Skip to main content Skip to main navigation menu Skip to site footer

Hubungan antara kadar homosistein (Hcy) dengan kejadian ketuban pecah dini (KPD) pada kehamilan preterm

  • Agrifa Eko Albert Sembiring ,
  • Tjokorda Gde Agung Suwardewa ,
  • Ketut Surya Negara ,
  • I Nyoman Gede Budiana ,
  • Ida Bagus Putra Adnyana ,
  • Evert Solomon Pangkahila ,

Abstract

Background: Premature rupture of membranes (PROM) has been a problem in obstetrics since ancient times until now. The incidence of PROM in the world ranges from 5% - 15% of all pregnancies, while the incidence in developing countries, especially Indonesia ranges from 4.5% to 7.6% of all pregnancies. Preterm is one of the highest contributors to perinatal mortality and morbidity. The incidence of preterm pregnancy in the world is around 9.6% of all births, while in Southeast Asia is around 11.1% It has been shown to have a significant effect on vascular endothelial pathology. 

Methods: The study was conducted with an analytic cross-sectional design involving  70 respondents of pregnant women with gestational age of 20 - < 37 weeks with and without PPROM who came to the outpatient clinic and maternity ward of Prof. Dr. I.G.N.G. Ngoerah Hospital Denpasar from May 2021 – July 2021. 

Results: The results of the analysis of this study found a statistically significant relationship between homocysteine (Hcy) levels and the incidence of preterm premature rupture of membranes (p = 0.001). The prevalence ratio value of 2.2 means that high homocysteine levels is a risk factor for premature rupture of membranes in preterm pregnancy (RP = 2.2; 95% CI = 1.33-2.94; p = 0.001).

Conclusion: High homocysteine level is a risk factor for premature rupture of membranes in preterm pregnancy.

 

Latar Belakang: Ketuban pecah dini (KPD) preterm merupakan masalah di bidang obstetrik sejak dahulu sampai sekarang. Insiden KPD di dunia berkisar antara 5% - 15% dari seluruh kehamilan. Insiden KPD di negara berkembang khususnya Indonesia berkisar 4,5% - 7,6% dari seluruh kehamilan. Kehamilan preterm menjadi salah satu penyumbang tertinggi angka mortalitas dan morbiditas perinatal. Insiden kehamilan preterm di dunia sekitar 9.6% dari semua kelahiran, sedangkan di Asia tenggara terdapat sekitar 11,1%. Hcy telah terbukti signifikan berpengaruh pada patologi endotel pembuluh darah.

Metode: Penelitian dilakukan dengan rancangan cross sectional analitik dengan melibatkan 70 responden wanita hamil dengan usia gestasi 20 - <70 minggu dengan atau tanpa KPD yang dating ke poliklinik dan ruang bersalin RSUP Prof. Dr. I.G.N.G. Ngoerah bulan Mei 2021 – Juli 2021.

Hasil: Diperoleh hubungan bermaksana secara statistik antara kadar homocycteine dengan kejadian ketuban pecah dini pada kehamilan preterm (p = 0, 001), dan rasio prevalensi 2,2 berarti kadar homosisteine yang tinggi merupakan faktor risiko terjadinya ketuban pecah dini pada kehamilan preterm (RP = 2.2; 95% CI = 1.33-2.94; p = 0.001).

Kesimpulan: Kadar homosistein yang tinggi merupakan faktor risiko terjadinya ketuban pecah dini pada kehamilan preterm.

