Amino acid supplementation to prevent or treat IUGR acts as an attractive potential therapeutic option. CALCIUM & Vit D supplementation has a role

1. PREDICTORS AND PREVENTION
OF PRECLAMPSIA

2. Dr. Niranjan Chavan
MD, FCPS, DGO, DFP, MICOG, DICOG, FICOG
Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H
Chairperson, FOGSI Oncology and TT Committee (2012-2014)
Treasurer, MOGS (2017- 2018)
Chair and Convener, FOGSI Cell- Violence against Doctors (2015-2016)
Chief Editor, AFG Times (2015-2017)
Editorial Board, European Journal of Gynecologic Oncology
Editor of FOGSI FOCUS, MOGS, AFG & IAGE Newsletters
Member, Managing Committee, IAGE (2013-2017)
Member , Oncology Committee, AOFOG (2013 -2015)
Recipient of 6 National & International Awards
Author of 15 Research Papers and 19 Scientific Chapters
Course Co-Ordinator, of 11 batches, of MUHS recognized Certificate Course of
Basic Infertility Management Including Endoscopy (BIMIE) at LTMGH

3. Pre-eclampsia (PE) is
a multi factorial pregnancy related disorder
characterized by hypertension and proteinuria after 20
weeks of gestation.
 2nd most common complication seen during pregnancy
 Incidence ranges between 5-15% of all pregnancies

4.  PIH* is reported to be a global problem complicating around 10-17% of
pregnancies1
 It is the 2nd most common medical disorder seen during pregnancy2
 It is one of the most common disorders associated with increased risk of
maternal and fetal complications3
*PIH = Pregnancy induced hypertension
1. Sharma A, Mahendra P, Bisht S. Management of pregnancy induced hypertension. IJRAP. 2010;1(2):390-8.
2. Parmar MT, Solanki HM, Gosalia VV. Study of risk factors of perinatal death in pregnancy induced hypertension (PIH). National Journal of Community Medicine.
2012;3(4):703-7.
3. Bangal VB, Giri PA, Mahajan AS. Maternal and foetal outcome in pregnancy induced hypertension: A study from rural tertiary care teaching hospital in India.
International Journal of Biomedical Research. 2011;2(12):595-9.
“Early detection and prompt treatment of PIH results in favorable
prognosis of
both the mother and the fetus1”
Incidence of
pregnancy induced
hypertension

5. PATHOGENESIS OF PRECLAMPSIA

6. PATHOGENESIS OF PRECLAMPSIA

8. Amino acid Role in pregnancy
Histidine-
rich
glycoprotein
May help prevent pre-eclampsia1
Methionine Provides methyl groups that help in fetal growth2
Threonine Provides essential protein and energy required to reduce
intrauterine growth restriction (IUGR)3
L-tryptophan Vital for protein synthesis and fetal growth and
development4
Glycine Reverses hypertension and protects the fetus from
abnormal programing of the cardiovascular system51. Bolin M, Akerud P, Hansson A, Akerud H. Histidine-rich glycoprotein as an early biomarker of preeclampsia. Am J Hypertens. 2011;24(4):496-501.
2. Kalhan SC, Marczewski SE. Methionine, homocysteine, one carbon metabolism and fetal growth. Rev Endocr Metab Disord. 2012;13(2):109-19.
3. Metcoff J, Cole TJ, Luff R. Fetal growth retardation induced by dietary imbalance of threonine and dispensable amino acids, with adequate energy and protein-
equivalent intakes, in
pregnant rats. J Nutr. 1981;111(8):1411-24.
4. Badawy AA. The tryptophan utilization concept in pregnancy. Obstet Gynecol Sci. 2014;57(4):249-59.
5. Brawley L, Torrens C, Anthony FW, Itoh S, Wheeler T, Jackson AA, et al. Glycine rectifies vascular dysfunction induced by dietary protein imbalance during
pregnancy. J Physiol.
2004;554(2):497-504.
ESSENTIAL AND NON-
ESSENTIAL AMINO ACIDS

9. RISK FACTORS FOR PRECLAMPSIA
 Family h/o of preclampsia
 First pregnancy
 Age < 20 yrs or > 40 yrs
 Increased intervals between pregnancy
 Obesity
 Multifetal gestation
 H/O medical disorders DM, kidney disorders,
rheumatoid arthritis
 Smoking

10. The ideal biochemical marker for preclampsia should
 Play a central role in pathogenesis
 Be specific for the condition
 Appear early or before the clinical manifestation
 Be easy or cheap to detect in maternal blood and urine
 Show high sensitivity and specificity
 Correlate with severity of condition
 Be non detected or in very low levels in normal
pregnancy

