Application of the Dietary Reference Intakes in developing a recommendation for pregnancy iron supplements in Canada 1 3

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1 Application of the Dietary Reference Intakes in developing a recommendation for pregnancy iron supplements in Canada 1 3 Kevin A Cockell, Doris C Miller, and Hélène Lowell ABSTRACT Background: For many pregnant Canadian women, usual iron intakes from food appear to be inadequate compared with Dietary Reference Intake requirement estimates. Objective: Dietary intake modeling was undertaken to determine an amount of iron supplementation that would confer acceptably low prevalence of apparently inadequate and apparently excessive intakes. Design: The distribution of usual dietary iron intakes was estimated with the use of 24-h recalls from pregnant women aged y in the Canadian Community Health Survey, Cycle 2.2. The prevalence of usual intakes below the Estimated Average Requirement for pregnancy (22 mg/d) or above the Tolerable Upper Intake Level (45 mg/d) was estimated. Iterative modeling with incremental iron supplement was performed to determine a suitable supplement amount. Because the sample of pregnant women was small (148 day 1 recalls), estimates of the tails of the distributions had large SDs, and supporting analyses based on intake data from nonpregnant women (4540 day 1 recalls) were made. Results: Daily supplementation shifted the intake distribution curve without changing its shape. Supplementation with 16 mg iron/d was consistent with low (,3%) prevalence of apparently inadequate intakes. This amount of supplementation should not be associated with an increase in apparently excessive intakes by pregnant women in this population. Conclusions: On the basis of Dietary Reference Intakes, an iron supplement of 16 mg/d throughout pregnancy is justified as both efficacious and safe for healthy women living in Canadian households. This does not preclude the need for therapeutic iron doses for some individuals on the basis of iron status. The method can be applied to other populations if suitable baseline iron intake data are available. Am J Clin Nutr 2009;90: INTRODUCTION Health Canada, Canada s federal health department, is currently reviewing its prenatal nutrition guidelines, which were last published in 1999 (1). Recommendations on nutrients of special concern, including iron, are being reviewed and updated to ensure they are consistent with the Dietary Reference Intakes (DRIs), in keeping with Health Canada s commitment to use the DRIs to inform its nutrition policies and guidelines. In the case of iron, it is generally accepted that many women who consume common diets in North America would have difficulty obtaining sufficient iron to meet the increased requirements of pregnancy from diet alone. Supplemental iron has been recommended for pregnant women in previous guidelines, including Health Canada s prenatal nutrition guidelines (1) and in the DRI report for iron (2). Many different approaches have been taken in determining an appropriate amount of iron supplementation for pregnant women. One common approach has been to urge supplementation at a dose equal to the Recommended Dietary Allowance for iron (3, 4). Others have recommended amounts of iron supplements that were seen to be associated with higher, if not the highest possible, maternal hemoglobin concentrations (5, 6). Few if any of these approaches had attempted to take into account the iron ingested in foods, although the recommendations from Health Canada s Scientific Review Committee for the 1990 Nutrition Recommendations for Canadians considered iron intake that comprised 13 mg from diet plus supplements of 5 and 10 mg/d in the second and third trimesters (7). Early recommendations did not appear to show major concerns about possible detrimental effects of high amounts of iron supplementation other than hemochromatosis, although warnings about possible harm of excess supplementation appeared by 1990 (4). With the publication of the DRIs for iron (2) and the separate detailed report on the application of the DRIs in dietary assessment (8), and with the availability of data from the Canadian Community Health Survey (CCHS) Cycle 2.2 Nutrition (9, 10), there is opportunity to consider the introduction of a new approach to establishing an appropriate, adequate, and safe amount of prenatal iron supplementation to be recommended for use by the general public. Such an approach is presented here and is built on recognition of the real purpose of nutrient supplements: to fill the gap between nutrient intake from food and estimated need (11). The specific objective of the present work was to apply the DRIs for iron in determining an amount of iron supplementation that could be recommended by Health Canada to pregnant women in the general healthy population of Canada. In developing such a recommendation, the distribution of usual intakes 1 From the Nutrition Research Division, Food Directorate (KAC) and the Office of Nutrition Policy and Promotion (DCM and HL), Health Products and Food Branch, Health Canada, Ottawa, Canada. 