References

  1. Beta J, Zhang W, Geris S, Kostiv V, Akolekar R. Procedure-related risk of miscarriage following chorionic villus sampling and amniocentesis. Ultrasound Obstet Gynecol. 2019 Oct;54(4):452-457. doi: 10.1002/uog.20293. Epub 2019 Sep 6. PMID: 30977213.
  2. Caughey AB, Robinson JN, Norwitz ER. Contemporary diagnosis and management of preterm premature rupture of membranes. Rev Obstet Gynecol. 2008 Winter;1(1):11-22. PMID: 18701929; PMCID: PMC2492588.
  3. Baldwin EA, Walther-Antonio M, MacLean AM, Gohl DM, Beckman KB, Chen J, White B, Creedon DJ, Chia N. Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery. PeerJ. 2015 Nov 26;3:e1398. doi: 10.7717/peerj.1398. PMID: 26644969; PMCID: PMC4671185.
  4. Beck V, Lewi P, Gucciardo L, Devlieger R. Preterm prelabor rupture of membranes and fetal survival after minimally invasive fetal surgery: a systematic review of the literature. Fetal Diagn Ther. 2012;31(1):1-9. doi: 10.1159/000331165. Epub 2011 Nov 19. PMID: 22104520.
  5. Bergen NE, Jaddoe VW, Timmermans S, Hofman A, Lindemans J, Russcher H, Raat H, Steegers-Theunissen RP, Steegers EA. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG. 2012 May;119(6):739-51. doi: 10.1111/j.1471-0528.2012.03321.x. PMID: 22489763.
  6. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol. 2013 Jan;28(1):1-19. doi: 10.1007/s10654-013-9762-6. Epub 2013 Feb 9. PMID: 23397514.
  7. Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GD, Eddleman K, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, D'Alton ME. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Med. 2009 May 5;6(5):e1000061. doi: 10.1371/journal.pmed.1000061. Epub 2009 May 12. PMID: 19434228; PMCID: PMC2671168.
  8. Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, Zheng Q, Fu L, Du J. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013 Feb 10;514(2):105-11. doi: 10.1016/j.gene.2012.10.091. Epub 2012 Nov 29. PMID: 23201418.
  9. Chaudhry SH, Taljaard M, MacFarlane AJ, Gaudet LM, Smith GN, Rodger M, Rennicks White R, Walker MC, Wen SW. The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort. BMC Pregnancy Childbirth. 2019 Feb 19;19(1):75. doi: 10.1186/s12884-019-2219-5. PMID: 30782144; PMCID: PMC6381683.
  10. Kinshella MW, Omar S, Scherbinsky K, Vidler M, Magee LA, von Dadelszen P, Moore SE, Elango R; PRECISE Conceptual Framework Working Group. Maternal nutritional risk factors for pre-eclampsia incidence: findings from a narrative scoping review. Reprod Health. 2022 Sep 5;19(1):188. doi: 10.1186/s12978-022-01485-9. PMID: 36064716; PMCID: PMC9442926.
  11. Chen Z, Du J, Shao L, Zheng L, Wu M, Ai M, Zhang Y. Prepregnancy body mass index, gestational weight gain, and pregnancy outcomes in China. Int J Gynaecol Obstet. 2010 Apr;109(1):41-4. doi: 10.1016/j.ijgo.2009.10.015. Epub 2009 Dec 16. PMID: 20018282.
  12. Choi R, Choi S, Lim Y, Cho YY, Kim HJ, Kim SW, Chung JH, Oh SY, Lee SY. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women. Nutrients. 2016 Dec 8;8(12):797. doi: 10.3390/nu8120797. PMID: 27941633; PMCID: PMC5188452.
