Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: A double blinded randomized placebo-controlled trial

Caroline Diguisto; Amelie Le Gouge; Marie-Sara Marchand; Pascal Megier; Yves Ville; Georges Haddad; Norbert Winer; Chloé Arthuis; Muriel Doret; Veronique Houfflin Debarge; Anaig Flandrin; Hélène Laurichesse Delmas; Denis Gallot; Pierre Mares; Christophe Vayssiere; Loïc Sentilhes; Marie-Therese Cheve; Anne Paumier; Luc Durin; Bruno Schaub; Veronique Equy; Bruno Giraudeau; Franck Perrotin; for the Groupe de Recherche en Obstétrique et Gynécologie (GROG)

doi:10.1371/journal.pone.0275129

. 2022 Oct 19;17(10):e0275129. doi: 10.1371/journal.pone.0275129

Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: A double blinded randomized placebo-controlled trial

Caroline Diguisto ^1,^2,^3,^*, Amelie Le Gouge ⁴, Marie-Sara Marchand ⁵, Pascal Megier ⁶, Yves Ville ^7,⁸, Georges Haddad ⁹, Norbert Winer ¹⁰, Chloé Arthuis ¹⁰, Muriel Doret ¹¹, Veronique Houfflin Debarge ¹², Anaig Flandrin ¹³, Hélène Laurichesse Delmas ¹⁴, Denis Gallot ¹⁴, Pierre Mares ^15,¹⁶, Christophe Vayssiere ^17,¹⁸, Loïc Sentilhes ¹⁹, Marie-Therese Cheve ²⁰, Anne Paumier ²¹, Luc Durin ²², Bruno Schaub ²³, Veronique Equy ²⁴, Bruno Giraudeau ^2,⁴, Franck Perrotin ^1,²; for the Groupe de Recherche en Obstétrique et Gynécologie (GROG)^¶

Editor: Patrick Rozenberg²⁵

¹Pôle de Gynécologie Obstétrique, Médecine Fœtale, Médecine et Biologie de la Reproduction, Centre Olympe de Gouges, CHRU de Tours, Tours, France

²Université de Tours, Tours, France

³Université de Paris, CRESS, Obstetrical Perinatal and Pediatric Epidemiology Research Team, EPOPé, INSERM, INRAE,F, Paris, France

⁴INSERM CIC1415, CHRU de Tours, Tours, France

⁵Service de Pharmacovigilance CHU Tours, Tours, France

⁶Department of Gynaecology and Obstetrics, Centre Hospitalier Régional d’Orléans, Orleans, France

⁷Centre de Dépistage PRIMA FACIE Université de Paris, Paris, France

⁸Maternité, AP-HP, Hôpital Necker, Paris, France

⁹Cabinet Mosaïque Santé, La Chaussée Saint Victor, France

¹⁰Department of Obstetrics and Gynecology, University Hospital of Nantes, Nantes, NUN, INRAE, UMR 1280, PhAN, Université de Nantes, Nantes, France

¹¹Service de Gynécologie-Obstétrique, HFME, Hospices Civils de Lyon, Lyon, France

¹²Department of Obstetrics, CHU Lille, Univ. Lille, ULR 2694—METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, Lille, France

¹³Service de Gynécologie-Obstétrique, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, Montpellier, France

¹⁴Service de Gynécologie-Obstétrique, Hôpital d’Estaing, CHU de Clermont-Ferrand, Maternité Clermont Ferrand, Clermont-Ferrand, France

¹⁵Département de Gynécologie Obstétrique, Centre Hospitalo-Universitaire Caremeau, Nîmes, France

¹⁶École de Maïeutique, Université de Montpellier, Site de Nîmes, Nîmes, France

¹⁷Department of Obstetrics and Gynaecology, Paule de Viguier Hospital, Toulouse University Hospital Center, Toulouse, France

¹⁸Centre for Epidemiology and Population Health Research, Team SPHERE, Toulouse III University, Toulouse, France

¹⁹Service de Gynécologie-Obstétrique, Groupe Hospitalier Pellegrin, CHRU de Bordeaux, Talence, France

²⁰Service de Gynécologie-Obstétrique, CHR Le Mans, Le Mans, France

²¹Service de Gynécologie-Obstétrique, Polyclinique de l’Atlantique, Saint-Herblain, France

²²Service de Gynécologie-Obstétrique, Polyclinique du Parc, Caen, France

²³Service de Gynécologie-Obstétrique, Maison de la Femme, de la Mère et de l’Enfant, CHU Martinique, Fort-de-France, Martinique, France

²⁴Service de Gynécologie-Obstétrique, Hôpital Couple Enfant, CHRU de Grenoble, La Tronche, France

²⁵Poissy-Saint Germain Hospital/Versailles Saint Quentin University, FRANCE

Competing Interests: The authors have declared that no competing interests exist.

¶ Membership of the Groupe de Recherche en Obstétrique et Gynécologie (GROG) is provided in the Acknowledgments.