2 Supported by Health Canada. 3 Address correspondence to KA Cockell, Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, 2203E Banting Research Centre, 251 Sir Frederick Banting Driveway, Ottawa, ON, Canada K1A 0K9. kevin_cockell@hc-sc.gc.ca. Received January 29, Accepted for publication July 24, First published online August 19, 2009; doi: /ajcn Am J Clin Nutr 2009;90: Printed in USA. Ó 2009 American Society for Nutrition 1023

2 1024 COCKELL ET AL of iron from food in this population was to be taken into account. The recommended supplement amount should complement the iron already ingested in food, with a combined (food + supplement) iron intake sufficient to meet the needs of almost all of the consumers and not so high as to potentially do harm to users. The general method presented here would be applicable to any population in which suitable baseline iron intake data and estimates of both requirements and Tolerable Upper Intake Levels (UL) are available. SUBJECTS AND METHODS Data source Data from the second cycle of Statistics Canada s CCHS (CCHS 2.2), collected between January 2004 and January 2005, were used (9, 10). The total survey sample (males and females, all ages) consisted of 35,107 respondents living in private residences in Canada s 10 provinces. Excluded by sample design were individuals in Canada s 3 northern territories and individuals either with no fixed address or living in institutions (9, 10). The original data were collected under the authority of the Statistics Act of Canada. The Statistics Canada CCHS 2.2 Share File used in the present work contains data only for respondents who have agreed to have their information shared with the Survey Share Partners, including Health Canada. Although the CCHS 2.2 Share File contains data for 95% of the respondents represented in the Master Files, the files are weighted so that the Master File and the Share File produce comparable results (9). The Share File, used in the present work, included estimated day 1 food intakes from 24-h recalls of 148 pregnant women aged y and 4540 nonpregnant women in the same age range. Repeat intake estimates (ie, day two 24-h recalls) were available for subsamples of these groups (55 pregnant women and 1474 nonpregnant women, aged y). Distributions of usual dietary iron intake (from food alone) were estimated from these 24-h recall data as described below. Only statistical aggregate data are included in this report, which cannot be used directly or indirectly to identify any person, business, organization, or specific product, in accordance with agreements between Health Canada and Statistics Canada on the use of the CCHS 2.2 Share File data. Description of the general approach The prevalence of apparently adequate iron intakes was assessed by estimating the proportion of women with intakes below the Estimated Average Requirement (EAR) for iron in pregnant women, 22 mg/d. This approach, referred to as the EAR cut-point method, has been described and validated by a DRI committee (8) as an extension and enhancement of the probability approach described much earlier (12). There are 3 conditions that must be met before the EAR cut-point method can be used (8): The requirement distribution must approach symmetry. This is the specific condition that is not met for iron in nonpregnant women, because menstrual iron losses are not symmetrically distributed (2). However, pregnant women are not menstruating, and the distribution of their iron requirements approaches symmetry. This has been confirmed through a Monte Carlo simulation of the distribution of requirements among 10,000 individuals, using the components of requirement as defined by the DRI panel. The same approach was used by the DRI panel in developing iron requirement distributions for all other groups except infants and very young children (2). The derived requirement distribution curve was demonstrably symmetrical and very close to normal (GH Beaton, personal communication, 2008). The variability of intake must exceed the variability of requirements. It is generally accepted that the distribution of intakes among free-living individuals is more variable than the distribution of requirements (8). In the case of pregnant women aged y in the CCHS 2.2 dataset, the SD of the estimated distribution of usual iron intakes was 5.5 mg/d. The estimated SD of