Prediction and prevention of Preeclampsia

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. 2 nd 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 pregnancies 1 It is the 2 nd most common medical disorder seen during pregnancy 2 It is one of the most common disorders associated with increased risk of maternal and fetal complications 3 *PIH = Pregnancy induced hypertension Sharma A, Mahendra P, Bisht S. Management of pregnancy induced hypertension. IJRAP . 2010;1(2):390-8. 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. 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 fetus 1 ” Incidence of pregnancy induced hypertension

5. PATHOGENESIS OF Preclampsia

6. Pathogenesis of preclampsia

7. Amino acid Role in pregnancy Histidine -rich glycoprotein May help prevent pre-eclampsia 1 Methionine Provides methyl groups that help in fetal growth 2 Threonine Provides essential protein and energy required to reduce intrauterine growth restriction (IUGR) 3 L-tryptophan Vital for protein synthesis and fetal growth and development 4 Glycine Reverses hypertension and protects the fetus from abnormal programing of the cardiovascular system 5 1. 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

8. 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

9. 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

10. 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

11. biochemical markers of pih Uric acid Microalbuminuria Urine albumin Fibronectin

12. 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

13. 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

14. 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

15. 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

16. 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%

17. 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.

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

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

25. 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

26. 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 .

27. 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

28. 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.

29. 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

30. Oxidative stress could inactivate nitric oxide (NO) and thus impair endothelium-dependent vasodilatation 1 Inhibition of oxidative stress can be an effective method for controlling BP 1 Oxidative stress also play a role in causing placental dysfunction and subsequent complications like growth restriction, hypertension, and preeclampsia 2 Li X, Xu J. Lycopene Supplement and Blood Pressure: An Updated Meta-Analysis of Intervention Trials. Nutrients . 2013;5(9):3696–12. 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 BP 1 ” How lycopene helps to reduce blood pressure (BP) in pregnancy?

31. 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

32. 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