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