Accepted: 21 July 2023 | Published Online 9 August 2023 DOI: 10.1111/1471-0528.17631 RESEARCH ARTICLE General obstetrics Mid-­trimester uterine artery Doppler for aspirin discontinuation in pregnancies at high risk for preterm pre-­eclampsia: Post-­hoc analysis of StopPRE trial Erika Bonacina1 | Pablo Garcia-­Manau1 | Monica López2 | Sara Caamiña3 | Àngels Vives4 | Eva Lopez-­Quesada5 | Marta Ricart6 | Anna Maroto7 | Laura de Mingo8 | Elena Pintado9 | Laura Castillo-­Ribelles10 | Lourdes Martín2 | Alicia Rodriguez-­Zurita3 | Esperanza Garcia4 | Mar Pallarols5 | Laia Vidal-­Sagnier6 | Mireia Teixidor7 | Carmen Orizales-­Lago8 | Adela Pérez-­Gomez3 | Vanesa Ocaña9 | Linda Puerto2 | Pilar Millán4 | Mercè Alsius11 | Sonia Diaz9 | Nerea Maiz1 | Elena Carreras1 | Anna Suy1 | Manel Mendoza1 1 Maternal Fetal Medicine Unit, Department of Obstetrics, Vall d'Hebron Barcelona Hospital Abstract Campus, Universitat Autònoma de Barcelona, Objective: To assess whether aspirin treatment can be discontinued in pregnancies Barcelona, Spain 2 with normal uterine artery pulsatility index (≤90th percentile) at 24–­28 weeks. Department of Obstetrics, Hospital Universitari de Tarragona Joan XXIII, Design: Post-­hoc analysis of a clinical trial. Tarragona, Spain Setting: Nine maternity hospitals in Spain. 3 Department of Obstetrics, Hospital Population or Sample: Pregnant individuals at high risk of pre-­ eclampsia at Universitario Nuestra Señora de Candelaria, 11–­13 weeks and normal uterine artery Doppler at 24–­28 weeks. Santa Cruz de Tenerife, Spain 4 Methods: All participants received treatment with daily aspirin at a dose of 150 mg. Department of Obstetrics, Consorci Sanitari de Terrassa, Terrassa, Spain Participants were randomly assigned, in a 1:1 ratio, either to continue aspirin treat- 5 Department of Obstetrics, Hospital ment until 36 weeks (control group) or to discontinue aspirin treatment (inter- Universitari Mútua Terrassa, Terrassa, Spain vention group), between September 2019 and September 2021. In this secondary 6 Department of Obstetrics, Hospital analysis, women with a UtAPI >90th percentile at 24–­28 weeks were excluded. The Universitari Germans Trias i Pujol, Badalona, non-­inferiority margin was set at a difference of 1.9% for the incidence of preterm Spain 7 pre-­eclampsia. Department of Obstetrics, Hospital Universitari de Girona Doctor Josep Trueta, Main outcome measures: Incidence of preterm pre-­eclampsia. Girona, Spain Results: Of the 1611 eligible women, 139 were excluded for UtAPI >90th percentile 8 Department of Obstetrics, Hospital or if UtAPI was not available. Finally, 804 were included in this post-­hoc analysis. Universitario Severo Ochoa, Leganés, Spain Preterm pre-­eclampsia occurred in three of 409 (0.7%) women in the aspirin discon- 9 Department of Obstetrics, Hospital tinuation group and five of 395 (1.3%) women in the continuation group (−0.53; 95% Universitario de Getafe, Getafe, Spain 10 CI −1.91 to 0.85), indicating non-­inferiority of aspirin discontinuation. Department of Biochemistry, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain Conclusions: Discontinuing aspirin treatment at 24–­28 weeks in women with a 11 Department of Biochemistry, Hospital UtAPI ≤90th percentile was non-­inferior to continuing aspirin treatment until Universitari de Girona Doctor Josep Trueta, 36 weeks for preventing preterm pre-­eclampsia. Girona, Spain Erika Bonacina and Pablo Garcia-­Manau: joint first authors. Anna Suy and Manel Mendoza: joint last authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd. 334 |  wileyonlinelibrary.com/journal/bjo BJOG. 2024;131:334–342. 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License UTERINE ARTERY FOR ASPIRIN DISCONTINUATION    | 335 Correspondence Manel Mendoza, Maternal Fetal Medicine K EY WOR DS Unit, Department of Obstetrics, Vall d'Hebron aspirin, Doppler, pre-­eclampsia, salicylic acid, screening, uterine artery Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-­129, 08035 Barcelona, Spain. Email: manel.mendoza@vallhebron.cat Funding information Instituto de Salud Carlos III; Roche Diagnostics 1 | I N T RODUC T ION 2 | M ET HODS Pre-­eclampsia (PE) is a serious multisystem disorder which 2.1 | Population typically develops as new-­onset hypertension and protein- uria after 20 weeks of gestation. It affects 2–­4% of pregnan- This