Angiogenic imbalance and prognostic criteria in the development of fetal growth restriction
DOI:
https://doi.org/10.15574/HW.2025.2(177).7078Keywords:
fetal growth restriction, preterm delivery, placental proteins, growth factors, PAPP-A, placental growth factorAbstract
Among the main obstetric complications that contribute to perinatal morbidity and mortality, fetal growth restriction (FGR) is an important one, the proportion of which ranges from 25% among full-term infants to 18-40% among premature newborns.
Аim - to evaluate the diagnostic value of biomarkers of placental dysfunction and certain angiogenesis factors in pregnant women with FGR and preterm delivery.
Materials and methods. A clinical and laboratory examination was performed in 88 patients aged 18 to 35 years with manifestations of FGR. The main group included 44 patients with FGR and early delivery, and the comparison group included 44 patients with FGR and urgent delivery. The control group consisted of 30 conditionally healthy pregnant women. The level of serum markers was assessed: PAPP-A and β-subunit of chorionic gonadotropin (β-hCG), and certain angiogenesis factors (PlGF, sFlt-1, VEGF).
Results. In the main group, the proportion of surgical delivery was 35.2%, preterm delivery - 52.3%, and low Apgar score - 47.7%. The risk of preterm delivery was 3.4 times higher in the case of early FGR. In the main group, the level of PAPP-A was consistently low (2.5 times), hCG β-subunit - by 2.4 times, and two thirds (70.5%) were diagnosed with haemodynamic disorders up to 28-30 weeks. The PlGF levels are already lower than normal at 12-14 weeks of pregnancy (47.7%), at 20-22 weeks (61.4%), VEGF-1 concentration is reduced by 1.9 times, and sFlt-1 levels increase by 1.9 times. In the case of an increase in the sFlt-1/PlGF ratio by 100 conditional units during 10-14 days of monitoring, the risk of haemodynamic disorders of feto-paternal circulation in patients with FGR increased by 3.0 times.
Conclusions. The data on the dynamics of secretion of certain placental proteins and growth factors can be used to formulate screening programmes. In women with FGR, PlGF content demonstrates low parameters, deviations in the proangiogenic factor VEGF-1, imbalance of vascular factors in the dynamics of pregnancy and an increase in the angiogenic coefficient, which can be considered as a prognostic marker of incomplete trophoblast invasion and the risk of placental dysfunction.
The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from participant.
The authors declare no conflict of interest.
References
ACOG. (2021). Fetal Growth Restriction. ACOG Practice Bulletin, Number 227. Obstet. Gynecol. 137: e16-e28. https://doi.org/10.1097/AOG.0000000000004251; PMid:33481528
Aviram A, Sherman C, Kingdom J, Zaltz A, Barrett J, Melamed N. (2019). Defining early vs late fetal growth restriction by placental pathology. Acta Obstet Gynecol Scand. (98): 365-73. https://doi.org/10.1111/aogs.13499; PMid:30372519
Beharier O, Kajiwara K, Sadovsky Y. (2021). Ferroptosis, trophoblast lipotoxic damage, and adverse pregnancy outcome. Placenta. 108: 32-8. https://doi.org/10.1016/j.placenta.2021.03.007; PMid:33812183 PMCid:PMC8127417
Berezhna VA. (2021). Imunolohichna optymizatsiia metodiv diahnostyky pry zatrymtsi vnutrishnoutrobnoho rozvytku ploda. Visnyk problem biolohii i medytsyny. 1(159): 23-26.
Bezemer RE, Schoots MH, Timmer A, Scherjon SA, Erwich JJHM, van Goor H et al. (2020). Altered Levels of Decidual Immune Cell Subsets in Fetal Growth Restriction, Stillbirth, and Placental Pathology. Front Immunol. 11: 1898. https://doi.org/10.3389/fimmu.2020.01898; PMid:32973787 PMCid:PMC7468421
Burton GJ, Jauniaux E. (2018). Development of the Human Placenta and Fetal Heart: Synergic or Independent. Front Physiol. (12); 9: 373. https://doi.org/10.3389/fphys.2018.00373; PMid:29706899 PMCid:PMC5906582
Cindrova-Davies T, Sferruzzi-Perri AN. (2022). Human placental development and function. Semin. Cell Dev. Biol. 131: 66-77. https://doi.org/10.1016/j.semcdb.2022.03.039; PMid:35393235
Covarrubias A, Aguilera-Olguín M, Carrasco-Wong I, Pardo F, Díaz-Astudillo P, Martín SS. (2023). Feto-placental Unit: From Development to Function. Adv. Exp. Med. Biol. 1428: 1-29. https://doi.org/10.1007/978-3-031-32554-0_1; PMid:37466767
