The Impact of Aspirin on Ultrasound Markers of Uteroplacental Flow in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT

Abstract

Objective This article evaluates the effect of low-dose aspirin on uterine artery (UtA) Doppler, placental volume, and vascularization flow indices in low-risk pregnancy.

Study Design In this secondary analysis of the TEST randomized controlled trial, low-risk nulliparous women were originally randomized at 11 weeks to: (1) routine aspirin 75 mg; (2) no aspirin; and (3) aspirin based upon the preeclampsia Fetal Medicine Foundation screening test. UtA Doppler, three-dimensional (3D) placental volume, and vascularization flow indices were assessed prior to and 6 weeks postaspirin commencement.

Results A total of 546 women were included (aspirin n = 192, no aspirin n = 354). Between first and second trimesters, aspirin use was not associated with a change in UtA Doppler, placental volume, or vascular flow indices. There was no significant difference in the change in UtA Doppler pulsatility index (PI) Z-scores or notching (PI Z-score –0.2 vs. –0.2, p = 0.17), nor was there a significant change in placental volume Z-score and vascular flow indices (volume Z-score change: 0.74 vs. 0.62, p = 0.34).

Conclusion Low-dose aspirin commenced at 11 weeks in low-risk women does not appear to improve uterine and placental perfusion or placental volume. Any perceived effect on uteroplacental vasculature is not reflected in changes in placental volume nor uteroplacental flow as assessed by two-dimensional and 3D ultrasound.

Keywords

aspirin - uteroplacental - uterine artery Doppler - placental volume - 3D ultrasound - three-dimensional power Doppler indices

