Subscribe to RSS
DOI: 10.1055/s-0042-1743093
The Role of High Concentrations of Homocysteine for the Development of Fetal Growth Restriction
O papel de altas concentrações de homocisteína para o desenvolvimento da restrição de crescimento fetalAbstract
Objective To assess homocysteine (Hcy) levels in the three trimesters of pregnancy in women with fetal growth restriction (FGR) and to evaluate the role of Hcy as a possible predictor of FGR.
Methods A total of 315 singleton pregnant women were included in the present prospective cohort study and were monitored since the 1st trimester of pregnancy before delivery. Newborns were monitored for the first 7 days of life. Patients who had risk factors for FGR were excluded. Fetal growth restriction was defined according to uterine fundal height (< 10 percentile), ultrasound fetometry (< 5 percentile), and anthropometry of newborns (< 5 percentile). The concentrations of Hcy were detected at between 10 and 14, between 20 and 24, and between 30 and 34 weeks of pregnancy by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristics (ROC) curve test and diagnostic odds ratio (DOR) were performed to evaluate the results of ELISA.
Results The concentration of Hcy in patients with FGR was 19.65 umol/L at between 10 and 14 weeks, compared with 9.28 umol/L in patients with normal fetal growth (p < 0.0001). The optimal cut-off level for Hcy in the 1st trimester of pregnancy was > 13.9 umol/L with AUC 0.788, sensitivity of 75%, specificity of 83.6%, and DOR of 15.2.
Conclusion Assessment of serum Hcy concentration may be used as a predictor of FGR, with the highest diagnostic utility in the 1st trimester of pregnancy.
Resumo
Objetivo Avaliar os níveis de homocisteína (Hcy) em três trimestres da gravidez em mulheres com restrição de crescimento fetal (FGR, na sigla em inglês) e avaliar o papel da Hcy como possível preditor de FGR.
Métodos Um total de 315 gestantes solteiras foram incluídas no presente estudo de coorte prospectivo e monitoradas desde o 1° trimestre de gravidez antes do parto. Os recém-nascidos foram acompanhados durante os primeiros 7 dias de vida. Pacientes que apresentam fatores de risco para FGR foram excluídos. A FGR foi definida de acordo com a altura do fundo do útero (< percentil 10), ultrassonografia fetometria (< percentil 5) e antropometria dos recém-nascidos (< percentil 5). As concentrações de Hcy foram detectadas entre 10 e 14, entre 20 e 24 e entre 30 e 34 semanas de gravidez por ensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). O teste da curva das características de operação do receptor (ROC, na sigla em inglês) e a razão de chances de diagnóstico (DOR, na sigla em inglês) foram realizados para avaliar os resultados do ELISA.
Resultados A concentração de Hcy em pacientes com FGR foi de 19,65 umol/L entre 10 e 14 semanas, em comparação com 9,28 umol/L em pacientes com crescimento fetal normal (p < 0,0001). O nível de corte ideal para Hcy no 1° trimestre da gravidez foi > 13,9 umol/L com AUC 0,788, sensibilidade de 75%, especificidade de 83,6%, e DOR 15,2.
Conclusão A avaliação da concentração sérica de Hcy pode ser usada como um preditor de FGR, com maior utilidade diagnóstica no 1° trimestre de gravidez.
Keywords
fetal growth restriction - homocysteine - hyperhomocysteinemia - prediction of fetal growth restrictionPalavras-chave
restrição de crescimento fetal - homocisteína - hiperhomocisteinemia - predição de restrição de crescimento fetalContributions
All authors had full access to all of the data in the present study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Akylbek Tussupkaliyev, Andrey Gaiday, Lazzat Balash. Acquisition of data: Akylbek Tussupkaliyev, Andrey Gaiday. Statistical analyses and data interpretation: Akylbek Tussupkaliyev, Andrey Gaiday, Lazzat Balash. Drafting of the manuscript: Andrey Gaiday, Lazzat Balash. Obtained funding: Akylbek Tussupkaliyev. Study supervision: Akylbek Tussupkaliyev.
