raleigh et al., 2005)—an encouraging finding, suggesting that women intending pregnancy may change behaviors prior to conception. In contrast, a longitudinal analysis showed no association between pregnancy intention and preconception health behaviors (Chuang et al., 2010). The current study examines future pregnancy intention in relation to relevant health behaviors in non-pregnant reproductive-age women in a large, nationally representative population-based dataset. METHODS Study Sample NIH-PA Author Manuscript The Behavioral Risk Factor Surveillance System (BRFSS) is a standardized telephone survey of U.S. adults conducted annually by state health agencies in collaboration with the Centers for Disease Control and Prevention. Post-stratification weights are used to partially correct for any bias caused by non-telephone coverage, as well as differences in probability of selection and nonresponse. The 2004 version of the BRFSS is the most recent that contains a Family Planning section in the core survey that was administered by all states, allowing for nationally representative data on pregnancy intention. Women were eligible for the current analysis if they were of reproductive age (18–44 years, n=72,768). Women were excluded if they were pregnant (n=3,082); had a hysterectomy (n=5,182); had tubal sterilization/partner with a vasectomy (n=17,069); and not sexually active, had a same sex partner, or were missing family planning data (n=12,084), resulting in an analytic sample of 35,351 women. Future Pregnancy Intention The main independent variable, future pregnancy intention, was categorized as intending pregnancy in less than 12 months from now, between 12 months to less than 2 years from now, in 2 or more years from now, not wanting to have a child in the future, or not sure/ ambivalent. Prev Med. Author manuscript; available in PMC 2012 July 1. Chuang et al. Page 3 Preconception Behaviors NIH-PA Author Manuscript Preconception behaviors were chosen that have been shown to impact pregnancy outcomes and were available in the BRFSS survey: 1) no current smoking (Do you now smoke cigarettes every day, some days, or not at all?)(Visscher et al., 2003, Ahern et al., 2003) 2) no heavy drinking (≤7 drinks/week)(Hanson et al., 1978, Kesmodel et al., 2002) and 3) daily folic acid supplementation (March of Dimes, 2006, Centers for Disease Control, 1992). Women who reported taking a daily multivitamin or other folic acid supplement were considered having daily folic acid supplementation (Centers for Disease Control and Prevention, 2008). Analysis of the folic acid variable was limited to the 14 states that obtained folic acid data (Arizona, Colorado, Florida, Kentucky, Minnesota, Montana, Nebraska, North Carolina, North Dakota, Puerto Rico, Texas, Virgin Islands, Virginia, and Wisconsin). Definition of Covariates NIH-PA Author Manuscript Health-related and sociodemographic variables hypothesized to be associated with either pregnancy intention or the health behaviors of interest were included as covariates. Health variables were self-reported diabetes and weight category (using body mass index (BMI) derived from self-reported height and weight). Sociodemographic variables were age group, race/ethnicity, marital status, education, and annual household income. Additionally, we hypothesized that women with previous births would be more likely to be knowledgeable about pregnancy-related health behaviors, but since the 2004 BRFSS did not include an indicator of previous births, we included a variable to indicate whether any children under 18 were living in the household as a proxy. Statistical Analysis Weighted frequencies of the study variables are presented. Bivariate analyses describe associations of pregnancy intention with the preconception health behavior variables. Multivariable logistic regressions were modeled to adjust for all covariates. To account for the complex sampling design of the BRFSS survey, analyses were performed using SAScallable SUDAAN 10 (RTI, Research Triangle Park, NC). RESULTS NIH-PA Author Manuscript Table 1 shows the frequencies and bivariate associations of the study variables. Eightpercent of the study sample reported no smoking, 94.3% reported no heavy alcohol use, and 42.6% reported daily folic acid use. In bivariate analysis, each of the health behaviors was significantly associated with pregnancy intention. Lowest rates of smoking and heavy alcohol use were reported among women intending pregnancy in less than 12 months (18.5% and 4.4%, respectively), with the highest rates reported among women intending pregnancy in 2 or more years (24.0% and 7.9%, respectively). Similarly, the highest folic acid supplementation rates were reported among women intending pregnancy in less than 12 months (54.3%) and the lowest rates were reported among women intending pregnancy in 2 or more years (35.3%). Table 2 shows the associations of future pregnancy intention and preconception health behaviors estimated in multivariable analyses. After adjusting for covariates, there was no association between pregnancy intention and non-smoking or no heavy alcohol use. Women intending pregnancy in less than 12 months had 57% higher odds of daily folic acid supplementation compared to those not intending any future pregnancy. Prev Med. Author manuscript; available in PMC 2012 July 1. Chuang et al. Page 4 DISCUSSION NIH-PA Author Manuscript In this large nationally representative population-based study, women intending pregnancy soon were not more likely to report healthy preconception behaviors, other than a modest increase in folic acid use. This is contrary to literature describing recall of healthier preconception behaviors among women with intended pregnancies (Dott et al., 2010, Hellerstedt et al., 1998), suggesting possible recall bias in studies of that type. Our findings are similar to what we observed in a regional longitudinal study of preconception women showing no relationship between intention for future pregnancy and health behaviors (Chuang et al., 2010). We found that obese women are less likely to be taking folic acid, which is of concern given the higher risk for neural tube defects, contraceptive nonuse, and unintended pregnancy in obese women compared with normal weight women (Doskoch, 2010, Stothard et al., 2009). Lower socioeconomic status and non-white race was also associated with less folic acid use, suggesting disparities in the uptake of guidelines recommending folic acid use for preconception women. NIH-PA Author Manuscript Limitations of this study include use of cross-sectional data, thus we were unable to evaluate how pregnancy intention may change over time, and whether preconception behaviors change accordingly. All data are self-report, which introduces the possibility of social desirability bias. Additionally, we were only able to report relevant preconception health behaviors that were available in the BRFSS survey. CONCLUSION In summary, preconception behaviors did not differ greatly by future pregnancy intention in this nationally representative sample from the BRFSS. Health behavior optimization should occur prior to conception, since organogenesis occurs in the earliest weeks of gestation (Korenbrot et al., 2002), often before pregnancy is recognized. Further research to understand determinants of preconception health behaviors will inform future interventions aimed at reducing preventable adverse pregnancy outcomes. 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Intent to become pregnant as a predictor of exposures during pregnancy: is there a relation? J Reprod Med. 2005; 50:389–396. [PubMed: 16050563] Visscher WA, Feder M, Burns AM, Brady TM, Bray RM. The impact of smoking and other substance use by urban women on the birthweight of their infants. Subst Use Misuse. 2003; 38:1063–1093. [PubMed: 12901449] Xaverius PK, Tenkku LE, Salas J, Morris D. Exploring health by reproductive status: an epidemiological analysis of preconception health. J Womens Health (Larchmt). 2009; 18:49–56. [PubMed: 19105688] Prev Med. Author manuscript; available in PMC 2012 July 1. NIH-PA Author Manuscript NIH-PA Author Manuscript 42.6 Folic acid use2 24.7 18.2 Overweight Obese Prev Med. Author manuscript; available in PMC 2012 July 1. 40.5 29.6 25–34 35–44 62.0 11.6 19.5 White, not Hispanic Black, not Hispanic Hispanic Race/Ethnicity 29.9 18–24 Age group Sociodemographic Variables 57.1 Not overweight/obese Weight Category3 Diabetes 1.5 94.3 No heavy drinking Health Related Variables 79.7 No smoking Healthy Preconception Behaviors Total 18.2 10.8 63.2 30.5 51.9 17.5 21.4 22.7 55.9 2.1 54.3 95.6 81.5 <12 months (9.3) 16.5 12.1 65.4 15.7 56.4 27.9 18.8 24.3 57.0 1.2 46.8 95.3 80.8 1–2 years (12.4) 16.8 11.0 64.4 3.8 35.8 60.5 13.2 20.6 66.2 1.2 35.3 92.1 76.0 2+ year (21.4) Intends Pregnancy 21.1 12.9 59.6 51.0 30.9 18.1 18.8 27.8 53.4 1.7 42.2 94.8 80.2 Not at all (33.2) Weighted Frequencies (%) 21.9 10.5 60.7 29.8 45.4 24.8 20.6 24.9 54.5 1.5 42.6 94.6 81.0 Ambivalent (23.7) 0.0001 <0.0001 <0.0001 1.10 <0.0001 0.0002 0.0002 pvalue1 Weighted frequencies of study variables for non-pregnant women ages 18–44 for the study sample and stratified by pregnancy intention (n=35,351). NIH-PA Author Manuscript Table 1 Chuang et al. Page 6 NIH-PA Author Manuscript Never married 24.7 28.7 36.5 Graduated high school Some college/technical school College/technical school graduate Prev Med. Author manuscript; available in PMC 2012 July 1. 15.9 11.7 14.5 36.1 11.0 $15,000–$24,999 $25,000–$34,999 $35,000–$49,999 $50,000 or more Don’t know/not sure/refused 65.3 Yes 57.1 42.9 9.4 48.3 12.3 8.6 13.7 7.7 44.3 24.5 22.6 8.6 3.8 9.7 5.0 81.6 7.8 59.9 40.1 8.3 39.7 16.7 13.1 14.6 7.6 44.7 25.9 22.1 7.3 5.5 22.2 10.0 62.4 6.1 1–2 years (12.4) 45.6 54.4 13.8 26.1 15.6 12.7 19.1 12.7 35.9 32.4 23.4 8.3 4.0 52.5 11.4 32.1 7.8 2+ year (21.4) 77.8 22.2 11.0 38.3 13.3 11.3 15.1 11.0 32.7 28.5 26.6 12.2 9.5 21.1 6.7 62.7 6.4 Not at all (33.2) 71.5 28.5 10.6 35.4 15.0 12.0 15.7 11.4 35.0 28.7 25.5 10.8 8.0 25.5 9.9 56.7 6.9 <0.0001 <0.0001 <0.0001 <0.0001 pvalue1 Chi-square statistics describing association between study variables and pregnancy intention. 1 Data source: Women ages 18–44 participating in the 2004 Behavioral Risk Factor Surveillance System Survey who were not pregnant, had not had a hysterectomy or tubal sterilization, did not have a partner with a vasectomy, did not have a same sex partner and were sexually active. 34.7 No Children under 18 living in household 10.7 <$15,000 Income 10.1 Did not graduate high school Education 6.9 8.7 27.9 Member of unmarried couple Divorced/Separated/Widow 56.5 6.9 Married Marital Status Other <12 months (9.3) Intends Pregnancy Ambivalent (23.7) NIH-PA Author Manuscript Total NIH-PA Author Manuscript Weighted Frequencies (%) Chuang et al. Page 7 NIH-PA Author Manuscript Weight category defined as not overweight/obese if body mass index (BMI) <25 kg/m2, overweight if BMI 25 kg/m2 to less than 30 kg/m2, and obese if BMI ≥30 kg/m2. Folic acid data were determined from the 14 states with available data, n=9,279. NIH-PA Author Manuscript 3 NIH-PA Author Manuscript 2 Chuang et al. Page 8 Prev Med. Author manuscript; available in PMC 2012 July 1. Chuang et al. Page 9 Table 2 NIH-PA Author Manuscript Multivariable association of future pregnancy intention and preconception health behaviors among nonpregnant women ages 18–44.1 Preconception Health Behaviors No Smoking No Heavy Drinking Folic Acid Use2 Adjusted OR (95% CI) n=33,077 Adjusted OR (95% CI) n=32,896 Adjusted OR (95% CI) n=8,669 Intends pregnancy <12 months 0.87 (0.73–1.04) 1.01 (0.69–1.46) 1.57 (1.21–2.04)* Intends pregnancy in 1 – 2 years 1.05 (0.87–1.28) 1.29 (0.93–1.79) 1.23 (0.97–1.56) Intends pregnancy in 2+ years 1.07 (0.91–1.26) 1.33 (1.01–1.76)* 0.84 (0.66–1.07) Reference Reference Reference 1.09 (0.95–1.26) 1.07 (0.83–1.37) 1.04 (0.85–1.28) 1.08 (0.75–1.55) 1.50 (0.69–3.23) 0.82 (0.48–1.39) Future Pregnancy Intention Does not intend pregnancy Not sure/Ambivalent Health Related Variables NIH-PA Author Manuscript Diabetes Weight Category Not overweight or obese Reference Reference Reference Overweight 0.90 (0.79–1.01) 1.46 (1.17–1.82)* 1.07 (0.89–1.27) Obese 0.85 (0.75–0.98)* 2.15 (1.60–2.89)* 0.78 (0.64–0.95)* 18–24 Reference Reference Reference 25–34 0.97 (0.83–1.12) 1.31 (1.03–1.67)* 1.16 (0.93–1.43) 35–44 1.21 (1.03–1.44)* 1.40 (1.06–1.83)* 1.46 (1.14–1.86)* White, not Hispanic Reference Reference Reference Black, not Hispanic 2.62 (2.20–3.11)* 2.51 (1.80–3.50)* 0.67 (0.51–0.89)* Hispanic 5.12 (3.96–6.63)* 1.57 (1.03–2.38)* 0.69 (0.56–0.85)* Other 1.88 (1.51–2.34)* 2.09 (1.39–3.14)* 0.91 (0.63–1.31) Reference Reference Reference Cohabiting 0.44 (0.36–0.53)* 0.42 (0.30–0.59)* 0.74 (0.53–1.03) Never married 0.50 (0.44–0.58)* 0.32 (0.25–0.41)* 0.97 (0.79–1.20) Divorced/Separated/Widowed 0.35 (0.30–0.42)* 0.34 (0.25–0.46)* 1.05 (0.82–1.33) Less than high school 0.17 (0.14–0.22)* 0.87 (0.53–1.40) 0.50 (0.36–0.70)* High school only 0.28 (0.24–0.33)* 1.01 (0.77–1.32) 0.69 (0.57–0.85)* At least some college 0.44 (0.38–0.50)* 0.67 (0.53–0.85)* 0.97 (0.80–1.16) Sociodemographic Variables Age Race/Ethnicity NIH-PA Author Manuscript Marital Status Married Education Prev Med. Author manuscript; available in PMC 2012 July 1. Chuang et al. Page 10 Preconception Health Behaviors NIH-PA Author Manuscript No Smoking No Heavy Drinking Folic Acid Use2 Adjusted OR (95% CI) n=33,077 Adjusted OR (95% CI) n=32,896 Adjusted OR (95% CI) n=8,669 Reference Reference Reference <$15,000 0.84 (0.69–1.03) 1.38 (0.97–1.96) 0.55 (0.40–0.77)* $15,000–$24,999 0.75 (0.64–0.89)* 1.60 (1.19–2.16)* 0.76 (0.59–0.97)* $25,000–$34,999 0.70 (0.59–0.84)* 1.61 (1.14–2.27)* 0.96 (0.76–1.21) $35,000–$49,999 0.84 (0.72–0.98)* 1.35 (1.05–1.73)* 1.02 (0.82–1.27) College or technical school graduate Income $50,000 or more Don’t know/not sure/refused Children under 18 living in household (Any vs. None) Reference Reference Reference 0.99 (0.80–1.23) 2.02 (1.40–2.91)* 0.63 (0.47–0.83)* 1.15 (1.02–1.30)* 1.83 (1.49–2.25)* 0.91 (0.77–1.07) NIH-PA Author Manuscript Data source: Women ages 18–44 participating in the 2004 Behavioral Risk Factor Surveillance System Survey who were not pregnant, had not had a hysterectomy or tubal sterilization, did not have a partner with a vasectomy, did not have a same sex partner and were sexually active. 1 Adjusted for all variables in the table. 2 Folic acid analysis was limited to the 14 states with available data, n=9,279. * p<0.05 Abbreviations: OR=odds ratio; CI = confidence interval NIH-PA Author Manuscript Prev Med. Author manuscript; available in PMC 2012 July 1.