Crispi F, Bijnens B, Figueras F, Bartrons J, Eixarch E, Le Noble F et al. (2010, Jun 8). Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation. 121(22): 2427-2436. https://doi.org/10.1161/CIRCULATIONAHA.110.937995; PMid:20497977
Crispi F, Miranda J, Gratacós E. (2018, Feb). Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease. Am J Obstet Gynecol. 218(2S): S869-S879. https://doi.org/10.1016/j.ajog.2017.12.012; PMid:29422215
Dai X, Zhang H, Wu B, Ning W, Chen Y, Chen Y. (2023). Correlation between elevated maternal serum alpha-fetoprotein and ischemic placental disease: A retrospective cohort study. Clin. Exp. Hypertens. 45: 2175848. https://doi.org/10.1080/10641963.2023.2175848; PMid:36849437
Dapkekar P, Bhalerao A, Kawathalkar A, Vijay N. (2023). Risk Factors Associated With Intrauterine Growth Restriction: A CaseControl Study. Cureus. 15: e40178. https://doi.org/10.7759/cureus.40178
Deinichenko OV, Siusiuka VH, Krut YuIa, Pavliuchenko MI, Kyryliuk DO, Bohuslavska NIu. (2022). Prohnozuvannia rozvytku zatrymky rostu ploda u vahitnykh z khronichnoiu arterialnoiu hipertenziieiu. Reproduktyvne zdorov'ia zhinky. 7(62): 14-20. https://doi.org/10.30841/2708-8731.7.2022.272466
Dixit S, Dixit NA, Rawat A, Bajpai A, Alelyani M et al. (2024). Color Doppler ultrasound in high-low risk pregnancies and its relationship to fetal outcomes: A cross-sectional study. Front. Pediatr. 11: 1221766. https://doi.org/10.3389/fped.2023.1221766; PMid:38444769 PMCid:PMC10912586
Figueras F, Caradeux J, Crispi F, Eixarch E, Peguero A, Gratacos E. (2018). Diagnosis and surveillance of late-onset fetal growth restriction. Am J Obstet Gynecol. 218(2): 790-802.e1. https://doi.org/10.1016/j.ajog.2017.12.003; PMid:29422212
Freedman AA, Keenan-Devlin LS, Borders A, Miller GE, Ernst LM. (2021). Formulating a Meaningful and Comprehensive Placental Phenotypic Classification. Pediatr Dev Pathol. 24(4): 337-50. https://doi.org/10.1177/10935266211008444; PMid:33872108 PMCid:PMC8277726
Głowska-Ciemny J, Szmyt K, Kuszerska A, Rzepka R, von Kaisenberg C, Kocyłowski R. (2024). Fetal and Placental Causes of Elevated Serum Alpha-Fetoprotein Levels in Pregnant Women. J. Clin. Med. 13: 466. https://doi.org/10.3390/jcm13020466; PMid:38256600 PMCid:PMC10816536
Gordijn SJ, Beune IM, Thilaganathan B. (2016). Consensus definition of fetal growth restriction: a Delphi. Ultrasound Obstet Gynecol. 48(3): 333-339. https://doi.org/10.1002/uog.15884; PMid:26909664
Graupner O, Kuschel B, Axt-Fliedner R, Enzensberger C. (2022). New Markers for Placental Dysfunction at Term - Potential for More. Geburtshilfe Frauenheilkd. 82(7): 719-726. https://doi.org/10.1055/a-1761-1337; PMid:35815096 PMCid:PMC9262629
Griffin M, Heazell AEP, Chappell LC, Zhao J, Lawlor DA. (2020). The ability of late pregnancy maternal tests to predict adverse pregnancy outcomes associated with placental dysfunction (specifically fetal growth restriction and pre-eclampsia): a protocol for a systematic review and meta-analysis of prognostic accuracy studies. Syst Rev. 9(1): 78. https://doi.org/10.1186/s13643-020-01334-5; PMid:32268905 PMCid:PMC7140577
Grzeszczak K, Łanocha-Arendarczyk N, Malinowski W, Zi˛etek P, Kosik-Bogacka D. (2023). Oxidative Stress in Pregnancy. Biomolecules. 13: 1768. https://doi.org/10.3390/biom13121768; PMid:38136639 PMCid:PMC10741771
Hong J, Kumar S. (2023). Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction. Clin Sci (Lond). 137(8): 579-595. https://doi.org/10.1042/CS20220300; PMid:37075762 PMCid:PMC10116344
Kuzmin N. (2021). Levels of TNF-α, IL-1, IL1β and calciferol and their relationship as markers of endothelial dysfunction in pregnant women with preeclampsia. Reprod Women's Health. (9-10): 88-93. https://doi.org/10.30841/2708-8731.9-10.2021.252600
Lean SC, Heazell AEP, Dilworth MR, Mills TA, Jones RL. (2017). Placental Dysfunction Underlies Increased Risk of Fetal Growth Restriction and Stillbirth in Advanced Maternal Age Women. Sci Rep. 7(1): 9677. https://doi.org/10.1038/s41598-017-09814-w; PMid:28852057 PMCid:PMC5574918
Leon-Martinez D, Lundsberg LS, Culhane J, Zhang J, Son M, Reddy UM. (2023). Fetal growth restriction and small for gestational age as predictors of neonatal morbidity: Which growth nomogram to use? Am. J. Obstet. Gynecol. 229: e1-e678. https://doi.org/10.1016/j.ajog.2023.06.035; PMid:37348779
