Ropivacaine 75mg versus placebo in perineal inltration for analgesic ecacy at mid- and long-term for episiotomy repair in postpartum women-The ROPISIO study: a two-center, randomized, double-blind, placebo-controlled trial.

Background Perineal pain due to episiotomy is commonly reported and can be severe enough to disturb the mother-infant dyad during the postpartum period. Its incidence at day 7 postpartum varies from 63% to 74%. Recent studies have already investigated the analgesic ecacy of perineal inltration of ropivacaine after episiotomy, but have only focused on the immediate postpartum period (at 24 and 48 hours after birth). Large, adequately powered, multicenter, randomized controlled trials are required to evaluate the impact of ropivacaine inltration on perineal pain and mid- and long-term quality of life before the widespread use of ropivacaine to prevent perineal pain after episiotomy can be recommended. Methods The ROPISIO study is a two-center, randomized, double-blind, placebo-controlled trial in La Roche sur Yon and Nantes, France. It will involve 272 women with vaginal singleton delivery and mediolateral episiotomy at term ( ≥ 37 weeks). Perineal inltration (ropivacaine 75mg or placebo) will be administrated just after vaginal birth and before episiotomy repair. The primary outcome will be the analgesic ecacy at day 7 postpartum (mid-term), dened by the numerical rating scale of pain (ENS NRS) strictly superior to 3/10 on the perineal repair area. Secondary outcomes will be the analgesic ecacy (ENS NRS), the impact of pain on daily behavior, on the quality of life (36-Item Short Form Health Survey), on the occurrence of symptoms of postpartum depression (Edinburgh Postnatal Depression Scale) and on sexuality (Female Sexual Function Index) at 3 and 6 months (long-term) using validated online questionnaires. This study will have 90% power to show approximately 30% relative risk reduction in the incidence of perineal pain at day 7, from 70.0% to 50.0%. study


Background
Episiotomy is a surgical enlargement of the vaginal ori ce performed with scissors which requires sutures to be repaired [1]. The midwife or the obstetrician can perform an episiotomy to facilitate the childbirth in case of severe fetal heart rate anomaly, and it is occasionally conducted to prevent obstetric anal sphincter injury in vaginal delivery [2]. Considering all maternal consequences of episiotomy, its routine use has been questioned, and restrictive episiotomy policies are recommended by clinical practice guidelines [3]. Despite this restrictive policy, episiotomy is still a common surgical procedure [4].
Perineal pain is a common consequence of episiotomy and affects up to 97% of women on day 1 postpartum [5,6], up to 70% of women at day 7 to 10 postpartum [7][8][9] and may persist until at least 5 months postpartum [10,11]. Pain after perineal wound (apart from episiotomy) are also reported but less studied because of the high variability of the localization and the depth of the tear. Postpartum perineal pain may have a negative maternal impact and can affect the quality of life of the mother and may be severe enough to disturb the postpartum period and the mother-infant dyad [5,6]. Symptoms of postpartum depression affect 10-15% of women [12,13]. An association between persistent perineal pain and symptoms of postpartum depression has been identi ed by several studies [14,15]. An increased risk for depression was showed at 4-6 weeks and 6 months among women who had perineal pain compared to those without perineal pain after adjusting for covariates [16]. In this prospective study, pain at 3-5 days postpartum was a predictor for symptoms of postpartum depression at 3 months [16]. Moreover, dyspareunia rate around 25% was observed in women who had an episiotomy [17]. Sexual disorders in women with postpartum perineal pain have previously been reported [10,18,19]. In addition, a clinical study showed that 12.8% of the women who underwent episiotomy presented chronic perineal pain at 5 months, related to obstetric and postpartum factors ( i.e. perineal pain in the rst 48 hours) [11].
Obstetric analgesia after a vaginal delivery received less attention than pain during labor or after a cesarean delivery. Epidural analgesia allows episiotomy to be performed without additional anesthesia. Therefore, local anesthetic injection at time of the episiotomy may be necessary, even for women with epidural analgesia. The anesthetic perineal in ltration is the subcutaneous, muscular-aponeurotic space or serosal injection of analgesic drug, next to the surgical site. Its effectiveness is based on the widest possible diffusion of the product and on the blocking of the most distal nerve endings [20]. The main property of local anesthetic drugs is to temporarily block pain message transmission from nociceptive terminations. Locally injected into an operative scar, their action exceeds this framework. Local anesthetics drugs have an anti-in ammatory effect which limits self-maintenance of pain in peripheral lesion. Furthermore, clinical studies con rm that local anesthetic in ltration, even in a single postoperative injection, is bene cial over a period that exceeds the product persistence at the site of administration. Another prospective randomized study concerning groin hernia surgery showed that local anesthesia was superior to regional or general anesthesia in decreasing postoperative complications, duration of surgery and anesthesia, length of postoperative hospital stay, and time to normal activity [22].
For same surgery, preoperative inguinal in ltration of ropivacaine provides bene ts for patients in terms of faster recovery, less pain, better mobilization and higher satisfaction throughout the 7 days postoperative [23]. For tonsillectomy under general anesthesia, a preoperative in ltration of tonsils with bupivacaine showed almost no constant pain occurred in the bupivacaine group at 5 days postoperative compared to normal saline serum, and the difference in pain intensity was present even on the 10 th postoperative day [24].
Ropivacaine is a drug already used in clinical practice for the treatment of acute pain in adults. For example, during childbirth (continuous or bolus epidural infusion), parietal in ltration or peripheral nerve blocks have been reported with high rate of decreased pain [25]. Ropivacaine is an anesthetic with longer duration when compared to lidocaine [26]. A complication of in ltration techniques is the systemic toxicity of local anesthetics. This results from large doses of anesthetic administration or from an injection into a space with important systemic resorption. In both cases, knowledge of the products and injection sites, and usual precautions when injecting a local anesthetic prevents this.
Mediolateral episiotomies are associated in early and mid-term postpartum with perineal pain. Both theoretical arguments and results from previous studies indicate that ropivacaine has promise in prevention of perineal pain. Nevertheless, there are not enough well conducted studies to reach any de nitive conclusion. We therefore designed the present randomized, controlled trial (ROPISIO). This study is a superiority study of ropivacaine 75 mg versus placebo in perineal in ltration for women receiving an episiotomy. The primary end point is analgesic e cacy at day 7 postpartum (mid-term) measured with the numerical scale of pain (NRS). The patient will be recruited at 2 centers.