is a post-­hoc analysis of the StopPRE trial, which was cies1 and accounts for more than 70 000 maternal deaths conducted at nine maternity units across Spain between and 500 000 fetal deaths worldwide annually.2 The exact September 2019 and September 2021. The study protocol has pathogenesis of PE is not well understood and various ma- been described previously.12 The StopPRE trial is registered ternal and placental factors may be involved; nevertheless, with Clini​calTr​ials.gov (NCT03741179) and clinicaltrialsreg- impaired placentation is believed to be a primary factor ister.eu (2018–­000811-­26). All participants provided their contributing to early-­onset and preterm cases.1,3 In normal written informed consent. In the StopPRE trial, all pregnant pregnancies, maternal spiral arteries convert from narrow women with a high risk of PE at the first-­trimester screen- muscular vessels into wide non-­muscular channels, and the ing were treated with daily aspirin at a dose of 150 mg. Cases impedance to flow in the uterine arteries (UtA) decreases with an sFlt-­1/PlGF ratio ≤38 at 24–­28 weeks were randomly between 6 and 24 weeks.4 Increased pulsatility index (PI) assigned, in a 1:1 ratio, either to continue aspirin treatment in UtA reflects their maladaptation to pregnancy changes, (control group) or to discontinue aspirin treatment (interven- which is more frequently found in pregnant women who will tion group). All participants were followed up every 4 weeks develop preterm PE.1,4 By contrast, normal mid-­trimester and all data and pregnancy outcomes were prospectively re- UtAPI has a negative predictive value (NPV) >96% to ex- corded in an electronic database. The primary outcome of the clude the development of PE.5 Impaired placentation also StopPRE trial was to demonstrate that the incidence of pre- results in uteroplacental ischaemia,6 with the ensuing ex- term PE in patients with an sFlt-­1/PlGF ratio ≤38 was similar, cess of anti-­angiogenic factors, such as soluble fms-­like regardless of whether they continued aspirin treatment. The tyrosine kinase-­1 (sFlt-­1), and decrease of pro-­a ngiogenic non-­inferiority margin was set at a 1.9% difference between factors, such as placental growth factor (PlGF).7 Therefore, both groups for the incidence of preterm PE; therefore, non-­ the sFlt-­1/PlGF ratio is increased several weeks before clin- inferiority was met if the upper limit of the 95% confidence ical onset of PE.8 UtAPI and PlGF can be used in the first-­ interval (CI) for the difference between both groups in pre- trimester screening for PE,9,10 which indicates the initiation term PE incidence was <1.9%. of aspirin treatment before 16 weeks, thereby decreasing the Inclusion criteria in the StopPRE trial were singleton preg- incidence of preterm PE by 62%.11 First-­t rimester screening nancy, maternal age ≥18 years, gestational age between 24+0 detects 60–­70% of women who will develop preterm PE at and 27+6 (24–­28) weeks, live fetus, high risk of preterm PE a 10% false-­positive rate.9,10 However, as the incidence of (≥1/170) during the first trimester (11+0 to 13+6 weeks) accord- preterm PE in high-­risk women is around 4%,11 more than ing to the screening algorithm,9,14 treatment with daily aspirin 95% of women classified as being at risk of PE would be at a dose of 150 mg initiated ≤16+6 weeks until randomisation false-­positive cases and will receive unnecessary treatment with a compliance of at least 50%, and an sFlt-­1/PlGF ratio <38 with aspirin. In a previous clinical trial, we showed that a between 24 and 28 weeks. Exclusion criteria were aspirin intol- normal sFlt-­1/PlGF ratio (≤38) at 24–­28 weeks can detect erance or allergy, fetus with known congenital abnormalities, false positives and makes it possible to identify patients for von Willebrand's disease, antiphospholipid syndrome, peptic whom aspirin can be discontinued without increasing the ulceration and any condition or factor that, according to the incidence of preterm PE (1.48% versus 1.73%, risk differ- investigator, might prevent adherence to the protocol. All par- ence −0.25 [−1.86 to 1.36]).12 Unfortunately, the sFlt-­1/PlGF ticipants provided written informed consent. ratio might not be available in all settings. As previous studies have shown a good correlation between angiogenic factors and UtAPI,13 