Over the past 20 years, the rise in obesity rates has been

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1 MOTHERISK ROUNDS Dosage Requirements for Periconceptional Folic Acid Supplementation: Accounting for BMI and Lean Body Weight Seth J. Stern, MSc, 1,2 Ilan Matok, PhD, 2 Bhushan Kapur, PhD, 1,2,3,4 Gideon Koren, MD 1,2 1 Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto ON 2 Department of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto ON 3 Department of Clinical Pathology, Sunnybrook Health Science Centre, Toronto ON 4 Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto ON Abstract Objective: To determine folic acid dosage requirements for individuals across a broad range of BMI values, using dose per kilogram lean body weight (LBW) as a primary predictor of systemic exposure. Steady-state folate concentrations of 15.9 nmol/l were assumed to be sufficient for reducing the risk for neural tube defects in the general population. Methods: Data from a recent study of single-dose folic acid pharmacokinetics among 12 obese and 12 non-obese women of childbearing age were analyzed to determine expected steady-state concentrations. The mean folic acid dose per kilogram LBW that achieved serum folate concentrations of 15.9 nmol/l was applied to a broad range of BMI values to evaluate daily dose requirements. Results: Modest differences in folic acid requirements were noted for individuals among the non-obese, overweight, and obese categories. The current supplementation guidelines suggesting a daily dose of 0.4 mg appear to satisfy the needs of women at even the upper extremes of obesity. However, because even with appropriate folate supplementation obese women have an increased risk of neural tube defects, and they may benefit from higher intake and higher serum concentrations of folic acid. Conclusion: Current guidelines recommend an adequate folic acid dose for obese women of childbearing age. Thus, it is unlikely that folate deficiency is associated with the elevated risk for neural tube defects in this population. Résumé Objectif : Déterminer les besoins posologiques en acide folique de femmes présentant une vaste gamme d IMC, en utilisant la dose par kilogramme de poids maigre (PM) à titre de facteur prédictif primaire de l exposition générale. Nous avons présumé que des concentrations en folate à l état stationnaire supérieures ou égales à 15,9 nmol/l étaient suffisantes aux fins de la réduction du risque d anomalie du tube neural dans la population générale. Key Words: Folic acid, obesity, periconceptional supplementation Competing Interests: See Acknowledgements. Méthodes : Les données issues d une récente étude sur la pharmacocinétique de l acide folique en dose unique menée auprès de 12 femmes obèses et de 12 femmes non obèses en âge de procréer ont été analysées afin de déterminer les concentrations à l état stationnaire attendues. La dose moyenne d acide folique par kilogramme PM ayant permis l atteinte de concentrations sériques en folate supérieures ou égales à 15,9 nmol/l a été appliquée à une vaste gamme de valeurs d IMC afin d évaluer les besoins posologiques quotidiens. Résultats : De modestes différences en matière de besoins en acide folique ont été constatées chez des femmes des catégories «non obèse», «surcharge pondérale» et «obèse». Les lignes directrices actuelles en matière de supplémentation suggérant une dose quotidienne de 0,4 mg semblent aussi répondre aux besoins des femmes qui se trouvent aux extrêmes supérieurs de l obésité. Toutefois, puisque les femmes obèses sont exposées à un risque accru d anomalies du tube neural même en présence d une supplémentation appropriée en folate, elles pourraient tirer avantage d un apport accru en acide folique et de l obtention de concentrations sériques supérieures de ce dernier. Conclusion : Les lignes directrices actuelles recommandent une posologie adéquate d acide folique en ce qui concerne les femmes obèses en âge de procréer. Ainsi, il est peu probable qu une carence en folate soit associée au risque élevé d anomalie du tube neural que l on constate chez cette population. J Obstet Gynaecol Can 2012;34(4): INTRODUCTION Over the past 20 years, the rise in obesity rates has been accompanied by the realization that elevated maternal weight is a risk factor for various major malformations. Among these is an increased risk for neural tube defects, often presenting as either spina bifida or anencephaly. 1 In 1994, Waller et al. hypothesized that the association of poor diet and metabolic disorders with obesity may lead to a direct relationship between obesity and the risk for 374 APRIL JOGC AVRIL 2012

