Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study

Abstract

Objective This study aimed to analyze the effect of pravastatin on angiogenic factors, feto–maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls.

Study Design This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe.

Results A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (−34.8 to 197.3) in the control group but decreased by a median (interquartile range) of −10.1 (−53.1 to −0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant.

Conclusion In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant.

Key Points

• Pravastatin improves sFlt-1/PlGF in FGR.

• Pregnancy duration tended to be greater in treated women.

• Birthweight tended to be greater in treated women.

Keywords

fetal growth restriction - pravastatin - PlGF - sFlt-1 - angiogenic factors - feto–placental Doppler

^* These authors contributed equally to this work.

Publication History

Received: 15 March 2020

Accepted: 19 May 2020

Article published online:
02 July 2020

• References

• 1 Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther 2014; 36 (02) 86-98
• 2 McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999; 340 (16) 1234-1238
• 3 Altshuler G, Russell P, Ermocilla R. The placental pathology of small-for-gestational age infants. Am J Obstet Gynecol 1975; 121 (03) 351-359
• 4 Mifsud W, Sebire NJ. Placental pathology in early-onset and late-onset fetal growth restriction. Fetal Diagn Ther 2014; 36 (02) 117-128
• 5 Levine RJ, Maynard SE, Qian C. et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350 (07) 672-683
• 6 Crispi F, Llurba E, Domínguez C, Martín-Gallán P, Cabero L, Gratacós E. Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol 2008; 31 (03) 303-309
• 7 Romero R, Nien JK, Espinoza J. et al. 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 2008; 21 (01) 9-23
• 8 Herraiz I, Quezada MS, Rodriguez-Calvo J, Gómez-Montes E, Villalaín C, Galindo A. Longitudinal change of sFlt-1/PlGF ratio in singleton pregnancy with early-onset fetal growth restriction. Ultrasound Obstet Gynecol 2018; 52 (05) 631-638
• 9 Temming LA, Dicke JM, Stout MJ. et al. Early second-trimester fetal growth restriction and adverse perinatal outcomes. Obstet Gynecol 2017; 130 (04) 865-869
• 10 Iacobelli S, Bonsante F, Robillard P-Y. Comparison of risk factors and perinatal outcomes in early onset and late onset preeclampsia: a cohort based study in Reunion Island. J Reprod Immunol 2017; 123: 12-16
• 11 Lecarpentier E, Morel O, Fournier T, Elefant E, Chavatte-Palmer P, Tsatsaris V. Statins and pregnancy: between supposed risks and theoretical benefits. Drugs 2012; 72 (06) 773-788
• 12 Costantine MM. Pravastatin to prevent obstetrical complications in women with antiphospholipid syndrome. J Clin Invest 2016; 126 (08) 2792-2794
• 13 Zarek J, DeGorter MK, Lubetsky A. et al. The transfer of pravastatin in the dually perfused human placenta. Placenta 2013; 34 (08) 719-721
• 14 Balan A, Szaingurten-Solodkin I, Swissa SS. et al. The effects of pravastatin on the normal human placenta: lessons from ex-vivo models. PLoS One 2017; 12 (02) e0172174
• 15 Brownfoot FC, Tong S, Hannan NJ. et al. Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia. Hypertension 2015; 66 (03) 687-697 , discussion 445
• 16 Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest 2016; 126 (08) 2933-2940
• 17 Figueras F, Meler E, Iraola A. et al. Customized birthweight standards for a Spanish population. Eur J Obstet Gynecol Reprod Biol 2008; 136 (01) 20-24
• 18 Baschat AA. Relationship between placental blood flow resistance and precordial venous Doppler indices. Ultrasound Obstet Gynecol 2003; 22 (06) 561-566
• 19 Gordijn SJ, Beune IM, Thilaganathan B. et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol 2016; 48 (03) 333-339
• 20 Macones GA, Hankins GDV, Spong CY, Hauth J, Moore T. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines. Obstet Gynecol 2008; 112 (03) 661-666
• 21 Figueras F, Gratacos E. Stage-based approach to the management of fetal growth restriction. Prenat Diagn 2014; 34 (07) 655-659
• 22 American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131
• 23 Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005; 5: 13
• 24 Molvarec A, Szarka A, Walentin S, Szucs E, Nagy B, Rigó Jr J. Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia. Hypertens Res 2010; 33 (09) 892-898
• 25 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 (01) 13-22
• 26 Baschat AA. Planning management and delivery of the growth-restricted fetus. Best Pract Res Clin Obstet Gynaecol 2018; 49: 53-65
• 27 Lees C, Marlow N, Arabin B. et al; TRUFFLE Group. Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound Obstet Gynecol 2013; 42 (04) 400-408
• 28 Jurisic A, Jurisic Z, Lefkou E, Pombo J, Girardi G. Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect. Vascul Pharmacol 2018; 110: 64-70
• 29 Chimini JS, Possomato-Vieira JS, da Silva MLS, Dias-Junior CA. Placental nitric oxide formation and endothelium-dependent vasodilation underlie pravastatin effects against angiogenic imbalance, hypertension in pregnancy and intrauterine growth restriction. Basic Clin Pharmacol Toxicol 2019; 124 (04) 385-393
• 30 Wyrwoll CS, Noble J, Thomson A. et al. Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess. Proc Natl Acad Sci U S A 2016; 113 (22) 6265-6270