Methods / Design
Aim, design and setting The aim of this study is to compare the analgesic effect of a perineal in ltration of ropivacaine after vaginal delivery with mediolateral episiotomy, versus placebo in a two-center, randomized, double-blind, placebo-controlled trial.
The outcomes are to assess the impact of perineal in ltration of ropivacaine 75mg on perineal pain after vaginal birth and mediolateral episiotomy for medical indication on different symptoms at short-, midand long-term. The speci c outcomes are as follows: Primary outcome: mid-term perineal pain at day 7 postpartum measured with the numerical rating scale of pain (NRS) strictly superior to 3/10 on the perineal repair area.

Secondary outcomes:
The short-term postpartum perineal pain (at 12, 24 and 48 hours) and the long-term perineal pain (at 3 and 6 months) using the numerical rating scale of pain (NRS).
The impact of pain on daily behavior with a scale of pain repercussions on daily behavior at D7, M3 and M6 postpartum. The ROPISIO study is a two-center randomized, double-blind, placebo-controlled trial in two tertiary centers (one general hospital and one university hospital) to test the hypothesis that ropivacaine perineal in ltration after mediolateral episiotomy will reduce postpartum pain at mid-and long-term and increase quality of life. Figure 1 shows an adapted version of the SPIRIT Figure for the ROPISIO trial.

Study population
Information on the trial will be provided to patient without planned cesarean by obstetricians and midwives during the 8 th month in La Roche sur Yon and Nantes maternity hospital, France. At the latest, this information will be given when the women arrive in delivery room. They will then con rm their participation and provide informed written consent before delivery. All randomized patients will be included in the full set of analysis (intent to treat basis).