Open Access Protocol Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania Brita Askeland Winje,1 Ingrid Kvestad,2 Srinivasan Krishnamachari,3 Karim Manji,4 Sunita Taneja,5 David C Bellinger,6 Nita Bhandari,5 Shruti Bisht,3,5 Anne Marie Darling,7 Christopher P Duggan,6,7 Wafaie Fawzi,7 Mari Hysing,2 Tivendra Kumar,5 Anura V Kurpad,3 Christopher R Sudfeld,7 Erling Svensen,8 Susan Thomas,3 Tor A Strand9,10 To cite: Winje BA, Kvestad I, Krishnamachari S, et al. Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania. BMJ Open 2018;8:e018962. doi:10.1136/ bmjopen-2017-018962 ►► Prepublication history for this paper is available online. To view these files, please visit the journal online (http://​dx.​doi.​ org/​10.​1136/​bmjopen-​2017-​ 018962). Received 2 August 2017 Revised 7 November 2017 Accepted 18 December 2017 For numbered affiliations see end of article. Correspondence to Professor Tor A Strand; ​tor.​strand@​uib.​no Abstract Introduction As many as 250 million children under the age of 5 may not be reaching their full developmental potential partly due to poor nutrition during pregnancy and the first 2 years of life. Micronutrients, including vitamin B12, are important for the development of brain structure and function; however, the timing, duration and severity of deficiencies may alter the impact on functional development outcomes. Consequently, to fully explore the effect of vitamin B12 on cognitive function, it is crucial to measure neurodevelopment at different ages, in different populations and with vitamin B12 supplementation at different times during the critical periods of neurodevelopment. Methods and analysis In this project, we follow up children from four recently completed randomised placebo-controlled trials of oral vitamin B12 supplementation, two in India and two in Tanzania, to explore the long-term effects on neurodevelopmental outcomes and growth. All the included trials provided at least two recommended dietary allowances of oral vitamin B12 daily for at least 6 months. Vitamin B12 was supplemented either during pregnancy, early infancy or early childhood. Primary outcomes are neurodevelopmental status, cognitive function and growth later in childhood. We apply validated and culturally appropriate instruments to identify relevant developmental outcomes. All statistical analyses will be done according to intention-to-treat principles. The project provides an excellent opportunity to examine the effect of vitamin B12 supplementation in different periods during early life and measure the outcomes later in childhood. Ethics and dissemination The study has received ethical approvals from all relevant authorities in Norway, USA, Tanzania and India and complies fully with ethical principles for medical research. Results will be presented at national and international research and policy meetings Strengths and limitations of this study ►► The current project takes advantage of recently completed randomised placebo-controlled trials to study long-term effects of oral vitamin B12 supplementation on neurodevelopmental outcomes and growth in children in Tanzania and India. ►► The project provides an excellent opportunity to examine the effect of vitamin B12 supplementation during different periods of the critical first 1000 days and measure the outcomes later in childhood. ►► The studies were not designed to follow the children up beyond the time of supplementation, which may lead to a somewhat high rate of loss to follow-up. ►► The effect measures may be difficult to standardise across the different studies. and published in peer-reviewed scientific journals, preferably open access. Trial registration number NCT00641862 (Bangalore); NCT00717730, updated CTRI/2016/11/007494 (Delhi); NCT00197548 and NCT00421668 (Dar es Salaam). Introduction New estimates based on proxy measures of stunting and poverty indicate that as many as 250 million children under the age of 5 from low-income and middle-income countries (LMICs) are at risk of not fulfilling their developmental potential partly because of poor nutrition during pregnancy and the first 2 years of life.1 Malnutrition and micronutrient deficiencies represent a major challenge to child health in many LMICs and are Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 1 Open Access associated with suboptimal cognitive function and poor growth.2 Many children in South Asia and Africa suffer from deficiencies of several nutrients including vitamin B12.3–7 Why vitamin B12 may be important for the developing brain Vitamin B12 plays a key role in normal brain development and function and is required for the folate-dependent enzyme, methionine synthase, which is necessary for the synthesis of methionine from homocysteine.8 Methionine in its activated form, S-adenosylmethionine, is the major methyl group donor used in human methylation reactions, including methylation of DNA and RNA. Deficient methylation reactions in the central nervous system can impair the methylation of myelin basic protein in the central as well as peripheral nervous system.9 The production of myelin is a key component of brain development from gestation, throughout childhood and well into middle age.10 The myelination of the brain is of importance for multiple brain systems and is highly related to neurodevelopment and subsequent cognitive functioning.11 Vitamin B12 also serves as a cofactor in numerous catalytic reactions in the human body, which are required for neurotransmitter synthesis and functioning. Vitamin B12 deficiency may cause pernicious anaemia with similar effects on cognitive development and functioning as anaemia caused by iron deficiency.12 Vitamin B12 deficiency can also result in neuropathy through degeneration of nerve fibres and irreversible brain damage.13 However, although subtle vitamin B12 deficiency is very common, the degree to which it has significant consequences for neurodevelopment and cognitive function is not established.14 15 Vitamin B12 and neurodevelopment There is ample evidence that vitamin B12 is important for cognitive development.11 In observational studies among adults and elderly, low levels of vitamin B12 are associated with cognitive decline and dementia.16 Although there are fewer observational studies in children, the association between vitamin B12 status and cognitive functioning has also been documented from early infancy to adolescence. Neonatal severe vitamin B12 deficiency causes failure to thrive and possible irreversible neurological manifestations.12 17 A study in the Netherlands showed that infants fed on a macrobiotic diet, which is low on vitamin B12, had delayed gross motor, speech and language development compared with infants on an omnivore diet.18 In adolescence, these same children who were fed a macrobiotic diet for the six first years of life had poorer performance on cognitive tests, independent of their current vitamin B12 status, compared with adolescents who were fed on an omnivorous diet.19 In an Indian infant cohort, we also demonstrated that poor vitamin B12 status was associated with lower scores on the Mental Development Index in the Bayley Scales of Infant and Toddler Development second edition.4 In a study from Nepal, we were able to demonstrate associations between early vitamin B12 status 2 (2–12 months) and cognitive functioning 5 years later.20 These long-term associations remained strong, even after adjusting for several potential confounders. There is also evidence for the significance of vitamin B12 to the developing brain in a few clinical trials. In a randomised controlled trial (RCT) Indian children aged 6–30 months were administered placebo or approximately twice the recommended daily allowances of vitamin B12 and/or folic acid for 6 months. Children provided with vitamin B12 and folic acid scored higher on a neurodevelopment assessment compared with the placebo group.21 The effects were most prominent in stunted children or children less than 2 years of age. A favourable effect of vitamin B12 was also demonstrated on motor development in two RCTs involving Norwegian infants with developmental regressions and signs of vitamin B12 deficiency 1 and 6 months following a 400 µg injection of vitamin B12.22 23 Knowledge gaps There is a need to clarify to what extent improving vitamin B12 status impacts developmental outcomes in children in LMICs. It is also important to identify populations in which such interventions can be beneficial and at what age vitamin B12 administration is most effective.11 Most studies in this field have used only motor function tests or general neurodevelopment assessments,21 22 24 while less is known on the effect of vitamin B12 on specific cognitive functions such as executive functions, attention and sensorimotor and visuospatial abilities.20 The functions and areas under development are most sensitive to negative influences and will provide the most specific outcomes in assessments.25 26 Consequently, to fully understand findings in developmental assessments, we must consider the developmental timing of an exposure, in this case, vitamin B12 supplementation (or lack thereof), as well as the timing of the assessment.25 Measuring neurodevelopment at different ages, in different populations and the effect of exposure at different times during the critical periods of neurodevelopment is needed to understand the role of vitamin B12 in cognition. Research on the impact of vitamin B12 on the neurophysiological outcomes in children is scarce. Event-related potential (ERP) are non-invasive, reliable measures of neurophysiological brain function27 that provide direct measure of underlying neural activity of higher mental processes. Behavioural assessments may sometimes not be sensitive enough to detect these small changes in brain functions28 and these neurophysiological processes may be important correlates of the cognitive abilities and give new insight into the nutritional impact on the developing brain.29 Study objectives The aim of the current study, the Vitabeginning project, is to determine the long-term effects of vitamin B12 supplementation given during the first 1000 days of life on neurodevelopmental outcomes and growth. Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 Open Access General objective To provide evidence for the role of vitamin B12 supplementation in pregnancy or early childhood on neurodevelopment in vulnerable children in LMICs. ►► ►► Specific objectives and objectives of the separate studies ►► In North Indian children aged 6 to 30 months at enrolment, measure to what extent 6 months’ administration of vitamin B12 (1.8 µg) with or without folic acid (150 µg) improves neurodevelopment and cognitive function 5 years after the end of supplementation. Age range at follow-up is 7–9 years. ►► In South Indian children, measure to what extent administration of daily vitamin B12 (50 µg) in combination with iron and folic acid from 14 weeks’ gestational age through 6 weeks postpartum improves neurodevelopment, cognition and neurophysiological function in childhood. Age range at follow-up is 5–6.5 years. ►► In Tanzanian children, measure to what extent administration of vitamin B12 (50 µg) given with other vitamins from 11 to 17 weeks’ gestational age until delivery improves neurodevelopment and cognitive function up to school age. Age range at follow-up is 11–15 years. ►► In Tanzanian children, measure to what extent administration of vitamin B12 (1 mg) given with other vitamins from week 6 to 18 months of age improves neurodevelopment and cognitive function up to school age. Age range at follow-up is 7–10 years. To estimate the effect of vitamin B12 administration on certain domains of neurodevelopment using pooled data from all of the above studies. Methods and analysis Study design and interventions This study is a follow-up of four recently completed doubleblind randomised placebo-controlled trials conducted in lower socioeconomic, semiurban and urban populations in Delhi (India),21 30 Bangalore (India)31 and Dar es Salaam (Tanzania)32 33 in 2001– 2011. All trials provided at least two recommended dietary allowances (RDA) of vitamin B12 daily (2×2.6 µg for adults and 9 µg for small children) for at least 6 months, with no vitamin B12 supplementation in the placebo groups. The two studies that enrolled pregnant women provided the highest dose of vitamin B12 (50 µg daily, which is approximately 20 times the RDA). An overview of the original trials and the follow-ups is presented in table 1. Table 1 Overview of study populations, study period and exposure in the original trials and in the Vitabeginning follow-up study Characteristics Bangalore Delhi Dares Salaam Original trials  Trial registration number NCT00641862 NCT00717730 NCT00197548 NCT00421668  Intervention period 09.2010–08.2011 01.2010–03.2011 08.2001–02.2005 07.2007–05. 2011  Original sample size 366 1000 8468 2400  Exposure Vitamin B12* Vitamin B12 and/or folic acid† Maternal multivitamins‡ Multivitamins and/ or zinc§  Timing of exposure Pregnancy (daily Infancy/early childhood (daily Pregnancy (daily supplement from supplement for 6 months from 6 supplement from 11<14 weeks gestational to 30 months) 17 weeks until delivery) age through 6-week postpartum) Infancy (daily supplement from 6 weeks to 18 months) 230 Vitabeginning follow-ups  Expected sample size 800–900 366 446  Age range at follow-up 5–6.5 years 7–9 years 11–15 years 7–10 years  Start date of enrolment 01.2015  Expected date for Estimated 07.2017 study completion 10.2016 Estimated 11.2017 07.2015 Estimated 11.2017 07.2015 Estimated 11.2017 *From <14 weeks gestational age to 6 weeks postpartum vitamin B12 50 µg daily. In addition, all women were given iron and folic acid supplementation throughout pregnancy. †From 6 to 30 months for 6 months; four groups: vitamin B12, vitamin B12 +folic acid, folic acid and placebo, doses >12 months: vitamin B12 1.8 µg and folic acid 150 µg (half doses for <12 months). ‡From 12 to 27 weeks gestational age until delivery: multivitamin B12 50 µg, vitamin B1 20 mg, vitamin B2 20 mg, vitamin B6 25 mg, niacin 100 mg, vitamin C 500 mg, vitamin E 30 mg, folic acid 0.8 mg. §From 6 weeks to 18 months, four groups; multivitamin + zinc, vitamin Z and placebo. Multivitamin <6m: vitamin B12 1 mg, vitamin B1 0.5 mg, vitamin B2 0.6 mg, vitamin B 60.6mg, niacin 4 mg, folic acid 130 µg, vitamin C 60 mg, vitamin E 8 mg. Zinc 5 mg >6 months multivitamins and zinc doses were double. Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 3 Open Access Table 2 Overview over inventories and data collection tools used in the different studies and the age of assessment Outcomes to be measured Bangalore Delhi Dar es Salaam Vitamin B12 exposure Pregnancy Child Pregnancy Child Outcomes to be measured Age (year) Age (year) Age (year) Age (year) General abilities  Modified KABC-II* EACABT 5, 6 11–15 7–10 INDIA 7–9  WISC-IV Verbal abilities  Crichton Vocabulary Scale, Hindi edition 7–9 Neurophysiological tests  Event-related potential† 6 Neuropsychological tests  NEPSY-II 7–9 Questionnaires  Brief‡ 5.5 7–9 11–15 7–10  SDQ 6.5 7–9 11–15 7–10  VSMS 5 7–9 Maternal assessment  Demography 5 11–15 7–10  Anthropometry 5, 5.5, 6, 6.5 11–15 7–10  Home environment 5.5 11–15 7–10 11–15 7–10 11–15 7–10 Nutrition  24-hour diet recall form 5, 5.5, 6, 6.5 7–9  Anthropometry 5, 5.5, 6, 6.5 7–9  Household food security questionnaire 5, 6 Medical morbidity  Morbidity questionnaire 5, 5.5, 6, 6.5 Biomarkers  Vitamin B12 5, 6 7–9  CBC, MMA, HcY, RBC folate, CRP  Haemoglobin 5, 6 5, 6 7–9 7–9 6–24 m§ 11–15 7–10 *In Bangalore: Atlantis, number recall, word order, pattern reasoning and triangles from KABC and Koh’s Block Design Test and Verbal Fluency in addition; in Dar es Salaam: the EACABT with permission from Savings Brain Multisite Study (WHO/BMGF) including Atlantis, hand movements, footsteps, story completion, Kilifi Naming Test, ROCF, NOGO, shift, people search, literacy and numeracy, HOME, Brief-P (modified from MAL-ED), SDQ, BQP, in addition to verbal fluency and Koh’s Block. †ENOBIO 32 (Device name)—brain monitoring and stimulation technologies, mismatch negativity, P300 (Neuroelectrics, Boston, MA) . ‡Different versions used in different sites: in Bangalore: Brief Parent; in Delhi: Brief Second Edition; in Dares es Salaam: Saving Brains/Gates/ WHO modified version from the malaria study. §On stored serum samples from Child II cohort (subject to funding). BMGF, Bill & Melinda Gates Foundation; BQP, Behavior Questionnaire for Parents; CBC, complete blood count; CRP, C reactive protein; EACBT, African Cognitive Assessment Battery; HcY, homocysteine; HOME, Home Observation Measurement of the Environment; KABC, Kaufman Assessment Battery for Children; MAL-ED, Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development, MMA, methylmalonic acid; NEPSY-II, A Developmental NEuroPSYchological Assessment; NOGO, go/no go test for sustained attention and response control; RBC folate, red blood cell folate analysis; ROCF, Rey–Osterrieth complex figure; SDQ, Strengths and Difficulties Questionnaire; VSMS, Vineland Social Maturity Scale; WISCIVINDIA, Wechsler Intelligence Scale for Children VI, Indian version. In Bangalore, South India, HIV-negative pregnant women recruited before or at 14 weeks gestational age were randomised to receive a daily dose of oral vitamin B12 (50 µg) or a placebo through 6 weeks postpartum. The primary objective was to determine the effect of vitamin B12 supplementation in improving maternal vitamin B12 4 status. Enrolment was completed in September 2010, and the last enrolled infant was born in August 2011. Oral vitamin B12 supplementation of women throughout pregnancy and early lactation, in combination with standard prenatal care with routine supplementation of iron and folate, significantly increased the vitamin B12 status Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 Open Access Figure 1 Estimated required total sample sizes based on relevant effect sizes. of women and their offspring.31 Neurodevelopment was measured at 9 and 30 months. In this follow-up study, we will measure the effect of maternal vitamin B12 supplementation on neurodevelopment and cognitive function several times 5–6.5 years after supplementation and on neurophysiological outcomes using ERP. In Delhi, North India, children 6–30 months of age were randomised to receive daily (1) vitamin B12, (2) vitamin B12 and folate, (3) folate or (4) placebo for 6 months. The supplementation included vitamin B12 (1.8 µg) and/or folate (150 µg) and with half doses for children <12 months. The primary objective was to measure the effect of these interventions on the incidence of diarrhoea and pneumonia. Neurodevelopment was a predefined secondary outcome and was measured in a subsample of 422 children. In total, 1000 children were enrolled between January 2010 and September 2011. Vitamin B12 and folic acid-supplemented children scored significantly higher on neurodevelopment scores at the age of 12–36 months, compared with those who received placebo.21 In this follow-up study, we will measure to what extent early supplementation of folic acid and/or vitamin B12 improves neurodevelopment and cognitive function 5–6 years after supplementation. The study is powered to measure the effect of vitamin B12, folic acid and the two vitamins combined on neurodevelopmental outcomes. The follow-up study will also measure to what extent vitamin D status in early life is associated with neurodevelopmental scores in early school years. Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 In Dar es Salaam, Tanzania, infants 6–10 weeks of age born to HIV-negative mothers were randomised to receive daily (1) zinc, (2) multivitamins, (3) zinc + multivitamin or (4) placebo. Multivitamins included vitamin B121 mg, B10.5 mg, B20.6 mg, B60.6 mg, niacin 4 mg, folic acid 130 µg, vitamin C 60 mg and vitamin E 8 mg and was provided alongside zinc 5 mg. Doses were doubled after 6 months. Children were followed for 18 months (ie, until age 19.5 months). The primary objective was to measure the incidence of diarrhoea and respiratory tract infections. Enrolment was completed in December 2009, and follow-up ended in May 2011. Neurodevelopmental outcomes were assessed in a subset of children at 15 months.32 Daily zinc supplementation lowered the burden of diarrhoea and respiratory tract infections. No added benefit was seen from the provision of multivitamins.33 In another trial in Dar es Salaam, Tanzania on micronutrients and adverse pregnancy outcomes, HIV-negative pregnant women at 12–27 weeks gestational age were randomised to receive daily oral supplementation of multivitamins including vitamin B12 or placebo. Multivitamins included vitamin B1250 µg, vitamin B120 mg, vitamin B220 mg, vitamin B625 mg, niacin 100 mg, vitamin C 500 mg, vitamin E 30 mg and folic acid 0.8 mg. All women received prenatal iron and folate supplementation. The primary objective was to measure the effect of vitamin supplementation on fetal loss, low birth weight and severe preterm birth. Enrolment was completed in July 2004, 5 Open Access and the last enrolled infant was born in February 2005. Multivitamin supplementation reduced the incidence of low birth weight and small for gestational age births but had no significant effects on prematurity or fetal death.34 The two studies from Tanzania are well suited for follow-up studies on potential impact of micronutrient supplementation on child health and neurodevelopmental outcomes in older children. Outcomes Neurodevelopment, cognitive function and linear growth will be key outcomes in the different studies. Neurodevelopment Neurodevelopmental status in young children has been assessed by the comprehensive assessment tool Bayley Scales of Infant and Toddler Development third edition35 and the easily administered screening tool Ages and Stages Questionnaire third edition in the original studies.21 36 In the follow-up, each site use their own unique collections of tests and questionnaires (table 2). General intellectual functioning is assessed by a modified Kaufmann ABC II (Bangalore and Dar es Salaam), the Wechsler Preschool and Primary Scale of Intelligence–III (Bangalore) or the Wechsler Intelligence Scale for Children VI, Indian version (Delhi). These are complemented by tests on specific cognitive functions by subtests from the developmental neuropsychological test battery A Developmental NEuroPSYchological Assessment, version 2 (NEPSY-II) including attention and executive functioning, language, social perception, sensorimotor and visuospatial processing (Delhi) and adaptive functioning by the Vineland Social Maturity Scale (Bangalore). Mental health and behaviour problems are measured by the parent-reported screening instrument Strengths and Difficulties Questionnaire and executive functions by the parent-reported questionnaire Behaviour Rating Inventory of Executive Function (all sites). Finally, in one study (Bangalore), we measure neurophysiological functions using event-related potentials as this may yield additional information on the effects of nutritional deficiencies on brain function. In the present study, we propose to use two well-characterised ERPs, P-300 and Mis-match Negativity that are known to reflect higher cognitive functions of attention and memory (see table 2 for details on the assessments at each site). Anthropometry Weight and height are measured using standard methods. In Delhi, height, weight and skin fold thickness were measured in children, using Seca scales (hight/weight) and Holtain Calipers. In Bangalore, weights of mothers and children were recorded using a digital balance (Salter’s 9016; Tonbridge) to the nearest 