Markers of angiogenesis and their role in prediction of preeclampsy in multiple pregnancy




assisted reproductive technologies, multiple pregnancy, preeclampsia, circulating biomarkers of angiogenesis sFlt-1 and PIGF


Purpose - to identify changes in biochemical markers of endothelial dysfunction, preclinical manifestations of preeclampsia in pregnant women with multiple pregnancies after the use of assisted reproductive technologies.

Materials and methods. A prospective study of pregnant women with dichorionic diamniotic twins after assisted reproductive technologies was conducted: 35 pregnant women with twins who were offered a developed monitoring algorithm (main (І) group) and 27 pregnant women who were monitored according to generally accepted methods of managing multiple pregnancies (control (ІІ) group). Statistical processing of the research results was carried out using standard programs “Microsoft Excel 5.0” and “Statistica 6.0”.

Results. During the analysis of the main and control observation groups, an increase in the pro-angiogenic biomarker PlGF was noted up to 28 weeks (I group 604.9 (83.4-814.5) pg/ml vs. 568.6 (68.1-765.3) pg/ml in the II group). Іn the term of 26-28 weeks, in the main group, we noted a decrease in the level of PlGF below 100 pg/ml in 4 (11.4%) women, and in the II group in 6 (22.2%), however, clinical manifestations of preeclampsia, in patients, it was not noted. In the period of 32-34 weeks, the results of PlGF below the level of 100 pg/ml were obtained in 6 (17.1%) women of the I group against 7 (25.9%) of the women of the II group. In the group I we found 2 cases of moderate preeclampsia at 32 and 33 weeks of pregnancy. In the II group 4 cases of preeclampsia were identified. Two cases of moderate preeclampsia, which clinically manifested at 30 weeks.

Conclusions. The anti-angiogenic factor, sFlt-1 and the pro-angiogenic factor PIGF, and their relationship are promising markers in the prediction and early diagnosis of preeclampsia in the multiple pregnancies after assisted reproductive technologies. Based on monitoring the growth dynamics of the sFlt-1/PIGF ratio, it is possible to predict the early development of preeclampsia even without clinical symptoms, and to make a decision about the possibility of extending the pregnancy or the need for urgent delivery.

The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies.

No conflict of interests was declared by the authors.


Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel J, Souza J. (2014). Preeclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization multicountry survey on maternal and newborn health. BJOG : an international journal of obstetrics and gynecology. 121: 14-24.; PMid:24641531

Alfaidy N et al. (2020). The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects. Frontiers in Physiology. 11: 591-850.; PMid:33281622 PMCid:PMC7689260

Anil Kumar KV, Kavitha S, Sreekanth KS. (2021). Regulatory proteins in placental angiogenesis. Biomedicine. 41 (4): 694-700.

Artyomenko VV, Berlinskaya LI. (2018). Placental syndrome as possible risk factor for preeclampsia development (Literature review). Health of woman. 6(132): 113-117.

Belinda J, Ananth Karumanchi S. (2017). Preeclampsia: pathogenesis, prevention, and long-term complications. Seminars in nephrology. 37: 4.; PMid:28711078

Binder J et al. (2021). Angiogenic markers and their longitudinal change for predicting adverse outcomes in pregnant women with chronic hypertension. American Journal of Obstetrics and Gynecology. 225 (3): 305-e1.; PMid:33812812

Boucoiran L, Thissier-Levy S, Wu Yr MD et al. (2013). Risks for Preeclampsia and Small for Gestational Age: Predictive Values of Placental Growth Factor, Soluble fms-like Tyrosine Kinase-1, and Inhibin A in Singleton and Multiple-Gestation Pregnancies. Am J Perinatal. 30: 607-612.; PMid:23208763

Cerdeira AS, O'Sullivan J, Ohuma EO, Harrington D, Szafranski P, Black R, Vatish M. (2019). Randomized interventional study on prediction of preeclampsia / eclampsia in women with suspected preeclampsia: INSPIRE. Hypertension. 74 (4): 983-990.; PMid:31401877 PMCid:PMC6756298

Cuffe JSM et al. (2017). Placental derived biomarkers of pregnancy disorders. Placenta. 54: 104-110.; PMid:28117143

Deshpande JS et al. (2021). Unravelling the potential of angiogenic factors for the early prediction of preeclampsia. Hypertension Research. 44 (7): 756-769.; PMid:33795844

Duhig KE, Myers J, Seed PT, Sparkes J, Lowe J, Hunter RM, Tuffnell D. (2019). Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. The Lancet. 393 (10183): 1807-1818.

