2. Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H, Sion Hospital
President, MOGS (2022-2023)
Joint Treasurer, FOGSI (2021-2025)
Organising Secretary, AICOG Mumbai 2025
Treasurer, AFG (2023-2024)
Member Oncology Committee, SAFOG (2021-2023)
Dean AGOG & Chief Content Director, HIGHGRAD & FEMAS Courses
Editor-in-Chief, FEMAS, JGOG & TOA Journal
67 publications in International and National Journals with 162 Citations
National Coordinator, FOGSI Medical Disorders in Pregnancy Committee (2019-2022)
Chair & Convener, FOGSI Cell Violence Against Doctors (2015-16)
Member, Oncology Committee AOFOG (2013-2015)
Coordinator of 11 batches of MUHS recognized Certificate Course of B.I.M.I.E at
L.T.M.G.H (2010-16)
Member, Managing Committee IAGE (2013-17), (2018-20), (2022-2023)
Editorial Board, European Journal of Gynaec. Oncology (Italy)
Course Coordinator of 3 batches of Advanced Minimal Access Gynaec Surgery (AMAS)
at LTMGH (2018-19)
DR. NIRANJAN CHAVAN
MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP,
DIPLOMA IN ENDOSCOPY (USA)
3. PROGRAMMING
Malnutrition and other adverse
environmental exposures during
development alter gene expression
and program the body’s structures and
functions for life.
The key factors influencing the early phase of life are
nutrition and nurture
4. MATERNAL DIET
• Maternal diet is one of the main players in this context, as macro
and micronutrients are direct regulators of DNA stability and
phenotypic adaptation, by influencing the availability of methyl
donors and mechanisms promoting DNA stability
Epigenetic modifications
Fetal gene
expression
Placental gene
expression
Fetal development
NUTRITIONAL PROGRAMMING
Cetin et al., Curr Opin Clin Nutr Metab Care, 2013
5. HOMOCYSTEINE
• Homocysteine is a non-protein forming, sulfur-containing amino
acid.
• It is formed exclusively by the demethylation of methionine,
during the conversion of methionine to cysteine.
• Previous studies have shown that increased homocysteine was
associated with an increased risk of vascular diseases and may
cause direct damage to endothelial cells both in vitro and in vivo.
J Diabetes Metab Disord. 2013;12(1):17
6.
7. HYPERHOMOCYSTEINEMIA
• The classification of hyperhomocysteinemia.
World Clinics Obstetrics and Gynecology: Recurrent Miscarriage by Mala Arora.
2011. Jaypee Publication
Test results Diagnosis
Normal 5-15mmol/l
Mild 15-30 mmol/l
Moderate 30-100mmol/l
Severe > 100mmol/l
8. EPIDEMIOLOGY IN INDIA
India predominantly
follows vegetarian food
habits
Higher levels of
homocysteine due to
Vitamin B12 deficiency
www.veganhealth.org
Homocysteine Levels
9. ETIOLOGY OF
HYPERHOMOCYSTEINEMIA
1. Vitamin Deficiencies
• Folic acid (vitamin B9)
• Vitamin B12
• Vitamin B6
2. Genetic causes
• Defects (due to gene mutation) in enzyme causing
metabolism of homocysteine (Rare)
Current Drug Metabol 2007 Jan;8(1):17-31
Int Arch Cardiovasc Dis 2018, 2:008
10. ONE CARBON METABOLISM
• It is regulated by its
• Cofactors (folate, vitamin B12, and vitamin B6),
• Substrates (methionine, cysteine) and
• Intermediates (SAM, SAH, and homocysteine).
• It thus entails pathways that conserve methionine to assure
methyl group availability and removes unwanted
homocysteine from the system.
Epigenetic Biomarkers and Diagnostics.edited by Jose Luis Garcia-Gimenez
11. FOLATE-DEPENDENT &
INDEPENDENT RE-METHYLATION
• Folate is a coenzyme in nucleic acid synthesis and methionine
regeneration.