• References

• 1 Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367 (9516): 1066-1074
• 2 Sibai BM. What to expect from expectant management in severe preeclampsia at <34 weeks gestation: pregnancy outcomes in developed vs developing countries. Am J Obstet Gynecol 2013; 209 (05) 400-401
• 3 Brosens JJ, Pijnenborg R, Brosens IA. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature. Am J Obstet Gynecol 2002; 187 (05) 1416-1423
• 4 Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204 (03) 193-201
• 5 Gómez O, Martínez JM, Figueras F. , et al. Uterine artery Doppler at 11-14 weeks of gestation to screen for hypertensive disorders and associated complications in an unselected population. Ultrasound Obstet Gynecol 2005; 26 (05) 490-494
• 6 Pilalis A, Souka AP, Antsaklis P. , et al. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11-14 weeks' gestation. Ultrasound Obstet Gynecol 2007; 29 (02) 135-140
• 7 Carter EB, Goetzinger K, Tuuli MG. , et al. Evaluating the optimal definition of abnormal first-trimester uterine artery Doppler parameters to predict adverse pregnancy outcomes. J Ultrasound Med 2015; 34 (07) 1265-1269
• 8 Velauthar L, Plana MN, Kalidindi M. , et al. First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women. Ultrasound Obstet Gynecol 2014; 43 (05) 500-507
• 9 Bower S, Vyas S, Campbell S, Nicolaides KH. Color Doppler imaging of the uterine artery in pregnancy: normal ranges of impedance to blood flow, mean velocity and volume of flow. Ultrasound Obstet Gynecol 1992; 2 (04) 261-265
• 10 Gómez O, Figueras F, Martínez JM. , et al. Sequential changes in uterine artery blood flow pattern between the first and second trimesters of gestation in relation to pregnancy outcome. Ultrasound Obstet Gynecol 2006; 28 (06) 802-808
• 11 Morel O, Pachy F, Chavatte-Palmer P. , et al. Correlation between uteroplacental three-dimensional power Doppler indices and true uterine blood flow: evaluation in a pregnant sheep model. Ultrasound Obstet Gynecol 2010; 36 (05) 635-640
• 12 Rizzo G, Silvestri E, Capponi A. , et al. Histomorphometric characteristics of first trimester chorionic villi in pregnancies with low serum pregnancy-associated plasma protein-A levels: relationship with placental three-dimensional power Doppler ultrasonographic vascularization. J Matern Fetal Neonatal Med 2011; 24 (02) 253-257
• 13 Odeh M, Ophir E, Maximovsky O, Grinin V, Bornstein J. Placental volume and three-dimensional power Doppler analysis in prediction of pre-eclampsia and small for gestational age between week 11 and 13 weeks and 6 days of gestation. Prenat Diagn 2011; 31 (04) 367-371
• 14 Moran MC, Mulcahy C, Zombori G, Ryan J, Downey P, McAuliffe FM. Placental volume, vasculature and calcification in pregnancies complicated by pre-eclampsia and intra-uterine growth restriction. Eur J Obstet Gynecol Reprod Biol 2015; 195: 12-17
• 15 Odibo AO, Goetzinger KR, Huster KM, Christiansen JK, Odibo L, Tuuli MG. Placental volume and vascular flow assessed by 3D power Doppler and adverse pregnancy outcomes. Placenta 2011; 32 (03) 230-234
• 16 Hafner E, Metzenbauer M, Stümpflen I, Waldhör T, Philipp K. First trimester placental and myometrial blood perfusion measured by 3D power Doppler in normal and unfavourable outcome pregnancies. Placenta 2010; 31 (09) 756-763
• 17 Pomorski M, Zimmer M, Florjanski J. , et al. Comparative analysis of placental vasculature and placental volume in normal and IUGR pregnancies with the use of three-dimensional power Doppler. Arch Gynecol Obstet 2012; 285 (02) 331-337
• 18 Guiot C, Gaglioti P, Oberto M, Piccoli E, Rosato R, Todros T. Is three-dimensional power Doppler ultrasound useful in the assessment of placental perfusion in normal and growth-restricted pregnancies?. Ultrasound Obstet Gynecol 2008; 31 (02) 171-176
• 19 Noguchi J, Hata K, Tanaka H, Hata T. Placental vascular sonobiopsy using three-dimensional power Doppler ultrasound in normal and growth restricted fetuses. Placenta 2009; 30 (05) 391-397
• 20 Luria O, Barnea O, Shalev J. , et al. Two-dimensional and three-dimensional Doppler assessment of fetal growth restriction with different severity and onset. Prenat Diagn 2012; 32 (12) 1174-1180
• 21 Dar P, Gebb J, Reimers L, Bernstein PS, Chazotte C, Merkatz IR. First-trimester 3-dimensional power Doppler of the uteroplacental circulation space: a potential screening method for preeclampsia. Am J Obstet Gynecol 2010; 203 (03) 238.e1-238.e7
