Hyperhomocysteinemia in pregnancy dr vivek patkar


Published on

Published in: Health & Medicine
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Hyperhomocysteinemia in pregnancy dr vivek patkar

  1. 1. Dr. Vivek D. Patkar [email_address]
  2. 2. Emerging Understandings about Nutrition in Pregnancy <ul><li>Fetal nutritional status is affected by the intrauterine and childhood nutritional experiences of the mother </li></ul><ul><li>Maternal nutritional status at time of conception is an important determinant of outcomes </li></ul><ul><li>Intrauterine nutritional environment affects health and development of the fetus throughout life </li></ul>
  3. 3. Top Three “Best Practices” to Improve Birth Outcomes & Reduce High Risk Births (NGA, June 2004) <ul><li>Improve access to medical care and health care services </li></ul><ul><li>Encourage good nutrition and healthy lifestyles </li></ul><ul><ul><li>Eating healthy foods </li></ul></ul><ul><ul><li>Taking folic acid ( Methylating agents) </li></ul></ul><ul><li>Reduce use of harmful substances </li></ul>
  5. 5. PREGNANCY INDUCED HYPERTENSION <ul><li>The incidence of PIH is 6 to 8 % of all pregnancies beyond 24 weeks. </li></ul><ul><li>Pregnancy hypertension is the most common cause for abnormal fetal growth. </li></ul>
  6. 6. PATHOPHYSIOLOGY OF PIH <ul><li>Endothelial injury plays central role in pathogenesis of PIH </li></ul><ul><li>Endothelial dysfunction precedes the clinical features of PIH </li></ul><ul><li>The intact endothelium has two major functions relevant to PIH </li></ul><ul><li>1. Prevention of coagulation (resists thrombus formation) </li></ul><ul><li>2. Modulation of vascular tone (promotes vasodilatation) </li></ul>
  7. 7. <ul><li>Trophoblasts can directly or indirectly produce factors that alter endothelial function: </li></ul><ul><li>cytokines, placental fragments, free radical, reactive oxygen species. </li></ul><ul><li>Production of Oxidative stress is the genesis of endothelial dysfunction </li></ul><ul><li>The disrupted endothelium is responsible for endothelial cell dysfunction compromising vasoactive agents: PGI 2 and NO </li></ul>
  8. 8. RISK FACTORS FOR PIH <ul><li>Primigravida (6-8 times the risk) </li></ul><ul><li>Age extremities (under 17/Over 35) </li></ul><ul><li>Diabetes </li></ul><ul><li>Pre-existing diseases such as HTN </li></ul><ul><li>Multiple Gestation </li></ul><ul><li>Fetal hydrops </li></ul><ul><li>Maternal malnutrition </li></ul>
  9. 9. <ul><ul><ul><ul><ul><li>BASIC PATHOLOGY OF PIH AT THE CELLULAR LEVEL </li></ul></ul></ul></ul></ul>VDP
  10. 10. VASOSPASM DHP /Na retention Maternal changes Placental changes Spiral artery Constriction (defective perfusion of Fetoplacental unit) <ul><li>Aging </li></ul><ul><li>Metabolic dysfunction </li></ul><ul><li>Morphological changes </li></ul><ul><li>Abruptio Placenta </li></ul>Progesterone Hypertension DIC Atherodamage Glomeruler endotheliosis EAF Poly Degran TFN Alpha VCA m1 VCA m2 Release IL CD 11 B CD 18 Tissue Damage IUGR Oligohyd Alt BPP IUFD Premature Labour Kidney Liver Lung Toxaemia Eclampsia CVA HE Fetal Maternal VDP
  11. 11. Hyperhomocystenemia as a risk factor____ <ul><li>Women who develop severe preeclampsia have higher plasma homocysteine levels in early pregnancy than women who remain normotensive throughout pregnancy. [ threefold risk ] --- </li></ul><ul><li>Cotter AM, Molloy AMet al, Am J Obstet Gynecol. 2002 May;186(5):1107; </li></ul><ul><li>Am J Obstet Gynecol. 2001 Oct;185(4):781-5. </li></ul>
