Hyperhomocysteinemia in pregnancy dr vivek patkar

Dr. Vivek D. Patkarvivekpatkar49@gmail.com

Emerging Understandings about Nutrition in Pregnancy

Fetal nutritional status is affected by the intrauterine and childhood nutritional experiences of the mother

Maternal nutritional status at time of conception is an important determinant of outcomes

Intrauterine nutritional environment affects health and development of the fetus throughout life

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 foods

Taking folic acid (Methylating agents)Reduce use of harmful substances

2 MAJOR PREGNANCY COMPLICATIONS

PIH

IUGR

PREGNANCY INDUCED HYPERTENSION

The incidence of PIH is 6 to 8 % of all pregnancies beyond 24 weeks.

Pregnancy hypertension is the most common cause for abnormal fetal growth.

PATHOPHYSIOLOGY OF PIHEndothelial injury plays central role in pathogenesis of

PIH

Endothelial dysfunction precedes the clinical features of PIH

The intact endothelium has two major functions relevant to PIH

1. Prevention of coagulation (resists thrombus formation)

2. Modulation of vascular tone (promotes vasodilatation)

Trophoblasts can directly or indirectly produce factors that alter endothelial function: cytokines, placental fragments, free radical, reactive oxygen species.

Production of Oxidative stress is the genesis of endothelial dysfunction

The disrupted endothelium is responsible for endothelial cell dysfunction compromising vasoactive agents: PGI2 and NO

RISK FACTORS FOR PIH

• Primigravida (6-8 times the risk)Primigravida (6-8 times the risk)

• Age extremities (under 17/Over 35)Age extremities (under 17/Over 35)

• DiabetesDiabetes

• Pre-existing diseases such as HTNPre-existing diseases such as HTN

• Multiple GestationMultiple Gestation

• Fetal hydropsFetal hydrops

• Maternal malnutrition

Failure of trophoblastic invasion of the spiral decidual arteriole in the

Placental Bed.

Ischaemia of placental bed

Stress

Immunological Response.

Activity of TNF : (cytokines) – in flicts damage to vascular endothelium

ROS : Reactive oxidising species

Polymorphonucleur neutrophil (PMN)

Vascular circulating adhesins

Adhesion of platelets

Periodic degranulation

Releases toxic substance

CD-11B, CD-18, CD62 L, Noxious substance (Multiple organ damage)

VCAM 1

VCAM 2

BASIC PATHOLOGY OF PIH AT THE CELLULAR LEVEL

VDP

VASOSPASM DHP /Na retention

Maternal changesPlacental changes

Spiral artery Constriction (defective perfusion of Fetoplacental unit)

•Aging •Metabolic dysfunction •Morphological changes• Abruptio Placenta

Progesterone

Hypertension DICAtherodamageGlomeruler endotheliosis

EAF

Poly Degran

TFN AlphaVCA m1VCA m2

Release

ILCD 11 BCD 18

Tissue Damage

IUGROligohyd

Alt BPP

IUFDPremature Labour

Kidney Liver Lung

Toxaemia

Eclampsia

CVA

HE

Fetal Maternal

VDP

Hyperhomocystenemia as a risk factor____Women who develop severe preeclampsia

have higher plasma homocysteine levels in early pregnancy than women who remain normotensive throughout pregnancy. [threefold risk ] ---

Cotter AM, Molloy AMet al, Am J Obstet Gynecol. 2002 May;186(5):1107;

Am J Obstet Gynecol. 2001 Oct;185(4):781-5.

Hyperhomocystenemia as a risk factor____

Pregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsia –

López-Quesada E, Vilaseca MA, Lailla JM. Eur J

Obstet Gynecol Reprod Biol. 2003 May 1;108(1):45-9.

Hyperhomocystenemia as a risk factor____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.

Hyperhomocystenemia as a risk factor____Both maternal and umbilical cord plasma

homocysteine concentrations were elevated in pregnancies complicated by pre-eclampsia compared to normotensive controls.

Aust N Z J Obstet Gynaecol. 2008 Jun;48(3):261-5.