100 g, and the heights were measured using a stadiometer to the nearest 0.1 cm. 6 Sample size calculation The data for our most relevant tests are expected to be normally distributed. We have decided that a standardised effect size of 0.35 SD is the minimally clinically relevant effect for the main psychometric tests. If the smallest group in any of our comparisons includes at least 130 children in each arm, and assuming a two-sided alpha error of 0.05 we will have 81%, 89% and 98% power to detect differences for effect sizes of 0.35, 0.4 and 0.6, respectively. As a result, all of the described studies have sufficient power to detect important differences between vitamin B12 and placebo recipients between individuals with poor and adequate vitamin B12 status or between other groups of other exposures as long as each of the groups contain at least 130 children. Statistical powers according to standardised mean effect sizes of .35, 0.4 and 0.6 and total sample sizes are depicted in figure 1. This graph was generated using the ‘power two means’ command in STATA V.13; it assumes equal group sizes and equal variances and a significance level of 0.05. Data collection Data collection for the primary and secondary outcomes are synchronised and selected to capture the same domains of development using different tools. Assessment tools for cognitive functions such as general abilities, achievement, verbal, visual spatial and sensorimotor skills, memory, executive functioning, general behaviour and social perception and maturity are dependent on the child’s age. We have carefully selected well-validated and developmentally sensitive instruments to ensure detection of the relevant predictors according to age and research questions. Instruments are adapted to ensure psychometric qualities, as well as cultural and linguistic appropriateness of the test at each site. Clinically useful tests will be prioritised to improve sustainability of test material and knowledge of developmental assessment at the specific sites. Assessments are administered by trained psychologists in the Indian sites and by trained healthcare workers in the Tanzania site. A group of experienced scientists with expertise in developmental, neuropsychological and neurophysiological assessments are responsible for the training and standardisation in the different sites. Analysis plan Several domains will be measured and compared between the study groups within each of the studies. In these analyses, we will initially use the Student’s t-test for the crude analyses and multiple linear regression models to adjust for potential baseline differences and when measuring effect modification. Each of the studies has several outcomes as we will compare both linear and ponderal growth, in addition to all the above-mentioned neurodevelopmental measures between the study groups. Thus, there will be several comparisons from each study, and negative and positive Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 Open Access effects will be reported to avoid focusing on spurious positive findings. For each of the planned publications, we will make a detailed plan of analysis before commencing the analysis. In these plans, we will include sections on how to deal with multiple comparisons and whether post hoc adjustments will be done. In addition to these standard per-protocol analysis, we will consider instrumental variable analysis in an attempt to estimate the true effect of vitamin B12 had it been given to all participants in the scheduled doses and intervals. The random allocation will be the instrument in these analyses. For per-protocol analysis, participants who received less than 50% of the projected doses during the period of intervention will not be included in the analyses, well acknowledging that the ensuing effect estimates may not only be biased but will certainly represent an effect higher than what can be achieved even in our well-resourced study setting. For our subgroup analyses, we will include interaction terms to measure whether or not the subgrouping variable significantly modifies the effect of the exposure of interest. All of our analyses will initially be done according to intent to treat. We will not be able to retain the complete number of children from these studies. We will compare the features of the population that is included in this analysis with the population that we failed to re-enrol into the study. We will also detect risk factors for poor neurodevelopment in multiple linear or binomial regression models. We will include socioeconomic and seasonal factors and dietary intake as exposures in the analyses. A significance level of 0.05 will be used. Ethics and dissemination Ethical and safety considerations The exposures under investigation in this study were included in the original trials. Informed written parental consent will be taken from one or both parents of participating children prior to enrolment in the follow-up study and assent will be obtained from children older than 7 years in the Delhi site. Parents unable to read or write will be encouraged to bring along a literate relative or neighbour as an impartial witness. Relevance and benefit to society The current project takes advantage of four recently completed randomised placebo-controlled trials to study the long-term effects of vitamin B12 supplementation on neurodevelopmental outcomes and growth in children in low- and middle-income countries. When measuring the effect of vitamin B12 on growth and development, long-term follow-up is important: vitamin B12 can be stored for years in the body, and the effect of an increased intake for a relatively short period such as 6 months may accordingly last much longer. Furthermore, for many of the neurodevelopmental outcomes, it might not be possible to estimate Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 the effect of early life exposures until later in childhood because of limitations in the assessment tools. Thus, to follow children for a long time, as in this project, is important to fully understand the role of vitamin B12 for brain development and growth. In most studies, follow-up for several years is not possible, so the results from our studies will be of great importance. Since none of the RCTs originally were designed for such long-term follow-up, there is risk that loss to follow-up can bias our effect estimates. There is, however, no reason to believe that the loss to follow-up rate will be different according to randomised regimen in any of the described studies. The risk of confounding of the main exposures (Vitamin B12 supplementation) is small because of the RCT design and the large number of randomization units. Substantial imbalances of potential confounding factors across study groups are unlikely. If positive effects of supplementation are observed, this may constitute important contributions to improve childhood nutrition in many LMICs. However, several factors may have profound impact on long-term neurodevelopment outcomes and growth and potentially dilute the effect of optimising vitamin B12 status in early life. Our findings, however, must be interpreted in light of the results from other RCTs that are measuring the effect of vitamin B12 supplementation on growth and development. If anything, our findings will guide our next step in understanding the role of vitamin B12 nutrition on child growth and development: Should there be additional follow-ups in the ongoing studies or will the results from our studies discourage further studies on vitamin B12 and child health? If none, or very few, of our several outcomes respond to vitamin B12 supplementation, alone or when given in combination with several other micronutrients, then poor vitamin B12 status is likely not an important contributor to impaired neurodevelopment. Thus, we believe that a negative result of our studies is also of substantial public health importance. Millions of children across the world grow up malnourished lacking essential nutrients, with high burden of infectious diseases and where parents may not have the resources to provide an optimal environment for nurturing care. Acting in early childhood, these factors may result in poorer chances for later success in school and work. The results from the RCTs can lead to dietary recommendations that can improve learning and academic achievements, which again can lift individuals from the vicious cycle of poverty and malnutrition. Programme designed to prevent or treat micronutrient deficiencies can be targeted towards specific recommendations. Any further evidence for the long-term effect of dietary supplements has potentially high impact and may provide sustainable improvements in health and equity. The suggested studies are geared towards rapid dissemination of results into national and international child 7 Open Access health promotion programme. We will actively use the potential influence of the international collaborators to ensure that our results reach the relevant health authorities. Planned publications Study results will be presented at national and international research and policy meetings, and published in peer-reviewed scientific journals, preferably open access. We will also discuss alternative strategies to inform the public. We will publish scientific papers as a consortium, specifically directed towards developmental and neuropsychological assessment methodology and site-specific publications. We expect each of the sites to generate approximately five publications in high-ranked international peer-reviewed journals. Author affiliations 1 Department of Vaccine Preventable Diseases, Norwegian Institute of Public Health, Oslo, Norway 2 Regional Centre for Child and Youth Mental Health and Child Welfare, Uni Research Health, Bergen, Norway 3 Division of Mental Health and Neurosciences, St John’s Research Institute, Bangalore, Karnataka, India 4 Department of Pediatrics and Child Health, Muhibili University of Health and Allied Sciences, Dar es Salaam, Tanzania 5 Centre for Health Research and Development, Society for Applied Studies, New Delhi, Delhi, India 6 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA 7 Department of Global Health and Population, Harvard T H Chan School of Public Health, Boston, Massachusetts, USA 8 Haukeland University Hospital, Helse Bergen, Bergen, Norway 9 Department of Research, Innlandet Hospital Trust, Lillehammer, Norway 10 Faculty of Medicine, Centre for International Health, University of Bergen, Bergen, Norway Contributors TAS, IK, CPD and WF took the initiative for the study. TAS, IK, CPD, WF, BAW, SK, KM, ST, MH, NB and ES were involved in developing the design and the study protocol. ST, SK and KM were responsible for setting up the study conduct in each site, with support from AMD, ST, TK, AK and SB. The statistical approach of the study was drafted by CRS, MH, TAS and WF. MH, IK, ES, DCB, and SK were responsible for the cognitive assessments. All authors approved the final version of the protocol. BAW, IK and TAS drafted the current manuscript. All authors have reviewed and accepted the final version of the manuscript. Funding The Vitabeginning study was funded by the Norwegian Research Council Grant number 234495. The original trial in Bangalore was funded by the Indian Council of Medical Research (grant 5/7/192/06-RHN) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant R03 HD054123). The study in Delhi was funded by the Thrasher Research Fund (grant no. 02827) and the Research Council of Norway (grant 172226). The trials in Tanzania were funded by National Institute of Child Health and Human Development (NICHD R01 37701) and the Eunice Kennedy Shriver NIH grant (R01 HD048969-01). CPD is supported by NIH (grants K24DK104676 and P30 DK040561). Competing interests None declared. Patient consent Detail has been removed from this/these case description/s to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making. Ethics approval Ethical Review Board in Norway (2014/1359, 2015/640), in addition to approvals from partners in USA, Tanzania and India. Provenance and peer review Not commissioned; externally peer reviewed. Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which 8 permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://​creativecommons.​org/​ licenses/​by-​nc/​4.​0/ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. References 1. Black MM, Walker SP, Fernald LCH, et al. Early childhood development coming of age: science through the life course. Lancet 2017;389:77–90. 2. Black MM. Micronutrient deficiencies and cognitive functioning. J Nutr 2003;133(11 Suppl 2):3927S–31. 3. Bhan MK, Sommerfelt H, Strand T. Micronutrient deficiency in children. Br J Nutr 2001;85(Suppl 2):S199–203. 