Randomization
The randomization will be centralized and strati ed by center and parity and performed according to a ratio 1:1. The randomization will be performed by non-varying size block. A computer-generated randomization list will be carried out by a statistician before the study began. Once a woman has been included, through the ling of an electronic case report directly by internet (Clinsight software), she will retain her randomization number (if it has been assigned to her) even if she withdraws from the study or refuses randomization afterwards.
Women will be randomized after episiotomy and before the beginning of the suture, to receive either 75mg of ropivacaine (Fresenius Kabi, Sèvres, France; Marketing authorization number: 3400957740832 [2009, RCP rév 08/09/2016]) in a 20-mL syringe (10-mL of ropivacaine 7.5mg/mL and 10-mL of normal saline) or 20-mL of placebo (normal saline, Fresenius Kabi, Sèvres, France; Marketing authorization number: 34009415 73941). The randomization list will be created by La Roche sur Yon Clinical Research Unit and transmitted to the pharmacy department of Nantes University Hospital , which will prepare the blinded products. Numbered and identically labelled boxes with the study number will be produced. Each box will contain a 20-mL vial of the study drug (ropivacaine or placebo according to the randomization number). The syringe will be prepared in a speci c room outside the delivery room by a midwife or an anesthetist not directly involved in the patient management. A label "ROPISIO Study" and the randomization number will be located on the syringe without any information about the product (ropivacaine or placebo) inside. Then, it will be given to the clinician who will be performing the suture of the episiotomy. Thus, the clinician and the mother will be blinded.

Study interventions
The intervention will consist of a perineal in ltration of a 20-mL blinded vial of the study drug (either 75mg of ropivacaine or placebo, according to the randomization group) in the margins of the episiotomy.
Careful aspiration before and during injection of the product should be performed to prevent intravascular injection. The entire 20-mL syringe will then be injected slowly at several points of in ltration. All planes will be in ltrated (vagina, muscle and skin) before episiotomy repair. In ltration will be performed by the midwife or the obstetrician, who performed the episiotomy and who is experienced at performing episiotomy sutures.
Except for the content of the study drug vial, all aspects of management of the third stage of labor and early postpartum period will be identical in the both arm: All drugs usually used in labor ward are allowed in this study, including prophylactic intravenous injection of 5 IU oxytocin at delivery to prevent postpartum hemorrhage.
Installation of a catheter for epidural anesthesia with continuous epidural infusion of sufentanil 5micrograms/mL, ropivacaine 0.75% and physiological saline serum.
A protocol for administration of analgesics will be carried out at the participating centers, namely: Level 1 of analgesia is proposed to the painful patient to H2 of the postpartum: paracetamol 1g, If the patient is still painful at the end of 6 hours, proposal of level 2 analgesia: paracetamol 1g + ibuprofen 200 mg, If the patient is still painful after 6 hours, proposal of level 3 analgesia: paracetamol 1g + ibuprofen 200 mg + tramadol 50 mg.
A meeting will be organized in each maternity unit before the beginning of the study to verify the attendants' agreement and the understanding of the protocol and their pro ciency in practicing the study procedures.

Study assessments
A summary of the study timeline and investigations is presented in Figure 1. Randomized women are provided with a study calendar to assist them to prospectively record data relevant to the study questionnaires. Research staff members are trained in standardized administration of all study questionnaires and data collection procedures. Midwives collecting data for the ROPISIO study during post-partum (H12, H24, H48, D7, M3 and M6) are blinded. Indeed, the patient medical record does not contain the result of the randomization.

Outcomes measures Primary outcome measure
The primary outcome is the analgesic e cacy of ropivacaine at day 7 postpartum (mid-term) measured with the numerical rating scale of pain (NRS), strictly superior to 3/10 on the perineal repair area. The systematic use of a numerical rating scale of pain (NRS) will allow an objective measurement of the perineal pain in the postpartum period. The NRS is a simple, widely used instrument to assess pain intensity [30]. The patient should rate their pain on a de ned scale ranging from 0 to 10 where 0 is no pain and 10 is the worst pain imaginable. This scale has already been used in several studies that assessed perineal pain after episiotomy [29,31].

Secondary outcomes
Short-and long-term analgesic effect Perineal pain will be measured by a numerical rating scale of the pain ( NRS) in the immediate postpartum period at H12, H24, and H48 by a midwife in the maternity ward. Perineal pain will also be measured by NRS at 3 months and 6 months using an online questionnaire.

Quality of life
The impact of perineal pain on quality of life will be assessed by the French version of the SF-36 using an online questionnaire at D7, M3 and M6 [32]. SF-36 is a validated and easily self-report quality-of-life measure for routine monitoring and assessment of care outcomes in adult patients. The SF-36 consists of 36 questions related to eight areas about the last four weeks: physical activity, life and relationships, pain, perceived health, vitality, mental limitations, physical condition and mental health. Internal consistency reliability was 0.83 to 0.93 for the eight scales and 0.94 and 0.89, respectively, for the physical (PCS) and mental (MCS) component summary measures [33]. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. A lower score is associated with the more disability [34].