Marichereda VH, Nadvorna OM, Rozhkovska NM. (2024). Biomarkery dysfunktsii platsenty. Klinichnyi dosvid. Reproduktyvne zdorov'ia zhinky. 5(76): 84-89. https://doi.org/10.30841/2708-8731.5.2024.310398
Markin LB, Fartushok TV. (2021). Prevention of disorders of functional differentiation of the placenta. Curr Issues Pediatr, Obstet Gynecol. (2): 106-110. https://doi.org/10.11603/24116-4944.2020.2.11847
Mosimann B, Amylidi-Mohr S, Surbek D et al. (2019). First trimester screening for preeclampsia - a systematic review. Hypertens Pregnancy. 39(1): 1-11. https://doi.org/10.1080/10641955.2019.1682009; PMid:31670986
Oshovskyi V, Nikolenko M, Polyakova E. (2021). Pregnancy outcomes in patients with an extremely high sFlt-1/PlGF ratio: a series of clinical cases. Reprod Women's Health. (1): 17-20. https://doi.org/10.30841/2708-8731.1.2021.229703
Pylypenko A, Medved V. (2022). To the question of the clinical predictive value of the sFlt-1:PlGF ratio for predicting placental dysfunction. Reprod Women's Health. (7): 21-29. https://doi.org/10.30841/2708-8731.7.2022.272468
Rizzo G, Mappa I, Bitsadze V, Słodki M, Khizroeva J et al. (2020). Role of Doppler ultrasound at time of diagnosis of late-onset fetal growth restriction in predicting adverse perinatal outcome: Prospective cohort study. Ultrasound Obstet. Gynecol. 55: 793-798. https://doi.org/10.1002/uog.20406; PMid:31343783
Sapantzoglou I, Vlachos D-E, Papageorgiou D, Varthaliti A, Rodolaki K, Daskalaki MA et al. (2024). Maternal Blood Adipokines and Their Association with Fetal Growth: A Meta-Analysis of the Current Literature. J. Clin. Med. 13: 1667. https://doi.org/10.3390/jcm13061667; PMid:38541892 PMCid:PMC10971104
Shu-Wei Li, Yi Ling, Song Jin et al. (2014). Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine. Asian Pacific Journal of Tropical Medicine. 7(8): 663-667. https://doi.org/10.1016/S1995-7645(14)60112-7; PMid:25149383
Shibata M, Ogawa K, Kanazawa S, Kawasaki M, Morisaki N, Mito A et al. (2021). Association of maternal birth weight with the risk of low birth weight and small-for-gestational-age in offspring: A prospective single-center cohort study. PLoS ONE. 16: e0251734. https://doi.org/10.1371/journal.pone.0251734; PMid:33989347 PMCid:PMC8121327
Stepanenko TO. (2024). Zatrymka rostu ploda - novitni molekuliarni mekhanizmy (Ohliad literatury). Reproduktyvne zdorov'ia zhinky. 8(79): 106-112. https://doi.org/10.30841/2708-8731.8.2024.320093
https://doi.org/10.30841/2708-8731.8.2024.320093
Tsikouras P, Antsaklis P, Nikolettos K, Kotanidou S, Kritsotaki N, Bothou A et al. (2024). Diagnosis, Prevention, and Management of Fetal Growth Restriction (FGR). J. Pers. Med. 14: 698. https://doi.org/10.3390/jpm14070698; PMid:39063953 PMCid:PMC11278205
Tsikouras P, Oikonomou E, Bothou A, Kyriakou D, Nalbanti T, Andreou S et al. (2024). Labor management and neonatal outcomes in cardiotocography categories II and III (Review). Med. Int. 4: 27. https://doi.org/10.3892/mi.2024.151; PMid:38628383 PMCid:PMC11019468
Us I, Zhuk S, Demyanyuk S. (2022). Evaluation of the hemostasis system in pregnant women with placental dysfunction by the method of rotational thromboelastometry. Reprod Women's Health. (3): 6-11. https://doi.org/10.30841/2708-8731.3.2022.262365
Vdovychenko YuP, Holianovskyi VO. (2021). Vyznachennia diahnostychnykh markeriv zatrymky rostu ploda u ranni terminy vahitnosti. Reproduktyvne zdorov'ia zhinky. (46): 61-65.
Walter A, Calite E, Berg C, Gembruch U, Müller A, Geipel A. (2022, Jan 10). Prenatal diagnosis of fetal growth restriction with polyhydramnios, etiology and impact on postnatal outcome. Sci Rep. 12(1): 415. https://doi.org/10.1038/s41598-021-04371-9; PMid:35013541 PMCid:PMC8748543
Wardinger JE, Ambati S. (2023, Jan). Placental Insufficiency [Internet]. In: StatPearls Treasure Island (FL): StatPearls Publishing. URL: https://www.ncbi.nlm.nih.gov/books/NBK563171/.
Zur RL, Kingdom JC, Parks WT, Hobson SR. (2020). The Placental Basis of Fetal Growth Restriction. Obstet Gynecol Clin North Am. 47(1): 81-98. https://doi.org/10.1016/j.ogc.2019.10.008; PMid:32008673
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