  13. Horan M.K., McGowan C.A., Gibney E.R., Donnelly J.M., McAuliffe F.M. The association between maternal dietary micronutrient intake and neonatal anthropometry—Secondary analysis from the rolo study. Nutr. J. 2015;14:105. doi: 10.1186/s12937-015-0095-z
  14. Corrado F, Cannata ML, La Galia T, Magliarditi M, Imbruglia L, D'anna R, Carlo Stella N. Pregnancy outcome following mid-trimester amniocentesis. J Obstet Gynaecol. 2012 Feb;32(2):117-9. doi: 10.3109/01443615.2011.633717. PMID: 22296417.
  15. Creus, M., Deulofeu, R., Peñarrubia, J., Carmona, F. & Balasch, J. (2013). Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. Clinical Chemistry and Laboratory Medicine, 51(3), 693-699. https://doi.org/10.1515/cclm-2012-0452
  16. Dhobale M, Chavan P, Kulkarni A, Mehendale S, Pisal H, Joshi S. Reduced folate, increased vitamin B(12) and homocysteine concentrations in women delivering preterm. Ann Nutr Metab. 2012;61(1):7-14. doi: 10.1159/000338473. Epub 2012 Jul 5. PMID: 22776827.
  17. Furness D, Fenech M, Dekker G, Khong TY, Roberts C, Hague W: Folate, Vitamin B12, vitamin B6 and homocysteine: impact on pregnancy outcome. Matern Child Nutr 2011, DOI: 10.1111/j.1740-8709.2011.00364.x.
  18. Dutta EH, Behnia F, Boldogh I, Saade GR, Taylor BD, Kacerovský M, Menon R. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod. 2016 Feb;22(2):143-57. doi: 10.1093/molehr/gav074. Epub 2015 Dec 21. PMID: 26690900.
  19. Enzensberger C, Pulvermacher C, Degenhardt J, Kawacki A, Germer U, Gembruch U, Krapp M, Weichert J, Axt-Fliedner R. Fetal loss rate and associated risk factors after amniocentesis, chorionic villus sampling and fetal blood sampling. Ultraschall Med. 2012 Dec;33(7):E75-E79. doi: 10.1055/s-0031-1299388. Epub 2012 May 23. PMID: 22623130.
  20. Gaiday AN, Tussupkaliyev AB, Bermagambetova SK, Zhumagulova SS, Sarsembayeva LK, Dossimbetova MB, Daribay ZZ. Effect of homocysteine on pregnancy: A systematic review. Chem Biol Interact. 2018 Sep 25;293:70-76. doi: 10.1016/j.cbi.2018.07.021. Epub 2018 Jul 24. PMID: 30053452.
  21. Gervasi MT, Romero R, Bracalente G, Chaiworapongsa T, Erez O, Dong Z, Hassan SS, Yeo L, Yoon BH, Mor G, Barzon L, Franchin E, Militello V, Palù G. Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. J Matern Fetal Neonatal Med. 2012 Oct;25(10):2002-13. doi: 10.3109/14767058.2012.683899. Epub 2012 May 30. PMID: 22524157; PMCID: PMC3498469.
  22. Heida KY, Velthuis BK, Oudijk MA, Reitsma JB, Bots ML, Franx A, van Dunné FM; Dutch Guideline Development Group on Cardiovascular Risk Management after Reproductive Disorders. Cardiovascular disease risk in women with a history of spontaneous preterm delivery: A systematic review and meta-analysis. Eur J Prev Cardiol. 2016 Feb;23(3):253-63. doi: 10.1177/2047487314566758. Epub 2015 Feb 9. PMID: 25665808.
  23. Hoffman M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses. 2011 Dec;77(6):1088-93. doi: 10.1016/j.mehy.2011.09.009. Epub 2011 Oct 2. PMID: 21963358.
  24. Hogeveen M, Blom HJ, den Heijer M. Maternal homocysteine and small-for-gestational-age offspring: systematic review and meta-analysis. Am J Clin Nutr. 2012 Jan;95(1):130-6. doi: 10.3945/ajcn.111.016212. Epub 2011 Dec 14. PMID: 22170376.
