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INDGMP3212007
Overview
HyperhomocysteinemiaPrevalence in pregnancyClinical outcomes in PregnancyDiagnostic MeasuresTreatment with emphasis on empirical managementRole of vitamin B6, B9 and B12 in management Clinical Evidence
Homocysteine
Naturally occurring sulphur containing amino acid Results from the demethylation of the essential amino
acid methionine.Normal serum levels: 5 to 15 micromol/litreHyperhomocysteinemia –
Etiology of Hyperhomocysteinemia
Vitamin Deficiencies :Folate (B9)Methyl Cobalamin (B12)Pyridoxine (B6)
Genetic causes:Defects (due to gene mutation )in Enzyme
causing metabolism of homocysteine ( Rare )
Current Drug Metabol 2007 Jan;8(1):17-31
Genetic factors
Physiological factors
Lifestyle
Clinical Conditions
Drugs
Folate deficiency ↑ ↑Vitamin B12 deficiency ↑ ↑Vitamin B6 deficiency ↑ Pregnancy ↓Renal failure ↑Hypothyroidism ↑
Determinants of Plasma homocysteine
Homocysteine levels in vegetarian and non vegetarian life style – Epidemiology in India
India predominantly follows vegetarian food habits
Higher levels of homocysteine due to Vitamin B12 deficiency
Homocysteine Levelswww.veganhealth.org as accessed on 28th April 2012
Homocysteine conc. decreased in pregnancy due to
HemodilutionRaised GFRHormonal changes of pregnancyIncreased fetal uptake
Homocysteine and Pregnancy
Hague WM Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3):459–469, 2003
Hyperhomocysteinemia in PregnancyIn an Indian maternal nutrition study, two thirds of
pregnant mothers had low levels of vitamin B12 Only an occasional mother had low folate concentration.Vitamin B12 and folate play vital role in one carbon (1-C)
metabolism, crucial for fetal growth
Katre P et al. Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12 and high folate status Asia Pac J Clin Nutr 2010;19 (3):335-343
This study showed that the plasma tHcy concentration at 34 weeks gestation was lower in those who received vitamin B12 supplementation compared to those who received only folic acid or no supplementation
Indian Study2010
Hyperhomocysteinemia is an independent causal factor in
pregnancy complications
……..Current Drug Metabol 2007 Jan;8(1):17-31
Clinical outcomes in Pregnancy Approximately 2-fold to 3-fold increased risk for :
• Pregnancy-induced hypertension• Abruptio placentae• Intrauterine growth restriction
Cobalamine deficiency : • HELLP syndrome• Abruptio placentae• Intrauterine growth restriction• Intrauterine fetal death
Pyridoxal 5-phosphate deficiency • Increased risk for pregnancy-induced hypertension 4-fold
Hyperhomocysteinemia, Pregnancy Complications and the Timing of InvestigationRe´gine P. Steegers-Theunissen,et al. VOL. 104, NO. 2, AUGUST 2004The American College of Obstetricians and Gynecologists as accessed on 29th April 2012
Hyperhomocysteinemia, Pregnancy Complications and the Timing of InvestigationRe´gine P. Steegers-Theunissen,et al. VOL. 104, NO. 2, AUGUST 2004The American College of Obstetricians and Gynecologists as accessed on 29th April 2012
NTDsNTDs
Other congenital defectsOther congenital defectsspontaneous spontaneous miscarriage recurrent abortionmiscarriage recurrent abortion
IUGRIUGR
Pre-eclampsiaPre-eclampsia
placental abruptionplacental abruption
Pre-term labour Pre-term labour
Intrauterine fetal deathIntrauterine fetal death
HyperhomocysteinemiaHyperhomocysteinemia
Association of Hyperhomocysteinemia &
Pregnancy complications, adverse pregnancy outcome. As evident by clinical studies………..
J Nutr. 2006 Jun;136(6 Suppl):1731S-1740S
Women with hyperhomocysteinemia have increased risk of pregnancy complications and adverse pregnancy outcome
BJOG. 2006 Dec;113(12):1412-8
Maternal hyperhomocysteinemia is a risk factor for Congenital Heart Disease
Clin Chem Lab Med 2005; 43(10): 1052-7
Early abortion, pregnancy complications and poor pregnancy outcomes have been linked to hyperhomocysteinemia
American Journal of Perinatology. January 2006; 23(1):31-35
Hyperhomocysteinemia during pregnancy is a risk factor for development of preeclampsia and its complications
Eur J. of Obs & Gynae & Reprod Biol 2003
Numerous studies have demonstrated association between increased levels of homocysteine and spontaneous miscarriages, IUGR, preeclampsia and fetal death
Pregnancy outcomes are multi-factorial
Sundrani D.P. et al. / Medical Hypotheses 77 (2011) 878–883
Hyperhomocysteinemia as risk factor
Pregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsia
Hyperhomocysteinemia associated with recurrent pregnancy loss
MHTFR mutation in 16% cases
López-Quesada E, Vilaseca MA, Lailla JM. Eur J Obstet Gynecol Reprod
Biol. 2003 May 1;108(1):45-9.