11. TESTS FOR PREDICTION OF PIH
 Roll over test
 Isometric hand grip test
 Angiotensin infusion test
 Mid trimester mean arterial pressure
 Platelet angiotensin II binding
 24 hours ambulatory BP monitoring
 Uterine artery doppler velocimetry

12. BIOCHEMICAL MARKERS OF PIH
 Uric acid
 Microalbuminuria
 Urine albumin
 Fibronectin

13. URIC ACID LEVELS
Elevated serum uric acid levels are associated with severity
of preeclampsia and perinatal outcome
Hyperuricaemia, an early sign of renal involvement,
occurs due to altered tubular processing of uric acid
preceding glomerular affliction which causes albuminuria

14. NEWER BIOCHEMICAL PREDICTORS
 HCG, AFP, Estriol
 PAPP A, Inhibin A, Activin A
 Placental protein 13
 Corticotropin releasing hormone
 C reactive protein
 Endothelins, homocysteine
 Anti phospholipid antibodies
 Plasminogen activator inhibitor
 Prostaglandins, thromboxanes

15.  Angiogenic factors
 placental growth factor,
 vascular endothelial growth factor,
 fms like tyrosine kinase receptor 1(s-FLT 1),
 endoglin.
 Atrial natriuretic peptide
 Anti thrombin 3
 Leptin
 Beta 2 microglobulin
 Free fetal DNA
 Serum proteomic markers

16. NOVEL URINARY MARKERS OF
PRECLAMPSIA
 Urinary soluble endoglin
 Soluble fms like tyrosine kinase 1
 Inhibin A
 Urinary kallikrein to creatinine ratio
 Urinary microtransferrin level
 Urinary N acetyl beta glucosaminidase levels

17.  Mid trimester Beta HCG levels correlate with severity of
preclampsia
 Combination of beta HCG, maternal age, body mass index
and parity superior in the prediction of preclampsia
 This multifactorial model can help predict preclampsia
with a sensitivity of 70% and specificity of 71%

18. PREGNANCY ASSOCIATED PLASMA
PROTEIN A
PAPP-A is a 1628 amino acid protease, mainly produced by
the placental trophoblasts
In fetuses with normal chromosomes,
decreased levels of PAPP A in first trimester
is associated with increased levels of early onset
preclampsia, IUGR, SGA and preterm delivery
D’Anna R, Baviera G, Giordano D, Russo S, Dugo N, 37. Santamaria A, et al. First trimester serum
PAPP-A and NGAL in the prediction of late-onset pre-eclampsia. Prenat Diagn 2009; 29 : 1066-8.

19. PLACENTAL PROTEIN 13
 PP13 is a 32 kDa dimeric protein produced by placental
tissue.
 PP13 levels gradually increase in normal pregnancy.
 Abnormally low levels of PP13 were found in women who
developed pre-eclampsia, IUGR and preterm delivery
during 2nd and 3rd trimesters

20. FETAL DNA
 Free extracellular fetal hemoglobin is involved in the
pathogenesis of preclampsia
 Increased mRNA of Hb F in placental tissue and free Hb
F are associated with increased risk of PIH

21. SOLUBLE FLT 1
 sFlt-1 is an anti-angiogenic soluble form of type -1 VEGF
receptor.
 Elevated level is associated with onset of preclampsia
and severity of illness
 Serum sFlt1 binds with both VEGF and PlGF, thereby
neutralizing them, and subsequently decreasing their
levels in circulation

22.  Soluble endoglin , a cell receptor of transforming growth
factor beta is localised to syncytiotrophoblast and
endothelial cells
 It is a second trimester marker of preclampsia
 Levels were found to be increased 2-3 months prior to
the onset of severe preclampsia

23. LEPTIN
 Leptin, the product of the ob gene, is produced in the
adipose cells
 Studies have shown high maternal leptin levels in the
second trimester of pregnancy in women with
preclampsia

24. DOPPLER ULTRASOUND
Ultrasound and Color doppler techniques allow the study of
umbilical and uterine arteries for the prediction of
preclampsia
 Association with preclampsia:
 High umbilical artery resistance waveform (S/D ratio)
 Notching of the uterine artery waveform in the second
trimester
 Oligohydramnios
Zimmerman P, Eirio V, Kosikinen J, et al. Ultrasound. Obstet Gynaecol. 1997;9:330–338