  25. Kacerovsky M, Vrbacky F, Kutova R, Pliskova L, Andrys C, Musilova I, Menon R, Lamont R, Nekvindova J. Cervical microbiota in women with preterm prelabor rupture of membranes. PLoS One. 2015 May 20;10(5):e0126884. doi: 10.1371/journal.pone.0126884. PMID: 25993616; PMCID: PMC4439143.
  26. Kamali M, Hantoushzadeh S, Borna S, Neamatzadeh H, Mazaheri M, Noori-Shadkam M, Haghighi F. Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta-Analysis. Iran Biomed J. 2018 Mar;22(2):78-89. doi: 10.22034/ibj.22.2.78. Epub 2017 Jul 23. PMID: 28734273; PMCID: PMC5786662.
  27. Kawamura M, Fukuda N, Suzuki A, Kobayashi Y, Matsuda M, Kanda R, Kiseki H, Tsukahara Y, Hashimura N. Use of fibrin monomer complex for screening for venous thromboembolism in the late pregnancy and post-partum period. J Obstet Gynaecol Res. 2014 Mar;40(3):700-4. doi: 10.1111/jog.12245. Epub 2013 Dec 10. PMID: 24321015.
  28. Knudtson EJ, Smith K, Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Meis PJ, Moawad AH, Vandorsten JP, Sorokin Y, Roberts JM, Das A; National Institutes of Child Health and Human Development Maternal-Fetal Medicine Units Network. Serum homocysteine levels after preterm premature rupture of the membranes. Am J Obstet Gynecol. 2004 Aug;191(2):537-41. doi: 10.1016/j.ajog.2003.12.005. PMID: 15343233.
  29. Kramer MS, Kahn SR, Rozen R, Evans R, Platt RW, Chen MF, Goulet L, Séguin L, Dassa C, Lydon J, McNamara H, Dahhou M, Genest J. Vasculopathic and thrombophilic risk factors for spontaneous preterm birth. Int J Epidemiol. 2009 Jun;38(3):715-23. doi: 10.1093/ije/dyp167. Epub 2009 Mar 31. PMID: 19336437.
  30. Lentz SR, Haynes WG. Homocysteine: is it a clinically important cardiovascular risk factor? Cleve Clin J Med. 2004 Sep;71(9):729-34. doi: 10.3949/ccjm.71.9.729. PMID: 15478704.
  31. Maayan-Metzger A, Lubetsky A, Kuint J, Rosenberg N, Simchen MJ, Kuperman A, Strauss T, Sela BA, Kenet G. The impact of genetic and environmental factors on homocysteine levels in preterm neonates. Pediatr Blood Cancer. 2013 Apr;60(4):659-62. doi: 10.1002/pbc.24352. Epub 2012 Sep 28. PMID: 23024114.
  32. Maged AM, Saad H, Meshaal H, Salah E, Abdelaziz S, Omran E, Deeb WS, Katta M. Maternal serum homocysteine and uterine artery Doppler as predictors of preeclampsia and poor placentation. Arch Gynecol Obstet. 2017 Sep;296(3):475-482. doi: 10.1007/s00404-017-4457-y. Epub 2017 Jul 8. PMID: 28689278.
  33. Mahmoodi Z, Hoseini F, Avval Shahr H, Ghodsi Z, Amini L. The Association between Maternal Factors and Preterm Birth and Premature Rupture of Membranes. J Family Reprod Health. 2010;4(3):135-139
  34. Mascarenhas M, Habeebullah S, Sridhar MG. Revisiting the role of first trimester homocysteine as an index of maternal and fetal outcome. J Pregnancy. 2014;2014:123024. doi: 10.1155/2014/123024. Epub 2014 May 5. PMID: 24883207; PMCID: PMC4027023.
  35. Masoura S, Kalogiannidis IA, Gitas G, Goutsioulis A, Koiou E, Athanasiadis A, Vavatsi N. Biomarkers in pre-eclampsia: a novel approach to early detection of the disease. J Obstet Gynaecol. 2012 Oct;32(7):609-16. doi: 10.3109/01443615.2012.709290. PMID: 22943702.