iron requirements in the DRI report and in the Monte Carlo modeling referred to earlier was 2.5 mg/d. Intake and requirement must be independent of one another or show a low correlation. Although this last condition cannot be directly tested, there is no reason to believe the condition is violated for iron. To assess the prevalence of intakes that might be associated with detrimental effects of higher exposure, the DRI estimate of the UL (45 mg/d) was applied. The general modeling approach adopted in this work was to add successive increments of iron to the reported food iron intakes and then estimate the new distribution of usual intakes. For modeling purposes, 2 assumptions were made: 1) all women consumed the same amount of supplement each day and 2) the total daily intake of iron was the sum of the dietary intake plus the modeled supplemental iron. For each distribution curve, intakes and proportions of individuals who would be expected to have intakes below the EAR or above the UL were evaluated. Clearly, the desirable amount of supplementation would be one that was associated with the lowest possible proportions for both. A practical goal was set as achieving expected prevalence,2 3% for apparently inadequate intakes, without raising the prevalence of apparently excessive iron intakes above the UL. This working goal was consistent with the approach discussed in both DRI reports on application (8, 13) and with targets set by Health Canada in developing the new Food Guide for Canadians (14). The number of pregnant women included in the CCHS 2.2 survey was small (148 in the dataset used), and, as a consequence, the usual iron intake estimates derived from this group had large SDs. As supporting evidence to help inform the decision process, analyses based on the much larger sample of nonpregnant women were undertaken, with the application of the EAR and UL values for pregnant women. There were 4540 day one 24-h recalls and 1474 day 2 recalls in this set. The focus of these supporting analyses was the behavior of the distribution tails and successive prevalence estimates with incremental iron supplement additions to the model. Three operating goals for this work were established as follows: 1) The distribution of dietary intake of iron by pregnant women in Canada would be taken into account. 2) The total iron intake (diet + supplement) should be sufficient to meet the needs of almost all (defined in the DRI process as 97 98%) pregnant women in the general population.

3 MODELING OF IRON SUPPLEMENTATION IN PREGNANCY ) The iron intake (diet + supplement) should not be associated with an increase in prevalence of excess intake for pregnant women in the general population. Estimating the distribution of usual iron intakes of pregnant women in Canada and prevalence of inadequacy and potential excess With the 148 day one and 55 day two 24-h dietary recalls of daily iron intake by pregnant women aged y from the CCHS 2.2 Share File, the baseline usual dietary iron intake distribution was estimated with the approach developed by Nusser et al (15). This approach was implemented with the use of Software for Intake Distribution Estimation (SIDE) developed at and distributed by the Iowa State University. SIDE version 1.11, written in SAS/IML, was used. SIDE is a generalized software product with default settings for some variables. All analysis variables were set to the default values. The effect of day-to-day variation in eating patterns was adjusted for in the analyses. In addition to the estimate of the mean, the percentiles of the usual intake distribution, and the prevalence estimates, the variance of these estimates was also calculated. The CCHS 2.2 has a complex survey design and therefore no mathematical formula exists to directly calculate the sampling variability. A replication method, bootstrap variance estimation, was used to estimate the variances (16, 17). The mean of the usual intakes was equal to the mean of the daily intake using day 1 recalls only. Using 500 bootstrap weights provided by Statistics Canada, 500 bootstrap estimates of the mean were obtained. Finally, the variance was calculated as the mean of the squared differences between the 500 individual bootstrap estimates and the mean of 500 bootstrap estimates. This provided an estimate of the variance of the mean. To estimate the variance of the percentiles and prevalence estimates, a slightly different method was used. Because SIDE may fail when using some of the 500 bootstrap weights, there may not be all 500 percentile estimates and prevalence estimates available. Instead of using the mean of the nonfailed bootstrap estimates in the variance formula, the variance was calculated as the mean of the squared differences