4. Taneja S, Bhandari N, Strand TA, et al. Cobalamin and folate status in infants and young children in a low-to-middle income community in India. Am J Clin Nutr 2007;86:1302–9. 5. Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr 2009;89:693S–6. 6. Ulak M, Chandyo RK, Adhikari RK, et al. Cobalamin and folate status in 6 to 35 months old children presenting with acute diarrhea in Bhaktapur, Nepal. PLoS One 2014;9:e90079. 7. Ulak M, Chandyo RK, Thorne-Lyman AL, et al. Vitamin status among breastfed infants in Bhaktapur, Nepal. Nutrients 2016;8:149. 8. Ueland PM, Monsen AL. Hyperhomocysteinemia and B-vitamin deficiencies in infants and children. Clin Chem Lab Med 2003;41:1418–26. 9. Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull 1999;55:669–82. 10. Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev 2010;20:327–48. 11. Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 2008;29(2 Suppl):S126–31. 12. Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev 2008;66:250–5. 13. Calvaresi E, Bryan J. B vitamins, cognition, and aging: a review. J Gerontol B Psychol Sci Soc Sci 2001;56:P327–39. 14. van de Rest O, van Hooijdonk LW, Doets E, et al. B vitamins and n-3 fatty acids for brain development and function: review of human studies. Ann Nutr Metab 2012;60:272–92. 15. Finkelstein JL, Layden AJ, Stover PJ. Vitamin B-12 and perinatal health. Adv Nutr 2015;6:552–63. 16. Selhub J, Morris MS, Jacques PF, et al. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 2009;89:702S–6. 17. Bjørke Monsen AL, Ueland PM. Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence. Am J Clin Nutr 2003;78:7–21. 18. Schneede J, Dagnelie PC, van Staveren WA, et al. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets. Pediatr Res 1994;36:194–201. 19. Louwman MW, van Dusseldorp M, van de Vijver FJ, et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr 2000;72:762–9. 20. Kvestad I, Hysing M, Shrestha M, et al. Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children. Am J Clin Nutr 2017;105:1122–31. 21. Kvestad I, Taneja S, Kumar T, et al. Vitamin B12 and folic acid improve gross motor and problem-solving skills in young North Indian children: a randomized placebo-controlled trial. PLoS One 2015;10:e0129915. 22. Torsvik I, Ueland PM, Markestad T, et al. Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study. Am J Clin Nutr 2013;98:1233–40. 23. Torsvik IK, Ueland PM, Markestad T, et al. Motor development related to duration of exclusive breastfeeding, B vitamin status and B12 supplementation in infants with a birth weight between 20003000 g, results from a randomized intervention trial. BMC Pediatr 2015;15:218. Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 Open Access 24. Strand TA, Taneja S, Ueland PM, et al. Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age. Am J Clin Nutr 2013;97:310–7. 25. Walder D, Jc S, Pulsifer M. Evidence-based practice in infant and early childhood psychology. Neurodevelopmental Assessment 2009:1 67–205. 26. Thompson RA, Nelson CA. Developmental science and the media. Early brain development. Am Psychol 2001;56:5–15. 27. Light GA, Willians LE, Minow F, et al. Electroencephalography (EEG) and Event-Related Potentials (ERPs) with Human Participants. Curr Protoc Neurosci 2010;6:1–24. 28. Uauy R, Peirano P. Breast is best: human milk is the optimal food for brain development. Am J Clin Nutr 1999;70:433–4. 29. deRegnier RA, Long JD, Georgieff MK, et al. Using event-related potentials to study perinatal nutrition and brain development in infants of diabetic mothers. Dev Neuropsychol 2007;31:379–96. 30. Taneja S, Strand TA, Kumar T, et al. Folic acid and vitamin B-12 supplementation and common infections in 6-30-mo-old children in India: a randomized placebo-controlled trial. Am J Clin Nutr 2013;98:731–7. 31. Duggan C, Srinivasan K, Thomas T, et al. Vitamin B-12 supplementation during pregnancy and early lactation increases Winje BA, et al. BMJ Open 2018;8:e018962. doi:10.1136/bmjopen-2017-018962 32. 33. 34. 35. 36. maternal, breast milk, and infant measures of vitamin B-12 status. J Nutr 2014;144:758–64. Locks LM, Manji KP, McDonald CM, et al. The effect of daily zinc and/or multivitamin supplements on early childhood development in Tanzania: results from a randomized controlled trial. Matern Child Nutr 2017;13:e12306. McDonald CM, Manji KP, Kisenge R, et al. Daily zinc but not multivitamin supplementation reduces diarrhea and upper respiratory infections in tanzanian infants: a randomized, double-blind, placebocontrolled clinical trial. J Nutr 2015;145:2153–60. Fawzi WW, Msamanga GI, Urassa W, et al. Vitamins and perinatal outcomes among HIV-negative women in Tanzania. N Engl J Med 2007;356:1423–31. Srinivasan K, Thomas T, Kapanee AR, et al. Effects of maternal vitamin B12 supplementation on early infant neurocognitive outcomes: a randomized controlled clinical trial. Matern Child Nutr 2017;13:e12325. Kvestad I, Taneja S, Kumar T, et al. The assessment of developmental status using the ages and stages questionnaire-3 in nutritional research in north Indian young children. Nutr J 2013;12:50. 9
U.S. Preventive Services Task Force Folic Acid Supplementation for the Prevention of Neural Tube Defects: Recommendation Statement As published by the U.S. Preventive Services Task Force. This summary is one in a series excerpted from the Recommendation Statements released by the USPSTF. These statements address preventive health services for use in primary care clinical settings, including screening tests, counseling, and preventive medications. The complete version of this statement, including supporting scientific evidence, evidence tables, grading system, members of the USPSTF at the time this recommendation was finalized, and references, is available on the USPSTF website at http://www. uspreventiveservicestask force.org/. This series is coordinated by Sumi Sexton, MD, Associate Deputy Editor. A collection of USPSTF recommendation statements published in AFP is available at http://www. aafp.org/afp/uspstf. Summary of Recommendation and Evidence The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid (Table 1). A recommendation. Rationale IMPORTANCE Neural tube defects are major birth defects of the brain and spine that occur early in pregnancy due to improper closure of the embryonic neural tube, which may lead to a range of disabilities or death. The most common neural tube defects are anencephaly (an underdeveloped brain and an incomplete skull) and spina bifida (incomplete closing of the spinal cord).1,2 Based on 2009-2011 data, the estimated average annual prevalence of anencephaly and spina bifida combined was 6.5 cases per 10,000 live births.1-3 Daily folic acid supplementation in the periconceptional period can prevent neural tube defects.1,2 Table 1. Folic Acid Supplementation for the Prevention of Neural Tube Defects: Clinical Summary of the USPSTF Recommendation Population Women who are planning or capable of pregnancy Recommendation Take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. Grade: A Risk assessment All women of childbearing age are at risk of having a pregnancy affected by neural tube defects. Some factors increase this risk, including a personal or family history of neural tube defects, use of particular antiseizure medications, maternal diabetes, obesity, and mutations in folate-related enzymes. Preventive medication Folic acid is the synthetic form of folate, a water-soluble B vitamin. Folic acid is usually given as a multivitamin, prenatal vitamin, or single supplement, and is also used to fortify cereal grain products. Folate occurs naturally in foods such as dark green leafy vegetables, legumes, and oranges. However, most women do not receive the recommended daily intake of folate from diet alone. Timing The critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy. Dosage Supplementation with a multivitamin containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid decreases the risk of neural tube defects. Balance of benefits and harms The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in the developing fetus is substantial for women who are planning or capable of pregnancy. For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, go to http://www.uspreventiveservicestaskforce.org/. NOTE: USPSTF = U.S. Preventive Services Task Force. May 15, 2017 ◆ Volume 95, Number 10 www.aafp.org/afp American Family Physician 652A USPSTF Folic acid is the synthetic form of folate, a water-soluble B vitamin (B9). Folic acid is usually given as a multivitamin, prenatal vitamin, or single supplement. It is also used to fortify cereal grain products. Folate occurs naturally in foods such as dark green leafy vegetables, legumes, and oranges.1 However, most women do not receive the recommended daily intake of folate from diet alone.1 National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2006 suggest that 75% of nonpregnant women aged 15 to 44 years do not consume the recommended daily intake of folic acid for preventing neural tube defects.1,2,4 RECOGNITION OF RISK STATUS Women who have a personal or family history of a pregnancy affected by a neural tube defect are at increased risk of having an affected pregnancy. However, most cases occur in the absence of any personal or family history. BENEFITS OF PREVENTIVE MEDICATION The USPSTF found convincing evidence that folic acid supplementation in the periconceptional period provides substantial benefits in reducing the risk of neural tube defects in the developing fetus. The USPSTF found inadequate evidence on how the benefits of folic acid supplementation may vary by dosage, timing relative to pregnancy, duration of therapy, or race/ethnicity. HARMS OF PREVENTIVE MEDICATION The USPSTF found adequate evidence that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. USPSTF ASSESSMENT not apply to women who have had a previous pregnancy affected by neural tube defects or who are at very high risk due to other factors (e.g., use of certain antiseizure medications or family history). These women may be advised to take higher doses of folic acid. ASSESSMENT OF RISK Although all women of childbearing age are at risk of having a pregnancy affected by neural tube defects and should take folic acid supplementation, some factors increase their risk, including a personal or family history (first- or second-degree relative) of neural tube defects.1 Women with a personal history of an affected pregnancy require special care and are not within the scope of this recommendation statement. Other risk factors include the use of particular antiseizure medications (e.g., valproic acid or carbamazepine), maternal diabetes, obesity, and mutations in folate-related enzymes.1 Questions persist regarding increased risk of neural tube defects in some racial/ethnic groups. Birth prevalence rates are highest among Hispanic women, followed by non-Hispanic white and non-Hispanic black women.1 Genetic mutations in folate-related enzymes may vary by race/ethnicity. Dietary folate or folic acid intake differs by race/ ethnicity. For example, Mexican American women may be at increased risk because of decreased consumption of fortified foods and greater intake of corn masa–based diets.1 Fewer Hispanic women (28%) report consuming 0.4 mg (400 µg) or more of folic acid daily through fortified food or supplements, compared with 39% of non-Hispanic white women.1,5 TIMING Clinical Considerations Half of all pregnancies in the United States are unplanned.6 Therefore, clinicians should advise all women who are capable of pregnancy to take daily folic acid supplements. The critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy.1,7,8 PATIENT POPULATION UNDER CONSIDERATION DOSAGE This recommendation applies to women who are planning or capable of pregnancy. It does Trials and observational studies conducted in settings without food fortification suggest The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in the developing fetus is substantial for women who are planning or capable of pregnancy. 