2 Dosage Requirements for Periconceptional Folic Acid Supplementation: Accounting for BMI and Lean Body Weight NTDs. 2 A case control study of NTD-affected births and healthy control subjects supported the hypothesis, finding an increased risk of having an NTD-affected infant as BMI rose above 30 kg/m 2. By 1996, three other groups undertook efforts to corroborate these findings and identify the associated etiology. 3 5 Conducting similar case control studies, each group found an NTD risk that escalated with the magnitude of obesity. Unfortunately, attempts to isolate potential etiological factors, including nutrient intake and diabetes, failed to explain the association. Most notably, folic acid supplementation was adjusted for in each of the three studies; the increased risk for NTDs among obese mothers remained even when their folic acid intake was at the recommended level. While folic acid intake may have been at the recommended level for these individuals, it is possible that the recommended amount may not have been sufficient for the obese mother. Watkins et al. acknowledged that obesityassociated metabolic alterations could have an impact on folate utilization or increase folate requirements. 4 Consequently, the studies did not rule out folate deficiency as a potential mediating factor responsible for the increased NTD risk. To further investigate this concern, Mojtabai collected data from two National Health and Nutrition Examination Surveys in the United States from before and after folic acid fortification. 6 Drawing on data solely from women of childbearing age, Mojtabai found a decreased serum folate status corresponding to increased levels of obesity. The study estimated that women in the highest BMI category ( 30 kg/m 2 ) would need an additional 350 μg of folic acid per day to reach folate levels similar to those in the lowest BMI category. In an attempt to close this knowledge gap, we conducted a study to compare the pharmacokinetics of folic acid between obese and non-obese women of childbearing age following weight-adjusted dosing. 7 Dosing according to total body weight resulted in an increased folic acid area under the curve for obese individuals, with the absence of any differences between the groups in total apparent clearance. As the data indicated incomplete distribution of folic acid into adipose tissue, alternative measures of body weight were sought to explain the differences. The dose per ABBREVIATIONS AUC area under the curve LBW NTD TBW lean body weight neural tube defect total body weight kilogram lean body weight was found to account for 90% of the variation in folic acid AUC among the participants. Using these findings, the present study aimed to identify the dose that would lead to protective steady-state serum folate concentrations for individuals across a wide range of BMI values. Previous work has found that pregnant women with serum folate concentrations 15.9 nmol/l had the lowest risk for NTD-affected births. 8 Accordingly, using the estimated steady-state serum folate levels from our data, we determined the dose of folic acid per kilogram LBW that would be expected to achieve and maintain serum folate at these concentrations. MATERIALS AND METHODS To assess folic acid dosing requirements to achieve protective serum concentrations according to LBW, we used pharmacokinetic data from a recently completed study. 7 We recruited, through advertisment, 12 non-obese (BMI 18.5 to 24.9 kg/m 2 ) and 12 obese (BMI 30 kg/m 2 ) healthy women of childbearing age for study. Non-obese women were randomized to take either 1.1 mg or 5.0 mg folic acid daily. Obese women were each paired to a nonobese woman, and allocated a folic acid dose equivalent (per kg total body weight) to the dose received by the paired non-obese woman. On the study day, participants arrived in the morning following an overnight fast. After a baseline blood sample, participants were orally administered their respective folic acid dose. Subsequent blood samples were taken over a 10-hour period, at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0 hours after baseline. Participants were given a standardized meal during the study day containing known amounts of folate. Blood samples were processed to isolate serum, and frozen at 20 C until analysis. All samples were analyzed as a batch using the Access Folate assay system (Beckman Coulter Inc., Fullerton, CA). Estimated steady-state serum levels were calculated for each participant by dividing the daily dose by total apparent clearance. Total apparent clearance was calculated as dose divided by AUC, with AUC derived using the trapezoidal rule. Estimated steady-state serum folate levels were plotted against dose received per kilogram LBW. Linear regression analysis was used to identify the dose per LBW that would result in reaching protective steady-state serum folate levels of 15.9 nmol/l. LBW was calculated for women across a range of BMI categories using the 2005 revised formula, as follows: APRIL JOGC AVRIL

