NTD prevention strategy in Nuevo León, Mexico

Transcription

1 NTD prevention strategy in Nuevo León, Mexico Dr. Laura Martínez de Villarreal Genetics Department Hospital Universitario Dr. Jose E. González Universidad Autonoma de Nuevo Leon Mexico

2 Introduction Nuevo Leon is a state located at Northeast Mexico Population (2016) 5 million Births: 90,000 /year. Birth defects: Second cause of infant mortality. NTD second cause of death for a birth defect. NTD incidence rate in 1999 = 10.6/ 10,000 Nuevo Leon

3 History Folic acid prevents NTDs (Smithells, et al,1992) Recommended dose of 400 ug/day (prevention of megaloblastic anemia, Daly et al, 1995) Food fortification (1998) 140 ug (Expected decrease 20%) Increase consumption of foods rich in folic acid. Expectative: 70% decrease of NTDs NTD rate had decreased but not as expected. Less than 30% compliance Food habits

4 Weekly folic acid administration In year 2000 No FA 400 micrograms tablets in Mexico Study to analyze the impact of 5mg / week in Serum and RBC Mothers with and without antecedent of a baby with NTD Compliance 91.4% RBC ng/ml = 432.1nMol/L After 3 mo. 5mg/wk Compliance 92%

5 Prevention Program Program was developed by the State Secretary of Health and the Medical School (University of Nuevo Leon) Registry of NTDs (Private and Public hospitals). Information and education of health professionals and population Free distribution of 5 mg tablets of FA to all women at reproductive age. Promotion and supervision of intake Analysis of results

6 % reduction SB

7 NTD Rates decrease in dose response matter; Daly et al, 1995 (n=84 NTD) RBC folate insufficiency threshold (n=56,000) RBC >400 ng/ml (906 nmol/l) steady state NTD Rates decrease in dose response matter Crider et al, 2014 (n=10,000) 0.1, 0.4, 4.0 mg/day and 4mg/wk RBC up to 1500 nmol/l steady state Wald, et al Most multivitamins contain 0.4, mg of FA Do not produce 906nMol/L

8 Pharmacokinetics and Pharmacodynamics Inter-individual variability Concentration and Time needed to achieve a steady-state concentration of folic acid in a woman planning pregnancy (6mo-1 yr). Poor compliance. Pregnancy planning: 50% of women do not plan their pregnancy Folic Acid metabolism: study showed that administration of 5mg/day increase AUC in Serum 5X but only 2X in RBC higher than 1 mg/day, indicating that, the body may take as much as it needs and limits excessive absorption. Diet: Many women do not consume sufficient amounts of folic acid. Degradation of natural folates. Oral Contraceptives. Genetics: MTHFR (677C>T), FA receptor, MTHD, TS. David Chitayat, et al The Journal of Clinical Pharmacology 2016, 56(2)

9 What is the ideal dose of FA for NTD prevention? Who should take 4-5 mg/day 1. Antecedent of NTD (previous child or close family member)*. 2. Obesity: In our State 45% of women with NTD were overweight/obese*. 3. Use of drugs with antifolate effects (anticonvulsant, Sulfonamides, Methotrexate, contraceptive drugs). 4. Genetic variants* in the folic acid metabolic pathway or folate receptors (In a previous study we found that 40% of mothers with a child with an NTD were Homozygous for the MTHFR variant 677C>T)** 6. Poorly controlled type 1 or type 2 diabetes mellitus* 7. Poor compliance with folic acid supplementation* 8. Smoking, passive or active 9. Use of oral contraceptives 10. Celiac and Crohn diseases * All these are risk factors for Mexican population. **Martínez de Villarreal LE et al. Folate levels and N(5),N(10)-methylenetetrahydrofolate reductase genotype (MTHFR) in mothers of offspring with neural tube defects: a case-control study.arch Med Res Jul-Aug;32(4): David Chitayat, et al The Journal of Clinical Pharmacology 2016, 56(2)

10 Evidence based folate consensus Guideline WHO/CDC Morbidity and Mortality Weekly Report. 2015;64(15): At the population level, RBC folate concentrations should be >400 ng/ml (906 nmol/l) in women of reproductive age to achieve the greatest reduction of NTDs. The RBC folate threshold of >400 ng/ml (906 nmol/l) can be used as an indicator of folate insufficiency in women of reproductive age. This threshold cannot predict the individual risk for having a NTD-affected pregnancy and thus is only useful at the population level. No serum folate threshold is recommended for prevention of NTDs in women of reproductive age at the population level Microbiological assay is recommended as the most reliable choice to obtain comparable results for RBC folate concentration across Birth defects surveillance continues to be critical for monitoring the prevalence of birth defects because not all NTDs are folate sensitive Amy M. Cordero, MPA; Krista S. Crider, PhD; Lisa M. Rogers, PhD; Michael J. Cannon, PhD; R.J. Berry, MD Morbidity and Mortality Weekly Report. 2015;64(15):

11 Implementation 1) Assess the RBC folate status among women of reproductive age. 2) Based on population status, determine the need for interventions, such as fortification of staple foods with folic acid or periconceptional folic acid supplementation, and how to best reach populations at risk for insufficient folate concentrations. 3) Implement interventions. 4) Reassess population RBC folate status (at least 6 12 months after the intervention) 5) Make adjustments to the prevention program as necessary.

12 Risks of take FA Neurocognitive disorders (Spain) when taken >5mg/day. Cáncer: Not sufficient evidence (colon, breast). Epigenetic changes: Still need more research.

13 What's next? Would it be possible to reduce more NTD incidence by increasing the dose of FA? Shall we do a research to obtain RBC folate levels? Non-folate Risk factors in Mexican population should be considered for additional folic acid? Should Mexicans take 4-5 mg /day of FA for NTD prevention?