  36. Mishra J, Puri M, Sachdeva MP, Kaur L, Saraswathy KN (2018) Hyperhomocysteinemia and Folate Deficiency in Preterm Premature Rupture of Membranes: A Hospital Based Case Control Study (India). J Womens Health, Issues Care 7:4. doi: 10.4172/2325-9795.1000319
  37. Moayeri M, Heida KY, Franx A, Spiering W, de Laat MW, Oudijk MA. Maternal lipid profile and the relation with spontaneous preterm delivery: a systematic review. Arch Gynecol Obstet. 2017 Feb;295(2):313-323. doi: 10.1007/s00404-016-4216-5. Epub 2016 Nov 2. PMID: 27807624; PMCID: PMC5281656.
  38. Nasiri M, Arsanjani Shirazi A, Sadeghi O, Bagheri Bidakhavidi M. The Relationship between Homocysteine Levels and Spontaneous Abortion in Iranian Women with Migraine. Iran J Public Health. 2017 Aug;46(8):1149-1151. PMID: 28894722; PMCID: PMC5575400.
  39. Fatrisia, Negara, K.S., Suwiyoga, K., Suwardewa, T.G.A., Megadhana, I.W., Darmayasa, M., Putra, I.G.M., Wiradnyana, A.A.G.P. 2020. Perbedaan ekspresi matriks metalloproteinase-2 dan caspase-3 sel amnion pada persalinan preterm dengan ketuban pecah dini dan tanpa ketuban pecah dini. Medicina 51(2): 108-114. DOI:10.15562/Medicina.v51i2.887.
  40. Nurfianto, S., Hadi, U., & Purnomo, W. (2019). Relationship between maternal age, gravida and gestational age with premature rupture of membrane in adolescent pregnancy. Indian Journal of Forensic Medicine and Toxicology, 13(4), 756-760. https://doi.org/10.5958/0973-9130.2019.00384.0
  41. Petersen SG, Gibbons KS, Luks FI, Lewi L, Diemert A, Hecher K, Dickinson JE, Stirnemann JJ, Ville Y, Devlieger R, Gardener G, Deprest JA. The Impact of Entry Technique and Access Diameter on Prelabour Rupture of Membranes Following Primary Fetoscopic Laser Treatment for Twin-Twin Transfusion Syndrome. Fetal Diagn Ther. 2016;40(2):100-9. doi: 10.1159/000441915. Epub 2016 Apr 14. PMID: 27073886.
  42. Qiu X, Gao F, Qiu Y, Bao J, Gu X, Long Y, Liu F, Cai M, Liu H. Association of maternal serum homocysteine concentration levels in late stage of pregnancy with preterm births: a nested case-control study. J Matern Fetal Neonatal Med. 2018 Oct;31(20):2673-2677. doi: 10.1080/14767058.2017.1351534. Epub 2017 Aug 11. PMID: 28797185.
  43. Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, Dong Z, Ahmed AI, Shaman M, Lannaman K, Yoon BH, Hassan SS, Kim CJ, Korzeniewski SJ, Yeo L, Kim YM. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2015 Aug;28(12):1394-409. doi: 10.3109/14767058.2014.958463. Epub 2014 Sep 29. PMID: 25190175; PMCID: PMC5371030.
  44. Sethi R, Tholandi M, Amelia D, Pedrana A, Ahmed S. Assessment of knowledge of evidence-based maternal and newborn care practices among midwives and nurses in six provinces in Indonesia. Int J Gynaecol Obstet. 2019 Feb;144 Suppl 1:51-58. doi: 10.1002/ijgo.12735. PMID: 30815873.
  45. Shahbazian N, Jafari RM, Haghnia S. The evaluation of serum homocysteine, folic acid, and vitamin B12 in patients complicated with preeclampsia. Electron Physician. 2016 Oct 25;8(10):3057-3061. doi: 10.19082/3057. PMID: 27957303; PMCID: PMC5133028.