^✉

* E-mail: carolindiguisto@gmail.com

Roles

Caroline Diguisto: Investigation, Validation, Visualization, Writing – original draft, Writing – review & editing

Amelie Le Gouge: Conceptualization, Data curation, Formal analysis, Funding acquisition, Writing – original draft, Writing – review & editing

Marie-Sara Marchand: Conceptualization, Supervision, Validation

Pascal Megier: Investigation, Software, Validation, Writing – review & editing

Yves Ville: Conceptualization, Data curation, Resources, Supervision

Georges Haddad: Data curation, Project administration, Resources, Writing – original draft, Writing – review & editing

Norbert Winer: Funding acquisition, Project administration, Resources, Supervision, Writing – original draft

Chloé Arthuis: Formal analysis, Methodology, Software, Supervision, Validation

Muriel Doret: Formal analysis, Methodology, Supervision, Visualization

Veronique Houfflin Debarge: Investigation, Project administration, Software, Writing – original draft, Writing – review & editing

Anaig Flandrin: Investigation, Writing – original draft, Writing – review & editing

Hélène Laurichesse Delmas: Investigation, Writing – original draft, Writing – review & editing

Denis Gallot: Investigation, Writing – original draft, Writing – review & editing

Pierre Mares: Investigation, Writing – original draft, Writing – review & editing

Christophe Vayssiere: Investigation, Writing – original draft, Writing – review & editing

Loïc Sentilhes: Writing – original draft, Writing – review & editing

Marie-Therese Cheve: Investigation, Writing – original draft, Writing – review & editing

Anne Paumier: Investigation, Writing – original draft, Writing – review & editing

Luc Durin: Investigation, Writing – original draft, Writing – review & editing

Bruno Schaub: Investigation, Writing – original draft, Writing – review & editing

Veronique Equy: Investigation, Writing – original draft, Writing – review & editing

Bruno Giraudeau: Conceptualization, Data curation, Investigation, Methodology, Resources, Writing – original draft, Writing – review & editing

Franck Perrotin: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision

Patrick Rozenberg: Editor

PMCID: PMC9581352 PMID: 36260615

Abstract

Introduction

This trial evaluates whether daily low-dose aspirin initiated before 16 weeks of gestation can reduce preeclampsia and fetal growth restriction in nulliparous women identified by first-trimester uterine artery Dopplers as at high risk of preeclampsia.

Methods

This randomized, blinded, placebo-controlled, parallel-group trial took place in 17 French obstetric departments providing antenatal care. Pregnant nulliparous women aged ≥ 18 years with a singleton pregnancy at a gestational age < 16 weeks of gestation with a lowest pulsatility index ≥ 1.7 or a bilateral protodiastolic notching for both uterine arteries on an ultrasound performed between 11+0 and 13+6 weeks by a certified sonographer were randomized at a 1:1 ratio to 160 mg of low-dose aspirin or to placebo to be taken daily from inclusion to their 34th week of gestation. The main outcome was preeclampsia or a birthweight ≤ 5th percentile. Other outcomes included preeclampsia, severe preeclampsia, preterm preeclampsia, preterm delivery before 34 weeks, mode of delivery, type of anesthesia, birthweight ≤ 5th percentile and perinatal death.

Results

The trial was interrupted due to recruiting difficulties. Between June 2012 and June 2016, 1104 women were randomized, two withdrew consent, and two had terminations of pregnancies. Preeclampsia or a birthweight ≤ 5th percentile occurred in 88 (16.0%) women in the low-dose aspirin group and in 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6; 5.9] p = 0.45). The two groups did not differ significantly for the secondary outcomes.

Conclusion

Low-dose aspirin was not associated with a lower rate of either preeclampsia or birthweight ≤ 5th percentile in women identified by their first-trimester uterine artery Doppler as at high risk of preeclampsia.

Trial registration

(NCT0172946).

Introduction

Preeclampsia complicates around 2 to 8% of pregnancies world wild [1, 2]. It can lead to maternal mortality and morbidity, which in turn lead to perinatal morbidity and mortality due to fetal growth restriction (FGR) and medically indicated prematurity [3, 4]. Antiplatelet agents are known to prevent preeclampsia and its consequences when they are administered before 16 weeks of gestation [5, 6]. The difficulty, however, is early identification of pregnancies at high risk of preeclampsia that could benefit from this preventive treatment [7, 8]. Parous women with a history of preeclampsia are candidates, but what is challenging is identifying nulliparous women who should receive this preventive treatment as they have roughly twice the risk to develop preeclampsia when compared to parous women [9, 10].

Preeclampsia and growth restriction are the consequence of abnormal placental implantation and inadequate utero-placental blood flow. Normal placentation comprises trophoblast cell invasion of the decidual and myometrial segments of spiral arteries, which induces reversible changes in the normal arterial wall architecture. Trophoblastic invasion starts from eight weeks’ gestation and studies have shown that abnormal uterine artery Doppler as early as the first trimester can identify women at high risk of preeclampsia and fetal growth restriction [11]. The pulsatility index, alone or combined with notching, are the most predictive uterine artery Doppler indices in the first trimester [12].

As women who develop preeclampsia have different uterine artery Doppler patterns on their first-trimester ultrasound [13, 14], we decided to conduct a trial to test the efficacy of low-dose aspirin to reduce the incidence of preeclampsia or growth restriction in nulliparous pregnant women identified at "high-risk" by their first-trimester ultrasound Doppler findings.

Material and methods

Study design

We conducted a randomized, blinded, placebo-controlled, parallel-group trial.

Population

Eligible women were those aged ≥ 18 years, with a singleton pregnancy, nulliparous at a gestational age < 16 weeks of gestation with an ultrasound performed between 11⁺⁰ and 13⁺⁶ weeks showing a lowest pulsatility index ≥ 1.7 for both uterine arteries or bilateral protodiastolic notching [15]. Women carrying a fetus with severe congenital anomalies (with or without termination of pregnancy) diagnosed on this first-trimester ultrasound, women receiving anticoagulant treatments or with any contraindications to antiplatelet treatment, and those with coagulopathies, lupus, or antiphospholipid syndrome were not included.