• Mild HHcy is usually caused by mild impairment of the
methylation pathway and is associated with folate or B12
deficiencies or the thermolability of MTHFR.
• Choline and betaine represent the essential sources of one-carbon
units, especially during folate deficiency.
EPMA Journal (2021) 12:477–505
12. The homocysteine level tends to drop in the first trimester;
it reaches its lowest value during the second trimester:
thereafter, it increases steadily at the end of pregnancy
until it reaches the level at the beginning of pregnancy.
The homocysteine level is lower during pregnancy
compared to its normal values.
13. HOMOCYSTEINE LEVELS
DURING PREGNANCY
Eur J Obstet Gynecol Reprod Biol. 2000 Dec;93(2):157-65.
EPMA Journal (2021) 12:477–505
Elevated levels of Hcy in blood plasma (> 15 μmol/L) is a
systemic medical condition known as hyperhomocysteinemia
15. PATHOPHYSIOLOGY
OF COMPLICATIONS
Hyperhomocysteinemia reduces the nitric
oxide released by the vascular endothelium.
Causes the formation of thrombosis.
Reduced placental perfusion.
Increases risk of abortive disease,
preeclampsia, premature delivery,
retroplacental hematoma, and intrauterine
growth restriction.
17. CLINICAL OUTCOMES IN
PREGNANCY
• Approximately 2-fold to 3-fold increased risk for :
• Pregnancy-induced hypertension.
• Abruptio placentae.
• Intrauterine growth restriction.
• Cobalamin Deficiency:
• HELLP syndrome.
• Abruptio placentae.
• Intrauterine growth restriction Intrauterine fetal death.
• Pyridoxal 5-phosphate deficiency:
• Increased risk for pregnancy-induced hypertension 4-fold.
Steegers-Theunissen RP, et al. Obstet Gynecol. 2004 Aug;104(2):336-43.
18. HYPERHOMOCYSTEINEMIA &
RECURRENT PREGNANCY LOSS
• 53% of cases remain of unexplained RPL.
• Hyperhomocysteinemia has been suggested as a risk factor for
recurrent miscarriages due to its pro-thrombotic effect.
• Hyperhomocysteinemia may
• Interferes with the function of fibrinolytic enzymes by causing them to
bind to the lysine residue of homocysteine.
• Lowers the production of nitric oxide (NO) by endothelial cells and
platelets.
• Increases production of reactive oxygen species (ROS).
Bahrain Medical Bulletin, Vol. 44, No. 3, September 2022. 1036-1040
19. SERUM HOMOCYSTEINE LEVELS
IN
PRE-ECLAMPSIA
• Pre-eclampsia was related to
• 4.5% higher blood homocysteine level and a
• 1.6-fold higher risk of presenting elevated homocysteine than women
with uncomplicated pregnancies.
• Homocysteine levels were elevated in women with a history of PE,
years after giving birth.
Memon SI, Acharya NS. Cureus. 2022 Nov 9;14(11):e31305. doi: 10.7759/cureus.31305
20. • Prospective study conducted over 2 years.
• Objective : To find the correlation between serum homocysteine levels,
relevant laboratory investigations and complications associated with PIH.
• N= 214 cases.
J Obst Gyne of India (September–October 2016) 66(S1):S167–S171
21. J Obst Gyne of India (September–October 2016) 66(S1):S167–S171
Homocysteine test is easy and less time consuming and can be reliably considered as
the predictive marker for pregnancy-induced hypertension.
22. • High homocysteine levels detected during early weeks of gestation
can be a warning about the miscarriage risk, and may also provide
insight about the obstetric complications that may develop in the
further weeks of gestation.
Perinatal Journal 2019;27(3):189–193
• 70 patients diagnosed with miscarriage between 5 and 12 weeks of gestation and 54 normal
pregnant women.
Mean serum Hcy level p value
Control group (N=54) 4.8―0.9 nmol/l
p <0.001
Threatened miscarriage group (N=17) 8.9±3.9 nmol/l
Missed miscarriage (N=26) 7.8±2.5 nmol/l
Incomplete group (N=17) 8.7±4.2 nmol/l
23. WHEN TO SCREEN FOR
HYPERHOMOCYSTEINEMIA?