between the nonfailed bootstrap estimates and the root estimate (the estimate based on the design weights). This accounted for some of the bias caused by SIDE failing for some bootstrap weights. Modeling approach for determining a suitable amount of iron supplementation for Canadian women during pregnancy Initially, 2 mg supplemental iron was added to each individual s day 1 and day 2 intakes, and the prevalence of both apparent inadequacy and excess was calculated. These steps were repeated in increments of 1 or 2 mg of supplemental iron until a low prevalence of apparent inadequacy (,3%) was achieved. The prevalence of potentially excessive intakes was then evaluated by comparison with the UL. In keeping with Statistics Canada and Health Canada practices for reporting of data derived from the CCHS 2.2 dataset (9,10),someprevalence estimates with higher uncertainty terms must be interpreted with caution or have been suppressed (as described in the footnotes to Tables 2 and 3). Given the small number of pregnant women available in the CCHS 2.2 dataset, we decided to perform, as supporting evidence, analyses with the use of intake data from nonpregnant women aged y. For these supporting analyses, the cutoff used was again the EAR for pregnant women (22 mg/d). This supporting modeling exercise effectively took advantage of the larger dataset of iron intake data and treated it as if it represented intakes of pregnant women. Analytic methods were as described earlier. Among nonpregnant women aged y, the SD of the estimated distribution of usual iron intakes was 3.6 mg/d, again showing higher variability in comparison to the estimated SD of iron requirements in the DRI report of 2.5 mg/d, so that the EAR cut-point method conditions were satisfied. RESULTS By supplementing every woman in the population with the same amount of iron every day, the intake distribution curve would be shifted to the right without changing its shape, as shown with the use of data from the CCHS 2.2 in nonpregnant Canadian women aged y (Figure 1). The baseline intake distribution curve (at the left side of the figure) is the same shape as the curves with 16 or 20 mg/d iron supplements added. Similar graphs based on data from pregnant women have been examined, and, although the small sample size (148 day one and 55 day two 24-h recalls) yielded curves with greater uncertainty terms, the same general pattern of curve shift without shape change was noted (data not shown). Comparison of iron intake estimates at specific percentiles in the distributions for pregnant and nonpregnant women aged y in the CCHS 2.2 dataset showed that the usual daily iron intake estimates for pregnant women were higher than the corresponding values for nonpregnant women (Table 1). However, the differences were not consistent across the distribution range. At the lower tail of the usual iron intake distributions the 95% CIs overlapped. Thus, in evaluating the prevalence of apparent inadequacy (at the lower tail of the distribution), we concluded that results from the modeling done with intake data from nonpregnant women reflect a similar situation in pregnant women. At the upper tail of the distribution curves, the 95% CIs of the percentile estimates did not overlap (Table 1). At baseline, without added supplement, the prevalence of apparently inadequate iron intakes from diet alone by pregnant women in Canada was very high, estimated at 85% in the present modeling exercise (Table 2). With incremental iron supplementation, the prevalence of inadequate intakes declined. In the modeling with pregnant women, excessive statistical uncertainty caused the suppression of prevalence estimates with iron supplement amounts of mg/d. With 16 mg supplemental iron/d, it was possible to conclude that the prevalence of apparently inadequate iron intakes for pregnant Canadian women should be,3% (Table 2). The larger sample size available for nonpregnant women, modeled with the EAR value for pregnant women, provided supporting evidence that the prevalence of apparently inadequate iron intakes would fall,3% at a supplement amount between 15 and 16 mg/d. An estimation of the prevalence of apparently excessive intakes proved to be more difficult with the available data. With the use of the small dataset for pregnant women, baseline prevalence of intakes greater than the UL for iron was estimated to be,1% (Table 3). With supplement amounts ranging from 14 to 24 mg/d, excessive statistical uncertainty caused suppression of the prevalence estimates for apparently excessive