we aimed to assess whether aspirin 2.2 | Study variables and outcomes treatment can be discontinued in patients with a normal UtAPI at 24–­28 weeks without increasing the incidence of UtAPI >95th percentile and >90th percentile perform simi- preterm PE. larly to assess the risk of PE; however, the 90th percentile has 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 336 |    BONACINA et al. a greater specificity and NPV to exclude the development of were reported as the mean and standard deviation or as the PE.15 Thus, for the purposes of this post-­hoc analysis, the median and interquartile range, and intervention effect for 90th percentile was considered more appropriate and we ex- the primary and secondary outcomes was quantified as the cluded those patients with an abnormal UtAPI (>90th per- absolute difference between groups in incidences, the rela- centile) or without an assessment of UtAPI at enrolment. In tive risk (RR) and the 95% confidence interval (95% CI). this post-­hoc analysis, we included all cases of the original Statistical significance level was set at P < 0.05. The non-­ study as well as all the cases excluded for having an sFlt-­1/ inferiority margin was set at a difference of 1.9% between PlGF ratio ≥38. However, as all participants with an sFlt-­1/ both groups for incidence of preterm PE, as in the original PlGF ratio ≥38 also had an abnormal UtAPI, these partici- study. Statistical analyses were performed on an intention-­ pants were finally excluded from analysis. Among patients to-­ t reat basis using the STATA Statistical Software with a normal UtAPI (≤90th percentile) at 24–­28 weeks, we (StataCorp 2017. Stata Statistical Software: Release 15. compared pregnancy outcomes for patients allocated to aspi- StataCorp LLC.). rin discontinuation and patients allocated to aspirin continu- ation until 36 weeks. The primary outcome was delivery due to PE before 37 weeks (preterm PE). Secondary outcomes were 3 | R E SU LT S PE or other adverse pregnancy outcomes before 34 weeks, any other adverse pregnancy outcomes <37 weeks, and PE or Between 5 March 2019 and 15 May 2021, a total of 13 983 other adverse pregnancy outcomes at ≥37 weeks; gestational women were screened for PE; of these, 1984 (14.2%) were hypertension, placental abruption, SGA, spontaneous deliv- identified as being at a high risk of preterm PE and were pre- ery without PE and stillbirth were considered other adverse scribed daily aspirin at a dose of 150 mg to be taken at bed- outcomes. SGA was defined as a birthweight below the 10th time until 36 weeks. However, 373 of these women (18.8%) percentile according to customised local charts.16 PE was de- did not meet the eligibility criteria (Figure 1). Of the 1611 fined according to the guidelines of the American College of eligible women (1604 had an sFlt-­1/PlGF ratio <38 as in the Obstetricians and Gynecologists: new-­onset high blood pres- StopPRE trial, and seven had an sFlt-­1/PlGF ratio ≥38), 139 sure (SBP >140 mmHg and/or DBP >90 mmHg) or worsen- were excluded in this study due to UtAPI >90th percentile ing of previous high blood pressure in addition to new-­onset or when UtAPI was not available. All cases with an sFlt-­1/ proteinuria (protein to creatinine ratio >300 or dipstick +) or PlGF ≥38 had a UtAPI >90th percentile and were therefore worsening of previous proteinuria or at least one of the follow- excluded from this study. Finally, 836 agreed to participate ing signs and symptoms: cerebral or visual symptoms, eleva- and were randomised in two groups, from 20 August 2019 tion of liver enzymes to twice the normal level, platelet count through 15 September 2021. After randomisation, three <100 000/mcl, serum creatinine >1.1 mg/dl or pulmonary women withdrew consent and 29 were lost to follow-­up. For oedema.17 Elective delivery was recommended at ≥37 weeks 804 women (96.2%) data were available for the primary and in women with PE without severe features and at ≥34 weeks secondary outcomes. Baseline characteristics of women in- in women with PE with severe features and/or HELLP syn- cluded and excluded in this study can be seen in Table 1 and drome.18 Immediate delivery was indicated in women with Table S1. pulmonary oedema, placental abruption, persistent hyper- Preterm PE occurred in three of 409 women (0.7%) in the tension despite appropriate antihypertensive therapy, per- intervention group and five of 395 women (1.3%) in the con- sistent cerebral or visual disturbances, oliguria (≤500 ml in trol group (absolute difference −0.53; 95% CI −1.91 to 0.85). 