Prediction of spontaneous onset of labor at term (PREDICT study): Research protocol.

BACKGROUND: Recent studies have shown that elective induction of labor versus expectant management after 39 weeks of pregnancy result in lower incidence of perinatal complications, while the proportion of cesarean deliveries remains stable, or even decreases. Still, evidence regarding collateral consequences of the potential increase of induction of labor procedures is still lacking. Also, the results of these studies must be carefully interpreted and thoroughly counter-balanced with women's thoughts and opinions regarding the active management of the last weeks of pregnancy. Therefore, it may be useful to develop a tool that aids in the decision-making process by differentiating women who will spontaneously go into labor from those who will require induction.
OBJECTIVE: To develop a predictive model to calculate the probability of spontaneous onset of labor at term.
METHODS: We designed a prospective national multicentric observational study including women enrolled at 39 weeks of gestation, carrying singleton pregnancies. After signing an informed consent form, several clinical, ultrasonographic, biophysical and biochemical variables will be collected by trained staff. If delivery has not occurred at 40 weeks of pregnancy, a second visit and evaluation will be performed. Prenatal care will be continued according to current hospital guidelines. Once recruitment is completed, the information gathered will be used to develop a logistic regression-based predictive model of spontaneous onset of labor between 39 and 41 weeks of gestation. A secondary exploration of the data collected at 40 weeks, as well as a survival analysis regarding time-to-delivery outcomes will also be performed. A total sample of 429 participants is needed for the expected number of events.
CONCLUSION: This study aims to develop a model which may help in the decision-making process during follow-up of the last weeks of pregnancy. TRIAL REGISTRATION: NCT05109247 (clinicaltrials.gov).

Introduction

Induction of labor (IOL) has long been associated with an increased risk of cesarean deliveries [1, 2]. However, the evidence supporting this observation was based on studies comparing the risk of cesarean deliveries in women who spontaneously started labor with those who required an IOL. Recent studies approached the problem from a different perspective and prospectively compared perinatal outcomes among women who were electively induced at different gestational ages to those who were expectantly managed (including women who enter labor spontaneously, but also women induced later in pregnancy for various indications) [3-5].

The approach of electively inducing labor at certain gestational ages, in order to reduce the incidence of adverse obstetric outcomes (including cesarean deliveries), has been assessed in the settings of advanced maternal age [6, 7], obesity [8], fetal macrosomia [4], or, more frequently, pregnancies over 41 weeks of gestation [3, 9, 10]. Most of these studies concluded that an active attitude towards IOL resulted in lower incidence of perinatal complications, while the proportion of cesarean deliveries remains stable, or even decreases. The most recent example of this strategy has been the “ARRIVE trial” [5], where low-risk nulliparous women were randomly allocated to elective IOL at 39 weeks or to an expectant management group. The main outcome (a composite of neonatal results, including perinatal death) was similar for both groups, but a secondary analysis revealed that the proportion of cesarean deliveries and hypertensive complications was higher in those women assigned to the expectant management group than in the IOL cohort.

Although this recent evidence might support IOL as a method of improving perinatal outcomes, other issues must be addressed. For example, the 0.18% absolute reduction in perinatal mortality after elective IOL at 41 weeks (compared to expectant management) [10] equates to more than 550 inductions needed to avoid one death, while, following the results of the ARRIVE trial, 27 inductions would be necessary in order to avoid one cesarean delivery [5]. Consequently, this strategy would substantially increase the number of inductions and would impact directly on the organization and the resources of contemporary delivery wards.

Additionally, women’s opinions in the matter of induction of labor should be considered. In fact, many women feel uncomfortable with the idea of facing an IOL, and more than half of them would rather not repeat the experience in subsequent pregnancies [11, 12]. Therefore, when the benefit is limited, it must be counterbalanced with maternal perceptions, choices, and points of view, especially when IOL will deprive them of the opportunity of spontaneously going into labor.

Having a tool capable of differentiating women who will spontaneously go into labor (thus theoretically benefiting from an expectant management) from those who will require IOL despite any period of expectancy would facilitate individualized counseling and tailored prognosis with regards to their options for managing the last weeks of pregnancy.

The prediction of spontaneous onset of labor becomes the keystone of this approach. However, it is unlikely that a single variable will explain and perfectly classify women into the two groups of interest, as onset of labor is still a poorly known issue and probably related to many processes. Hence, the multifactorial outcome needs to be addressed by a multiple and simultaneous evaluation of many of the features that may be related to the effect of interest, supported by an adequate statistical layout and design.

In summary, our hypothesis is that the combination of different clinical, ultrasonographic, biochemical, and biophysical features will allow prediction of the probability of spontaneous onset of labor during the remaining days of pregnancy, hence allowing discrimination between those women who will spontaneously go into labor from those who will require an induction of labor due to post-term pregnancy.

Material and methods

Study overview and aims

We designed a prospective and multicentric observational study including women enrolled at the 39th week of pregnancy, whose deliveries will take place at one of the participating University Hospitals in Switzerland (Geneva University Hospitals and University Hospital Basel). The primary aim is to develop and evaluate a multivariate predictive model able to estimate, between 38+5 and 39+6 weeks of pregnancy, the probability of spontaneous onset of labor before 41 weeks of pregnancy. Secondarily, we will analyze the individual accuracy of each of the evaluated characteristics at 39 and 40 weeks of pregnancy, isolated and within predictive models, to diagnose the onset of spontaneous labor within 1 or 2 weeks. We will also study the influence of each variable at 39 and 40 weeks of pregnancy, alone and in predictive models, in the daily probability of spontaneous onset of labor within 1 or 2 weeks.