Publication History
Received: 24 March 2021
Accepted: 17 December 2021
Article published online:
17 February 2022
© 2022. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil
-
References
- 1 Nardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Marçal VMG. et al. Fetal growth restriction: current knowledge. Arch Gynecol Obstet 2017; 295 (05) 1061-1077 DOI: 10.1007/s00404-017-4341-9.
- 2 Melchiorre K, Sharma R, Khalil A, Thilaganathan B. Maternal cardiovascular function in normal pregnancy: evidence of maladaptation to chronic volume overload. Hypertension 2016; 67 (04) 754-762 DOI: 10.1161/HYPERTENSIONAHA.115.06667.
- 3 Maršál K. Physiological adaptation of the growth-restricted fetus. Best Pract Res Clin Obstet Gynaecol 2018; 49: 37-52 DOI: 10.1016/j.bpobgyn.2018.02.006.
- 4 Wang Y, Gu Y, Granger DN, Roberts JM, Alexander JS. Endothelial junctional protein redistribution and increased monolayer permeability in human umbilical vein endothelial cells isolated during preeclampsia. Am J Obstet Gynecol 2002; 186 (02) 214-220 DOI: 10.1067/mob.2002.119638.
- 5 Triunfo S, Lobmaier S, Parra-Saavedra M, Crovetto F, Peguero A, Nadal A. et al. Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion. Placenta 2014; 35 (06) 398-403 DOI: 10.1016/j.placenta.2014.03.021.
- 6 Hughes AE, Sovio U, Gaccioli F, Cook E, Charnock-Jones DS, Smith GCS. The association between first trimester AFP to PAPP-A ratio and placentally-related adverse pregnancy outcome. Placenta 2019; 81: 25-31 DOI: 10.1016/j.placenta.2019.04.005.
- 7 Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol 2017; 232 (01) R27-R44 DOI: 10.1530/JOE-16-0340.
- 8 Ji L, Brkić J, Liu M, Fu G, Peng C, Wang YL. Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med 2013; 34 (05) 981-1023 DOI: 10.1016/j.mam.2012.12.008.
- 9 Sherrell H, Dunn L, Clifton V, Kumar S. Systematic review of maternal Placental Growth Factor levels in late pregnancy as a predictor of adverse intrapartum and perinatal outcomes. Eur J Obstet Gynecol Reprod Biol 2018; 225: 26-34 DOI: 10.1016/j.ejogrb.2018.03.059.
- 10 Herraiz I, Simón E, Gómez-Arriaga PI, Quezada MS, García-Burguillo A, López-Jimenez EA. et al. Clinical implementation of the sFlt-1/PlGF ratio to identify preeclampsia and fetal growth restriction: A prospective cohort study. Pregnancy Hypertens 2018; 13: 279-285 DOI: 10.1016/j.preghy.2018.06.017.
- 11 Bækgaard Thorsen LH, Bjørkholt Andersen L, Birukov A, Lykkedegn S, Dechend R, Jørgensen JS, Christesen HK. et al. Prediction of birth weight small for gestational age with and without preeclampsia by angiogenic markers: an Odense Child Cohort study. J Matern Fetal Neonatal Med 2020; 33 (08) 1377-1384 DOI: 10.1080/14767058.2018.1519536.
- 12 Tussupkaliyev A, Gaiday A, Bermagambetova S, Aniuliene R. [Hypertension of Pregnancy Associated with Hypergomocysteinemia of the First Trimester of Pregnancy]. Georgian Med News 2018; (276) 40-46
- 13 Tussupkaliyev A, Gaiday A, Bermagambetova S, Arenova S, Kaldigulova L, Dinets A. Urinary placental growth factor determined in the first trimester of pregnancy as a predictor of preeclampsia. Pregnancy Hypertens 2020; 21: 63-67 DOI: 10.1016/j.preghy.2020.05.003.