  12. 12. Hyperhomocystenemia as a risk factor____ <ul><li>Pregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsia – </li></ul><ul><li>López-Quesada E, Vilaseca MA, Lailla JM. Eur J Obstet Gynecol Reprod Biol. 2003 May 1;108(1):45-9. </li></ul>
  13. 13. Hyperhomocystenemia as a risk factor____ <ul><li>Hyperhomocysteinemia is associated with pre-eclampsia as well as eclampsia, but in eclampsia the severity of homocysteine elevation is more compared to that in pre-eclampsia . ___ Hoque MM, Bulbul T, Mahal M, Islam NA, Bangladesh Med Res Counc Bull. 2008 Apr;34(1):16-20. </li></ul>
  14. 14. Hyperhomocystenemia as a risk factor____ <ul><li>Both maternal and umbilical cord plasma homocysteine concentrations were elevated in pregnancies complicated by pre-eclampsia compared to normotensive controls. </li></ul><ul><li>Aust N Z J Obstet Gynaecol. 2008 Jun;48(3):261-5. </li></ul>
  15. 15. Homocysteine <ul><li>Naturally occuring sulpher containing amino acid </li></ul><ul><li>Results from the demethylation of the essential aminoacid methionine </li></ul>
  16. 16. Homocysteine metabolism <ul><li>Fifty percent is re-methylated back into methionine </li></ul><ul><li>Other fifty percent is transulfurated to cystathionine, a source of cysteine </li></ul>
  17. 18. <ul><li>Homocysteine conc regulated by </li></ul><ul><li>Genetic factors </li></ul><ul><li>Nutritional factors </li></ul><ul><li>Age </li></ul><ul><li>Pregnancy </li></ul><ul><li>Normal value – 5-15micromol/lit </li></ul>
  18. 19. Historical Perspective <ul><li>Homocystinuria [Homocystine excreted in the urine] ___first reported in 1962. </li></ul><ul><li>Associated with </li></ul><ul><li>-cerebrovascular disease </li></ul><ul><li>-coronary vascular disease </li></ul><ul><li>-peripheral vascular disease </li></ul>
  19. 20. Hyperhomocysteinemia <ul><li>‘ Elevated Homocysteine levels’ </li></ul><ul><li>It is graded as________ </li></ul><ul><li>Mild-15-30mmol/lit </li></ul><ul><li>Moderate-30-100mmol/lit </li></ul><ul><li>Severe->100mmol/lit </li></ul>
  20. 21. Etiology of Hyperhomocysteinemia <ul><li>Vitamin deficiencies </li></ul><ul><li>-folate </li></ul><ul><li>-methyl cobalamin[B12] </li></ul><ul><li>-pyridoxin[B6] </li></ul>
  21. 22. Etiology of Hyperhomocysteinemia <ul><li>Enzyme defects </li></ul><ul><li>- methylenetetrahydrofolate reductase ( MTHFR ) </li></ul><ul><li>[ two types of defects noted-c677t and thermolabile variant] </li></ul><ul><li>- cystathionine beta-synthase ( CBS ) </li></ul><ul><li>- methionine synthase ( MS ). </li></ul><ul><li>Homozygosity is important </li></ul>
  22. 23. Prevalance <ul><li>Exact prevalance unknown[ 5-7 % for mild disease] 1,2 </li></ul><ul><li>MHTFR mutation- 15 % in European population </li></ul><ul><li>- 1.4 % in African population </li></ul><ul><li>- 30 % heterozygous </li></ul><ul><li>CBS mutation- </li></ul><ul><li>- 0.4-1.4 %heterozygous </li></ul><ul><li>-rarely homozygous </li></ul>
  23. 24. HOMOCYSTEINE & PREGNANCY <ul><li>Homocysteine conc. decreased in pregnancy due to </li></ul><ul><li>Hemodilution </li></ul><ul><li>Raised GFR </li></ul><ul><li>Hormonal changes of pregnancy </li></ul><ul><li>Increased fetal uptake </li></ul>