• Values in early pregnancy are more reliable.
• Second-trimester plasma homocysteine concentrations do
not predict the subsequent development of
• Pregnancy-induced Hypertension,
• Eclampsia &
• Intrauterine Growth Restriction.
Hogg BB, et al. J Obstet Gynecol. 2000 Oct;183(4):805-9.
Zeeman GG, et al. Obstet Gynecol. 2003 Aug;189(2):574-6
24. HOW TO TREAT ?
• Treat with Homocysteine lowering therapy
• Supplementation of Vitamin B6, B9, B12.
• Folic acid and cobalamin supplementation ensure that methionine
synthase cofactor stores are adequate, thereby promoting normal
tetrahydrofolate metabolism and re-methylation of homocysteine to
methionine.
Maron BA, Loscalzo J. Annu Rev Med. 2009;60:39-54. doi: 10.1146/annurev.med.60.041807.123308.
25. FOLIC ACID IN
HYPERHOMOCYSTEINEMIA
• Adequate folate status is needed to re-methylate homocysteine
into methionine.
• Supplementation with folic acid in amounts of 0.5–5 mg per day
has been found to reduce homocysteine levels by around 25%.
26.
27. VITAMIN B6
• Reduces the level of homocysteine by the process of trans-
sulfuration to cysteine & hence related pregnancy complications
are reduced.
• Vitamin B6 levels of mothers at the onset of pregnancy have a
positive correlation with the birth weight of newborns.
• The usual therapeutic dose of pyridoxine does not have
teratogenic effects.
Int J Vitam Nutr Res. 1978;48(4):341-7
Curr Pediatr Res 2017; 21 (4): 613-619
28. VITAMIN B6
• Vitamin B6 is abundant in meat, fish, and poultry.
EPMA Journal (2021) 12:477–505
29. VITAMIN B12
• In Vitamin B12 deficiency, folate is trapped as unusable MTHF,
causing functional folate deficiency.
• Vitamin B12 deficiency is more common among Indian pregnant
women as compared to folate deficiency.
30.
31. Imbalance in the maternal micronutrients with
an increasing ratio of folate to vitamin B12 was
associated with an
• ↑ in plasma Homocysteine( p = 0.014),
• ↓ neonatal birth weight ( p = 0.009),
• ↓ birth length ( p =0.034),
• ↓ head circumference ( p =0.018)
Supplementation of Vit.B12 in addition to folic acid may improve the birth outcome
and lower homocysteine. Gadgil M et al. Eur J Clin Nutr. 2014 Jun;68(6):726-9. doi: 10.1038/ejcn.2013.289
32. WHY ACTIVE FORMS OF
B VITAMINS?
Synthetic Vit. B6
PLP
(metabolically active
Oxidized to
Pyridoxal form
Cyanocobalamin
Methylcobalamin
(metabolically active
Decyanization
Cobalamin II
reduction
SAMe Methyl
Transfer
Phosphorylation
Ann N Y Acad Sci. 1990;585:110-7
http://hsfighters.bioactivhealth.com/b12_case.htm
33. TAKE HOME MESSAGE
• Impaired Homocysteine metabolism is an important risk factor in
pregnant women.
• Hyper-homocysteine is associated with several pregnancy-related
complications.
• At present, homocysteine test can be considered selectively in patients
with high risks or women with poor maternal history.
• B vitamin supplementation should be considered from early
pregnancy to reduce the complications associated with hyper-
homocysteinemia.
• Supplementation of active forms of B vitamins can be considered as it
is now widely available in supplements with economical cost.
HHcy can be related to increased Hcy
production by transmethylation, decreased Hcy removal by
transsulfuration or remethylation, or a decrease in the Hcy
excretion
Epigenetic Biomarkers and Diagnostics.edited by Jose Luis Garcia-Gimenez
Many recent studies supported the theory of a correlation between increased levels of HCys and high blood pressure, both independent risk factors for cardiovascular disease and stroke.