Pain characteristics
The pain characteristics will be assessed by the French version of the DN4 questionnaire using an online questionnaire at D7, M3 and M6 [35]. The simpli ed DN4 is a self-report questionnaire that can be useful in helping to diagnose neuropathic pain, and consists of 4 questions and 10 items. If the patient's score is greater than or equal to 4/7, the pain may be considered as neuropathic [35,36]. A cut-off score of 4 resulted in the highest percent of correctly identi ed patients (86.0%), sensitivity (82.9%) and speci city (89.9%) of this 10-item questionnaire including both sensory descriptors and sensory examination. The inter-rater reliability was con rmed by Kappa values ranging between 0.70 and 0.96 [36].

Sexual function
The impact of perineal pain on female sexuality will be assessed by the French validated version of the FSFI [37,38] using an online questionnaire at D7, M3 and M6. This 19-items questionnaire is adapted for both sexually active and non-active women, and allows the assessment of the different parts of sexual function (desire, arousal, lubrication, orgasm, satisfaction and pain) over the past four weeks. The total score ranges between 2 and 36; higher scores are associated with a lower degree of female sexual dysfunction (FSD). A consensus seems to be found in the literature for values of less than 23 to de ne FSD [37,39]. A good reliability has been described for the French version with intraclass correlation coe cients superior to 0.75 and Cronbach's coe cients superior to 0.8 similarly to the original English version. Convergent validity was assessed as excellent (100%) and discriminant validity was satisfactory (89.5%) [37].

Postpartum symptoms of depression
The impact of perineal pain on mood will be assessed by the French version of the EPDS [40,41] using an online questionnaire at D7, M3 and M6. The EPDS is a 10-item self-report scale, and the total score ranges between 0 and 30; higher scores are associated with more symptoms. EPDS has good sensitivity and speci city for identifying probable clinical postpartum depression in community samples [42] and a good reliability for internal consistency of the global scale (Cronbach's alpha: 0.76) and its good short term test-retest reliability (0.98) [41]. A score of ≥12 on the EPDS was used as a measure of symptoms of maternal postpartum depression [43,44].

Statistical analysis
Both intention-to-treat and per-protocol analysis will be conducted, following the CONSORT guidelines for randomized controlled trials and will be conducted with the statistician and researchers blinded to group status. The two groups will be described for demographic characteristics and risk factors for perineal pain after episiotomy. The existence of a "Ropivacaine effect", that is, a difference between the two groups for the primary outcome measure and the secondary outcome measures will be analyzed. In case of missing data for the primary end-point, two types of imputation will be realized: multiple imputation and worst cases imputation: NRS strictly superior to 3/10 on the perineal repair area. The percentage of patient with an NRS strictly superior to 3/10 on the perineal repair area at D7 will be compared between groups (ropivacaine versus placebo) by a mixed effects logistic model in order to take in consideration the parity, the center and the group in xed effects. A sensitivity analysis will be realized to consider analgesic administration at H2 and D7. The analgesic consumption will be added in xed effect model. A generalized linear mixed regression approach will be realized for 3 criteria: the impact of perineal pain on sexuality (FSFI), on depression (EPDS) and on quality of life (SF-36) at D7, M3 and M6. This analysis allows taking into account intra-individual and inter-individual variability. The group and temporal effects will thus be estimated.

Sample size
According to previous research [5,8,9], approximately 70% of the patients suffered from perineal pain due to an episiotomy at D7 postpartum. To show a relative reduction of at the least 30% in this incidence in the ropivacaine arm, with 90% power at the 5% level of signi cance, and a bilateral test, the study requires 124 women with episiotomy in each group. In order to ensure a su cient power in the event of participant drop out, an additional 10% will be recruited. Therefore a total of 272 patients should be included in the study (136 in both groups).

Feasibility
The participating centers have worked together in previous trials. There are approximatively 4000 births at Nantes hospital and 2500 births at La Roche sur Yon hospital yearly, 10% of which require episiotomy, therefore recruiting 300 participants over 3 years is a reasonable target. Moreover, the participating centers belong to the GROG (Groupe de Recherche en Obstétrique et Gynécologie) national network.