3 Figure 1. Correlation of dose per kilogram lean body weight with estimated steady-state serum folate concentrations 160 R² = Steady-State (nmol/l) Dose (mg/kg LBW ) LBW (kg) = 9270 kg LBW (kg) = BMI The dose per LBW was multiplied by LBW to identify the dose expected to lead to protective steady-state serum folate levels. The study was approved by the Research Ethics Board of The Hospital for Sick Children in Toronto. RESULTS The dose per kilogram LBW was found to correlate strongly with estimated steady-state serum folate levels (R 2 = 0.96) (Figure 1). Using this regression line, the average dose per kilogram LBW that would lead to steady-state serum folate concentrations of 15.9 nmol/l was identified as mg/kg LBW. A table was created presenting the BMI of women at various weights (45 to 150 kg) and heights (1.44 to 1.96 m). After calculating the LBW for each individual at a given weight and height, the LBW was multiplied by mg/kg LBW to find the expected daily dose of folic acid that would lead to protective steadystate serum folate levels (Figure 2). DISCUSSION While maternal obesity has been established as a risk factor for NTD-affected pregnancies, the underlying etiology remains unknown. It has been hypothesized that folate deficiency in obese individuals may play a role in the increased risk among this population. Accordingly, the Society of Obstetricians and Gynaecologists of Canada and the Motherisk Program have recommended that obese women of childbearing age supplement with 5.0 mg of folic acid daily three months prior to and throughout the first trimester of pregnancy. 9 These recommendations, however, were based on the knowledge that folate deficiency associated with these at-risk populations can increase the risk for NTDs. It will be important to confirm whether an elevated folic acid dose for these individuals can effectively reduce the risk for major malformations. In a recent study, we have shown that 90% of the variability in folic acid levels is explained by LBW rather than TBW. 8 Using the dose per kilogram LBW, we calculated the daily folic acid dose that would be estimated to lead to protective serum folate levels for individuals at a given weight and height. The findings indicate that, on the whole, obese individuals require only a slightly higher dose based on LBW (approximately 0.3 to 0.5 mg) than normal-weight individuals (approximately 0.2 to 0.4 mg), since differences in LBW are not as extensive as those in TBW across a wide BMI range. As dosing is based on LBW rather than TBW, folic acid requirements appear to be more closely tied to differences in height than in weight. For example, a normal-weight woman with a weight of 80 kg and height of 1.90 m would require a dose of 0.38 mg. However, 376 APRIL JOGC AVRIL 2012

4 Dosage Requirements for Periconceptional Folic Acid Supplementation: Accounting for BMI and Lean Body Weight Figure 2. Estimated daily folic acid dose required to maintain serum folate status 15.9 nmol/l for individuals at given weight and height Height (m) Weight (kg) Underweight Normal Weight Overweight Obese Underweight (BMI 18.4 kg/m 2 ) Normal weight (BMI 18.5 to 24.9 kg/m 2 ) Overweight (BMI 25.0 to 29.9 kg/m 2 ) Obese (BMI 30.0 kg/m 2 ) an obese woman with a weight of 110 kg and height of 1.46 m would only require a dose of 0.34 mg. Most notably, our results strongly suggest that folate deficiency may not explain the increased risk for NTD among obese individuals. According to our findings, those individuals at the upper extremes of obesity would require a daily dose of approximately 0.4 mg to reach protective folate levels. However, as previously mentioned, studies that identified an increased risk for NTD-affected pregnancies among obese mothers found the risk remained even after supplementation with folic acid. As general supplementation guidelines have always recommended a folic acid dose of at least 0.4 mg daily, our data would suggest that these individuals were likely supplementing at sufficient levels. Consequently, these results demonstrate that considering pharmacokinetic variabilities only, periconceptional guidelines already recommend adequate folic acid supplementation to obese individuals. It is possible that obese women need higher levels of folic acid to overcome the metabolic causes of spina bifida. It remains possible that the increased risk for NTDs among obese mothers is related to elevations in LBW, which are more pronounced for taller individuals classified as obese. As can be noted in Figure 2, daily folic acid doses approaching 0.5 mg would be required for obese women 1.80 m in height. Furthermore, results obtained by Werler and colleagues appeared to indicate a non-significant trend towards an elevated NTD risk among taller individuals. 5 However, this does not account for the fact that the NTD risk was found consistently to rise with BMI, with morbidly obese individuals at the highest risk. Our study does have several limitations. First, steady-state serum folate concentrations were estimated from singledose pharmacokinetic data. Actual steady-state data should be established prior to changing current supplementation guidelines. Second, while our data would indicate that current folic acid supplementation recommendations during the periconceptional period are sufficient for obese individuals, it is conceivable that a functional deficiency exists. Obese women have higher incidences of gestational APRIL JOGC AVRIL