An excess of HCys can favor atherogenesis being therefore harmful for the cardiovascular s, important role in the pathogenesis of various diseases affecting the nervous system, such as stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, etc., although its mole, HHCys has been related to Alzheimer's and Parkinson diseases, particularly in the late stages of the illnesses or after long-term levodopa treatmencular mechanism in this role is not yet fully defined.
Rheumatic diseases are frequently associated with a high prevalence of coronary events, indeed patients with rheumatoid arthritis (AR) and systemic lupus erythematosus (LES) develop precocious atherosclerosis and show increased mortality
HHCys may contribute to the alteration of cerebral flow, with risk of thrombosis and alteration of the cerebral oxygen transport, ultimately promoting migraine aura events.
HHCys seemed to be associated with psoriatic disorder and with platelet hyperactivity that promotes prothrombotic events, which determine increased risk of death caused by arterial and venous thrombosis
Obstet Gynecol
. 2004 Aug;104(2):336-43.
doi: 10.1097/01.AOG.0000129955.47943.2a.
Hyperhomocysteinemia, pregnancy complications, and the timing of investigation
Régine P Steegers-Theunissen 1, Carola A Van Iersel, Petronella G Peer, Willianne L Nelen, Eric A Steegers
Affiliations expand
PMID: 15292008
DOI: 10.1097/01.AOG.0000129955.47943.2a
Abstract
Objective: To assess associations between vitamin-dependent homocysteine metabolism and vascular-related pregnancy complications by considering interval between delivery and postpartum investigation and maternal age.
Methods: Case-control study performed at the University Medical Center Nijmegen in the Netherlands. Patients had experienced pregnancy-induced hypertension (n = 37), preeclampsia (n = 144), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 104), recurrent early pregnancy loss (n = 544), abruptio placentae (n = 135), intrauterine growth restriction (n = 144), or intrauterine fetal death (n = 104). Controls comprised 176 women with uncomplicated obstetric histories. Oral methionine loading tests and fasting vitamin profiles were performed more than 6 weeks after delivery. Odds ratios and 95% confidence intervals were calculated after logistic regression analysis.
Results: Hyperhomocysteinemia was associated with an approximately 2-fold to 3-fold increased risk for pregnancy-induced hypertension, abruptio placentae, and intrauterine growth restriction. Cobalamin deficiency was associated with HELLP syndrome, abruptio placentae, intrauterine growth restriction, and intrauterine fetal death. Pyridoxal 5-phosphate deficiency increased the risk for pregnancy-induced hypertension 4-fold. These associations lost their significance after adjustment for time interval and maternal age. High red cell folate was associated with a decreased risk for abruptio placentae and intrauterine growth restriction. An increased creatinine concentration was associated with pregnancy-induced hypertension, preeclampsia, HELLP syndrome, and abruptio placentae.
Conclusion: Hyperhomocysteinemia and vitamin deficiencies are largely determined by the interval between delivery and postpartum investigation and by maternal age. Time interval and maternal age should be considered in the risk estimation for vascular-related pregnancy complications.
Objective: To investigate the relationship between high maternal homocysteine levels and early pregnancy losses.
Methods: Seventy patients diagnosed with miscarriage (missed, incomplete and threatened) between 5 and 12 weeks of gestation and 54 pregnant women without any problem during their follow-up were compared in terms of homocysteine levels during pregnancy.
Results: The highest mean serum homocysteine level among the miscarriage groups was in the threatened miscarriage group (8.9―3.9 nmol/l), followed by 7.8}2.5 and 8.7}4.2 nmol/l in the missed and incomplete miscarriage groups, respectively. The mean serum homocysteine level in the control group was 4.8}0.9 nmol/l. The
homocysteine levels of the control group were significantly lower than all three miscarriage groups (p<0.01). On the other hand, there was no significant difference between the homocysteine levels of the miscarriage groups (p>0.05). When compared to the control group, the most significant difference among the serum homocysteine levels was found in the missed miscarriage (p<0.01).