652B American Family Physician www.aafp.org/afp Volume 95, Number 10 ◆ May 15, 2017 USPSTF that supplementation with a multivitamin containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid decreases the risk of neural tube defects.1,7,8 Evidence shows that most women in the United States are not consuming fortified foods in a quantity needed to demonstrate optimal benefit.8 An analysis of NHANES data found that 48% of respondents of childbearing age consumed the recommended amount of folic acid from mandatorily fortified foods only.1,9 According to the National Academy of Sciences Food and Nutrition Board, the tolerable upper intake level of folic acid in women 19 years and older is 1 mg/d (1,000 µg/d) from supplements or fortified food (excluding naturally occurring folate) and 0.8 mg/d (800 µg/d) for those aged 14 to 18 years.10 Fewer than 3% of girls and women aged 14 to 50 years receive more than 1 mg/d (1,000 µg/d) of folic acid from supplements or food.3,11,12 ADDITIONAL APPROACHES TO PREVENTION The Community Preventive Services Task Force recommends community-wide education campaigns to encourage women of childbearing age to take folic acid supplements.13 In 2016, the U.S. Food and Drug Administration approved folic acid fortification of corn masa flour. This allows manufacturers to voluntarily add folic acid to corn masa flour at levels consistent with those found in other enriched cereal grains.14 This recommendation statement was first published in JAMA. 2017;317(2):183-189. The “Other Considerations,” “Discussion,” “Update of Previous USPSTF Recommendation,” and “Recommendations of Others” sections of this recommendation statement are available at https://www. uspreventiveservicestaskforce.org/Page/Document/ UpdateSummaryFinal/folic-acid-for-the-prevention-ofneural-tube-defects-preventive-medication. The USPSTF recommendations are independent of the U.S. government. They do not represent the views of the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, or the U.S. Public Health Service. REFERENCES 1. Viswanathan M, Treiman KA, Kish Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK. Folic Acid Supplementation:​An Evidence Review for the US Preventive May 15, 2017 ◆ Volume 95, Number 10 Services Task Force:​Evidence Synthesis No. 145. Rockville, Md.:​Agency for Healthcare Research and Quality;​ 2017. AHRQ publication no. 14-05214-EF-1. 2. Williams J, Mai CT, Mulinare J, et al.;​Centers for Disease Control and Prevention. Updated estimates of neural tube defects prevented by mandatory folic acid fortification:​United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;​6 4(1):​1-5. 3. Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK. Folic acid supplementation for the prevention of neural tube defects:​an updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017;​317(2):​190-203. 4. Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among U.S. women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med. 2010;​38(5):​534-542. 5. Bentley TG, Willett WC, Weinstein MC, Kuntz KM. Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification. Am J Public Health. 2006;​96(11):​2040-2047. 6. Finer LB, Zolna MR. Unintended pregnancy in the United States:​incidence and disparities, 2006. Contraception. 2011;​8 4(5):​478-485. 7. Wolff T, Witkop CT, Miller T, Syed SB. Folic Acid Supplementation for the Prevention of Neural Tube Defects:​ An Update of the Evidence for the U.S. Preventive Services Task Force:​Evidence Synthesis No. 70. Rockville, Md.:​Agency for Healthcare Research and Quality;​ 2009. AHRQ publication no. 09-051132-EF-1. 8. U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects:​U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;​150(9):​626-631. 9. Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol. 2015;​103(6):​517-526. 10. Institute of Medicine Food and Nutrition Board. Dietary Reference Intakes:​Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC:​National Academy Press;​1998. 11. Dietary Guidelines Advisory Committee;​Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Advisory Report to the Secretary of Health and Human Services. Rockville, Md.:​U.S. Department of Health and Human Services and U.S. Department of Agriculture;​ 2015. 12. National Institutes of Health, Office of Dietary Supplements. Folate:​dietary supplement fact sheet. https:// ods.od.nih.gov/factsheets/Folate-HealthProfessional/. 2016. Accessed November 22, 2016. 13. Community Preventive Services Task Force. Birth defects:​ community-wide campaigns to promote the use of folic acid supplements. https://www.thecommunity​ guide.org /findings /birth-defects-community-widecampaigns-promote-use-folic-acid-supplements. 2004. Accessed November 22, 2016. 14. U.S. Food and Drug Administration. FDA approves folic acid fortification of corn masa flour. http://www.fda. gov/ NewsEvents / Newsroom / PressAnnouncements / ucm496104.htm. April 14, 2016. Accessed November 22, 2016. ■ www.aafp.org/afp American Family Physician 652C
Clinical Review & Education JAMA | US Preventive Services Task Force | RECOMMENDATION STATEMENT Folic Acid Supplementation for the Prevention of Neural Tube Defects US Preventive Services Task Force Recommendation Statement US Preventive Services Task Force Editorial page 144 IMPORTANCE Neural tube defects are among the most common major congenital anomalies Author Audio Interview in the United States and may lead to a range of disabilities or death. Daily folic acid supplementation in the periconceptional period can prevent neural tube defects. However, most women do not receive the recommended daily intake of folate from diet alone. Related article page 190 OBJECTIVE To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on folic acid supplementation in women of childbearing age. CME Quiz at jamanetworkcme.com Related article at jamapediatrics.com EVIDENCE REVIEW In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in infants. The current review assessed new evidence on the benefits and harms of folic acid supplementation. FINDINGS The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation. CONCLUSIONS AND RECOMMENDATION The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid. (A recommendation) Author/Group Information: The US Preventive Services Task Force (USPSTF) members are listed at the end of this article. JAMA. 2017;317(2):183-189. doi:10.1001/jama.2016.19438 Corresponding Author: Kirsten Bibbins-Domingo, PhD, MD, MAS (chair@uspstf.net). T he US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms. It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms. Summary of Recommendation and Evidence The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid (A recommendation) (Figure 1). jama.com Rationale Importance Neural tube defects are major birth defects of the brain and spine that occur early in pregnancy due to improper closure of the embryonic neural tube, which may lead to a range of disabilities or death. The most common neural tube defects are anencephaly (an underdeveloped brain and an incomplete skull) and spina bifida (incomplete closing of the spinal cord).1,2 Based on 20092011 data, the estimated averageannual prevalence of anencephaly and spina bifida combinedwas 6.5 cases per 10 000 live births.1-3 Daily folic acid supplementation in the periconceptional period can prevent neural tube defects.1,2 Folic acid is the synthetic form of folate, a water-soluble B vitamin (B9). Folic acid is usually given as a multivitamin, prenatal vitamin, or single supplement. It is also used to fortify cereal grain products. Folate occurs naturally in foods such as dark green leafy vegetables, legumes, and oranges.1 However, most women do not receive the recommended daily intake of folate from diet alone.1 National Health and Nutrition Examination Survey (Reprinted) JAMA January 10, 2017 Volume 317, Number 2 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 183 Clinical Review & Education US Preventive Services Task Force USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects Figure 1. US Preventive Services Task Force Grades and Levels of Certainty What the USPSTF Grades Mean and Suggestions for Practice Grade Definition Suggestions for Practice A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the Clinical Considerations section of the USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. I statement USPSTF Levels of Certainty Regarding Net Benefit Level of Certainty Description High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as the number, size, or quality of individual studies. inconsistency of findings across individual studies. limited generalizability of findings to routine primary care practice. lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of the limited number or size of studies. important flaws in study design or methods. inconsistency of findings across individual studies. gaps in the chain of evidence. findings not generalizable to routine primary care practice. lack of information on important health outcomes. More information may allow estimation of effects on health outcomes. The USPSTF defines certainty as “likelihood that the USPSTF assessment of the net benefit of a preventive service is correct.” The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service. (NHANES) data from 2003 to 2006 suggest that 75% of nonpregnant women aged 15 to 44 years do not consume the recommended daily intake of folic acid for preventing neural tube defects.1,2,4 benefits in reducing the risk of neural tube defects in the developing fetus. The USPSTF found inadequate evidence on how the benefits of folic acid supplementation may vary by dosage, timing relative to pregnancy, duration of therapy, or race/ethnicity. Recognition of Risk Status 184 Women who have a personal or family history of a pregnancy affected by a neural tube defect are at increased risk of having an affected pregnancy. However, most cases occur in the absence of any personal or family history. Harms of Preventive Medication Benefits of Preventive Medication USPSTF Assessment The USPSTF found convincing evidence that folic acid supplementation in the periconceptional period provides substantial The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in The USPSTF found adequate evidence that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. JAMA January 10, 2017 Volume 317, Number 2 (Reprinted) Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 jama.com USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects US Preventive Services Task Force Clinical Review & Education Figure 2. Folic Acid Supplementation for the Prevention of Neural Tube Defects: Clinical Summary Population Recommendation Risk Assessment Women who are planning or capable of pregnancy Take a daily supplement containing 0.4 to 0.8 mg (400-800 µg) of folic acid. Grade: A All women of childbearing age are at risk of having a pregnancy affected by neural tube defects. Some factors increase this risk, including a personal or family history of neural tube defects, use of particular antiseizure medications, maternal diabetes, obesity, and mutations in folate-related enzymes. Preventive Medication Folic acid is the synthetic form of folate, a water-soluble B vitamin. Folic acid is usually given as a multivitamin, prenatal vitamin, or single supplement and is also used to fortify cereal grain products. Folate occurs naturally in foods such as dark green leafy vegetables, legumes, and oranges. However, most women do not receive the recommended daily intake of folate from diet alone. Timing The critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy. Dosage Supplementation with a multivitamin containing 0.4 to 0.8 mg (400-800 μg) of folic acid decreases the risk of neural tube defects. Balance of Benefits and Harms The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in the developing fetus is substantial for women who are planning or capable of pregnancy. For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go to https://www.uspreventiveservicestaskforce.org. USPSTF indicates US Preventive Services Task Force. the developing fetus is substantial for women who are planning or capable of pregnancy. Clinical Considerations Patient Population Under Consideration This recommendation applies to women who are planning or capable of pregnancy (Figure 2). It does not apply to women who have had a previous pregnancy affected by neural tube defects or who are at very high risk due to other factors (eg, use of certain antiseizure medications or family history). These women may be advised to take higher doses of folic acid. Assessment of Risk Although all women of childbearing age are at risk of having a pregnancy affected by neural tube defects and should take folic acid supplementation, some factors increase their risk, including a personal or family history (first- or second-degree relative) of neural tube defects.1 Women with a personal history of an affected pregnancy require special care and are not within the scope of this recommendation statement. Other risk factors include the use of particular antiseizure medications (eg, valproic acid or carbamazepine), maternal diabetes, obesity, and mutations in folate-related enzymes.1 Questions persist regarding increased risk of neural tube defects in some racial/ethnic groups. Birth prevalence rates are highest among Hispanic women, followed by non-Hispanic white and non-Hispanic black women. 