24 hours or <20 ml/hour) or eclampsia. Other secondary out- Median (interquartile range) gestational age at delivery for comes were minor antepartum bleeding complications (nose cases with PE <37 weeks was 35.1 (34.0–­35.3) weeks in the and/or gum bleeding), major antepartum bleeding complica- intervention group and 36.3 (34.7–­36.6) weeks in the con- tions (digestive and/or vaginal bleeding, haemoptysis), ma- trol group (P = 0.297). More details can be found in Figure 2. ternal intracranial haemorrhage; postpartum haemorrhage, There were no significant differences between groups in stillbirth, neonatal death, low birthweight (below the 3rd or terms of incidence of other adverse outcomes with delivery 10th percentile),16 neonatal complications, and neonate re- <37 weeks or any adverse outcome with delivery <34 weeks. quiring therapy. The incidence of adverse outcomes at ≥37 weeks of gestation No patients were involved in the development of the re- did not differ significantly between groups. Median (in- search study. No core outcome set was used as an outcome terquartile range) gestational age at delivery for cases with in this study. PE at ≥37 weeks was 38.7 (37.9–­39.4) weeks in the interven- tion group and 38.3 (37.3–­39.6) weeks in the control group (P = 0.509). 2.3 | Statistical analysis The incidence of minor antepartum haemorrhage was 7.6% in the intervention group and 13.2% in the control Categorical data were reported as frequency and percent- group (absolute difference −5.59; 95% CI −9.79 to −1.38). age and comparisons between groups were estimated by At least one bleeding complication occurred in 33 of 409 the χ 2 or Fisher tests, as appropriate. Continuous variables participants (8.1%) in the intervention group and 54 of 409 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License UTERINE ARTERY FOR ASPIRIN DISCONTINUATION    | 337 FIGU R E 1 Flowchart. participants (13.7%) in the control group (absolute differ- compliance was verified, tablet intake was ≥90% in all visits ence −5.60; 95% CI −9.90 to −1.31). The incidence of other for ≥81% of participants. bleeding complications or adverse neonatal events (Figure 2) did not differ significantly between groups; however, the incidence of placental abruption at <37 weeks of gestation 4 | DISC US SION (no cases versus three [0.8%] cases, P = 0.077) and neona- tal distress syndrome (6 [1.5%] cases versus 13 [3.3%] cases, 4.1 | Main findings P = 0.089) tended to be greater in participants that continued aspirin treatment until 36 weeks. Figure 2 shows a forest plot Aspirin discontinuation in women with normal UtAPI for all outcomes. (≤90th percentile) at 24–­28 weeks is non-­inferior to aspirin Despite being assigned to the intervention group, four continuation until 36 weeks for preventing preterm PE and participants (0.98%) continued aspirin treatment with a me- other pregnancy complications. Additionally, women in the dian (interquartile range) tablet intake of 100% (100–­100). intervention group had significantly fewer minor bleeding In the control group, aspirin treatment compliance could complications and tended to have less placental abruption at not be verified by tablet counts in six of 395 participants <37 weeks and neonatal respiratory distress syndrome than (1.5%). Among the 389 women for whom aspirin treatment women in the control group. 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 338 |    BONACINA et al. TA BL E 1 Characteristics of the trial participants. Intervention group Control group Characteristic (n = 409) (n = 395) Gestational age at randomisation, weeks 26.1 (25.7–­26.7) 26.3 (25.9–­26.6) Age, years 32.6 (28.1–­36.5) 32.8 (27.9–­36.3) Body mass index, kg/m2 28.0 (24.6–­32.3) 28.4 (24.6–­32.6) a Race or ethnic group White 384 (93.9) 363 (91.9) Black 15 (3.7) 14 (3.5) South Asian 3 (0.7) 9 (2.3) East Asian 2 (0.5) 2 (0.5) Mixed race 5 (1.2) 7 (1.8) Method of conception Natural 400 (97.8) 389 (98.5) Assisted by use of ovulation drugs 1 (0.2) 1 (0.3) In vitro fertilisation 8 (2.0) 5 (1.2) Cigarette smoking 33 (8.1) 39 (9.9) Medical history Chronic hypertension 16 (3.9) 13 (3.3) Systemic lupus