Eur J Clin Nutr
. 2014 Jun;68(6):726-9.
doi: 10.1038/ejcn.2013.289. Epub 2014 Jan 22.
Imbalance of folic acid and vitamin B12 is associated with birth outcome: an Indian pregnant women study
M Gadgil 1, K Joshi 1, A Pandit 2, S Otiv 3, R Joshi 2, J T Brenna 4, B Patwardhan 1
Affiliations expand
PMID: 24448492
DOI: 10.1038/ejcn.2013.289
Abstract
Background/objectives: Maternal nutrient supplementation in developing countries is generally restricted to provision of iron and folic acid. Along with folic acid, vitamin B12 is also an important determinant of fetal growth and development. During pregnancy, the increased requirement of folic acid is met with supplementation, while vitamin B12 remains untreated and possibly deficient. The objective of our study was to study the combined effect of maternal plasma folate and vitamin B12, and their ratio on birth anthropometrics.
Subjects/methods: We carried out an observational study on 49 full-term pregnant women at KEM Hospital, Pune, India, during 2006-2008, and measured plasma folate, vitamin B12 and homocysteine in venous blood at 36 weeks of gestation. Neonatal anthropometrics (birth weight, length, head circumference, abdominal circumference, mid arm circumference, chest circumference, triceps skinfold and subscapular skinfold thickness) were measured within 24 h of birth.
Results: Maternal plasma folate and vitamin B12 were not correlated to neonatal anthropometrics. The combined association of folate and vitamin B12 expressed as folate to vitamin B12 ratio was correlated to the neonatal anthropometrics. Imbalance in the maternal micronutrients with increasing ratio of folate to vitamin B12 was associated with an increase in plasma homocysteine (P=0.014), lowering of neonatal birth weight (P=0.009), birth length (P=0.034), head circumference (P=0.018) and chest circumference (P=0.009), while no significant association to other anthropometrics was observed.
Conclusions: Supplementation of vitamin B12 in addition to supplementation of folic acid in pregnancy may be important for improving birth weight, birth length, head circumference and chest circumference.
Vitamin B6
The B6 vitamers (pyridoxine, pyridoxamine, and pyridoxal) are primarily metabolized in liver to pyridoxal 5'-phosphate (PLP) and the deadend catabolite 4-pyridoxic acid.
Vitamin B6 (Pyridoxine) is absorbed in the intestines and converted to its active form, pyridoxal-5′-phosphate, in the liver by the enzyme pyridoxal kinase. However, in some people their liver function is slow or impaired so the production of P5P will be limited.
Pyridoxal-5-Phosphate, or P5P as it is commonly known, is the active form of vitamin B6. In foods or most supplements, vitamin B6 is found in one of three forms: pyridoxine hydrochloride, pyridoxal, or pyridoxamine. Inside the body, these forms of B6 have to be converted by the liver to the active form the body needs – P5P. Low rates of conversion from the inactive to the active form of vitamin B6 have been reported, especially in people with impaired liver function, celiac’s disease, older adults, and in children with autism. By consuming vitamin B6 in the active P5P form, conversion is no longer necessary, and the full benefits are available immediately after absorption.
Vitamin B12
When Vitamin B12 succeeds at entering the bloodstream it then must be converted to an active coenzyme before it is beneficial to our health. Three steps are required to convert the manmade B12 you encounter in many vitamin supplements (called cyanocobalamin) into methylcobalamin, the body ready coenzyme of B12 provided in the HS Fighters formula.
Step one of the conversion sequence above is for your body to remove a molecule of cynanide from cyanocobalamin, although the amount cyanide in this form of B12 is not considered toxic.
Dose for dose, there is substantially greater retention of useable B12 when taking methylcobalamin as a supplement ingredient. The amount of B12 (simple cobalamin) excreted in the urine after a dose of methylcobalamin is about one-third that of a similar dose of cyanocobalamin. It takes approximately 1-2 months for cyanocobalamin to be converted to active B12, assuming an adequate supply of necessary cofactors is available.