4 1026 COCKELL ET AL FIGURE 1. Population distribution curves of usual intakes of iron from food and modeled addition of iron supplement for nonpregnant women aged y in the general household population of the 10 provinces of Canada (excluding federal territories) in 2004 (n = 4540 day 1 intake estimates, 1474 day 2 intake estimates), compared with the Estimated Average Requirement (EAR; 22 mg/d) and Tolerable Upper Intake Level (UL; 45 mg/d) values for pregnant women aged y. The data contained in this figure are based on the Canadian Community Health Survey Cycle 2.2 on Nutrition, Statistics Canada, intakes. With 27 mg iron supplement/d, the estimated prevalence of intakes above the UL emerged as % of the pregnant population. With the larger dataset for nonpregnant women, the prevalence of intakes above the UL was estimated to be,1% up to supplement amounts of 20 mg/d, and with 24 mg iron supplement/d the prevalence of apparently excessive intakes was,3%. However, because of the separation in the upper tail of the distributions in which intakes of pregnant women were higher than those of nonpregnant women, and given that statistical uncertainty did not allow for estimating the prevalence of intakes above the UL for pregnant women with iron supplement amounts ranging from 14 to 24 mg/d, it was not possible to unequivocally establish the amount of iron supplementation that would be associated with an apparently excessive intake prevalence of,3%. Within these limitations, the totality of the available evidence suggests that an iron supplement of 16 mg/d should yield low prevalence of apparently inadequate intakes TABLE 1 Baseline distributions of usual iron intakes from food alone among pregnant and nonpregnant women aged y in the general household population of the 10 provinces of Canada (excluding federal territories) 1 Pregnant women (n = 148) Nonpregnant women (n = 4540) mg/d mg/d Mean 15.8 (14.1, 17.5) 12.4 (12.1, 12.7) 5th Percentile 9.1 (6.2, 12.0) 7.4 (7.0, 7.8) 10th Percentile 10.0 (7.2, 12.8) 8.3 (7.9, 8.7) 25th Percentile 11.9 (9.1, 14.7) 10.0 (9.6, 10.3) 50th Percentile 15.3 (12.9, 17.8) 12.1 (11.7, 12.4) 75th Percentile 19.7 (16.2, 23.2) 14.6 (14.1, 15.1) 90th Percentile 23.3 (18.9, 27.7) 17.2 (16.5, 18.0) 95th Percentile 25.6 (20.3, 30.9) 19.1 (18.1, 20.0) 1 Values are means; 95% CIs in parentheses. Data are based on the Canadian Community Health Survey Cycle 2.2 on Nutrition, Statistics Canada, and should not increase the prevalence of apparently excessive intakes for pregnant women in the general healthy population of Canada. DISCUSSION The baseline intake distribution modeling shown here with the use of data for pregnant Canadian women aged y supports the generally accepted notion that iron intakes from food alone do not meet the needs for pregnancy in a substantial proportion of the population. Supplementation has been suggested to be a suitable approach to making up the difference between usual dietary intakes and estimated nutritional needs of specific population groups, such as iron for pregnant women (2, 11). In offering nutritional guidelines for pregnant women in the general Canadian population, Health Canada can advocate iron supplementation of 16 mg/d as being safe and efficacious. It is important to note that this refers to the total of all sources of supplemental iron taken; it is not a recommended addition to other existing iron-containing supplements. The approach used to determine this amount of supplementation is consistent with the intended application of the DRIs and has been designed to minimize both the risk of apparently inadequate intakes and the risk of potentially excessive intakes. The survey data used in these modeling exercises included women who were identified as members of households in the 10 provinces of Canada, thereby excluding those in institutions and those with no fixed address (9). Furthermore, the 3 northern federal territories of Canada were not included in the CCHS 2.2 survey, and with that exclusion some of the indigenous population of Canada. Interpretation and application of these analyses must therefore be confined to women in the household population of the 10 provinces of Canada. The same analytic approach could be applied to other population groups if intake data become available. There is no reason to believe that iron requirements are different for the excluded groups of Canadian