Setting

Recruitment took place in 16 French maternity units including tertiary university hospitals, general hospitals, and private obstetrics departments, and one private imaging center.

Screening for participants

As the inclusion criteria involved sonographic parameters, sonographers (physicians or midwives) screened the women. All sonographers had validated an online certificate (Collège Français d’Échographie Fœtale) for first-trimester uterine artery Doppler examinations ([13] https://www.epp-echofoetale.fr). Sonographers were invited to an information meeting held in each participating unit before the trial began to review the aims and the protocol of the study. Eligible women were screened and informed of the study during their first trimester ultrasound. All eligible women were seen in a specific consultation with a physician or midwife in the participating unit. This provider explained the aims and scope of the study, checked inclusion and exclusion criteria, and obtained written consent from the women who met all inclusion and no exclusion criteria and were willing to participate.

Randomization and blinding

Women were randomly allocated in a 1:1 ratio to 160 mg of low-dose aspirin daily or to a placebo. A secure computer-generated, online, centralized web-based system managed the randomization (with a fixed block size of four units, in a sequence generated by a statistician from INSERM CIC 1415 not involved in patient recruitment) and concealment processes. Women, clinicians, and outcome assessors were blinded to allocation. The dataset was unblinded for analysis once the data collection was finalized. In case of a serious adverse event which would require unblinding, this was possible at any time of the study; however this has never been necessary.

Intervention group

After randomization, hospital pharmacists dispensed to women in the experimental group a sufficient quantity of low-dose aspirin to be taken daily during their evening meal from the day of inclusion until they reached their 34^th week of gestation. The purchased product was in the form of 288-g sachets of DLlysine acetylsalicylate powder, corresponding to 160 mg of low-dose aspirin (Kardegic®), to be dissolved in water for administration. They were asked to store it in a dry place at a temperature less than 25° Celsius.

Control group

Women randomized to the control group received placebo powder (purchased from Bertin Pharma), in similar-looking sachets as the intervention group, to be stored and taken according to the same protocol.

Follow-up

The women received a notebook, which they had to return to the investigating center after childbirth, to indicate any possible side effects, together with a card stating that they were participating in the study, with the contact details required in case of a medical emergency for which an unblinding procedure was absolutely necessary. Follow-up was identical in the two groups and women’s pregnancies were monitored and managed by their physician or midwife according to French guidelines. After childbirth, women were asked to bring back all the remaining treatments and packaging to the pharmacists of their center to assess adherence to the treatment.

Outcomes

The main outcome was a composite of preeclampsia or newborn with a birthweight ≤ 5th percentile. Preeclampsia was defined by hypertension in pregnancy (systolic blood pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg, measured twice at least 4 hours apart), and proteinuria greater than 300 mg/24 hour after 20 weeks or in the post-partum period [16, 17]. To determine birthweights ≤ 5th percentile, we used the EPOPé growth curves, adjusted for the newborn’s gestational age and sex and the mother’s parity, height, and weight [18].

The secondary outcomes were preeclampsia, severe preeclampsia, defined as women with preeclampsia and any of the following: systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 110 mmHg, proteinuria ≥ 5 g/day, oliguria, HELLP syndrome, eclampsia, acute pulmonary edema, placental abruption, or stillbirth. The rate of preterm preeclampsia (<37 weeks’ gestation) was added as a secondary outcome after the trial’s registration at clinicaltrials.gov to be able to compare results with those of the ASPRE trial [19]. Secondary outcomes also included preterm delivery before 34 weeks, mode of delivery (vaginal or caesarean) and the type of anaesthesia for delivery. Secondary outcomes for infants included a birthweight ≤ 5th percentile or perinatal death, defined as a stillbirth from 22 weeks through a neonatal death in the first 7 days. Any kind of bleeding was also studied as a secondary outcome. Serious adverse events, defined as any event, reaction or unexpected adverse reaction that results in death, is life threatening or requires hospitalization were also reported and coded according to MedDra dictionary (version 19.1) (https://admin.meddra.org/sites/default/files/guidance/file/94911910_termselptc_r4_12_sep2016.pdf.)

Sample size

According to an unpublished study conducted in our unit, the presence of first trimester bilateral notching and/or a high pulsatility index among nulliparas is predictive of the occurrence of pre-eclampsia with a sensitivity of 75% and a specificity of 67% and predictive of growth restriction with a sensitivity of 55% and a specificity of 67%. Based on this performance we hypothesized that low-dose aspirin could reduce the primary outcome, expected to be 21.2% in the control group (protocol in S3 File), by 15% [20–22]. To show a relative reduction from 21.2% to 18.0% in the occurrence of preeclampsia or birthweight ≤ 5th percentile with a power of 80% and a two-tailed type I error of 5%, we required 2415 women in each group. As we expected that some pregnancies would end in termination, and we planned four intermediate analyses (every 1000 inclusions) to counter the unknown precise expected rates of outcome in the control group, we planned to include 2486 women in each group. The study protocol (S3 File) describes the sample size calculation in fuller detail.