  24. 25. NORMAL UTEROPLACENTAL CIRCULATION <ul><li>Increased placental site perfusion is due to successful trophoblastic invasion of spiral arteries </li></ul><ul><li>The intact vascular endothelium releases the following </li></ul><ul><li>vasoactive substances that promotes vascular dilatation: </li></ul><ul><li>Prostacycline - PGI 2 </li></ul><ul><li>Nitric Oxide (NO) from the precursor L-arginine </li></ul><ul><li>The endothelium plays a major role in regulating vascular smooth muscle responses to endogenous vasoconstrictors. </li></ul>
  25. 26. HEMODYNAMICS IN NORMAL PREGNANCY <ul><li>NO mediates the vasodilatating effect of estradiol and plays a role in regulating the uteroplacental blood flow during pregnancy. </li></ul><ul><li>The resulting hemodynamic situation is one of </li></ul><ul><li>high volume, high flow, and low resistance. </li></ul>
  26. 27. How does hyperhomocysteinemia leads to PIH ? <ul><li>Homocysteine is primarily responsible for endothelial cell damage leading to pro-atherogenic effects,thromboembolic effects and hypoperfusion of placenta </li></ul><ul><li>It also has been implicated in the overproduction of free radicals </li></ul>
  27. 28. How does hyperhomocysteinemia leads to PIH? <ul><li>Suboptimal methylation </li></ul><ul><li>Increased levels of homocysteine </li></ul><ul><li>Excessive generation of free radicals leading to </li></ul><ul><li>oxidative damage </li></ul><ul><li>Leads to DNA oxidation and endothelial dysfunction </li></ul>
  29. 30. Also …..….. <ul><li>Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses ___ Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK. Obstet Gynecol. 2000 Apr;95(4):519-24. </li></ul><ul><li>Hyperhomocysteinemia could affect IVF outcome . ___ Pacchiarotti A, Mohamed MA, J Assist Reprod Genet. 2007 Oct;24(10):459-62. Epub 2007 Sep 1 </li></ul>
  30. 31. Also …..….. <ul><li>Maternal hyperhomocysteinaemia is associated with an increased risk of CHD ___ Verkleij-Hagoort AC, Verlinde M, BJOG. 2006 Dec;113(12):1412-8 . </li></ul><ul><li>The occurrence of IUGR increased with low maternal and cord concentrations of folate and high maternal levels of tHcy ___ Lindblad B, Zaman S Acta Obstet Gynecol Scand. 2005 Nov;84(11):1055-61 </li></ul>
  31. 32. Hyperhomocysteinemia in pregnancy <ul><li>PIH </li></ul><ul><li>IUGR </li></ul><ul><li>Placental abruption </li></ul><ul><li>Cong anomalies[NTD] </li></ul><ul><li>Preterm Birth </li></ul><ul><li>LBW </li></ul><ul><li>Recurrent abortion </li></ul><ul><li>Infertility </li></ul>
  32. 33. INTRA UTERINE GROWTH RESTRICTION <ul><li>IUGR occurs in 5 to 10 % of pregnancies and is associated with a 4 to 10 fold increase in perinatal mortality and a substantial increase in perinatal morbidity, including neurodevelopmental disorders. </li></ul><ul><li>Atleast 70 % of still births have antenatal evidence of IUGR (Boehm and Gabbe, 2002) </li></ul>
  33. 34. Placental Abruption <ul><li>Premature seperation of normally situated placenta </li></ul><ul><li>Hyperhomocysteinemia ____Independent risk factor </li></ul><ul><li>2.5X increased risk in MHTFR mutation </li></ul><ul><li> </li></ul><ul><li> </li></ul>
  34. 35. Recurrent Pregnancy Loss <ul><li>Hyperhomocysteinemia found in 30% cases </li></ul><ul><li>MHTFR mutation in 16% cases </li></ul>
  35. 36. Congenital Anomaly <ul><li>Cleft lip/ palate[15.6%] </li></ul><ul><li>Neural tube defects[25-30%] </li></ul><ul><li>Club foot </li></ul><ul><li>CHD </li></ul><ul><li>May be an indicator of underlying abberant folate metabolism </li></ul><ul><li>Or itself may be teratogenic </li></ul>