Flint EJ et al. (2019). The role of angiogenic factors in the management of preeclampsia. Acta obstetricia et gynecologica Scandinavica. 98 (6): 700-707.; PMid:30667052

Ives ChW et al. (2020). Preeclampsia-pathophysiology and clinical presentations: JACC state-of-the-art review. Journal of the American College of Cardiology. 76 (14): 1690-1702.; PMid:33004135

Jim В, Рhipps Е, Polsani S. (2013). Emerging New Biomarkers of Preeclampsia. Advances in Chronic Kidney Disease. 20 (3): 271-279.; PMid:23928393

Kenny LC, Black MA, Poston L et al. (2014). Early pregnancy prediction of pre- eclampsia in nulliparous women, combining clinical risk and biomarkers: The Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension. 64 (3): 644-652.; PMid:25122928

Kleinrouweler C, Wiegerinck M, Ris-Stalpers C, Bossuyt P, van der Post J, von Dadelszen P, Mol B, Pajkrt E. (2012). Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG. 119: 778-787.; PMid:22433027

Nzelu D et al. (2020). First trimester serum angiogenic and anti-angiogenic factors in women with chronic hypertension for the prediction of preeclampsia. American Journal of Obstetrics and Gynecology. 222 (4): 374-e1.; PMid:31705883

Poon LC et al. (2019). The International Federation of Gynecology and Obstetrics (FIGO) initiative on preeclampsia (PE): a pragmatic guide for first trimester screening and prevention. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 145 (1): 1.

Rana S, Burke SD, Karumanchi SA. (2020). Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. American Journal of Obstetrics and Gynecology.

Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H et al. (2008). A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 21 (1): 9-23.; PMid:18175241 PMCid:PMC2587364

Saleh L et al. (2018). The predictive value of the sFlt-1 / PlGF ratio on short-term absence of preeclampsia and maternal and fetal or neonatal complications in twin pregnancies. Pregnancy hypertension. 14: 222-227.; PMid:29678353

Stanca MC et al. (2018). Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 59 (2): 455-467.

Stepan H et al. (2015). Implementation of the sFlt-1 / PLGF ratio for prediction and diagnosis of preeclampsia in in singleton pregnancy: implications for clinical practice. Ultrasound Obstet. Gynecol. 45 (3): 241-246.; PMid:25736847 PMCid:PMC4369131

Stepan H et al. (2016). A comparison of the diagnostic utility of the sFlt-1 / PlGF ratio versus PlGF alone for the detection of preeclampsia / HELLP syndrome. Hypertension in pregnancy. 35 (3): 295-305.; PMid:27028698 PMCid:PMC5309866

Thilaganathan В. (2017). Placental syndromes: getting to the heart of the matter. Ultrasound Obstet Gynecol. 49: 7-9. doi: 10.1002/uog.17378.; PMid:28067440

Umapathy A, Chamley LW, James JL. (2020). Reconciling the distinct roles of angiogenic / anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies. Angiogenesis. 23 (2): 105-117.; PMid:31707538

Verlohren S et al. (2022). Clinical interpretation and implementation of the sFlt-1 / PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertension. 27: 42-50.; PMid:34915395

Verlohren S, Dröge LA. (2020). The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia. American Journal of Obstetrics and Gynecology.

Webster K, Fishburn S, Maresh M, Findlay SC, Chappell LC. (2019). Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance. Bmj: 366.; PMid:31501137

Weckman AM, Ngai M, Wright J, McDonald CR, Kain KC. (2019). The impact of infection in pregnancy on placental vascular development and adverse birth outcomes. Frontiers in Microbiology. 10: 1924.; PMid:31507551 PMCid:PMC6713994

World Health Organization. (2021). WHO recommendations on antiplatelet agents for the prevention of pre-eclampsia.

Zeisler H et al. (2016). Predictive value of the sFlt-1: PlGF ratio in women with suspected preeclampsia. N Engl J Med. 374: 13-22.; PMid:26735990