5 MODELING OF IRON SUPPLEMENTATION IN PREGNANCY 1027 TABLE 2 Estimated prevalence of inadequate iron intakes determined from usual intakes from food and modeled addition of iron supplementation among pregnant women (n = 148 and 55 for day 1 and day 2 intake estimates, respectively) and nonpregnant women (n = 4540 and 1474 for day 1 and day 2 intake estimates, respectively), aged y in 2004, living in the general household population of the 10 provinces of Canada (excluding federal territories) compared with the Estimated Average Requirement (EAR; 22 mg/d) for pregnant women aged y 1 Amount of iron addition (intake) Pregnant women with less than EAR for pregnancy Nonpregnant women with less than EAR for pregnancy % % Baseline Supplement + 2 mg/d ND + 4 mg/d ND + 6 mg/d ND + 8 mg/d ND + 10 mg/d 5 ND + 12 mg/d 5 ND + 14 mg/d mg/d mg/d, mg/d,3 6, mg/d, mg/d mg/d mg/d mg/d Data are based on the Canadian Community Health Survey Cycle 2.2 on Nutrition, Statistics Canada, ND, not determined. 2 Usual iron intake from diet alone. 3 Mean 6 SD (all such values). 4 CV of %; interpret with caution. 5 CV. 33.3% and 95% CI not entirely between 0% and 3%; data suppressed. 6 CV. 33.3% and 95% CI entirely between 0% and 3%; interpret with caution. 7 SD, 0.1%. women, but usual iron intakes might be substantially different from those seen in the general population. In addition, it must be recognized that the general population guidelines issued by Health Canada are designed to be preventive in nature. Some pregnant women will present situations in which iron therapy, involving higher amounts of administration, may be indicated. It is assumed that pregnant women in the general population of Canada have access to prenatal services and that therapeutic amounts of iron can and will be prescribed on clinical indication. Therefore, there is no reason to urge therapeutic amounts of iron intake for all pregnant women in Canada. This work addresses the amount of iron supplementation that could and should be promoted in Canada as safe and adequate for pregnant women. The expected prevalence of apparent inadequacy and potential excess presented here refer to women who take the supplement daily. The choice of an appropriate supplement amount does not diminish the need for educational and other activities designed to encourage use of the supplement. There is one aspect of the proposed amount of supplementation that might favorably affect compliance. The UL for iron was set on the basis of reported gastrointestinal side effects (2). If the TABLE 3 Estimated prevalence of excessive intakes determined from usual intakes of iron from food and modeled addition of iron supplementation among pregnant women (n = 148 and 55 for day 1 and day 2 intake estimates, respectively) and nonpregnant women (n = 4540 and 1474 for day 1 and day 2 intake estimates, respectively), aged y in 2004, living in the general household population of the 10 provinces of Canada (excluding federal territories) compared with the Tolerable Upper Intake Level (UL; 45 mg/d) for women aged y 1 Amount of iron addition (intake) Pregnant women with greater than UL for adults % Nonpregnant women with greater than UL for adults % % % Baseline 2, ,5 Supplement +14 mg/d 6, mg/d 6, mg/d 6, mg/d 6, mg/d mg/d mg/d mg/d Data are based on the Canadian Community Health Survey Cycle 2.2 on Nutrition, Statistics Canada, Usual iron intake from diet alone. 3 CV. 33.3% and 95% CI entirely between 0% and 1%; interpret with caution. 4 Mean 6 SD (all such values). 5 SD, 0.1%. 6 CV. 33.3% and 95% CI not entirely between 0% and 3%; data suppressed. 7 CV of %; interpret with caution. expected prevalence of intakes above the UL is held as low as possible, such side effects of supplementation may be reduced, and compliance with daily use of the supplement may be enhanced. The present recommendation of supplementation with 16 mg iron/d during pregnancy is similar to the results of a randomized clinical trial wherein iron supplementation of 20 mg/d from week 20 of pregnancy until delivery was shown to be effective in reducing the incidence of maternal iron deficiency and anemia, compared with a matched placebo, without causing any noticeable side effects (18). The results of the intake modeling exercise presented here do not fundamentally disagree with these clinical observations. It is of interest to note that, if past practices are continued and supplements equal to the Recommended Dietary Allowance for pregnant women (27 mg/d) are used, the prevalence of apparently inadequate intakes would indeed be very close to zero, but the expected prevalence of potentially excessive intakes would be elevated. If there are major changes in food fortification practices affecting the usual dietary intakes of pregnant women, the recommended amount of iron supplementation would need to be reviewed and possibly adjusted. The approach outlined in this work would be appropriate to that task, assuming that the existence of suitable intake data reflected the changes in the food supply. The present, innovative approach to evaluation of a desirable amount of iron supplementation, taking into account the distribution of usual iron intakes from food in the target population, is a generalizable model of DRI application.