erythematosus 0 (0) 0 (0) Diabetes mellitus type 1 or 2 16 (3.9) 11 (2.8) Renal disease 0 (0) 0 (0) Obstetrical history Nulliparous 217 (53.1) 200 (50.6) Multiparous without pre-­eclampsia 164 (40.1) 177 (44.8) Multiparous with pre-­eclampsia 28 (6.8) 18 (4.6) Risk of preterm pre-­eclampsia as assessed at screening at 11–­13 weeksb, % 2.0 (1.0–­6.0) 2.0 (1.0–­5.0) Gestational age for sFlt-­1/PlGF measurement at randomisation, weeks 25.1 (24.8–­25.8) 25.3 (24.9–­25.9) sFlt-­1/PlGF at randomisation 3.89 (2.55–­5.89) 3.77 (2.43–­5.64) Estimated fetal weight at randomisation, grams 931.0 (860.0–­1024.0) 923.0 (847.0–­1009.0) Estimated fetal weight <10th percentile at randomisation 3 (0.7) 2 (0.5) Uterine artery pulsatility index at randomisation 0.81 (0.69– ­0.94) 0.82 (0.70– ­0.95) Note: Data are number of events (%) or median (IQR). a Race and ethnicity were self-­reported by participants from predefined categories. b Risk of preterm pre-­eclampsia was assessed by means of a Gaussian algorithm that combined maternal factors, mean arterial blood pressure, mean uterine artery pulsatility index, maternal serum pregnancy-­associated plasma protein A, and placental growth factor.9 4.2 | Strengths and limitations participants were aware of group assignment, and pla- cebo was not used in the intervention group, as PE is not The main strength of this study is its prospective design in a subjective outcome measure and because the research- a large cohort of women at a high risk of PE. Additionally, ers aimed to simulate a real clinical setting. Thirdly, the we provide novel evidence that a UtAPI ≤90th percentile trial was not powered enough to assess the effect of aspirin is a good alternative to an sFlt-­1/PlGF ≤38, which can be treatment discontinuation for rarer complications. Finally, used alone or in combination with the sFlt-­1/PlGF ratio the incidence of all adverse outcomes was low and for this to identify patients for whom aspirin treatment can be reason, the participating site could not be used as a clus- discontinued, thereby reducing exposure time to aspi- ter variable in analysis, which may have lowered standard rin treatment and aspirin-­related complications during errors and the possibilities of reaching the non-­i nferiority pregnancy. margin. Nevertheless, E-­values were calculated to assess This study also has several limitations. First, it is a the robustness of our findings to unmeasured confound- post-­hoc analysis of a previous clinical trial and its results ing, showing that in most cases considerable unmeasured should therefore be interpreted with caution. Secondly, it confounding would be needed to explain away the results shares the limitations of the original trial: Physicians and of this study (see Table S2). 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License UTERINE ARTERY FOR ASPIRIN DISCONTINUATION    | 339 F I G U R E 2 Pregnancy outcomes. Data are number of events (%), relative risk (95% CI) and incidence difference (95% CI). *The status of being small for gestational age was defined as a birthweight below the 10th percentile. Birthweight percentiles were calculated according to gestational age at birth by customised charts.16 †Minor antepartum haemorrhage: nose and/or gum bleeding. ‡Major antepartum haemorrhage: haemoptysis, digestive and/or vaginal bleeding. 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 340 |    BONACINA et al. 4.3 | Interpretation trial, the screen-­positive rate at 24–­28 weeks according to the sFlt-­1/PlGF ratio (i.e. patients with sFlt-­1/PlGF>38) was Two meta-­analyses showed that a greater prevention of PE 0.7% (7/975) and, according to this, aspirin treatment could was achieved when aspirin was initiated before 16 weeks and be discontinued in 99.3% (968/975) of pregnant women at a that a daily dose ≥100 mg initiated after 16 weeks may be as- high risk of PE. By contrast, in the present post-­hoc analy- sociated with an increased relative risk of placental abrup- sis, the screen-­positive rate based on the UtAPI (i.e. patients tion and other bleeding complications.19,20 For this reason, with a UtAPI >90th percentile) was 13.9% (135/971) and aspirin treatment should be initiated in the first trimester therefore, aspirin treatment could be safely discontinued and discontinued at term or before onset of labour. Despite in 