Analysis

A statistical analysis plan was finalized before the dataset was frozen. Because the trial was stopped prematurely, no interim analysis was performed. Women were analysed according to their randomization group (intention to treat). Baseline characteristics were reported per group with numbers and percentages for categorical variables and with medians and interquartile ranges for continuous variables. For the primary outcome, missing data were managed with simple imputation by assuming that women with missing data for the primary outcome had preeclampsia or that their infant had a birthweight < 5^th percentile. A complete-case analysis was also conducted. Rates were then compared with the Chi-square test. The between-group difference in proportions was estimated as well as its 95% confidence interval (CI) (Wald method). Results were also presented as crude odd ratios (ORs) with their 95% CIs. No imputation was performed for secondary outcomes, which were also compared with Chi-square tests. The between-group difference and odds ratios were also presented for secondary outcomes. Statistical analyses were performed with SAS version 9.4 and R version 3.3.1 software.

Ethics

The study protocol (S3 File) and patient information documents were approved by the competent French authorities: Agence Nationale de Sécurité du Médicament et des produits de santé (number of approval A120316-72 on the 07/05/2012) and Comité de Protection des Personnes (number 2012-R8; 27/03/2012). The study protocol was registered at ClinicalTrials.gov (NCT01729468) and in the European EudraCT database (2011-003536-30).

Results

Between June 2012 and June 2016, 1104 women were randomized. The trial was stopped after 4 years due to recruiting difficulties resulting in a failure to conduct any of the four initially planned intermediate analyses. Because two women withdrew their consent and two terminations of pregnancy occurred after randomization, 1100 women were finally analysed: 550 in the intervention (low-dose aspirin) and 550 in the control (placebo) group (Fig 1).

The mean age of the women were 28.3 ± 4.9 years and 28.7 ± 4.7 years in the aspirin and the placebo group, respectively. Eight percent of women were of white ethnicity, S1 Table. The median gestational age at delivery were 39.7 [38.5–40.6] and 39.7 [38.5–40.8] in the aspirin and the placebo group, respectively. The number (rate) of cases of preeclampsia or infants with a birthweight ≤ 5th percentile was 88 (16.0%) in the low-dose aspirin group versus 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6; 5.9], p = 0.45 OR 1.14 95%CI (0.82–1.58)), S2 Table. These findings were supported by our complete-case analysis, which showed 76 (14.1%) and 72 (13.3%) with preeclampsia or infants with birthweight ≤ 5th percentile in the low-dose aspirin and the placebo groups, respectively (P = 0.68). The two groups did not differ for secondary outcomes. Also in each group, during treatment, around 25% of the women reported bleeding (epistaxis or gingival bleeding (80%) and metrorrhagia (20%)) as an adverse effect. Overall, 112 (20%) and 120 (22%) women, respectively, experienced at least one serious adverse event (S3 Table). In all, around 25% of the women in each group stopped their treatment before their 34^th week.

Discussion

In this trial conducted among women identified at high risk of preeclampsia by their first-trimester uterine artery Doppler examination, the rate of preeclampsia or birthweight<5^th percentile in women who received low-dose aspirin before 16 weeks gestation was not statistically different from that of women receiving placebo.

This trial was planned before the results from the ASPRE trial which also evaluated an intervention among women at high risk of preeclampsia [19]. They identified women by using an algorithm including demographic, clinical, biological, and Doppler findings, which produced a population very different from ours, with 30% of the women parous and 10% with a history of preeclampsia. In the ASPRE trial, approximately forty percent of the primary outcomes occurred in parous women. Being limited to nulliparas is the main strength of our trial, as parous women differ substantially in terms of risk assessment for preeclampsia and are not the women for whom the decision about preventive treatment is challenging. Other strengths include that all sonographers were certified for uterine artery Dopplers and also that all women were administered their treatment before 16 weeks of gestation which is the only way the preventive treatment can be effective.

Nevertheless, our trial has limitations, including that we were not able to reach the number of inclusions initially planned, although we extended our inclusion period by one year. This may be explained partly by an inaccurate initial assessment of feasibility and the lower than expected number of eligible women. Recruitment may also have been difficult as healthy nulliparous women may not have understood how their participation could improve outcomes for them or the baby as, by definition, nulliparas have never experienced adverse pregnancy outcomes. Another limitation was the lower than expected rate for the main outcome in the control group (14% of events versus 21% expected). Our hypothesis and sample size were built on numbers of outcomes which were not specific from the French population. A French study conducted when the trial was designed found that preeclampsia affected only 1.7% of nulliparous women whereas we used an expected rate of 6% [10]. It is likely that the lower than expected rate for the main outcome may be explained, in part, by this erroneous assessment of the rate of preeclampsia in nulliparous women in France [9]. Thus, we can speculate that if an intermediate analysis would have been conducted, it is likely that the trial would have been stopped for futility. One in four woman interrupted their treatment before their 34^th week of gestation which is concordant with compliance findings from metanalysis evaluating the effect of aspirin to prevent preeclampsia in the pregnant population [5]. The reported rates of women who were fully compliant in the studies included in the metanalysis varied between 60 and 90%. Detailed compliance was not assessed precisely or regularly through the follow up of the pregnancy so we are unable to explain these adherence rates. Also, the screening took place in 17 participating units and we were not able to assess how many first-trimester ultrasound examinations of nulliparous women were conducted by sonographers during the inclusion period. We are therefore unable to estimate how many women were screened. Finally, we suspect some of the adverse events may have been under-reported. Indeed, some of the adverse events were also secondary outcomes (metrorrhagia and preterm delivery) and there are some discrepancies between the numbers of outcomes and adverse events which is why we are cautious in the interpretation our adverse event data.