HomocysteineNaturally occuring sulpher containing amino acid

Results from the demethylation of the essential aminoacid methionine

Homocysteine metabolismFifty percent is re-methylated back into methionine

Other fifty percent is transulfurated to cystathionine, a source of cysteine

Homocysteine conc regulated byGenetic factorsNutritional factorsAgePregnancy

Normal value – 5-15micromol/lit

Historical Perspective

Homocystinuria [Homocystine excreted in the urine] ___first reported in 1962.

Associated with

-cerebrovascular disease

-coronary vascular disease

-peripheral vascular disease

Hyperhomocysteinemia‘Elevated Homocysteine levels’ It is graded as________Mild-15-30mmol/litModerate-30-100mmol/litSevere->100mmol/lit

Etiology of HyperhomocysteinemiaVitamin deficiencies -folate -methyl cobalamin[B12] -pyridoxin[B6]

Etiology of HyperhomocysteinemiaEnzyme defects - methylenetetrahydrofolate reductase

(MTHFR) [ two types of defects noted-c677t and

thermolabile variant] - cystathionine beta-synthase (CBS) - methionine synthase (MS). Homozygosity is important

Prevalance Exact prevalance unknown[ 5-7% for mild

disease]1,2

MHTFR mutation- 15% in European population

-1.4% in African population -30% heterozygousCBS mutation- - 0.4-1.4%heterozygous -rarely homozygous

HOMOCYSTEINE & PREGNANCYHomocysteine conc. decreased in pregnancy

due toHemodilutionRaised GFRHormonal changes of pregnancyIncreased fetal uptake

NORMAL UTEROPLACENTAL CIRCULATION

• Increased placental site perfusion is due to successful trophoblastic invasion of spiral arteries

• The intact vascular endothelium releases the following vasoactive substances that promotes vascular dilatation:1. Prostacycline - PGI2

2.2. Nitric Oxide (NO)Nitric Oxide (NO) from the precursor L-arginine

The endothelium plays a major role in regulating vascular smooth muscle responses to endogenous vasoconstrictors.

HEMODYNAMICS IN NORMAL PREGNANCYNO mediates the vasodilatating effect of estradiol and

plays a role in regulating the uteroplacental blood flow during pregnancy.

The resulting hemodynamic situation is one of

high volume, high flow, and low resistance.

How does hyperhomocysteinemia leads to PIH ?

Homocysteine is primarily responsible for endothelial cell damage leading to pro-atherogenic effects,thromboembolic effects and hypoperfusion of placenta

It also has been implicated in the overproduction of free radicals

How does hyperhomocysteinemia leads to PIH?

Suboptimal methylation

Increased levels of homocysteine

Excessive generation of free radicals leading to oxidative damage

Leads to DNA oxidation and endothelial dysfunction

IUGR

Pre-eclampsia

VTE

ENDOTHELIAL FUNCTION

IUGR

PIH - Pre-eclampsia

VTE

ENDOTHELIAL FUNCTION

Also …..…..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.

Hyperhomocysteinemia could affect IVF outcome. ___Pacchiarotti A, Mohamed MA, J Assist Reprod Genet. 2007 Oct;24(10):459-62. Epub 2007 Sep 1

Also …..…..Maternal hyperhomocysteinaemia is

associated with an increased risk of CHD ___Verkleij-Hagoort AC, Verlinde M, BJOG. 2006

Dec;113(12):1412-8.

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

Hyperhomocysteinemia in pregnancyPIHIUGRPlacental abruptionCong anomalies[NTD]Preterm BirthLBWRecurrent abortionInfertility

INTRA UTERINE GROWTH RESTRICTION

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.

Atleast 70 % of still births have antenatal evidence of IUGR (Boehm and Gabbe, 2002)

Placental Abruption Premature seperation of normally situated

placentaHyperhomocysteinemia ____Independent risk

factor2.5X increased risk in MHTFR mutation

Recurrent Pregnancy LossHyperhomocysteinemia found in 30% casesMHTFR mutation in 16% cases

Congenital AnomalyCleft lip/ palate[15.6%]Neural tube defects[25-30%]Club footCHDMay be an indicator of underlying abberant

folate metabolismOr itself may be teratogenic

When to screen?Values in early pregnancy are more

reliableSecond-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):805-9.