Data management
The clinical research technician will complete data throughout the trial with EnnovClinical software, under the responsibility of each investigator. The electronic case report le (eCRF) for each woman will contain: In case patient does not answer the survey at D7, they will be called by phone at D10. An email will be sent one day before M3 and M6. In case the patient will not answer, 7 days after a second reminder will be sent by email. Data on D7 can be collected until D10 for analysis. Data at M3 and M6 will be accepted until 15 days after M3 and M6.
During the research, all the patient data will be anonymized and provided by the investigator to the promotor. Patients name and address will never appear in the CRF. Only the rst letter of the rst name and surname, the month and year of birth will be recorded with the randomization number. The email address will be collected by the medical team at the inclusion and be registered in a speci c database that will not be connected to the data accessible by the promotor. This enables to send to the patient an username and a keyword to connect at the research platform and complete the questionnaires online.
The data management and statistical aspects will be handled centrally by the La Roche sur Yon Hospital (Clinical Research Centre). Quality control will be conducted according to the standard operating procedures of the sponsor concerning trials in the investigational centers which comply with the Declaration of Helsinki and Good Clinical Practices. An independent data monitoring committee will control the quality and the safety of the trial procedures and the data collected, with regular visits and reports in each center by clinical research assistants. The standard operating procedures of the sponsor concerning trials (compliance with the de ned research protocol, veri cation of all informed consent for included women, accuracy and the examination of the source documents and their comparison with the data reported in the eCRF, consistency of the data and the missing data) will be reviewed at each inspection in each center. A nal report will be prepared for the funding body, and article will be prepared for publication with national and international dissemination.
In case of protocol amendments, the investigators will be informed by a newsletter and an email including all the speci c modi cations and the updated documents (e.g. protocol, patient inform and consent form). If several modi cations will be presented, a comparative table of the old and new document version will be produced. All the amendments will be carried out by the promotor on Clinical Trial database. Only the study promotor will have access to the complete nal trial dataset. Each investigator will received at the end of the study a copy of the data from the women include in his center.

Safety consideration
As recommended for trials using drugs in France, an Safety Monitoring Committee (SMC) composed of Nantes pharmacovigilance unit members will meet at minimum once a year to examine recruitment gures, baseline data, retention and adverse events. The trial coordinator will report to the ANSM within 72h all suspected unexpected serious adverse reactions (SUSARs), including maternal death, myocardial infarction, seizure, or suspected drug reactions. In particular in cases of strong suspicion of SUSARS related to the Investigational Medicinal Products, the blinding will be broken by the SMC if considered appropriate. The SMC will also inform the ANSM, the trial sponsor and the Chair of the Ethics Committee, and is authorized to recommend to the Scienti c Committee that the trial be stopped. In case of emergency (unexpected serious adverse reactions for example), the blinding will be broken and the midwife or the anesthetist who prepared the syringe (who is not directly involved in the patient management) will have to reveal the product contains in the syringe. In this case, the investigator must informed the trial coordinator as early as possible and will have to justify the purpose of unblinding procedure.

Discussion
The ROPISIO study will assess the e cacy of ropivacaine in ltration to reduce perineal pain in the postpartum period at mid-and long-term and increase the quality of life. This antalgic management could improve the women's quality of life in postpartum (earlier mobilization, better interaction with the baby, decrease analgesics used). At long term, we expect a decrease in dyspareunia and a better overall quality of life for the women.
Most studies on analgesic management of pregnant patients focused on pain during labor or following a cesarean section. Perineal pain in association with an episiotomy has been much less studied and often underestimated. Ropivacaine is a promising candidate drug, inexpensive and easy to administer and in ltration with this analgesic could be added to the routine management of all women after episiotomy worldwide. The evidence currently available is too limited to justify its widespread use for perineal pain prevention in postpartum period. This adequately powered, multicenter, randomized placebo-controlled trial aims to determine if the risk-bene t ratio favors the systematic use of Ropivacaine after episiotomy to prevent postpartum perineal pain. Declarations achievement. For the present protocol GD conceived the study, led study design and coordination, and commented on the manuscript. CC assisted with study design and drafted the manuscript. NW, VD, and SP were involved in conception and design of the study during several meetings and are local investigators in the participating centers. All authors mentioned in the manuscript are members of the ROPISIO-study group or collaborators. ALT assisted with study design and in particular the development of study databases. CC and GD edited the manuscript. All authors read and approved the nal manuscript.