The observed rate of preterm preeclampsia in our control group was half that in the ASPRE trial control group, which means that their algorithm was more successful in identifying women at risk of preeclampsia. We found another study also focusing on the evaluation of first trimester uterine Doppler among a population of nulliparas who were not particularly at high risk [23]. They found a rate of preeclampsia in their population (4.9%) which was close to what we observed in our study thereby confirming that we were unable to identify a high-risk population. Bujold et al.’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia [24]. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.

Algorithms that aim to identify women at high risk of preeclampsia by clinical, biological, and ultrasound parameters have been published and have sparked enthusiasm, but the cost effectiveness of their implementation at a population level is still debated [25–28]. The trial was designed in 2008 and at the time, none of those algorithms were recommended which is why we selected our population differently. Until now, those algorithms are still not recommended by national guidelines even if recommended by the International Federation of Gynecology and Obstetrics, the International Society of ultrasound in obstetrics and Gynecology and the International Society for the Study of Hypertension in Pregnancy [29, 30]. Many studies were published during the elapsed time between de design of the trial (2008) and the publication (2022). This delay was mainly due to motivation issues and organisation difficulties. Inclusion criteria to select women at high risk of preeclampsia which seemed appropriate at the time are now obsolete. Because women in most high-income countries are advised to undergo a first-trimester ultrasound, screening for preeclampsia through clinical and Doppler findings would not require a major increase in cost [31]. Accordingly, a combination of clinical and Doppler findings should be used in further studies to evaluate interventions to reduce preeclampsia.

Conclusion

In our study, low-dose aspirin was not associated with a lower rate than placebo of either preeclampsia or FGR in women identified as at high risk of preeclampsia during a first-trimester uterine artery Doppler examination. We interpret our results cautiously because of the lack of power related to insufficient number of patients recruited.

Supporting information

S1 Table. Characteristics of the trial participants.

Results are numbers and percentages unless stated otherwise.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S2 Table. Outcomes according to randomization group.

(DOCX)

Click here for additional data file.^{(15.6KB, docx)}

S3 Table. Serious adverse events.

(DOCX)

Click here for additional data file.^{(14KB, docx)}

S1 File. Supporting information CONSORT checklist.

(DOC)

Click here for additional data file.^{(218KB, doc)}

S2 File. Supporting information dataset.

(XLSX)

Click here for additional data file.^{(169.1KB, xlsx)}

S3 File. Supporting information protocol.

(DOC)

Click here for additional data file.^{(552KB, doc)}

Acknowledgments

We thank all the women who agreed to participate in the study. We would like to thank Anne Rebion for her analysis, Hélène Bourgoin for her help with the pharmacy. We also thank the research assistants who helped to conduct this trial Yoann Desvignes and Catherine Fermont and the participating members of the “Groupe de Recherche en Obstétrique et Gynécologie (GROG)”, Thomas Schmitz, Elie Azria, Catherine Deneux-tharaux, Anne Ego, Francois Goffinet, Cyril Huissoud, Gilles Kayem, Bruno Langer, Camille Le Ray, Olivier Morel, Marie-Victoire Senat and Damien Subtil.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The trial was funded by a government grant “Programme Hospitalier de Recherche Clinique National” PHRCN-2008. The government did not have a role in designing the study, interpreting the results or writing the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0275129.r001

Decision Letter 0

Patrick Rozenberg

1 Jun 2022

PONE-D-22-07025Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trialPLOS ONE

Dear Dr. Diguisto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

As highlighted by Reviewer 3, although this trial was interrupted prematurely, the results of this study are interesting. However, this manuscript needs major modifications. Therefore, responses to reviewers' comments should be done carefully, especially Reviewer 2 comments.

==============================

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: A randomized controlled clinical trial was conducted which aimed to evaluate whether daily low-dose aspirin reduces preeclampsia and growth restriction in nulliparous women at high risk for the condition. The proportion of women who developed preeclampsia was not significantly different in the two randomization arms.

Minor revisions:

1- Line 190: Provide a measure of dispersion for age.

2- Table 1: It is customary to report means and standard deviations for normally distributed variables and median, first and third quartiles for non-normally distributed variables.

3- Table 2: Provide a p-value comparing the association of anesthesia and arm. Perhaps this p-value is 0.94. If so, move the p-value to the line labeled “Anesthesia (n=539 vs 537).”

4- Table 3: Provide p-values comparing the proportions with adverse events.

5- Indicate if adverse events were collected according to a standardized method such as the Common Terminology Criteria for Adverse Events (CTCAE).

Reviewer #2: Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial; by Diguisto C et al.

This study addresses a very interesting question: the usefulness of low-dose aspirin (LDA) to prevent preeclampsia and growth restriction in high risk nulliparous women identified by early uterine artery Doppler. The article is well-written and easy to read.

I have some major comments:

In the introduction section the rational of the study in insufficiently detailed:

- Line 82-86, the authors discuss the use of algorithms involving biological, maternal and ultrasound parameters to select high risk women. This is off-topic in the introduction and the authors should mention the articles they are relying on to carry out the study. In addition, in their rational they refer to articles published after the start of the trial, which is illogical (ref 9,11,12)), and they use a reference in which uterine doppler was performed in the second trimester (ref 11)

- Amazingly, I did not find any reference in the introduction section supporting the use of early uterine Doppler alone to select high risk nulliparous women. This is essential for the calculation of the number of patients to be included in the study

- Instead of citing general articles concerning the rate of PE (line 74, ref 1 and 2) the authors are lucky to have French publications on the subject, with a risk of PE in nulliparous women of 1.7% (Subtil et Al, ERASME trial Part 1, BJOG. 2003;110:475-484), and in general population of 0.7% (Goffinet et al. BJOG. 2001;108:510-8.)