• 22 Plasencia W, González-Dávila E, González Lorenzo A, Armas-González M, Padrón E, González-González NL. First trimester placental volume and vascular indices in pregnancies complicated by preeclampsia. Prenat Diagn 2015; 35 (12) 1247-1254
• 23 Costa J, Rice H, Cardwell C, Hunter A, Ong S. An assessment of vascularity and flow intensity of the placenta in normal pregnancy and pre-eclampsia using three-dimensional ultrasound. J Matern Fetal Neonatal Med 2010; 23 (08) 894-899
• 24 Artunc Ulkumen B, Pala HG, Uyar Y, Koyuncu FM, Bulbul Baytur Y. The assessment of placental volume and mean gray value in preeclamptic placentas by using three-dimensional ultrasonography. J Matern Fetal Neonatal Med 2015; 28 (09) 1010-1013
• 25 Chen CY, Wang KG, Chen CP. Alteration of vascularization in preeclamptic placentas measured by three-dimensional power Doppler ultrasound. J Matern Fetal Neonatal Med 2013; 26 (16) 1616-1622
• 26 Hashish N, Hassan A, El-Semary A, Gohar R, Youssef MA. Could 3D placental volume and perfusion indices measured at 11-14 weeks predict occurrence of preeclampsia in high-risk pregnant women?. J Matern Fetal Neonatal Med 2015; 28 (09) 1094-1098
• 27 Bujold E, Effendi M, Girard M. , et al. Reproducibility of first trimester three-dimensional placental measurements in the evaluation of early placental insufficiency. J Obstet Gynaecol Can 2009; 31 (12) 1144-1148
• 28 Rizzo G, Capponi A, Cavicchioni O, Vendola M, Arduini D. First trimester uterine Doppler and three-dimensional ultrasound placental volume calculation in predicting pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2008; 138 (02) 147-151
• 29 Bujold E, Roberge S, Lacasse Y. , et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1): 402-414
• 30 Roberge S, Giguère Y, Villa P. , et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol 2012; 29 (07) 551-556
• 31 Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol 2013; 41 (05) 491-499
• 32 Mone F, Mulcahy C, McParland P. , et al. An open-label randomized-controlled trial of low dose aspirin with an early screening test for pre-eclampsia and growth restriction (TEST): trial protocol. Contemp Clin Trials 2016; 49: 143-148
• 33 Mone F, Mulcahy C, McParland P. , et al. Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial. BMJ Open 2018; 8 (07) e022056
• 34 Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001; 20 (01) IX-XIV
• 35 Redman CWG. Hypertension in pregnancy: the NICE guidelines. Heart 2011; 97 (23) 1967-1969
• 36 Snoep JD, Hovens MMC, Pasha SM. , et al. Time-dependent effects of low-dose aspirin on plasma renin activity, aldosterone, cortisol, and catecholamines. Hypertension 2009; 54 (05) 1136-1142
• 37 Rolnik DL, Wright D, Poon LC. , et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377 (07) 613-622
• 38 Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for prevention of preeclampsia. Drugs 2017; 77 (17) 1819-1831
• 39 Khalil A, Nicolaides KH. How to record uterine artery Doppler in the first trimester. Ultrasound Obstet Gynecol 2013; 42 (04) 478-479
• 40 Bhide A, Acharya G, Bilardo CM. , et al. ISUOG practice guidelines: use of Doppler ultrasonography in obstetrics. Ultrasound Obstet Gynecol 2013; 41 (02) 233-239
• 41 Campbell S. Placental vasculature as visualized by 3D power Doppler angiography and 3D color Doppler imaging. Ultrasound Obstet Gynecol 2007; 30 (06) 917-920
• 42 Pairleitner H, Steiner H, Hasenoehrl G, Staudach A. Three-dimensional power Doppler sonography: imaging and quantifying blood flow and vascularization. Ultrasound Obstet Gynecol 1999; 14 (02) 139-143
• 43 Cabezas López E, Martínez-Payo C, Engels Calvo V, San Frutos Llorente L, Pérez-Medina T. Reproducibility of first trimester three-dimensional placental measurements. Eur J Obstet Gynecol Reprod Biol 2016; 201: 156-160
• 44 Gómez O, Figueras F, Fernández S. , et al. Reference ranges for uterine artery mean pulsatility index at 11-41 weeks of gestation. Ultrasound Obstet Gynecol 2008; 32 (02) 128-132
• 45 de Paula CF, Ruano R, Campos JA, Zugaib M. Quantitative analysis of placental vasculature by three-dimensional power Doppler ultrasonography in normal pregnancies from 12 to 40 weeks of gestation. Placenta 2009; 30 (02) 142-148
• 46 Moran M, Zombori G, Ryan J, McAuliffe FM. 3D power Doppler ultrasound and computerised placental assessment in normal pregnancy. Radiography 2014; 20: 112-116
• 47 Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ. Placental pathology suggesting that preeclampsia is more than one disease. Am J Obstet Gynecol 2014; 210 (01) 66.e1-66.e7