___Zeeman GG, Alexander JM, McIntire DD, Devaraj S, Leveno KJ. Am J Obstet Gynecol. 2003 Aug;189(2):574-6

Sample Collection Overnight fasting mustMorning sampleEDTA bulbTo be centrifuged immediatelyOr kept on wet ice till centrifugation

Methods Chromatography

Enzyme Immunoassay [used routinely]

Why to treat ?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.

Folic acid-containing multivitamins may reduce the risk of gestational hypertension ___Hernández-Dà az .Am J Epidemiol. 2002 Nov

1;156(9):806-12.

Why to treat ?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.

METHYLATON ENHANCEMENTMaintaining & enhancing methylation is the most important factor in

preventing pregnancy complications like PIH & IUGR.

Restoring S-ADENOSYL METHIONINE (SAMe ) is the key to enhancing methylation.

Best strategy is intake of methyl enhancers

Free radical damage can also be reversed by methylating agents.

Treatment Dietary modificationFolate supplementation[500-

5000microgram/day]Methylcobalamin supplementation[100-

500 microgram/day] particulary for indian population due to

high prevalance of vegeterian dietSupplementation of pyridoxine[B6]Anticagulation if history of thrombosis

FOLIC ACID

Adequate intake minimizes DNA uracil and plasma Hcy accumulation, resulting in reduced risk of chromosome breaks.

Folic acid-vitamin B supplementation significantly reduce tHcy levels (Bostom et al, 2002).

Low conc associated with risk of preterm delivery, Low birth weight infants and FGR

AJCN. 2000; 71: 1295S-1303S, Am J Obstet Gynecol. 2004 Dec;191(6):1851-7.

Important cofactor in the Remethylation of Homocysteine

FOLIC ACID

CONCLUSIONS: Homocysteine concentrations increase in late pregnancy toward nonpregnant values;

an increase that can be limited by enhancing folate status through continued folic acid supplementation.

These results indicate a potential role for continued folic acid supplementation in reducing pregnancy complications associated with hyperhomocysteinemia.

Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22. Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.

FOLIC ACID

Risk of gestational hypertension in relation to folic acid and Vit B6 supplementation during pregnancy.

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).

This finding suggests that folic acid-containing multivitamins may reduce the risk of gestational hypertension.

Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22. Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.

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 transulphuration 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 (Int J Vitam Nutr Res. 1978;48(4):341-7)

Needed for CNS formation of fetus

A cofactor, Pyridoxal Phosphate in methylation

FOLIC ACID & Vit B6

RESULTS: All patients who underwent a methionine loading test after vitamin supplementation had a completely normalized methionine loading test.

Of the 14 pregnancies in women receiving vitamins and aspirin, 7 had mild preeclampsia.

Birth weights were 2867 +/- 648 g compared with 1088 +/- 570 g in the previous pregnancies.

Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia appears to be favorable.

Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22. Clin Chem. 2005 Mar;51(3):629-34. Epub 2004 Dec 22.

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)

CHOLINE

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

Helps in converting Homocysteine to Methionine

Normalizes the Homocysteine levels

Important for the formation of Betaine

ANTIOXIDANTSSelenium..a trace element which has antioxidant &

anticancer properties

Vitamin E …A powerful antioxidant…protects against damaging effect of free radicalsCombats oxidative stress….which is an important factor in IUGR, NTD, PLACENTAL ABRUPTION

Vitamin C……Antioxidant & has a role in immune system.

ANTIOXIDANTS

Lycopene…the carotenoid potent antioxidant with beneficial effects of 70% to 80% reduction in IUGR. Reversal of IUGR also reported

Green Tea Extract…green tea is not fermented, hence retains antioxidant properties

Powerful vasodilator, lowers fibrinogen, inhibits platelet aggregation…hence reduces thromboembolic phenomenon & hence reduces IUGR & PLACENTAL ABRUPTION