- In addition, do the authors have any idea on the performance of early uterine Doppler to select high risk nulliparous women in a french cohort (pilot study for instance)

In the Screening for participants section (line 101) the authors should mention how many women were approached before randomization, the reasons of refusals, and put all these informations in the flow-chart.

In sample size section, I do not understand how the authors calculated the number of patients to recruit. They must provide the articles they rely on because the two references cited by the authors (ref 18 and 19) do not address prediction of SGA < 5th centile. The authors should discuss and may be use the findings of Pilalis et al ( Acta Obstetrica et Gynecologica. 2007; 86:530-34.) where these authors found the same composite outcome of 14%. This article might have helped the author to calculate the number needed to recruit.

In Analysis section, the authors should present the data of an RCT as RR and absolute risk reduction. In addition, they should mention when they did the unblinding compared to the analysis of complications

In the results section:

Table 2, the authors must separate primary outcome from secondary outcomes, add two columns ( one for RR and one for ARR)

They must add a specific par for side effects. In addition, Table 3 is not clear: serious events are different from those of Table 2?, for instance, rates of preterm delivery are different ?; What are the maternal hypertensive complications? Why the numbers are not similar for perinatal death? I encourage the authors to detail serious events.

In the discussion section:

Line 271, add after was not “statistically”…

You must discuss in first why you have such difference of primary outcome (21.2% expected and 14.4% observed), almost 32%.

In the conclusion section, you must add that your results are uncertain because of lack of power related to insufficient number of patients recruited in the study.

Reviewer #3: This is a randomized, blinded, placebo-controlled, parallel-group trial assessing whether daily low-dose aspirin initiated before 16 weeks of gestation can reduce preeclampsia and growth restriction in nulliparous women identified by first-trimester uterine artery Dopplers as at high risk of preeclampsia. Aspirin was administered at the appropriated doe of 160 mg/day. Preeclampsia or a birthweight ≤ 5th percentile occurred in 88 (16.0%) women in the low-dose aspirin group and in 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6 ; 5.9] p=0.45). The two groups did not differ significantly for the secondary outcomes.

The manuscript by Diguisto et al. is well written. The methodology is clear and clearly explained. Although, the trial was interrupted after including 44% of the expected number of patients (1104 of the 2486 planned), the results of this study are interesting and need to be published.

In the introduction, please mention the prevalence of preeclampsia (PE) in France in the general population and in nulliparous women. This will allow to show that the patients of the placebo group are at higher risk of PE.

The result section is very limited. Please describe the results in this section. Gestational age at delivery should be added.

In the discussion, please present the results of the previous studies evaluating first trimester uterine Doppler (such The Great Obstetrical Syndrome Study) and show how the outcomes of the placebo group are comparable to these studies. Please also discuss the previous studies assessing the effect of low dose aspirin in patients first trimester uterine Doppler and show how the outcomes of the placebo (Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis; Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial).

Please also discuss that 2/3 of preeclampsia cases occurred after 37WG. This is normal but may contribute to the results of the trial.

Line 121 : the sentence is not clear. Did the patients receive Kardegic sachets or a reconditioned for of aspirin? If patients received Kardegic sachets please explain how the patients and the investigators were blinded to the treatment?

Lines 301-303: The sentence is not clear. Please who was more successful in identifying women at risk.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2022 Oct 19;17(10):e0275129. doi: 10.1371/journal.pone.0275129.r002

Author response to Decision Letter 0

15 Jul 2022

The Editor-in-Chief, Plosone

July, 2022

Dear Editor,

We would be grateful if you would consider our revised manuscript PONE-D-22-07025-R1 “Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial “which we hope is now suitable for publication in Plosone. You will find below our responses to each of the editor’s and reviewers’ comments and suggestions. We have changed the manuscript as requested by the editor and reviewers, when appropriate.

The authors have declared that no competing interests exist.

Caroline Diguisto, MD, PhD, on behalf of all authors

Pôle de gynécologie obstétrique, médecine fœtale, médecine et biologie de la reproduction, centre Olympe de Gouges, CHRU de Tours, 37 044 Tours, France Tel: +33 2 47 47 47 47

Email carolinediguisto@gmail.com

Thank you for stating the following in the Financial Section of your manuscript:

“The trial was funded by a government grant “Programme Hospitalier de Recherche Clinique National” PHRCN-2008.”

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

The funding statement is accurate, it is fine as it is.

Thank you for stating the following in your Competing Interests section:

“NO authors have competing interests”

This information should be included in your cover letter; we will change the online submission form on your behalf.

We have added this statement in the cover letter.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

We have changed our data availability statement and now provide, as requested a minimal dataset.

Participating members of the “Groupe de Recherche en Obstétrique et Gynécologie (GROG)” were Thomas Schmitz, Elie Azria, Catherine Deneux-tharaux, Anne Ego, Francois Goffinet, Cyril Huissoud, Gilles Kayem, Bruno Langer, Camille Le Ray, Olivier Morel, Marie-Victoire Senat and Damien Subtil. Their name has been added in the acknowledgments section. There is no lead author for this group.

Additional Editor Comments:

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Minor revisions:

1- Line 190: Provide a measure of dispersion for age.

We have added this information and presented the mean age and the standard deviation for both groups “The mean age of the women were 28.3 ± 4.9 years and 28.7 ± 4.7 years in the aspirin and the placebo group, respectively.”

2- Table 1: It is customary to report means and standard deviations for normally distributed variables and median, first and third quartiles for non-normally distributed variables.