1 Genetic mutations in jama.com folate-related enzymes may vary by race/ethnicity. Dietary folate or folic acid intake differs by race/ethnicity. For example, Mexican American women may be at increased risk because of decreased consumption of fortified foods and greater intake of corn masa–based diets.1 Fewer Hispanic women (28%) report consuming 0.4 mg (400 μg) or more of folic acid daily through fortified food or supplements, compared with 39% of non-Hispanic white women.1,5 Timing Half of all pregnancies in the United States are unplanned. 6 Therefore, clinicians should advise all women who are capable of pregnancy to take daily folic acid supplements. The critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy.1,7,8 Dosage Trials and observational studies conducted in settings without food fortification suggest that supplementation with a multivitamin containing 0.4 to 0.8 mg (400-800 μg) of folic acid decreases the risk of neural tube defects.1,7,8 Evidence shows that most women in the United States are not consuming fortified foods in a quantity needed to demonstrate optimal benefit.8 An analysis of NHANES data found that 48% of respondents of childbearing age consumed the recommended amount of folic acid from mandatorily fortified foods only.1,9 According to the National Academy of Sciences Food and Nutrition Board, the tolerable upper intake level of folic acid in women 19 years and older is 1 mg/d (1000 μg/d) from supplements (Reprinted) JAMA January 10, 2017 Volume 317, Number 2 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 185 Clinical Review & Education US Preventive Services Task Force or fortified food (excluding naturally occurring folate) and 0.8 mg/d (800 μg/d) for those aged 14 to 18 years.10 Fewer than 3% of girls and women aged 14 to 50 years receive more than 1 mg/d (1000 μg/d) of folic acid from supplements or food.3,11,12 Additional Approaches to Prevention The Community Preventive Services Task Force recommends community-wide education campaigns to encourage women of childbearing age to take folic acid supplements.13 In 2016, the US Food and Drug Administration approved folic acid fortification of corn masa flour. This allows manufacturers to voluntarily add folic acid to corn masa flour at levels consistent with those found in other enriched cereal grains.14 Other Considerations Research Needs and Gaps Study results on the effectiveness of folic acid supplementation in reducing neural tube defects among Hispanic women compared with white or black women have been inconsistent. Future research should continue to evaluate differences in diverse populations.1 Discussion Burden of Disease During early fetal development, a neural tube forms that later becomes the spinal cord, brain, and neighboring protective structures (eg, spinal column), with complete closure occurring by the fourth week of pregnancy. Incomplete neural tube closure results in defects such as anencephaly and spina bifida. These defects vary in level of disability and may lead to death. Neural tube defects are among the most common major congenital anomalies in the United States.1 Based on 2009-2011 data from the Centers for Disease Control and Prevention, the estimated average annual prevalence of anencephaly and spina bifida combined was 6.5 cases per 10 000 live births.1,2 Since widespread recommendations on folic acid supplementation and the implementation of food fortification laws by the US Food and Drug Administration in 1998, prevalence rates of infants born with neural tube defects have decreased.1,2 Prevalence of neural tube defects declined from 10.7 cases per 10 000 live births before the implementation of food fortification (1995 to 1996) to 7.0 cases per 10 000 live births after fortification (1999 to 2011).2 Folic acid supplementation prevents about 1300 annual births from being affected by neural tube defects, according to recent estimates.2 Although supplementation recommendations and food fortification laws have reduced the prevalence of neural tube defects, it is still difficult for most women to consume the daily requirement of 0.4 mg (400 μg) of folic acid from food alone. The 2007-2012 NHANES found that 48% of respondents of childbearing age reported consuming folic acid from mandatorily fortified foods only. Only 29% of all respondents reported taking a daily folic acid supplement.9 Among women who were taking a daily folic acid supplement, about half (14.6% of all women) were taking a supplement containing less than the daily recommended dose of 0.4 mg (400 μg).1,9 186 USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects Scope of Review In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in infants.7 The current review assessed new evidence on the benefits and harms of folic acid supplementation. The USPSTF did not review the evidence on folic acid supplementation in women with a history of pregnancy affected by neural tube defects or other high-risk factors. Evidence on folic acid fortification, counseling to increase dietary intake of folic acid or naturally occurring food folate, or screening for neural tube defects is also outside the scope of this review. Effectiveness of Preventive Medication In 2009, the USPSTF reviewed the evidence on folic acid supplementation in women of childbearing age and found that the benefits are well-established and outweigh the harms.8 In the current review, the USPSTF evaluated 1 randomized clinical trial (RCT), 2 cohort studies, 8 case-control studies, and 2 publications from the previous USPSTF review for evidence of effectiveness of folic acid supplementation (n = at least 41 802 participants). Results were not pooled because of study heterogeneity and differences in food fortification over time. A fair-quality RCT conducted in Hungary (1984-1992) assessed women (n = 5453) without a personal history of pregnancy affected by neural tube defects.1,15 Participants were randomized to receive either a daily vitamin supplement containing 0.8 mg (800 μg) of folic acid (experimental group) or a daily trace-element supplement (control group) in the periconceptional period. The trial reported no cases of neural tube defects in the experimental group and 6 cases in the control group (0% vs 0.25%; P = .01 by Fisher exact test).15 These results indicate a statistically significant lower odds of neural tube defects with folic acid supplementation (Peto odds ratio [OR], 0.13 [95% CI, 0.030.65]; P = .01).1,15 Evidence from older, fair-quality observational studies provide additional support that folic acid supplementation is beneficial.1,5 A fair-quality prospective cohort study (n = 6112) conducted in Hungary compared women who were provided a vitamin supplement containing 0.8 mg (800 μg) of folic acid before conception with unsupplemented women at the first prenatal visit (between 8 and 12 weeks of pregnancy) and showed a statistically significant effect on the odds of neural tube defects (OR, 0.11 [95% CI, 0.01-0.91]). 1,16 A fair-quality retrospective cohort study conducted in the United States in women undergoing α-fetoprotein testing or amniocentesis between 15 and 20 weeks of pregnancy showed a statistically significant effect on the odds of neural tube defects among 10 713 women who took multivitamins containing folic acid in weeks 1 through 6 of pregnancy compared with 3157 women who did not take any supplements (OR, 0.27 [95% CI, 0.11-0.63]).1,17 The 8 remaining studies were fair-quality case-control studies of births occurring over 3 decades, from 1976 through 2008.1 Studies compared infants who had malformations caused by neural tube defects with either nonmalformed infants or infants who had malformations not caused by neural tube defects. Data were drawn from 2 multistate studies (National Birth Defects Prevention Study and the Slone Epidemiology Center Birth Defects Study), a 2-state study (National Institute of Child Health and JAMA January 10, 2017 Volume 317, Number 2 (Reprinted) Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 jama.com USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects Human Development Neural Tube Defects Study), and 2 singlestate studies (Texas Neural Tube Defect Project and the California Birth Defects Monitoring Program).1 Older case-control studies conducted before implementation of food fortification laws were generally consistent with the more recent evidence showing that folic acid supplementation is beneficial for the prevention of neural tube defects (OR range, 0.6-0.7 [in 3 of 4 studies]). Newer casecontrol studies conducted after food fortification did not show a protective effect of folic acid supplementation on neural tube defects (OR range, 0.93-1.40 [95% CI included the null]).1 Ethical considerations limited the use of RCT methods to study the effects of folic acid supplementation after food fortification. The newer studies are more subject to design issues than the older ones, which had fewer design flaws.1 Case-control studies have the potential for selection and recall bias, both of which can reduce the observed effect of folic acid supplementation on neural tube defects. Another issue with all study designs is the relative rarity of the outcome and the challenge of adequately powering studies to determine benefits. Another potential explanation for the findings is that the majority of cases of neural tube defects due to folate deficiency have now been prevented, and subsequent cases result from a different etiology. Despite this possible rationale, evidence indicates that most women are not consuming fortified foods at the level needed for optimal benefit. Inadequate folate intake continues to leave nearly one-fourth of the US population with suboptimal red blood cell folate concentration.1,9 Three fair-quality case-control studies (n = 11 154) examined the effects of folic acid supplementation by race/ethnicity.1,18-20 One study found that folic acid supplementation may be less protective among Hispanic women compared with white or black women. 18 A second study found a statistically nonsignificant increased risk of neural tube defects with supplementation among Hispanic women (OR adjusted for consistent users vs nonusers, 2.20 [95% CI, 0.98-4.92]).19 A third study found that periconceptional supplementation did not decrease the risk of neural tube defects and reported no differences in effect by race/ethnicity.20 These inconsistent results among Hispanic women could be a result of chance due to small sample sizes. Eight fair-quality case-control studies addressed dose, timing, or duration of therapy.1 Of these 8 studies, 4 (n = 26 791) provided information on dose, 5 (n = 26 808) provided information on timing, and none provided information on duration. Across the studies, evidence was inconsistent that the benefits of folic acid supplementation differ by dosage or timing.1 Potential Harms of Preventive Medication The USPSTF found adequate evidence that folic acid supplementation does not have serious harms. One fair-quality trial and 1 fairquality cohort study did not find evidence of a statistically significant increased risk of pregnancy with twins in women.1 In the Hungarian trial (n = 5453), the rate of twin pregnancy was not statistically significantly different between the multivitamin and trace-element groups (OR, 1.4 [95% CI, 0.89-2.21]).1,21 In a retrospective, population-based cohort study in Norway (n = 176 042), no association was found between folic acid supplementation and twin pregnancy (OR, 1.04 [95% CI, 0.91-1.18]) after adjusting for use of in vitro fertilization, maternal age, and parity.22 jama.com US Preventive Services Task Force Clinical Review & Education The Hungarian trial examined adverse events in women and found a potential increased risk of maternal weight gain, diarrhea, and constipation at 12 weeks of pregnancy. However, there was a low event rate, and these symptoms could have occurred by chance. These symptoms are also associated with pregnancy.1,15 Three systematic reviews of observational studies (n = at least 14 438 participants) evaluated childhood asthma, wheezing, or allergies and found inconsistent evidence of harms. 