The impact of not having a ductus arteriosus on clinical outcomes in foetuses diagnosed with tetralogy of Fallot.

BACKGROUND: Foetuses with simple tetralogy of Fallot almost universally have a patent ductus arteriosus. Two recently identified cases had an absent patent ductus arteriosus, requiring emergent intervention at birth. The objective of this study was to determine whether foetuses diagnosed with tetralogy of Fallot and no patent ductus arteriosus have poorer outcomes compared with those with tetralogy of Fallot+patent ductus arteriosus. METHODS: All foetal cases of tetralogy of Fallot between January, 2000 and 2012 were retrospectively identified from The Hospital for Sick Children (Toronto, Canada) database. Cases - tetralogy of Fallot+no patent ductus arteriosus confirmed on postnatal echo - and controls - tetralogy of Fallot+patent ductus arteriosus, matched for gestational age - were identified from prenatal records, and both clinical and echocardiographic data were reviewed. Optimal outcome was defined as valve-sparing repair with no residual lesions. Student's t-tests and Fisher's exact χ2 were used to compare groups. RESULTS: n=115 foetuses were diagnosed with tetralogy of Fallot: 11 (9%) had no patent ductus arteriosus, and were matched to 22 controls - mean gestational age at diagnosis 23.2±4.2 weeks, 23.4±6.6 weeks, respectively. Cases had a higher proportion of right aortic arches (64% versus 14%, p<0.001). Foetal and postnatal echocardiographic data did not reveal significant differences in branch pulmonary artery sizes, pulmonary valve sizes, or ventricular function. No differences were identified for cyanosis at birth (2/10 versus 7/20, p=0.67), or catheter intervention (5/10 versus 4/22, p=0.12). Optimal outcome rates were similar between cases and controls (4/11 (36%) versus 5/21 (24%), p=0.68). CONCLUSIONS: The patent ductus arteriosus does not appear to have an impact on clinical outcome in foetuses with tetralogy of Fallot.

Dosage requirements for periconceptional folic acid supplementation: accounting for BMI and lean body weight.

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.

A comparison of folic acid pharmacokinetics in obese and nonobese women of childbearing age.

BACKGROUND: Although maternal folate deficiency during the periconceptional period represents a major risk factor for neural tube defects, obesity has been recognized as an additional risk factor. Studies have identified an increased risk for neural tube defect-affected births among obese mothers even after adjusting for folic acid supplementation. However, although folic acid intake may have been at the recommended dose in these samples, blood folate concentrations were not monitored to ensure that protective levels were reached. Hence, there is a need to compare folic acid pharmacokinetics in obese and nonobese women of childbearing age. METHODS: Healthy obese (n=12) and nonobese (n=12) women of childbearing age volunteered to participate. Each obese participant was matched to a nonobese participant and assigned an equivalent dose of folic acid per kilogram body weight. Folic acid was orally administered after a 6-hour fast, and blood samples were taken over a 10-hour period to evaluate pharmacokinetic parameters. RESULTS: Area under the time-concentration curve (AUC) was found to be significantly higher in the obese group (P=0.008). Defining AUC as a function of dose per kilogram lean body weight (LBW) was found to be a stronger predictor than dose per kilogram total body weight (r=0.90 and 0.76, respectively). CONCLUSIONS: This indicates that the body tightly controls systemic exposure to folic acid, with 90% of the variability in AUC controlled by the dose per kilogram LBW. Periconceptional supplementation recommendations may need to be adjusted to account for LBW differences in the obese population.

Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis.

Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms "folic acid," "folate," "colorectal cancer," "methylenetetrahydrofolate reductase," "MTHFR." Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95-1.10) and for 677TT versus CC was 0.88 (95% CI 0.80-0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56-0.89) and the 677TT genotype 0.63 (95% CI 0.41-0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes.

Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis.

INTRODUCTION: Folic acid fortification and supplementation to prevent neural tube defects has led to concerns regarding increased risk of colorectal cancer. The results of existing studies have been inconclusive. The purpose was to examine the relationship between level of folate intake and the incidence of colorectal cancer. METHODS: A systematic review and meta analysis were conducted. MEDLINE, Embase, and SCOPUS were searched from inception to October 2009 with the following search terms "folic acid," "folate", "colorectal cancer," "colon neoplasms," rectal neoplasms." Observational studies in adult populations were included that defined levels of folate intake and incidence of colorectal cancer. RESULT: Out of 6427 references, 27 studies met our inclusion criteria. The summary risk estimate for case control studies comparing high versus low total folate intake was 0.85 (CI 95% 0.74-0.99) with no significant heterogeneity among studies. Similarly, for cohort studies, the resulting summary risk estimate for high versus low dietary folate intake was 0.92 (CI 95% 0.81-1.05) with no significant heterogeneity. However, defining what represents a higher intake of folic acid is difficult as there is variability in the upper limit of folic acid intake used in the studies. DISCUSSION: These results suggest that higher folate intake levels offer a reduction in one of the perceived risks associated with developing colorectal cancer. These data can serve to help reassure women planning a pregnancy to increase folic intake during the preconception period to levels sufficient to prevent neural tube defects.