86.1% (836/971) of participants. Thus, aspirin discon- the safety concerns associated with aspirin treatment dur- tinuation based on the UtAPI may be more convenient and ing pregnancy, discontinuation of aspirin treatment before cost-­effective for some settings than aspirin discontinuation term has been evaluated in only one study.21 In that study, a based on the sFlt-­1/PlGF ratio. On the other hand, aspirin Japanese cohort study, aspirin treatment was discontinued at treatment would be discontinued in a lower proportion of 28 weeks following the Japanese national recommendations patients when using the UtAPI alone (99.3 versus 86.1%). for aspirin use in pregnancy, and the study compared the in- Additionally, in this study we show that aspirin discon- cidence of PE with that of untreated historical controls. The tinuation in pregnant women with normal UtAPI did not in- authors Kawaguchi et al.21 found no reduction in PE inci- crease the risk of preterm PE, which supports the hypothesis dence; nevertheless, participants were selected according to that an abnormal placentation can be identified by Doppler maternal risk factors and not by a multivariable algorithm. studies and is a major cause of PE, especially in its earlier The the incidence of preterm PE was surprisingly high in forms. both groups (12.0 versus 13.1%), the daily dose of aspirin was only 100 mg, and compliance in the aspirin group was not reported. For these reasons, those authors concluded 4.4 | Clinical and research implications that further studies were needed to determine when aspirin treatment should be discontinued during pregnancy. The This study has important clinical implications, as it provides Stop-­PRE trial showed that aspirin treatment discontinua- evidence that aspirin can be safely discontinued in those tion in patients with an sFlt-­1/PlGF ratio ≤38 at 24–­28 weeks women at a high risk of PE who have a normal UtAPI at was non-­inferior to prevent preterm PE compared with con- 24–­28 weeks, which may reduce the risk of bleeding and po- tinuing aspirin treatment until 36 weeks.12 Several studies tentially other iatrogenic complications of aspirin treatment have demonstrated that a normal UtAPI in the second and such as neonatal respiratory distress syndrome and pla- third trimesters has an NPV above 90% for excluding PE.15 cental abruption when discontinued in larger populations. However, no previous studies have evaluated the usefulness Therefore, the results of the current study may be used as an of UtA Doppler for deciding whether to discontinue aspirin alternative to use of the sFlt-­1/PlGF ratio in those settings treatment in women at a high risk of PE. In the Stop-­PRE where this value is not available. Additionally, our findings FIGU R E 3 Options for aspirin discontinuation based on mean uterine artery pulsatility index. 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License UTERINE ARTERY FOR ASPIRIN DISCONTINUATION    | 341 may complement those of the Stop-­PRE trial, and one po- have no other conflicts of interest to disclose. Completed tential management protocol may be done in two steps, as disclosure of interests forms are available to view online as follows: in the first step, aspirin may be discontinued in the supporting information. 804 (86.1%) women with UtAPI ≤90th percentile. In the second step, aspirin may be discontinued in the remaining DATA AVA I L A BI L I T Y S TAT E M E N T 132 (13.9%) women with UtAPI >90th percentile and nor- The data that support the findings of this study are available mal sFlt-­1/PlGF (≤38). This two-­step approach would allow from the corresponding author upon reasonable request. discontinuation of aspirin in the same proportion of women as in the Stop-­PRE trial and would therefore have the same E T H IC S S TAT E M E N T outcomes as those of the Stop-­PRE trial but with the dif- The study protocol was approved by the institutional review ference that sFlt-­1/PlGF measurement would be performed board at each participating centre and by the Spanish Agency in a smaller proportion of patients (13.9% instead of 100%). for Medicines and Medical Devices (AEMPS). Participants (Figure 3). provided written informed consent. ORC I D 5 | C ONC LUSION Erika Bonacina https://orcid.org/0000-0002-8042-8247 Pablo Garcia-­Manau https://orcid. Discontinuing aspirin treatment at 24–­28 