• 48 Demers S, Roberge S, Bujold E. The use of aspirin during pregnancy. Am J Obstet Gynecol 2013; 208 (02) 161-162
• 49 Leducet F, Park F, McMaster Fay R, Johnson JM, Hyett J. Does low dose aspirin effect mean uterine artery Doppler pulsatility index in women deemed high risk for early preeclampsia?. Ultrasound Obstet Gynecol 2015; 46 (Suppl. 01) 185-228
• 50 Scazzocchio E, Oros D, Diaz D. , et al. Impact of aspirin on trophoblastic invasion in women with abnormal uterine artery Doppler at 11-14 weeks: a randomized controlled study. Ultrasound Obstet Gynecol 2017; 49 (04) 435-441
• 51 Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11-14 weeks of gestation. Ultrasound Obstet Gynecol 2001; 18 (06) 583-586
• 52 Alves JAG, Silva BY, de Sousa PC, Maia SB, Costa FdaS. Reference range of uterine artery Doppler parameters between the 11th and 14th pregnancy weeks in a population sample from Northeast Brazil. Rev Bras Ginecol Obstet 2013; 35 (08) 357-362
• 53 Espinoza J, Kusanovic JP, Bahado-Singh R. , et al. Should bilateral uterine artery notching be used in the risk assessment for preeclampsia, small-for-gestational-age, and gestational hypertension?. J Ultrasound Med 2010; 29 (07) 1103-1115
• 54 Panagodage S, Yong HEJ, Da Silva Costa F. , et al. Low dose acetylsalicylic acid treatment modulates the production of cytokines and improves trophoblast function in an in vitro model of early onset preeclampsia. Am J Pathol 2016; 186 (12) 3217-3224
• 55 Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101 (10) 1206-1218
• 56 Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017; 216 (02) 110-120
• 57 Maree AO, Curtin RJ, Dooley M. , et al. Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol 2005; 46 (07) 1258-1263
• 58 Dumont A, Flahault A, Beaufils M, Verdy E, Uzan S. Effect of aspirin in pregnant women is dependent on increase in bleeding time. Am J Obstet Gynecol 1999; 180 (1 Pt 1): 135-140
• 59 Caron N, Rivard GÉ, Michon N. , et al. Low-dose ASA response using the PFA-100 in women with high-risk pregnancy. J Obstet Gynaecol Can 2009; 31 (11) 1022-1027
• 60 de Paula CF, Ruano R, Campos JA, Zugaib M. Placental volumes measured by 3-dimensional ultrasonography in normal pregnancies from 12 to 40 weeks' gestation. J Ultrasound Med 2008; 27 (11) 1583-1590
• 61 Wright D, Akolekar R, Syngelaki A, Poon LCY, Nicolaides KH. A competing risks model in early screening for preeclampsia. Fetal Diagn Ther 2012; 32 (03) 171-178
• 62 Cuckle HS. Screening for pre-eclampsia--lessons from aneuploidy screening. Placenta 2011; 32 (Suppl): S42-S48
• 63 Guyomard A, Macé G, Ferdynus C, Franceschini C, Rousseau T, Sagot P. Reference ranges and distribution of placental volume by 3-dimensional virtual organ computer-aided analysis between 11 weeks and 13 weeks 6 days. J Ultrasound Med 2013; 32 (08) 1477-1482
• 64 Effendi M, Demers S, Giguère Y. , et al. Association between first-trimester placental volume and birth weight. Placenta 2014; 35 (02) 99-102
• 65 Simcox LE, Higgins LE, Myers JE, Johnstone ED. Intraexaminer and interexaminer variability in 3D fetal volume measurements during the second and third trimesters of pregnancy. J Ultrasound Med 2017; 36 (07) 1415-1429
• 66 Merce LT, Barco MJ, Bau S, Kupesic S, Kurjak A. Assessment of placental vascularization by three-dimensional power Doppler “vascular biopsy” in normal pregnancies. Croat Med J 2005; 46 (05) 765-771
• 67 Tuuli MG, Houser M, Odibo L, Huster K, Macones GA, Odibo AO. Validation of placental vascular sonobiopsy for obtaining representative placental vascular indices by three-dimensional power Doppler ultrasonography. Placenta 2010; 31 (03) 192-196
• 68 Lai PK, Wang YA, Welsh AW. Reproducibility of regional placental vascularity/perfusion measurement using 3D power Doppler. Ultrasound Obstet Gynecol 2010; 36 (02) 202-209
• 69 Jones NW, Raine-Fenning NJ, Mousa HA, Bradley E, Bugg GJ. Evaluating the intra- and interobserver reliability of three-dimensional ultrasound and power Doppler angiography (3D-PDA) for assessment of placental volume and vascularity in the second trimester of pregnancy. Ultrasound Med Biol 2011; 37 (03) 376-385
• 70 Farina A. Placental vascular indices (VI, FI and VFI) in intrauterine growth retardation (IUGR). A pooled analysis of the literature. Prenat Diagn 2015; 35 (11) 1065-1072
• 71 Raine-Fenning NJ, Nordin NM, Ramnarine KV. , et al. Determining the relationship between three-dimensional power Doppler data and true blood flow characteristics: an in-vitro flow phantom experiment. Ultrasound Obstet Gynecol 2008; 32 (04) 540-550