1,23,24 Evidence was also inconsistent on the harms of folic acid supplementation differing by dosage and timing. No evidence was found on harms differing by duration of therapy.1 Other potential hypothesized harms of folic acid supplementation include the masking of symptoms of vitamin B12 deficiency and subsequent neurologic complications, carcinogenic effects, asthma/allergic reactions, and interactions with medications.1,7,10 The USPSTF found no significant evidence of these potential harms. Estimate of Magnitude of Net Benefit The USPSTF found no new substantial evidence on the benefits and harms of folic acid supplementation that would lead to a change in its recommendation from 2009.7 The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid.8 How Does Evidence Fit With Biological Understanding? Genetic predisposition and environmental influences are thought to contribute to neural tube defects. These environmental influences are being investigated. An important environmental influence is the consumption of folate. The mechanism of action of folate in the prevention of neural tube defects is unknown. Folate acts as a coenzyme in the synthesis of nucleic acids and the metabolism of amino acids. An important function of folate is its role in single-carbon transfers, which are important in methylation reactions and in purine and pyrimidine synthesis. Folate is necessary for the regulation of DNA synthesis and function; reduced concentrations of folate may limit the number of methyl groups available for DNA replication and methylation.1,7,10 Evidence suggests that mutation in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase, is a risk factor for neural tube defects. This enzyme regulates folate and homocysteine levels. Persons who have this gene mutation have decreased folate levels, which reduces the conversion of homocysteine to methionine and may increase the risk of neural tube defects.1,25 Folic acid consumption may help diminish the effects of the gene mutation. Response to Public Comment A draft version of this recommendation statement was posted for public comment on the USPSTF website from May 10 to June 6, 2016. Some comments requested a more detailed definition of “excessive” folic acid. In response, the USPSTF added information (Reprinted) JAMA January 10, 2017 Volume 317, Number 2 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 187 Clinical Review & Education US Preventive Services Task Force about tolerable upper intake levels for folic acid. Other comments suggested emphasizing that many women do not meet daily recommended amounts of folic acid and adding language on the potential harms of folic acid supplementation. The USPSTF added language about the harms of supplementation and the difficulty of consuming enough folic acid from food alone. Update of Previous USPSTF Recommendation This recommendation reaffirms the 2009 recommendation statement on folic acid supplementation in women of childbearing age.8 The current statement recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid. ARTICLE INFORMATION The US Preventive Services Task Force (USPSTF) members: Kirsten Bibbins-Domingo, PhD, MD, MAS; David C. Grossman, MD, MPH; Susan J. Curry, PhD; Karina W. Davidson, PhD, MASc; John W. Epling Jr, MD, MSEd; Francisco A.R. García, MD, MPH; Alex R. Kemper, MD, MPH, MS; Alex H. Krist, MD, MPH; Ann E. Kurth, PhD, RN, MSN, MPH; C. Seth Landefeld, MD; Carol M. Mangione, MD, MSPH; William R. Phillips, MD, MPH; Maureen G. Phipps, MD, MPH; Michael P. Pignone, MD, MPH; Michael Silverstein, MD, MPH; Chien-Wen Tseng, MD, MPH, MSEE. Affiliations of The US Preventive Services Task Force (USPSTF) members: University of California, San Francisco (Bibbins-Domingo); Group Health Research Institute, Seattle, Washington (Grossman); University of Iowa, Iowa City (Curry); Columbia University, New York, New York (Davidson); State University of New York Upstate Medical University, Syracuse (Epling); Pima County Department of Health, Tucson, Arizona (García); Duke University, Durham, North Carolina (Kemper); Fairfax Family Practice Residency, Fairfax, Virginia (Krist); Virginia Commonwealth University, Richmond (Krist); Yale University, New Haven, Connecticut (Kurth); University of Alabama at Birmingham (Landefeld); University of California, Los Angeles (Mangione); University of Washington, Seattle (Phillips); Brown University, Providence, Rhode Island (Phipps); University of Texas at Austin (Pignone); Boston University, Boston, Massachusetts (Silverstein); University of Hawaii, Manoa (Tseng). Author Contributions: Dr Bibbins-Domingo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The USPSTF members contributed equally to the recommendation statement. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Authors followed the policy regarding conflicts of interest described at https://www .uspreventiveservicestaskforce.org/Page/Name /conflict-of-interest-disclosures. All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Funding/Support: The USPSTF is an independent, voluntary body. The US Congress mandates that 188 USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects Recommendations of Others The Health and Medicine Division of the National Academies (formerly the Institute of Medicine), American College of Obstetricians and Gynecologists, American Academy of Family Physicians, US Public Health Service, Centers for Disease Control and Prevention, American Academy of Pediatrics, American Academy of Neurology, and American College of Medical Genetics and Genomics recommend that women who are capable of becoming pregnant should take at least 0.4 mg (400 μg) of folic acid daily.10,26-30 The American College of Obstetricians and Gynecologists, Centers for Disease Control and Prevention, and several other organizations recommend that women with a history of neural tube defects or other high-risk factors take 4 mg (4000 μg) of folic acid daily.31-33 the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF. Role of the Funder/Sponsor: AHRQ staff assisted in the following: development and review of the research plan, commission of the systematic evidence review from an Evidence-based Practice Center, coordination of expert review and public comment of the draft evidence report and draft recommendation statement, and the writing and preparation of the final recommendation statement and its submission for publication. AHRQ staff had no role in the approval of the final recommendation statement or the decision to submit for publication. Disclaimer: Recommendations made by the USPSTF are independent of the US government. They should not be construed as an official position of AHRQ or the US Department of Health and Human Services. Additional Contributions: We thank Iris Mabry-Hernandez, MD, MPH (AHRQ), who contributed to the writing of the manuscript, and Lisa Nicolella, MA (AHRQ), who assisted with coordination and editing. REFERENCES 1. Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJL, Nicholson WK. Folic Acid Supplementation: An Evidence Review for the US Preventive Services Task Force: Evidence Synthesis No. 145. Rockville, MD: Agency for Healthcare Research and Quality; 2017. AHRQ publication 14-05214-EF-1. 2. Williams J, Mai CT, Mulinare J, et al; Centers for Disease Control and Prevention. Updated estimates of neural tube defects prevented by mandatory folic acid fortification—United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;64(1):1-5. 3. Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. doi:10.1001/jama.2016 .19193 4. Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among U.S. women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med. 2010;38(5): 534-542. 5. Bentley TG, Willett WC, Weinstein MC, Kuntz KM. Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification. Am J Public Health. 2006;96(11): 2040-2047. 6. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-485. 7. Wolff T, Witkop CT, Miller T, Syed SB. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the US Preventive Services Task Force: Evidence Synthesis No. 70. Rockville, MD: Agency for Healthcare Research and Quality; 2009. AHRQ publication 09-051132-EF-1. 8. US Preventive Services Task Force. Folic acid for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(9):626-631. 9. Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol. 2015;103(6):517-526. 10. Institute of Medicine Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998. 11. Dietary Guidelines Advisory Committee; Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Advisory Report to the Secretary of Health and Human Services. Rockville, MD: US Department of Health and Human Services and US Department of Agriculture; 2015. 12. National Institutes of Health, Office of Dietary Supplements. Folate: dietary supplement fact sheet. https://ods.od.nih.gov/factsheets/Folate -HealthProfessional/. 2016. Accessed November 22, 2016. 13. Community Preventive Services Task Force. Birth defects: community-wide campaigns to promote the use of folic acid supplements. https://www.thecommunityguide.org/findings /birth-defects-community-wide-campaigns -promote-use-folic-acid-supplements. 2004. Accessed November 22, 2016. JAMA January 10, 2017 Volume 317, Number 2 (Reprinted) Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 jama.com USPSTF Recommendation: Folic Acid to Prevent Neural Tube Defects US Preventive Services Task Force Clinical Review & Education 14. US Food and Drug Administration. FDA approves folic acid fortification of corn masa flour. http://www.fda.gov/NewsEvents/Newsroom /PressAnnouncements/ucm496104.htm. April 14, 2016. Accessed November 22, 2016. 21. Czeizel AE, Métneki J, Dudás I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma). 1994;43 (3-4):175-184. 28. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41(RR-14):1-7. 15. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327(26):1832-1835. 22. Vollset SE, Gjessing HK, Tandberg A, et al. Folate supplementation and twin pregnancies. Epidemiology. 2005;16(2):201-205. 29. American Academy of Pediatrics Committee on Genetics. Folic acid for the prevention of neural tube defects. Pediatrics. 1999;104(2, pt 1):325-327. 23. Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(5):1272-1281. 30. Harden CL, Pennell PB, Koppel BS, et al; American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):142-149. 16. Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2004;70(11):853-861. 17. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989;262(20):2847-2852. 18. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology. 1995;6(3):219-226. 19. Ahrens K, Yazdy MM, Mitchell AA, Werler MM. Folic acid intake and spina bifida in the era of dietary folic acid fortification. Epidemiology. 2011; 22(5):731-737. 20. Mosley BS, Cleves MA, Siega-Riz AM, et al; National Birth Defects Prevention Study. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am J Epidemiol. 2009;169(1): 9-17. jama.com 24. Yang L, Jiang L, Bi M, et al. High dose of maternal folic acid supplementation is associated to infant asthma. Food Chem Toxicol. 2015;75:88-93. 25. Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286-1294. 26. Cheschier N; ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin: neural tube defects. number 44, July 2003 (replaces committee opinion number 252, March 2001). Int J Gynaecol Obstet. 2003;83(1):123-133. 27. American Academy of Family Physicians. Clinical Preventive Service Recommendation: neural tube defects. http://www.aafp.org/patient -care/clinical-recommendations/all/neural-tube -defects.html. Accessed November 22, 2016. 31. Toriello HV; Policy and Practice Guideline Committee of the American College of Medical Genetics. Policy statement on folic acid and neural tube defects. Genet Med. 2011;13(6):593-596. 32. American College of Obstetricians and Gynecologists. ACOG committee opinion number 313, September 2005: the importance of preconception care in the continuum of women’s health care. Obstet Gynecol. 2005;106(3):665-666. 33. Centers for Disease Control (CDC). Use of folic acid for prevention of spina bifida and other neural tube defects—1983-1991. MMWR Morb Mortal Wkly Rep. 1991;40(30):513-516. (Reprinted) JAMA January 10, 2017 Volume 317, Number 2 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: on 12/21/2018 189

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Running Head: PREPARING FOR THE LITERATURE REVIEW

Preparing for the Literature Review
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Bibbins-Domingo, K., Grossman, D. C., Curry, S. J., Davidson, K. W., Epling, J. W., García, F.
A., ... & Mangione, C. M. (2017). Folic acid supplementation for the prevention of neural tube
defects: US Preventive Services Task Force recommendation statement. Jama, 317(2), 183-189.
A study presented by Bibbins-Domingo et al., (2017) shows essential information about
the possible impacts that the failure of pregnant women or those who have the capacity of
bearing children to take folic acid supplements may bring on the resulting babies. The failure to
take folic acid supplements may contribute towards the occurrence of incidents such as the
neural tube defects. This study uses clinical trial data as the primary methodology to document
the presented recommendations. Also, the study looks at the past data about the effects of failing
to intake folic acid supplements from diverse peer-reviewed sources in making the conclusions.
This article will play a huge role in that it will form the u...

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