  36. 37. When to screen? <ul><li>Values in early pregnancy are more reliable </li></ul><ul><li>Second-trimester plasma homocysteine concentrations do not predict the subsequent development of pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction. </li></ul><ul><li>___ Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Am J Obstet Gynecol. 2000 Oct;183(4):805-9. </li></ul><ul><li>___Zeeman GG, Alexander JM, McIntire DD, Devaraj S, Leveno KJ. Am J Obstet Gynecol. 2003 Aug;189(2):574-6 </li></ul>
  37. 38. Sample Collection <ul><li>Overnight fasting must </li></ul><ul><li>Morning sample </li></ul><ul><li>EDTA bulb </li></ul><ul><li>To be centrifuged immediately </li></ul><ul><li>Or kept on wet ice till centrifugation </li></ul>
  38. 39. Methods <ul><li>Chromatography </li></ul><ul><li>Enzyme Immunoassay </li></ul><ul><li>[used routinely] </li></ul>
  39. 40. Why to treat ? <ul><li>Supplementation of multivitamins containing folic acid in the second trimester is associated with reduced risk of preeclampsia. __ Wen SW, Chen XK, Rodger .Am J Obstet Gynecol. 2008 Jan;198(1):45.e1-7. </li></ul><ul><li>Folic acid-containing multivitamins may reduce the risk of gestational hypertension ___ Hernández-Díaz .Am J Epidemiol. 2002 Nov 1;156(9):806-12 . </li></ul>
  40. 41. Why to treat ? <ul><li>Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia who are teated appears to be favorable. ____ Leeda M, Riyazi .Am J Obstet Gynecol. 1998 Jul;179(1):135-9. </li></ul>
  41. 42. METHYLATON ENHANCEMENT <ul><li>Maintaining & enhancing methylation is the most important factor in preventing pregnancy complications like PIH & IUGR. </li></ul><ul><li>Restoring S-ADENOSYL METHIONINE (SAMe ) is the key to enhancing methylation. </li></ul><ul><li>Best strategy is intake of methyl enhancers </li></ul><ul><li>Free radical damage can also be reversed by methylating agents. </li></ul>
  42. 43. Treatment <ul><li>Dietary modification </li></ul><ul><li>Folate supplementation[500-5000microgram/day] </li></ul><ul><li>Methylcobalamin supplementation[100-500 microgram/day] </li></ul><ul><li>particulary for indian population due to high prevalance of vegeterian diet </li></ul><ul><li>Supplementation of pyridoxine[B6 ] </li></ul><ul><li>Anticagulation if history of thrombosis </li></ul>
  43. 44. FOLIC ACID <ul><li>Adequate intake minimizes DNA uracil and plasma Hcy accumulation, resulting in reduced risk of chromosome breaks. </li></ul><ul><li>Folic acid-vitamin B supplementation significantly reduce tHcy levels (Bostom et al, 2002). </li></ul><ul><li>Low conc associated with risk of preterm delivery, Low birth weight infants and FGR </li></ul><ul><li>AJCN. 2000; 71: 1295S-1303S, </li></ul><ul><li>Am J Obstet Gynecol. 2004 Dec;191(6):1851-7. </li></ul>Important cofactor in the Remethylation of Homocysteine
  44. 45. FOLIC ACID <ul><li>CONCLUSIONS: Homocysteine concentrations increase in late pregnancy toward nonpregnant values; </li></ul><ul><li>an increase that can be limited by enhancing folate status through continued folic acid supplementation. </li></ul><ul><li>These results indicate a potential role for continued folic acid supplementation in reducing pregnancy complications associated with hyperhomocysteinemia. </li></ul>Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.