We have changed table 1, it turns out only the variable “age” has a normal distribution. It is now presented as a mean and a standard deviation

3- Table 2: Provide a p-value comparing the association of anesthesia and arm. Perhaps this p-value is 0.94. If so, move the p-value to the line labeled “Anesthesia (n=539 vs 537).”

Indeed 0.94 concerns the anesthesia variable. We have moved 0.94 to the appropriate line

4- Table 3: Provide p-values comparing the proportions with adverse events.

We have compared the rates of patients with at least one serious adverse event and added this information in table 3 (p=0.55). We would rather not compare individually each event as we prefer the strategy of a composite outcome structure, also called the basket which has been proposed to capture the unexpected side effect in clinical trials (Tugwell et al. J Clin Epidemiol 2005;58:785-790). We provide p values only for those adverse events that are secondary outcomes.

5- Indicate if adverse events were collected according to a standardized method such as the Common Terminology Criteria for Adverse Events (CTCAE).

The adverse events were not collected according to a standardized method but were coded according to MedDra dictionary (version 19.1) . This was added in the methods section.

I have some major comments:

In the introduction section the rational of the study in insufficiently detailed:

We have changed the introduction section. The introduction section is now appropriate to the perspective of when the trial was designed. We removed the text which concerns biological parameters.

In addition, in their rational they refer to articles published after the start of the trial, which is illogical (ref 9,11,12)), and they use a reference in which uterine doppler was performed in the second trimester (ref 11)

We have changed the references and have a reference that refers to uterine artery doppler in the first trimester.

We have added some references which support the use of early uterine doppler: reference 11 and 12.

We have added the suggested references in the introduction. They are also mentioned in the discussion section as the numbers we have used to build our hypothesis are slightly different. This difference may explain in part the lower than expected numbers for the main outcome.

- In addition, do the authors have any idea on the performance of early uterine Doppler to select high risk nulliparous women in a french cohort (pilot study for instance)

According to an unpublished study conducted in our unit, which we used to calculate the size of our sample, the presence of bilateral notching and/or a high pulsatility index is predictive of the occurrence of pre-eclampsia among nulliparas, and this with a sensitivity of 75% and a specificity of 67%. According to the same study, the presence of bilateral notching and/or a high pulsatility index is predictive of the occurrence of growth restriction with a sensitivity of 55% and a specificity of 67%, also among nulliparas. Based on those performances to predict preeclampsia and growth restriction, the sample size was calculated as explained in the protocol which we have attached as supplementary file. Unfortunately this study has not been published. We changed the “sample size” section to better explain this.

Unfortunately, because it is really difficult to maintain correctly a screening log, especially when physicians are from the private sector, the number of women who were approached was unavailable. This is already mentioned in the discussion section “Finally the screening took place in 17 participating units and we were not able to assess how many first-trimester ultrasound examinations of nulliparous women were conducted by sonographers during the inclusion period. We are therefore unable to estimate how many women were screened. “

We used a pilot study conducted in our unit to calculate the number of patients to recruit. The performance to predict preeclampsia and growth restriction is explained above and has been used to calculate the size of the sample. The detailed calculations for this sample size are in the protocol, and we have made the sample size section more explicit.

In Analysis section, the authors should present the data of an RCT as RR and absolute risk reduction.

We agree and in agreement with the CONSORT Statement have added two columns in table 2 to add this information.

In addition, they should mention when they did the unblinding compared to the analysis of complications

We have added this information in the methods section “The dataset was unblinded for analysis once the data collection was finalized. In case of a serious adverse event which would require unblinding, this was possible at any time of the study however this has never been necessary.”

In the results section:

Table 2, the authors must separate primary outcome from secondary outcomes, add two columns ( one for RR and one for ARR)

We have added two columns in table 2 to add this information

Hypertensive disorders were defined as any gestational hypertension or preeclampsia in pregnancy. Some adverse events such as metrorrhagia and preterm birth were also secondary outcomes. Those were more frequently observed as outcomes than as adverse events. This may be due to some under-reporting of adverse events by investigators which has not been. For this reason we are cautious in the interpretation of our data on adverse events. This point has been added in our discussion section.

In the discussion section:Line 271, add after was not “statistically”…

We have added “statistically”

You must discuss in first why you have such difference of primary outcome (21.2% expected and 14.4% observed), almost 32%.

It is likely that the lower than expected rate for the main outcome may be explained, in part, by this erroneous assessment of the rate of preeclampsia in nulliparous women in France. Our hypothesis was that it would concern 6% of women whereas the true rate of preeclampsia in nulliparous women is closer to 2%. We have added this in the discussion section “Our hypothesis and sample size were built on numbers of outcomes which were not specific from the French population. A French study conducted when the trial was designed found that preeclampsia affected only 1.7% of nulliparous women whereas we used an expected rate of 6% which is erroneous (10). It is likely that the lower than expected rate for the main outcome may be explained, in part, by this erroneous assessment of the rate of preeclampsia in nulliparous women in France(9).”

In the conclusion section, you must add that your results are uncertain because of lack of power related to insufficient number of patients recruited in the study.

We have added this in the conclusion section

In the introduction, please mention the prevalence of preeclampsia (PE) in France in the general population and in nulliparous women.

This will allow to show that the patients of the placebo group are at higher risk of PE.

We have added two references suggested by the reviewer: Subtil et al BJOG 2003 and Goffinet et al BJOG 2001

The result section is very limited. Please describe the results in this section. Gestational age at delivery should be added.

