Angiogenic factors (sFlt-1, PlGF) in twin pregnancy with placentaassociated complications

Aim: to determine reference values of angiogenic factors dynamics in pregnancy for female patients with twins and different types of placentation for early diagnostics and assessment of preeclampsia (PE) severity.
Materials and Methods. There was conducted 2020–2021 prospective study enrolling 93 females with twin pregnancy to examine 68 with dichorionic diamniotic (DCDA) twins and 25 with monochorionic diamniotic (MCDA) twins. All patients were divided into 2 groups: group I consisted of 65 women with twin pregnancy without PE, group II included 28 women with twin pregnancy complicated by PE. In blood serum of pregnant women the level of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and their ratio were studied for diagnosing and predicting PE severity at 4 time points of gestation (20.0–23.6 weeks, 24.0–28.6 weeks, 29.0–33.6 weeks, 34.0–36.6 weeks).
Results. No significant difference was found in angiogenic factors level and their ratio in pregnant women with uncomplicated DCDA and MCDA twins. Regardless of placentation type, sFlt-1/PlGF ratio in women with twin pregnancy and PE at 24 weeks of gestation was 103.3, by 20-fold exceeding this level than in uncomplicated twin pregnancy. Cut-off values for sFlt-1/PlGF ratio were determined allowing highly reliable to rule out diagnosis PE (sFlt-1/PlGF < 21.85; sensitivity 100 %, specificity 85 %) and to diagnose PE (sFlt-1/PlGF > 49.4; sensitivity 71.1 %, specificity 100 %). The sFlt-1/PlGF ratio was higher in pregnant women with severe PE compared with the moderate degree of the disease throughout pregnancy (р < 0.05). In pregnant women with early PE, the angiogenic factors ratio exceeded the upper threshold value from 24 weeks of gestation, with late PE – from 34.0–36.6 weeks. Significantly higher sFlt-1 level (18359 ± 8656 pg/ml vs. 5526 ± 2808 pg/ml; р < 0.001) and the sFlt-1/PlGF ratio (118,0 ± 65,2 vs. 32,8 ± 18,6; р < 0.03) as well as severe degree of PE were noted in patients with induced twin pregnancy from 24.0–28.6 weeks of gestation compared with spontaneous multiple pregnancy (42,2 and 22,2 % respectively; p < 0,05).
Conclusion. The developed reference values of the sFlt-1/PlGF ratio in pregnant women with twins and different types of placentation can be used not only to diagnose PE, but also to assess the severity and timing of the disease manifestation.

1. Sidorova I.S., Nikitina N.A., Unanyan A.L. Preeclampsia and reduction of maternal mortality in Russia. [Preeklampsiya i snizhenie materinskoj smertnosti v Rossii]. Akusherstvo i ginekologiya. 2018;(1):107–12. (In Russ.). https://doi.org/10.18565/aig.2018.1.107-112.

2. Kurtser M.A., Shamanova M.B., Sinitsina O.V. et al. Clinical rationale for determining the ratio sFlt-1/PlGF for early detection and evaluation of the severity of preeclampsia. [Klinicheskoe obosnovanie opredeleniya sootnosheniya sFlt-1/PlGF s cel'yu rannego vyyavleniya i ocenki stepeni tyazhesti preeklampsii]. Akusherstvo i ginekologiya. 2018;(11):114–20. (In Russ.). https://doi.org/10.18565/aig.2018.11.114-120.

3. Say L., Chou D., Gemmill A. et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323–33. https://doi.org/10.1016/S2214-109X(14)70227-X.

4. Redman C.W., Staff A.C. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am J Obstet Gynecol. 2015;213(4 Suppl):S9.e1, S9–11. https://doi.org/10.1016/j.ajog.2015.08.003.

5. Sánchez O., Llurba E., Marsal G. et al. First trimester serum angiogenic/ anti-angiogenic status in twin pregnancies: relationship with assisted reproduction technology. Hum Reprod. 2012;27(2):358–65. https://doi.org/10.1093/humrep/der394.

6. Zeisler H., Llurba E., Chantraine F. et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13–22. https://doi.org/10.1056/NEJMoa1414838.

7. Karumanchi S.A., Maynard S.E., Stillman I.E. et al. Preeclampsia: a renal perspective. Kidney Int. 2005;67(6):2101–13. https://doi.org/10.1111/j.1523-1755.2005.00316.x.

8. Narang K., Szymanski L.M. Multiple gestations and hypertensive disorders of pregnancy: What do we know? Curr Hypertens Rep. 2020;23(1):1. https://doi.org/10.1007/s11906-020-01107-4.