  46. Sharif ME, Mohamedain A, Ahmed AA, Nasr AM, Adam I. Folic acid level and preterm birth among Sudanese women. Matern Health Neonatol Perinatol. 2017 Dec 1;3:25. doi: 10.1186/s40748-017-0065-x. PMID: 29214043; PMCID: PMC5709970.
  47. Sonne SR, Bhalla VK, Barman SA, White RE, Zhu S, Newman TM, Prasad PD, Smith SB, Offermanns S, Ganapathy V. Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth. Biochim Biophys Acta. 2013 Aug;1832(8):1149-58. doi: 10.1016/j.bbadis.2013.04.006. Epub 2013 Apr 8. PMID: 23579073.
  48. Strauss JF 3rd. Extracellular matrix dynamics and fetal membrane rupture. Reprod Sci. 2013 Feb;20(2):140-53. doi: 10.1177/1933719111424454. Epub 2012 Jan 19. PMID: 22267536; PMCID: PMC3826277.
  49. Stepan M, Cobo T, Musilova I, Hornychova H, Jacobsson B, Kacerovsky M. Maternal Serum C-Reactive Protein in Women with Preterm Prelabor Rupture of Membranes. PLoS One. 2016 Mar 4;11(3):e0150217. doi: 10.1371/journal.pone.0150217. PMID: 26942752; PMCID: PMC4778871.
  50. Tchirikov M, Schlabritz-Loutsevitch N, Maher J, Buchmann J, Naberezhnev Y, Winarno AS, Seliger G. Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome. J Perinat Med. 2018 Jul 26;46(5):465-488. doi: 10.1515/jpm-2017-0027. PMID: 28710882.
  51. Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers. 2012 Jul;16(7):806-11. doi: 10.1089/gtmb.2011.0318. Epub 2012 Feb 7. PMID: 22313097.
  52. Yu H, Wang X, Gao H, You Y, Xing A. Perinatal outcomes of pregnancies complicated by preterm premature rupture of the membranes before 34 weeks of gestation in a tertiary center in China: A retrospective review. Biosci Trends. 2015 Feb;9(1):35-41. doi: 10.5582/bst.2014.01058. PMID: 25787907.
  53. Zhong Y, Cahill AG, Macones GA, Zhu F, Odibo AO. The association between prepregnancy maternal body mass index and preterm delivery. Am J Perinatol. 2010 Apr;27(4):293-8. doi: 10.1055/s-0029-1241736. Epub 2009 Oct 12. PMID: 19823961.
  54. Kolelupun, M., Surya, I.G.P., Sanjaya, I.N.H., Suwardewa, T.G.A., Megadhana, I.W., Putra, I.G.M., Budiana, I.N.G., Putra, I.W.A. 2022. High level of highly sensitivity c-reactive protein levels (hs-CRP) as a risk factor for preterm delivery. Bali Medical Journal 11(1): 40-43. DOI: 10.15562/bmj.v11i1.2966.
  55. Adnyana IBP, Liwang F, Negara KS, Manuaba IBP, Bhargah A, Prabawa IPY. Clinical risk factor of preeclampsia: a five-year retrospective study in Bali Royal Hospital, Bali-Indonesia. Gineco. eu. 2018: 14(3), 89-93.

How to Cite

Sembiring, A. E. A., Suwardewa, T. G. A., Negara, K. S., Budiana, I. N. G., Adnyana, I. B. P., & Pangkahila, E. S. (2022). Hubungan antara kadar homosistein (Hcy) dengan kejadian ketuban pecah dini (KPD) pada kehamilan preterm. Intisari Sains Medis, 13(2), 554–559. https://doi.org/10.15562/ism.v13i2.1369

HTML
0

Total
0

Share

Search Panel

Agrifa Eko Albert Sembiring
Google Scholar
Pubmed
ISM Journal


Tjokorda Gde Agung Suwardewa
Google Scholar
Pubmed
ISM Journal


Ketut Surya Negara
Google Scholar
Pubmed
ISM Journal


I Nyoman Gede Budiana
Google Scholar
Pubmed
ISM Journal


Ida Bagus Putra Adnyana
Google Scholar
Pubmed
ISM Journal


Evert Solomon Pangkahila
Google Scholar
Pubmed
ISM Journal