6 1028 COCKELL ET AL We thank George H Beaton, Emeritus Professor, Department of Nutritional Sciences, University of Toronto, who provided expert advice on the methodology for the modeling of supplement amount and dietary iron adequacy. The authors responsibilities were as follows All authors contributed to conception, design, conduct, and interpretation of this work. KAC, DCM, and HL are employees of Health Canada. None of the authors declared a conflict of interest. REFERENCES 1. Health Canada. Nutrition for a healthy pregnancy national guidelines for the childbearing years. Ottawa, ON, Canada: Ministry of Public Works and Government Services Canada, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc. Washington, DC: National Academy Press, American College of Obstetricians and Gynecologists. Standards for obstetric-gynecologic services. 6th ed. Washington, DC: American College of Obstetricians and Gynecologists, Food and Nutrition Board, Institute of Medicine. Nutrition during pregnancy: weight gain, nutrient supplements. Washington, DC: National Academy Press, Fairbanks VF. Iron in medicine and nutrition. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. 8th ed. Malvern, PA: Lee and Febiger, 1994: McGanity WJ, Dawson EB, Fogelman A. Nutrition in pregnancy and lactation. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. 8th ed. Malvern, PA: Lea and Febiger, 1994: Health Canada. Nutrition recommendations: the report of the Scientific Review Committee. Ottawa, ON, Canada: Ministry of Supply and Services Canada, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: applications to dietary assessment. Washington, DC: National Academy Press, Health Canada. Canadian Community Health Survey, Cycle 2.2, Nutrition (2004). A Guide to Accessing and Interpreting the Data. Office of Nutrition Policy and Promotion, Health Products and Food Branch, Health Canada. Ottawa, ON, Canada: Publications, Health Canada, Available from: commun/index_e.html (cited 21 July 2008). 10. Statistics Canada. Canadian Community Health Survey (CCHS) Cycle 2.2 (2004). Nutrition General Health (including Vitamin & Mineral Supplements) & 24-Hour Dietary Recall Components. User Guide. Ottawa, ON, Canada: Publications, Statistics Canada, 2008.Available from: eng.pdf (cited 8 April 2009). 11. L Abbé MR, Cockell KA, Lee NS. Micronutrient supplementation: when is best and why? Proc Nutr Soc 2003;62: Food and Nutrition Board, Institute of Medicine. Nutrient adequacy: assessment using food consumption surveys. Washington, DC: National Academy Press, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: applications in dietary planning. Washington, DC: National Academy Press, Katamay SW, Esslinger KA, Vigneault M, et al. Eating Well with Canada s Food Guide (2007): development of the food intake pattern. Nutr Rev 2007;65: Nusser SM, Carriquiry AL, Dodd KW, Fuller WA. A semiparametric transformation approach to estimating usual daily intake distributions. J Am Stat Assoc 1996;91: Rao JNK, Wu CFJ. Resampling inference with complex survey data. J Am Stat Assoc 1988;83: Yeo D, Mantel H, Liu TP. Bootstrap variance estimation for the National Population Health Survey. Proceedings of the Survey Research Methods Section, American Statistical Association 1999: Available from: at (cited 31 July 2009). 18. Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. Am J Clin Nutr 2003;78: