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1.  Folate1 
Advances in Nutrition  2013;4(1):123-125.
doi:10.3945/an.112.003392
PMCID: PMC3648733  PMID: 23319130
2.  Folate during reproduction: the Canadian experience with folic acid fortification 
Nutrition Research and Practice  2007;1(3):163-174.
Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration
doi:10.4162/nrp.2007.1.3.163
PMCID: PMC2849017  PMID: 20368933
Folic acid; fortification; periconceptional period; pregnancy; lactation
3.  Impact of maternal metabolic abnormalities in pregnancy on human milk and subsequent infant metabolic development: methodology and design 
BMC Public Health  2010;10:590.
Background
Childhood obesity is on the rise and is a major risk factor for type 2 diabetes later in life. Recent evidence indicates that abnormalities that increase risk for diabetes may be initiated early in infancy. Since the offspring of women with diabetes have an increased long-term risk for obesity and type 2 diabetes, the impact of maternal metabolic abnormalities on early nutrition and infant metabolic trajectories is of considerable interest. Human breast milk, the preferred food during infancy, contains not only nutrients but also an array of bioactive substances including metabolic hormones. Nonetheless, only a few studies have reported concentrations of metabolic hormones in human milk specifically from women with metabolic abnormalities. We aim to investigate the impact of maternal metabolic abnormalities in pregnancy on human milk hormones and subsequently on infant development over the first year of life. The objective of this report is to present the methodology and design of this study.
Methods/Design
The current investigation is a prospective study conducted within ongoing cohort studies of women and their offspring. Pregnant women attending outpatient obstetrics clinics in Toronto, Canada were recruited. Between April 2009 and July 2010, a total of 216 pregnant women underwent a baseline oral glucose tolerance test and provided medical and lifestyle history. Follow-up visits and telephone interviews are conducted and expected to be completed in October 2011. Upon delivery, infant birth anthropometry measurements and human breast milk samples are collected. At 3 and 12 months postpartum, mothers and infants are invited for follow-up assessments. Interim telephone interviews are conducted during the first year of offspring life to characterize infant feeding and supplementation behaviors.
Discussion
An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may assist in the development of optimal prevention and intervention strategies and in the protection of nutritionally vulnerable offspring who are at risk for obesity and diabetes later in life.
doi:10.1186/1471-2458-10-590
PMCID: PMC2965719  PMID: 20925937
4.  DoMINO: Donor milk for improved neurodevelopmental outcomes 
BMC Pediatrics  2014;14:123.
Background
Provision of mother’s own milk is the optimal way to feed infants, including very low birth weight infants (VLBW, <1500 g). Importantly for VLBW infants, who are at elevated risk of neurologic sequelae, mother’s own milk has been shown to enhance neurocognitive development. Unfortunately, the majority of mothers of VLBW infants are unable to provide an adequate supply of milk and thus supplementation with formula or donor milk is necessary. Given the association between mother’s own milk and neurodevelopment, it is important to ascertain whether provision of human donor milk as a supplement may yield superior neurodevelopmental outcomes compared to formula.
Our primary hypothesis is that VLBW infants fed pasteurized donor milk compared to preterm formula as a supplement to mother’s own milk for 90 days or until hospital discharge, whichever comes first, will have an improved cognitive outcome as measured at 18 months corrected age on the Bayley Scales of Infant Development, 3rd ed. Secondary hypotheses are that the use of pasteurized donor milk will: (1) reduce a composite of death and serious morbidity; (2) support growth; and (3) improve language and motor development. Exploratory research questions include: Will use of pasteurized donor milk: (1) influence feeding tolerance and nutrient intake (2) have an acceptable cost effectiveness from a comprehensive societal perspective?
Methods/Design
DoMINO is a multi-centre, intent-to-treat, double blinded, randomized control trial. VLBW infants (n = 363) were randomized within four days of birth to either (1) pasteurized donor milk or (2) preterm formula whenever mother’s own milk was unavailable. Study recruitment began in October 2010 and was completed in December 2012. The 90 day feeding intervention is complete and long-term follow-up is underway.
Discussion
Preterm birth and its complications are a leading cause long-term morbidity among Canadian children. Strategies to mitigate this risk are urgently required. As mother’s own milk has been shown to improve neurodevelopment, it is essential to ascertain whether pasteurized donor milk will confer the same advantage over formula without undue risks and at acceptable costs. Knowledge translation from this trial will be pivotal in setting donor milk policy in Canada and beyond.
Trial registration
ISRCTN35317141; Registered 10 August 2010.
doi:10.1186/1471-2431-14-123
PMCID: PMC4032387  PMID: 24884424
Human milk; Donor milk; Neurodevelopment; Very low birth weight infants
5.  Relative bioavailability of iron and folic acid from a new powdered supplement compared to a traditional tablet in pregnant women 
Background
Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence. However, before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women.
Methods
Eighteen healthy pregnant women (24 – 32 weeks gestation) were randomized to receive the supplements in a crossover design. Following ingestion of each supplement, the changes (over baseline) in serum iron and folate over 8 hours were determined. The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 μg folic acid; the tablet contained 27 mg iron from ferrous fumarate and 1000 μg folic acid.
Results
Overall absorption of iron from the powdered supplement was significantly lower than the tablet (p = 0.003). There was no difference in the overall absorption of folic acid between supplements. Based on the differences in the area under the curve and doses, the relative bioavailability of iron from powdered supplement was lower than from the tablet (0.22).
Conclusion
The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports. However, since pills and capsules are known to be poorly accepted by some women during pregnancy, it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose.
Trial Registration
ClinicalTrials.gov NCT00789490
doi:10.1186/1471-2393-9-33
PMCID: PMC2724426  PMID: 19635145
6.  Effect of iron content on the tolerability of prenatal multivitamins in pregnancy 
Background
Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation. In a previous study, suboptimal tolerability was observed among pregnant women taking a large tablet (18 mm × 8 mm × 8 mm) multivitamin with high elemental iron content (60 mg as ferrous fumarate). The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were randomized to commence supplementation with a small-tablet prenatal multivitamin, containing either low or high iron content.
Methods
Pregnant women who called the Motherisk Program (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospective, randomized, open-label, 2-arm study. Women were randomized to take a small-size (16 mm × 9 mm × 4 mm), low elemental iron content (35 mg as ferrous fumarate) multivitamin ('35 mg' group); or a small-size (5 mm radius, 5 mm thickness), high elemental iron content (60 mg as ferrous sulphate) multivitamin ('60 mg' group). Follow-up interviews documented pill intake and adverse events. Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves.
Results
Of 167 randomized women, 92 in the '35 mg' group and 75 in the '60 mg' group were included in the analysis. Despite ideal conditions and regular follow-ups, mean adherence based on pill intake recall, in both groups was approximately 50%. No statistically significant difference was detected in proportions of women who actually started taking either multivitamin. Among those who started, no difference was detected in rates of adherence or reported adverse events.
Conclusion
The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins. Combined with our previous study, tablet size may be the more definitive factor affecting adherence.
doi:10.1186/1471-2393-8-17
PMCID: PMC2405769  PMID: 18482454
7.  How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study 
Background
In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate.
Methods
The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55).
Results
Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, P < 0.001) and RBC (r = 0.36, P < 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 μg/d (3rd and 4th quartile).
Conclusion
Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 μg.
doi:10.1186/1471-2393-7-25
PMCID: PMC2231404  PMID: 17961229
8.  Prevalence and predictors of low vitamin D concentrations in urban Canadian toddlers 
Paediatrics & Child Health  2011;16(2):e11-e15.
OBJECTIVES:
To determine the prevalence of low vitamin D concentrations in a cohort of healthy two-year-old children living in a large Canadian city, and to explore whether body mass index (BMI) and cow’s milk intake are associated with low vitamin D concentrations.
METHODS:
A cross-sectional study was performed on healthy two-year-old children attending a well-child visit in Toronto, Ontario (latitude 43.4°N). Dietary exposures were measured by questionnaire. The primary outcome was the prevalence of low vitamin D concentrations (25-hydroxyvitamin D concentration of lower than 50 nmol/L or lower than 75 nmol/L).
RESULTS:
A total of 91 healthy children 24 to 30 months of age were recruited between November 2007 and May 2008. The prevalence of low vitamin D concentrations (lower than 50 nmol/L) was 32% (29 of 92, 95% CI 22% to 42%) and the prevalence of vitamin D concentrations of lower than 75 nmol/L was 82% (75 of 91, 95% CI 73% to 89%). Using multivariable logistic regression, the odds of vitamin D concentrations being lower than 50 nmol/L decreased by 0.44 (95% CI 0.2 to 0.96) for each additional cup of cow’s milk intake per day and increased by 1.2 to 2.6 per unit BMI depending on BMI level (P=0.07).
CONCLUSIONS:
A total of 30% to 80% of toddlers in the present study’s urban Canadian setting demonstrated low vitamin D concentrations – the highest prevalence of low vitamin D in toddlers outside of Alaska. Modifiable factors associated with low vitamin D were lower cow’s milk intake and higher BMI. The vitamin D status of toddlers in urban Canada may require specific attention.
PMCID: PMC3043048  PMID: 22294872
Obesity; Primary care; Toddlers; Vitamin D
9.  Folate status of the population in the Canadian Health Measures Survey 
Background
Low folate concentrations are inversely associated with birth defects, including neural tube defects, congenital heart disease and oral clefts. Conversely, high folate concentrations may be associated with adverse outcomes, including increased risk of colorectal cancer among those with pre-existing neoplasms. The purpose of our study was to investigate the folate status of a nationally representative sample of Canadians, including a subset of women of childbearing age.
Methods
We examined red blood cell folate concentrations among members of the general population aged 6–79 years (n = 5248) and separately among women of childbearing age (15–45 yr, n = 1162), as recorded by the Canadian Health Measures Survey and measured by immunologic assay. We assessed the data for significant differences by age, sex and socioeconomic status.
Results
Less than 1% of Canadians showed folate deficiency (red blood cell folate < 305 nmol/L) and 40% showed high folate concentrations (> 1360 nmol/L). Among women of childbearing age, 22% showed concentrations below those considered optimal for maximal neural tube defect-risk reduction (< 906 nmol/L). Significant differences by age and socio-economic status, but not sex, were evident in median red blood cell folate concentrations, although concentrations in all groups exceeded recommended levels. No differences by age or income were found among women of child-bearing age.
Interpretation
Folate deficiency is virtually nonexistent in the Canadian population, although high folate concentrations are evident. Additional research is needed to better understand the determinants of red blood cell folate among women of childbearing age who have concentrations below levels that are maximally protective against neural tube defects. Ongoing monitoring of the folate status of Canadians and the relationship between red blood cell folate and health outcomes is warranted.
doi:10.1503/cmaj.100568
PMCID: PMC3033951  PMID: 21149516

Results 1-9 (9)