9. Francisco C., Wright D., Benkő Z. et al. Competing-risks model in screening for pre-eclampsia in twin pregnancy according to maternal factors and biomarkers at 11–13 weeks' gestation. Ultrasound Obstet Gynecol. 2017;50(5):589–95. https://doi.org/10.1002/uog.17531.

10. Kozłowski S., Stelmaszczyk-Emmel A., Szymusik I. et al. sFlt-1, not PlGF, is related to twin gestation choronicity in the first and third trimesters of pregnancy. Diagnostics (Basel). 2021;11(7):1181. https://doi.org/10.3390/diagnostics11071181.

11. Phipps E.A., Thadhani R., Benzing T., Karumanchi S.A. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):275–89. https://doi.org/10.1038/s41581-019-0119-6. Erratum in: Nat Rev Nephrol. 2019;15(6):386. https://doi.org/10.1038/s41581-019-0156-1.

12. Fisher S.J. Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol. 2015;213(4 Suppl):S115–22. https://doi.org/10.1016/j.ajog.2015.08.042.

13. Volochaeva M.V., Baev O.R. Current views on the pathogenesis of fetal growth restriction. [Sovremennye predstavleniya o patogeneze zaderzhki rosta ploda]. Akusherstvo i ginekologiya. 2021;(8):13–7. (In Russ.). https://doi.org/10.18565/aig.2021.8.13-17.

14. Bujold E., Romero R., Chaiworapongsa T. et al. Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin. J Matern Fetal Neonatal Med. 2005;18(1):9–16. https://doi.org/10.1080/14767050500202493.

15. Nagamatsu T., Fujii T., Kusumi M. et al. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology. 2004;145(11):4838–45. https://doi.org/10.1210/en.2004-0533.

16. Hytten F. Blood volume changes in normal pregnancy. Clin Haematol. 1985;14(3):601–12.

17. Kurtser M.A., Sichinava L.G., Alazhazhi A.O. et al. Prognostic value of angiogenic factors (sFlt-1/PlGF ratio) as a marker for pre-eclampsia in twin pregnancy. [Prognosticheskaya znachimost' sootnosheniya angiogennyh faktorov sFlt-1/PlGF v kachestve markera preeklampsii u beremennyh dvojnej]. Voprosy ginekologii, akusherstva i perinatologii. 2022;21(2):5–13. (In Russ.). https://doi.org/10.20953/1726-1678-2022-2-5-12.

18. Faupel-Badger J.M., McElrath T.F., Lauria M. et al. Maternal circulating angiogenic factors in twin and singleton pregnancies. Am J Obstet Gynecol. 2015;212(5):636.e1–8. https://doi.org/10.1016/j.ajog.2014.11.035.

19. Letter of the Ministry of Health of the Russian Federation dated June 07, 2016 N 15-4/10/2-3483 “On the direction of clinical recommendations (treatment protocol) “Hypertensive disorders during pregnancy, childbirth and the postpartum period. Preeclampsia. Eclampsia". Clinical guidelines (Treatment Protocol). [Pis'mo Ministerstva zdravoohragegiya Rossijskoj Federacii ot 07 iyunya 2016 g. N 15-4/10/2-3483 «O napravlenii klinicheskih rekomendacij (protokola lecheniya) «Gipertenzivnye rasstrojstva vo vremya beremennosti, v rodah i poslerodovom periode. Preeklampsiya. Eklampsiya». Klinicheskie rekomendacii (Protokol lecheniya)]. Moscow, 2016. 40 p. (In Russ.). Available at: https://rokb.ru/sites/default/files/pictures/gipertenzivnye_rasstroystva_vo_vremya_beremennosti_v_rodah_i_poslerodovom_periode._preeklampsiya._eklampsiya.pdf. [Assessed: 01.06.2022].

20. Recommendations for treatment of arterial hypertension. ESH/ESC 2013. [Rekomendacii po lecheniyu arterial'noj gipertonii. ESH/ESC 2013]. Rossijskij kardiologicheskij zhurnal. 2014;19(1):7–94. (In Russ.).

21. Khodzhaeva Z.S., Kholin A.M., Vikhlyaeva E.M. Early and late preeclampsia: pathobiology paradigms and clinical practice. [Rannyaya i pozdnyaya preeklampsiya: paradigmy patobiologii i klinicheskaya praktika]. Akusherstvo i ginekologiya. 2013;(10):4–11. (In Russ.).

22. Brandão A.H., Evangelista A.A., Martins R.M. et al. Prediction of early and late preeclampsia by flow-mediated dilation of the brachial artery. Radiol Bras. 2014;47(4):206–9. https://doi.org/10.1590/0100-3984.2013.1894.