We have added this in the result section in text. This is not a baseline characteristic or an outcome so it did not fit in any of our tables.

Please also discuss that 2/3 of preeclampsia cases occurred after 37WG. This is normal but may contribute to the results of the trial.

We have changed the discussion section and mentioned these two references. We also discuss our findings according to those two studies.

We have added in the discussion section that 2/3 of preeclampsia occurred after 37 WG in our study. Those late/term preeclampsie are not particularly prevented by low dose aspirin which could explain why our trial is negative. This paragraph has been added to the discussion: “Bujold et al’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.”

We have changed the control paragraph to make things clearer « Women randomized to the control group received placebo powder (purchased from Bertin Pharma), in similar-looking sachets as the intervention group, to be stored and taken according to the same protocol.“

Lines 301-303: The sentence is not clear. Please who was more successful in identifying women at risk.

We have changed this phrase to make it more easier to understand, it is now line 286 “The observed rate of preterm preeclampsia in our control group was half that in the ASPRE trial control group, which means that their algorithm was more successful in identifying women at risk of preeclampsia.”

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

PLoS One. doi: 10.1371/journal.pone.0275129.r003

Decision Letter 1

Patrick Rozenberg

1 Aug 2022

PONE-D-22-07025R1Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trialPLOS ONE

Dear Dr. Diguisto,

ACADEMIC EDITOR:

You made appropriate changes following the Reviewers comments. However, an edit shown in the response to Reviewer #3 was overlooked and not inserted into the edited text: "We have added in the discussion section that 2/3 of preeclampsia occurred after 37 WG in our study. Those late/term preeclampsie are not particularly prevented by low dose aspirin which could explain why our trial is negative. This paragraph has been added to the discussion: “Bujold et al’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.” Please correct this oversight and modify the text accordingly before final acceptance.

Please submit your revised manuscript by Sep 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Patrick Rozenberg, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The authors made appropriate changes following the Reviewers comments.

However, an edit shown in the response to Reviewer #3 was overlooked and not inserted into the edited text:

"We have added in the discussion section that 2/3 of preeclampsia occurred after 37 WG in our study. Those late/term preeclampsie are not particularly prevented by low dose aspirin which could explain why our trial is negative. This paragraph has been added to the discussion: “Bujold et al’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.”

The authors should correct this oversight and modify the text accordingly before final acceptance.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

PLoS One. 2022 Oct 19;17(10):e0275129. doi: 10.1371/journal.pone.0275129.r004

Author response to Decision Letter 1

2 Sep 2022

The Editor-in-Chief, Plosone

September, 2022

Dear Editor,

Please find attached our revised manuscript PONE-D-22-07025-R2 “Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial “which we hope is now suitable for publication in Plosone.

We have made a response to the editor’s comment below.

The authors have declared that no competing interests exist.

Caroline Diguisto, MD, PhD, on behalf of all authors

Pôle de gynécologie obstétrique, médecine fœtale, médecine et biologie de la reproduction, centre Olympe de Gouges, CHRU de Tours, 37 044 Tours, France Tel: +33 2 47 47 47 47

Email carolinediguisto@gmail.com

EDITOR

We have inserted the missing paragraph in the discussion section and apologize for this oversight.

PLoS One. doi: 10.1371/journal.pone.0275129.r005

Decision Letter 2

Patrick Rozenberg

12 Sep 2022

Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial

PONE-D-22-07025R2

Dear Dr. Diguisto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Patrick Rozenberg, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This manuscript have been appropriately corrected and can be published

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0275129.r006

Acceptance letter

Patrick Rozenberg

22 Sep 2022

PONE-D-22-07025R2

Dear Dr. Diguisto:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Patrick Rozenberg

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Characteristics of the trial participants.

Results are numbers and percentages unless stated otherwise.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S2 Table. Outcomes according to randomization group.

(DOCX)

Click here for additional data file.^{(15.6KB, docx)}

S3 Table. Serious adverse events.

(DOCX)

Click here for additional data file.^{(14KB, docx)}

S1 File. Supporting information CONSORT checklist.

(DOC)

Click here for additional data file.^{(218KB, doc)}

S2 File. Supporting information dataset.

(XLSX)

Click here for additional data file.^{(169.1KB, xlsx)}

S3 File. Supporting information protocol.

(DOC)

Click here for additional data file.^{(552KB, doc)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: A double blinded randomized placebo-controlled trial

Caroline Diguisto

Amelie Le Gouge

Marie-Sara Marchand

Pascal Megier

Yves Ville

Georges Haddad

Norbert Winer

Chloé Arthuis

Muriel Doret

Veronique Houfflin Debarge

Anaig Flandrin

Hélène Laurichesse Delmas

Denis Gallot

Pierre Mares

Christophe Vayssiere

Loïc Sentilhes

Marie-Therese Cheve

Anne Paumier

Luc Durin

Bruno Schaub

Veronique Equy

Bruno Giraudeau

Franck Perrotin

Roles

Abstract

Introduction

Methods

Results

Conclusion

Trial registration

Introduction

Material and methods

Study design

Population

Setting

Screening for participants

Randomization and blinding

Intervention group

Control group

Follow-up

Outcomes

Sample size

Analysis

Ethics

Results

Fig 1.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Patrick Rozenberg

Roles

Author response to Decision Letter 0

Decision Letter 1

Patrick Rozenberg

Roles

Author response to Decision Letter 1

Decision Letter 2

Patrick Rozenberg

Roles

Acceptance letter

Patrick Rozenberg

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

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