- 14 Yeter A, Topcu HO, Guzel AI, Ozgu E, Danisman N. Maternal plasma homocysteine levels in intrauterine growth retardation. J Matern Fetal Neonatal Med 2015; 28 (06) 709-712 DOI: 10.3109/14767058.2014.929110.
- 15 Gaiday AN, Tussupkaliyev AB, Bermagambetova SK, Zhumagulova SS, Sarsembayeva LK, Dossimbetova MB. et al. Effect of homocysteine on pregnancy: A systematic review. Chem Biol Interact 2018; 293: 70-76 DOI: 10.1016/j.cbi.2018.07.021.
- 16 Maged AM, Saad H, Meshaal H, Salah E, Abdelaziz S, Omram E. et al. Maternal serum homocysteine and uterine artery Doppler as predictors of preeclampsia and poor placentation. Arch Gynecol Obstet 2017; 296 (03) 475-482 DOI: 10.1007/s00404-017-4457-y.
- 17 Jiang HL, Cao LQ, Chen HY. Blood folic acid, vitamin B12, and homocysteine levels in pregnant women with fetal growth restriction. Genet Mol Res 2016; 15 (04) 1-8 DOI: 10.4238/gmr15048890.
- 18 Pandey K, Dubay P, Bhagoliwal A, Gupta N, Tyagi G. Hyperhomocysteinemia as a risk factor for IUGR. J Obstet Gynaecol India 2012; 62 (04) 406-408 DOI: 10.1007/s13224-012-0287-9.
- 19 Dymara-Konopka W, Laskowska M. The role of nitric oxide, ADMA, and homocysteine in the etiopathogenesis of preeclampsia-review. Int J Mol Sci 2019; 20 (11) 2757 DOI: 10.3390/ijms20112757.
- 20 Audette MC, Kingdom JC. Screening for fetal growth restriction and placental insufficiency. Semin Fetal Neonatal Med 2018; 23 (02) 119-125 DOI: 10.1016/j.siny.2017.11.004.
- 21 Vayssière C, Sentilhes L, Ego A, Bernard C, Camborieu D, Flamant C. et al. Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians. Eur J Obstet Gynecol Reprod Biol 2015; 193: 10-18 DOI: 10.1016/j.ejogrb.2015.06.021.
- 22 O'Gorman N, Salomon LJ. Fetal biometry to assess the size and growth of the fetus. Best Pract Res Clin Obstet Gynaecol 2018; 49: 3-15 DOI: 10.1016/j.bpobgyn.2018.02.005.
- 23 Hiersch L, Melamed N. Fetal growth velocity and body proportion in the assessment of growth. Am J Obstet Gynecol 2018; 218 (2S): S700-711.e1 DOI: 10.1016/j.ajog.2017.12.014.
- 24 Walker KF, Thornton JG. Delivery at term: when, how, and why. Clin Perinatol 2018; 45 (02) 199-211 DOI: 10.1016/j.clp.2018.01.004.
- 25 Committee Opinion No 700: Methods for Estimating the Due Date. Obstet Gynecol 2017; May; 129 (05) e150-e154 https://journals.lww.com/greenjournal/Fulltext/2017/05000/Committee_Opinion_No_700__Methods_for_Estimating.50.aspx
- 26 Pillay P, Janaki S, Manjila C. A comparative study of gravidogram and ultrasound in detection of IUGR. J Obstet Gynaecol India 2012; 62 (04) 409-412 DOI: 10.1007/s13224-012-0292-z.
- 27 Nicolaides KH, Wright D, Syngelaki A, Wright A, Akolekar R. Fetal Medicine Foundation fetal and neonatal population weight charts. Ultrasound Obstet Gynecol 2018; 52 (01) 44-51 DOI: 10.1002/uog.19073.
- 28 WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl 2006; 450: 76-85 DOI: 10.1111/j.1651-2227.2006.tb02378.x.
- 29 Sundrehagen E, Axis Biochemicals AS. inventors. Enzymatic assay for homocysteine and a kit therefor. European Patent EP 623174/US5631127. 1990
- 30 Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol 2003; 56 (11) 1129-1135 DOI: 10.1016/s0895-4356(03)00177-x.
- 31 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44 (03) 837-845
- 32 Bergen NE, Schalekamp-Timmermans S, Jaddoe VW, Hofman A, Lindemans J, Russhcher H. et al. Maternal and neonatal markers of the homocysteine pathway and fetal growth: The Generation R Study. Paediatr Perinat Epidemiol 2016; 30 (04) 386-396 DOI: 10.1111/ppe.12297.
- 33 Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK. et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 2000; 71 (04) 962-968 DOI: 10.1093/ajcn/71.4.962.
- 34 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 2013; 9 (02) 155-166 DOI: 10.1111/j.1740-8709.2011.00364.x.
- 35 Gadhok AK, Sinha M, Khunteta R, Vardey SK, Upadhyaya C, Sharma TK. et al. Serum homocysteine level and its association with folic acid and vitamin B12 in the third trimester of pregnancies complicated with intrauterine growth restriction. Clin Lab 2011; 57 (11-12): 933-938
- 36 D'Anna R, Baviera G, Corrado F, Ientile R, Granese D, Stella NC. Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction. Acta Obstet Gynecol Scand 2004; 83 (02) 155-158 DOI: 10.1111/j.0001-6349.2004.00291.x.
- 37 Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Second-trimester plasma homocysteine levels and pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction. Am J Obstet Gynecol 2000; 183 (04) 805-809 DOI: 10.1067/mob.2000.109044.
- 38 Cawley S, O'Malley EG, Kennedy RAK, Reynolds CME, Molloy AM, Turner MJ. The relationship between maternal plasma homocysteine in early pregnancy and birth weight. J Matern Fetal Neonatal Med 2020; 33 (18) 3045-3049 DOI: 10.1080/14767058.2019.1567705.
- 39 Gomes TS, Lindner U, Tennekoon KH, Karandagoda W, Gortner L, Obeid R. Homocysteine in small-for-gestational age and appropriate-for-gestational age preterm neonates from mothers receiving folic acid supplementation. Clin Chem Lab Med 2010; 48 (08) 1157-1161 DOI: 10.1515/CCLM.2010.235.
- 40 Murphy MM, Scott JM, Arija V, Molloy AM, Fernandez-Ballart JD. Maternal homocysteine before conception and throughout pregnancy predicts fetal homocysteine and birth weight. Clin Chem 2004; 50 (08) 1406-1412 DOI: 10.1373/clinchem.2004.032904.
- 41 Chaudhry SH, Taljaard M, MacFarlane AJ, Gaudet LM, Smith GN, Rodger M. et al. The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort. BMC Pregnancy Childbirth 2019; 19 (01) 75 DOI: 10.1186/s12884-019-2219-5.
- 42 Steegers-Theunissen RP, Van Iersel CA, Peer PG, Nelen WL, Steegers EA. Hyperhomocysteinemia, pregnancy complications, and the timing of investigation. Obstet Gynecol 2004; 104 (02) 336-343 DOI: 10.1097/01.AOG.0000129955.47943.2a.
- 43 Pagán K, Hou J, Goldenberg RL, Cliver SP, Tamura T. Mid-pregnancy serum homocysteine and B-vitamin concentrations and fetal growth. Nutr Res 2002; 22 (10) 1133-1141
- 44 Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willet W, Selhub J. et al. Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 2002; 76 (06) 1385-1391 DOI: 10.1093/ajcn/76.6.1385.
- 45 Infante-Rivard C, Rivard GE, Gauthier R, Théorêt Y. Unexpected relationship between plasma homocysteine and intrauterine growth restriction. Clin Chem 2003; 49 (09) 1476-1482 DOI: 10.1373/49.9.1476.