weeks in women org/0000-0002-2415-1626 at a high risk of PE with a UtAPI ≤90th percentile was non-­ Laura Castillo-­Ribelles https://orcid. inferior to continuing aspirin treatment until 36 weeks org/0000-0001-9380-7839 for preventing preterm PE and other related disorders. Linda Puerto https://orcid.org/0000-0001-5539-6397 Therefore, a UtAPI ≤90th percentile may be used alone or in Manel Mendoza https://orcid.org/0000-0002-3030-3833 combination with the sFlt-­1/PlGF ratio to identify patients for whom aspirin treatment can be discontinued, which R EFER ENCES could reduce bleeding risk and other iatrogenic complica- 1. Magee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J tions of aspirin treatment. Med. 2022;386(19):1817–­32. 2. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia. Circ Res. 2019;124(7):1094–­112. AU T HOR C ON T R I BU T ION S 3. O'Gorman N, Tampakoudis G, Wright A, Wright D, Nicolaides Conceptualisation: MM and AS. Methodology: MM, EB, KH. Uterine artery pulsatility index at 12, 22, 32 and 36 weeks' ges- PG-­M and AS. Data collection: All authors. Statistical tation in screening for pre-­eclampsia. Ultrasound Obstet Gynecol. analysis: MM. Data interpretation: MM, EB, PG-­M and AS. 2016;47(5):565–­72. 4. Plasencia W, Maiz N, Poon L, Yu C, Nicolaides KH. Uterine ar- Drafting of the article: EB and PG-­M. Article review and ed- tery Doppler at 11 + 0 to 13 + 6 weeks and 21 + 0 to 24 + 6 weeks iting: All authors. in the prediction of pre-­ eclampsia. Ultrasound Obstet Gynecol. 2008;32(2):138–­46. AC K N O​W L E​D G E​M E N T S 5. Papageorghiou AT, Yu CKH, Cicero S, Bower S, Nicolaides KH. This study has been funded by the Instituto de Salud Second-­trimester uterine artery Doppler screening in unselected pop- ulations: a review. J Matern Fetal Neonatal Med. 2002;12(2):​78–­88. Carlos III (ISCIII) through the project “PI17/01944” 6. Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger and co-­funded by European Union (ERDF, “A way to JP. Pathophysiology of hypertension during preeclampsia: linking make Europe”). This work was supported by the Spanish placental ischemia with endothelial dysfunction. Am J Physiol Heart Clinical Research Network (SCReN), co-­financed by the Circ Physiol. 2008;294(2):H541–­50. ISCIII-­Subdirección General de Evaluación y Fomento de 7. Rana S, Burke SD, Karumanchi SA. Imbalances in circulating angio- genic factors in the pathophysiology of preeclampsia and related dis- la Investigación. Roche Diagnostics provided the reagents orders. Am J Obstet Gynecol. 2022;226(2 Suppl):S1019–­34. used in this study. Roche Diagnostics had no influence on 8. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. the study design, data collection, or analysis and interpre- Circulating angiogenic factors and the risk of preeclampsia. N Engl J tation of results. We thank all the physicians and nurses Med. 2004;350(7):672–­83. who recruited individuals for the STOP-­PRE trial, all par- 9. Serra B, Mendoza M, Scazzocchio E, Meler E, Nolla M, Sabrià E, et al. A new model for screening for early-­onset preeclampsia. Am J Obstet ticipants who agreed to take part in the study; and Jemina Gynecol. 2020;222(6):608.e1– ­608.e18. Moreto (Trialance SCCL) and María del Mar Jiménez 10. Tan MY, Syngelaki A, Poon LC, Rolnik DL, O'Gorman N, Delgado Quesada for medical writing support. JL, et al. Screening for pre-­eclampsia by maternal factors and bio- markers at 11-­ 13 weeks' gestation. Ultrasound Obstet Gynecol. F U N DI N G I N F OR M AT ION 2018;52(2):186–­95. 11. Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Instituto de Salud Carlos III (PI17/01944). Roche diagnostics MC, et al. Aspirin versus placebo in pregnancies at high risk for provided the reagents. preterm preeclampsia. N Engl J Med. 2017;377(7):613–­22. 12. Mendoza M, Bonacina E, Garcia-­Manau P, López M, Caamiña S, C ON F L IC T OF I N T E R E S T S TAT E M E N T Vives À, et al. Aspirin discontinuation at 24 to 28 Weeks' gestation MM has received lecture fees from Roche Diagnostics out- in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329(7):542–­50. side the submitted work. The other authors report that they 14710528, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17631 by Readcube (Labtiva Inc.), Wiley Online Library on [02/02/2024]. 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