25. PREVENTION OF PRECLAMPSIA
 Primary: Contraception
 Secondary:
 Aspirin
 Calcium supplementation
 Tertiary: (Prevention of complications)
 Anti hypertensives
 MgSO4
 L arginine, Lycopene

26. Pre-eclampsia is characterised by an imbalance in
prostacyclin/thromboxane A2 ratio
Low-dose aspirin is known to correct the prostaglandin
imbalance
RCOG guidelines recommend that
low dose aspirin started prior to 16 weeks of gestation
has demonstrated a statistically significant effect in
the prevention of pre-eclampsia

27. CALCIUM SUPPLEMENTATION
Studies have suggested that the frequency of pre-
eclampsia/eclampsia is inversely proportional to nutritional
calcium intake.
Calcium supplementation (1.5-2 gms/day) is found to be
protective in
populations with a low baseline calcium intake.
Marcoux S, Brisson J, Fabia J. Calcium intake from dairy products and supplements and the
risks of preeclampsia and gestational hypertension. Am J Epidemiol 1991; 133: 1266–72.

28. Free radical mediated lipid peroxidation is involved in
endothelial damage seen in preclampsia
Lycopene is a carotenoid micronutrient with anti oxidant
properties
Several studies have shown that lycopene is effective in
reducing the occurrence of preeclampsia and IUGR.
Palan PR, Mikhail MS, Romney SL. Placental and serum levels of carotenoids in pre-
eclampsia. Obstet Gynecol 2001;98:459 –462

29. Nitric oxide is a potent endothelium derived vasodilator
produced by nitric oxide synthase in endothelial cells,
which uses circulating L-arginine as a substrate.
 In a population of women at high risk of pre-eclampsia,
dietary supplementation with Larginine and antioxidant
vitamins is shown to reduce occurrence of the disease
 Germain AM, Valdez G, Romanik MC, Reyes S. Letter to the editor: evidence supporting a
beneficial role for long term L-arginine supplementation in high-risk pregnancies. Hypertension
2004;44:e1.

30.  BCAAs* promote fetal growth by encouraging:
• Improved placental and fetal perfusion
• Tissue-specific growth and metabolism OR
• Through undiscovered mechanisms
 Leucine possesses the greatest capacity to increase the synthesis of
muscle protein, via signaling pathways involving the mammalian target of
rapamycin (mTOR)
*BCAAs = Branched-chain amino acids
Brown LD, Green AS, Limesand SW, Rozance PJ. Maternal amino acid supplementation for intrauterine growth restriction. Front Biosci (Schol Ed). 2011;3:428–44.
“BCAAs helps to encourage placental and fetal perfusion and
promote tissue specific growth and metabolism”
Evidence supporting the role of
branched-chain amino acids in
pregnancy

31.  Oxidative stress could inactivate nitric
oxide (NO) and thus impair endothelium-
dependent vasodilatation1
 Inhibition of oxidative stress can be an
effective method for controlling BP1
 Oxidative stress also play a role in causing
placental dysfunction and subsequent
complications like growth restriction,
hypertension, and preeclampsia2
1. Li X, Xu J. Lycopene Supplement and Blood Pressure: An Updated Meta-Analysis of Intervention Trials. Nutrients. 2013;5(9):3696–12.
2. Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care. 2008;31 Suppl 2:S181-4.
“Lycopene inhibits oxidative stress and helps to reduce BP1”
How lycopene helps to reduce
blood pressure (BP) in pregnancy?

32. A study conducted by Sharma et al.
showed that lycopene 4 mg is
effective in:
 Reducing PIH: Mean diastolic
blood pressure was significantly
lower (86.7±3.80 mmHg) in the
lycopene group than in the placebo
group (92.2±5.8 mmHg) (p=0.012)
 Reducing pre-eclampsia by 51%
and IUGR by 49% (Figure 6)
Sharma JB, Kumar A, Kumar A, Malhotra M, Arora R, Prasad S, et al. Effect of lycopene on pre-eclampsia and intra-uterine growth retardation in primigravidas. Int J
Gynaecol Obstet. 2003;81(3):257-62.
Figure 5: Incidence of IUGR and
pre-eclampsia after treatment with
lycopene
Evidence supporting the role of
lycopene in controlling BP and
pregnancy complications like IUGR
and preeclampsia

33.  Amino acid supplementation to prevent or treat
IUGR acts as an attractive potential therapeutic
option
 CALCIUM & Vit D supplemenation has a role
 Lycopene, one of the most powerful antioxidant,
inhibits oxidative stress and helps to reduce BP
NUTRITIONAL
SUPPLEMENTS