  45. 46. FOLIC ACID <ul><li>Risk of gestational hypertension in relation to folic acid and Vit B6 supplementation during pregnancy. </li></ul><ul><li>The multivariate-adjusted relative risk of developing gestational hypertension during the month after folic acid supplementation, compared with not using folic acid during that same month, was 0.55 (95% confidence interval: 0.39, 0.79). </li></ul><ul><li>This finding suggests that folic acid-containing multivitamins may reduce the risk of gestational hypertension. </li></ul>Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.
  46. 47. VITAMIN B 12 <ul><li>Enzyme, catalyses the transfer of CH 3 group from </li></ul><ul><li>MethylTetrahydrofolate Homocysteine </li></ul><ul><li>In Vit. B 12 def, folate is trapped as unusable MTHF, causing functional folate deficiency. </li></ul><ul><li>Thus plays a key role in the remethylation of Homocysteine to Methionine. </li></ul>A cofactor, Methionine Synthetase (MS) in methylation
  47. 48. VITAMIN B 6 <ul><li>Reduces the level of homocysteine by the process of transulphuration to cysteine & hence related pregnancy complications are reduced. </li></ul><ul><li>Vitamin B6 levels of mothers at the onset of pregnancy have a positive correlation with birth weight of newborns (Int J Vitam Nutr Res. 1978;48(4):341-7) </li></ul><ul><li>Needed for CNS formation of fetus </li></ul>A cofactor, Pyridoxal Phosphate in methylation
  48. 49. FOLIC ACID & Vit B6 <ul><li>RESULTS: All patients who underwent a methionine loading test after vitamin supplementation had a completely normalized methionine loading test. </li></ul><ul><li>Of the 14 pregnancies in women receiving vitamins and aspirin, 7 had mild preeclampsia. </li></ul><ul><li>Birth weights were 2867 +/- 648 g compared with 1088 +/- 570 g in the previous pregnancies. </li></ul><ul><li>Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia appears to be favorable . </li></ul>Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.
  49. 50. L – METHIONINE Methyl donor, antioxidant L-methionine is a precursor to L-cysteine Important factor for the normal fetal growth Essential amino acid which predicts the birth weight and length Increased concentrations of methionine in extraembryonic and amniotic fluid are directly related to low levels of homocysteine (BJOG. 2005; 104(1): 20-24)
  50. 51. CHOLINE <ul><li>Essential AA, important for the structural integrity of our cell membranes, the breakdown and utilization of fat for energy, cholesterol transport & elimination from the body </li></ul><ul><li>Helps in converting Homocysteine to Methionine </li></ul><ul><li>Normalizes the Homocysteine levels </li></ul>Important for the formation of Betaine
  51. 52. ANTIOXIDANTS <ul><li>Selenium.. a trace element which has antioxidant & anticancer properties </li></ul><ul><li>Vitamin E …A powerful antioxidant…protects against damaging effect of free radicals </li></ul><ul><li>Combats oxidative stress….which is an important factor in IUGR, NTD, PLACENTAL ABRUPTION </li></ul><ul><li>Vitamin C ……Antioxidant & has a role in immune system. </li></ul>
  52. 53. ANTIOXIDANTS <ul><li>Lycopene …the carotenoid potent antioxidant with beneficial effects of 70% to 80% reduction in IUGR. Reversal of IUGR also reported </li></ul><ul><li>Green Tea Extract… green tea is not fermented, hence retains antioxidant properties </li></ul><ul><li>Powerful vasodilator, lowers fibrinogen, inhibits platelet aggregation…hence reduces thromboembolic phenomenon & hence reduces IUGR & PLACENTAL ABRUPTION </li></ul>
  53. 54. THANK YOU