5 diabetes, insulin resistance, elevated testosterone levels, and other metabolic disorders, which may increase NTD risk via unrecognized folate interactions. 10,11 Further studies must investigate whether the pharmacodynamics of folic acid are altered in obese individuals, or if bodily stores of folate are directed in ways that may result in fetal deficiency. It remains possible, however, that supratherapeutic levels of folic acid may attenuate these risks. Our study is based on the assumption that achieving serum folate concentrations of 15.9 nmol/l will lead to a sufficient reduction in NTD risk among obese women of childbearing age. This premise may not necessarily be accurate. The initial study data upon which Daly and colleagues arrived at their conclusions regarding blood folate status were collected from a population of pregnant women in Ireland between 1986 and Although participant information regarding weight or BMI was not provided, there is little reason to believe that the study was conducted within a largely obese sample. Thus, it may not be suitable to generalize these results to obese women. Additionally, Daly et al. were unable in that study to correlate further increases in folate status with the risks for NTDs. 8 It is possible that increases in serum folate concentrations beyond 15.9 nmol/l will lead to a further reduction in NTD risk. This possibility, if true, would justify elevating the dosage guidelines for non-obese as well as for obese individuals. A 2005 Canadian Community Health Survey found only 57.7% of women supplement with folic acid for at least three months prior to pregnancy. 12 A recent study in the United States indicated that obese women of childbearing age are 24% less likely to supplement with folic acid daily, even after controlling for advice from a health care provider and the knowledge that folic acid prevents certain birth defects. 13 As adherence appears to be reduced in the obese population, higher doses of folic acid may be necessary to ensure a protective folate status is maintained despite missed doses. Furthermore, because 39% to 57% of pregnancies in Canada and the US are unplanned, 14 higher doses may be required to more rapidly achieve a protective folate status prior to neural tube closure. CONCLUSION Our results suggest that the association between obesity and NTD risk may not be related to the failure of folate supplementation in obese women to achieve the generally accepted protective level. It is possible that obese women need higher levels of folic acid to overcome the metabolic causes of neural tube defects. Based on dosing folic acid per kilogram LBW, current guidelines appear to satisfy requirements even for those in the upper BMI categories. It is important to note that present trends in supplementation rates among women of childbearing age warn against altering guidelines based on this information. ACKNOWLEDGEMENT Source of funding: Duchesnay Inc. (Blainville, Quebec). REFERENCES 1. Rasmussen SA, Chu SY, Kim SY, Schmid CH, Lau J. Maternal obesity and risk of neural tube defects: a metaanalysis. Am J Obstet Gynecol 2008;198: Waller DK, Mills JL, Simpson JL, Cunningham GC, Conley MR, Lassman MR, et al. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol 1994;170: Shaw GM, Velie EM, Schaffer DM. Risk of neural tube defect-affected pregnancies among obese women. JAMA 1996;275: Watkins ML, Scanlon KS, Mulinare J, Khoury MJ. Is maternal obesity a risk factor for anencephaly and spina bifida? Epidemiology 1996;7: Werler MM, Louik C, Shapiro S, Mitchell A. Prepregnant weight in relation to risk of neural tube defects. JAMA 1996;275: Mojtabai R. Body mass index and serum folate in childbearing age women. Eur J Epidemiol 2004;19: Stern SJ, Matok I, Kapur B, Koren G. A comparison of folic acid pharmacokinetics in obese and non-obese women of childbearing age. Ther Drug Monit 2011;33: Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274: Wilson RD, Johnson JA, Wyatt PR, Allen V, Gagnon A, Langlois S, et al.; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada and The Motherisk Program. Joint SOGC-Motherisk Clinical Practice Guideline, No. 201, December Pre-conceptional vitamin/ folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 2007;29: Kissebah AH, Peiris AN. Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1989;5: Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, JAMA 2003;289: Public Health Agency of Canada. What mothers say: the Canadian maternity experiences survey. Ottawa: PHAC; Case AP, Ramadhani TA, Canfield MA, Beverly L, Wood R. Folic acid supplementation among diabetic, overweight, or obese women of childbearing age. J Obstet Gynecol Neonatal Nurs 2007;36: Forrest JD. Epidemiology of unintended pregnancy and contraceptive use. 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