Diagnostic Measures
When to Screen ?
Values in early pregnancy are more reliable
Second-trimester plasma homocysteine concentrations do not predict the subsequent development of pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction
Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Am J Obstet Gynecol. 2000 Oct;183(4):805-9Zeeman GG, Alexander JM, McIntire DD, Devaraj S, Leveno KJ. Am J Obstet Gynecol. 2003 Aug;189(2):574-6 as accessed on 28th April 2012
Sample Collection
Overnight fasting mustMorning sampleEDTA bulbTo be centrifuged immediatelyOr kept on wet ice till centrifugation
Treatment
Dietary modificationFolate supplementation[500-5000microgram/day] Vitamin B12 supplementation
particulary for indian population due to high prevalance of vegeterian diet
Supplementation of pyridoxine[B6]
Sundrani D.P. et al. / Medical Hypotheses 77 (2011) 878–883Hague WM Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3):459–469, 2003
Role of vitamin B6, B9 and B12 in management
Methionine is an essential amino acid obtained from protein in the diet
Some methionine is turned into homocysteineThe body turns much of this homocysteine back into
methionine with the help of vitamin B12Low vitamin B6 status can also cause elevated
homocysteine in some people
www.brewboost.com as accessed on 1st May 2012
Methionine synthase
Cystathionine beta synthase
MTHFR- methyl tetrahydrofolate reductase
Demethylation
Transsulfuration
Role of vitamin B6, B9 and B12 in management
Available at www.medscape.com as accessed on Aug 2012
FOLIC ACID
Making of new cells and cell replication
Folic acid-vitamin B supplementation significantly reduce total Hcy levels
Low conc associated with risk of preterm delivery, Low birth weight infants and IUGR
Important cofactor in the Remethylation of Homocysteine
AJCN. 2000; 71: 1295S-1303S, Am J Obstet Gynecol. 2004 Dec;191(6):1851-7.Bostom et al, 2002
VITAMIN B12
Enzyme, catalyses the transfer of CH3 group from
MethylTetrahydrofolate Homocysteine
In Vit. B12 def, folate is trapped as unusable MTHF, causing functional folate deficiency.
Thus plays a key role in the remethylation of Homocysteine to Methionine.
A cofactor, Methionine Synthetase (MS) in methylation
VITAMIN B6
Reduces the level of homocysteine by the process of transulfuration to cysteine & hence related pregnancy complications are reduced
Vitamin B6 levels of mothers at the onset of pregnancy have a positive correlation with birth weight of newborns
Effective in the treatment of nausea and vomiting of pregnancy
A cofactor, Pyridoxal Phosphate in methylation
Int J Vitam Nutr Res. 1978;48(4):341-7
Clinical Evidence
Folate, Vitamin B12 & B6 - effective & safe to reduce homocysteine levels
The relationship between serum homocysteine (hcy) levels and pregnancy complications was studied
Homocysteine lowering effects of folate, vitamin B12 and Vitamin B6
332 pregnant womenThey were given-
folate- 5 mg/day, vitamin B12- 1000 mcg/day and of vitamin B6- 1000 mcg/day
Quereshi S et al. JPMA 60:741; 2010
for 6 weeks
Quereshi S et al. JPMA 60:741; 2010
Folate, Vitamin B12 & B6 - effective & safe to reduce homocysteine levels
Conclusion
Folate, Vitamin B12 & B6 supplementation is effective & safe to reduce homocysteine levels
Quereshi S et al. JPMA 60:741; 2010
ConclusionVitamins (folate, B6, B12) play important role in metabolism
of homocysteineDeficiency of vitamins (folate, B6, B12) is associated with
hyperhomocysteinemiaHyperhomocysteinemia may be associated with some of the
complications in preganancySupplementation of Folic acid, B6 and B12 is effective and safe
in reducing homocysteine levels
Prophylaxis
Folic acid and vitamins B6 and B12 are necessary in metabolism of Hcys; therefore they can be used for both treatment and prophylaxis of hyperhomocysteinemia
Proper dietAbstaining from tobacco or smokingOptimal physical activity
http://www.czytelniamedyczna.pl/3431,prophylaxis-and-treatment-of-hyperhomocysteinemia.html
Top Three “Best Practices” to Improve Birth Outcomes & Reduce High Risk Births (NGA, June 2004)
Improve access to medical care and health care services
Encourage good nutrition and healthy lifestylesEating healthy foodsTaking folic acid (Methylating agents)
Reduce use of harmful substances
Available at http://www.nga.org/cms/home/nga-center-for-best-practices/ as accessed on Aug 2012
Hyperhomocysteinemia is independent causal factor for pregnancy complications
Folic acid, methylcobalamin and pyridoxine deficiencies lead to hyperhomocysteinemia and are prevalent in pregnant women
Supplementation of folic acid, methylcobalamin and pyridoxine helps in management of hyperhomocysteinemia
Summary