Sample size calculation

According to unpublished data that has been previously collected in our center, approximately 78% of women will start their labor spontaneously before 41 weeks. Hence, considering 10 events (spontaneous onset of labor) for each of the collected variables, 13 participants will be necessary for each of the 15 assessed predictors. For the development of two predictive models (logistic and Cox regressions), these quantities should be doubled which leads to a required sample size of 390 women. An additional 10% has been added to compensate for potential loss of participants, discontinuation due to medical indication of delivery before the post-term period, or the missing values in at least one predictor. Hence, 429 participants will be recruited.

Eligibility criteria and obtaining informed consent

Term pregnant women who will deliver at any of the participating hospitals will be invited to participate in the study. Inclusion criteria comprise carrying a single and alive fetus, in cephalic presentation and with intact membranes. Gestational age for entering the study should be comprised between 38+5 and 39+6 weeks of pregnancy. Women with fetal malformations, symptomatic uterine contractions, any contraindication for vaginal delivery, medical indication for IOL or elective cesarean delivery, language barrier or inability to give consent, or requesting labor induction will be excluded. Moreover, the use of Pregnolia® aspiration system has specific exclusion criteria, which are listed in the S1 Appendix. If any of these criteria is met, the measurement of cervical stiffness using Pregnolia aspiration device will not be performed, but the participant will still be enrolled.

Patient follow-up will be performed according to local guidelines, without introducing any modification due to their participation. Besides current standard of care, clinical, ultrasonographic biochemical and biophysical parameters will be collected for the purpose of this study. Women will have the possibility to withdraw their consent at any point. Likewise, their participation (or their refusal) will not imply any change in the medical management of the pregnancy.

The recruitment, clinical care and data collection will be organized as follows: The pregnant woman will have her standard medical appointment at 34–38 weeks of gestation and the eligibility criteria will be reviewed. If the criteria are met, the study will be presented to the participant including a study information sheet and a copy of the informed consent. The patient will be contacted by phone within 48 hours to confirm her willing to participate in the study. After confirmation of participation, the first study visit will be scheduled. During this appointment, any study-related question will be answered, and the two copies of the informed consent will be signed (one for the patient and the other to be kept in the study files).

Outcomes and potential predictors

The main outcome has been defined as a dichotomous variable comprising either the number of participants spontaneously going into labor between 39 and 41+3 weeks of pregnancy or the number of women needing an induction of labor from 41+3 to 42 weeks due to post-term. The secondary outcome was established as the number of days occurring between the date in which the sample collection was performed and the date of delivery. If induction of labor must be performed due to any indication other than gestational age over 41+3 weeks, or if prelabor rupture of membranes occurs and it is not followed by spontaneous onset of labor after 12 hours of expectant management, the record will be censored and only considered for analysis up to the date at which the event took place.

We will collect the following variables as potential predictors of the outcome:

Clinical variables: maternal age, maternal height, maternal weight at admission, previous vaginal and/or cesarean deliveries (retrieved from medical records), and cervical status, assessed through Bishop score (vaginal examination).

Ultrasonographic variables: cervical length, fetal head to internal cervical os distance, posterior cervical angle, cervical consistency index (vaginal ultrasound), and estimated fetal weight (abdominal ultrasound).

Biochemical variables: quantitative fetal fibronectin and qualitative placental alpha microglobulin-1 determinations (obtained from vaginal secretions).

Biophysical variables: Cervical stiffness index using Pregnolia® system (assessed directly on the cervix using a speculum).

First study visit:

One of the researchers will conduct a directed interview with the pregnant women to collect the required clinical variables, which will be registered in the case report form (CRF).

Woman will be asked to empty her bladder and, once she is ready, to lay on her back in gynecological position.

A sterile and disposable speculum will be carefully introduced in the vagina.

Two different vaginal samples will be obtained from the posterior fornix using the swabs provided by the manufacturers to quantitatively measure the concentration of fetal fibronectin, as well as to qualitatively evaluate the presence of Placental Alpha Microglobulin-1. Both tests will be performed in situ, with the available commercialized kits for this purpose. The results of these tests will be registered in the CRF, and the vaginal samples and the single-use medical devices will be discarded following hospital guidelines.

Next, we will assess cervical stiffness using Pregnolia® system device. The probe must be applied to the anterior cervical lip, if there is no specific contraindication to its use (see S1 Appendix for further information). During the speculum application, three consecutive cervical stiffness measurements (known as Cervical Stiffness Indices) will be obtained and reported in the CRF. The procedure is done according to the instructions for use, considering that cervical stiffness indices are valid only if the first measurement was successful. This exam has been included in the study in November 2021 after an amendment accepted by the ethics committee.

The speculum will be retrieved, and a digital vaginal exam will be performed. The five items of Bishop score will be assessed and reported in the CRF.

Using a transvaginal sonographic probe, two different images from the uterine cervix will be obtained (ideally on the same frame, using split view):

A first sagittal view of the cervix on which the internal and external ora could be identified clearly, obtained without exerting any pressure on the cervix.

A second sagittal view obtained at maximum compression of the cervix, after applying pressure with the transvaginal probe until no further deformation of the tissue is identified, following the previously described technique for cervical consistency index assessment [13].

Both images will be recorded for off-line analysis. No measurements will be performed at the time of the visit to blind the results from the participant as much as possible.

A transabdominal ultrasonographic scan will be performed to assess estimated fetal weight, using Hadlock’s formula.

If any anomaly is detected during the ultrasound scan (e.g., oligoamnios or fetal malpresentation), the women will be referred to the obstetric unit and managed according to current guidelines.

All results will be blinded to physicians in charge and to the participants (double blind).

All extracted data will be recorded in the CRF, and the researcher will ask the woman if she is willing to continue with her participation. If so, an appointment will be scheduled 7–10 days later when the woman will be re-examined in the same way, except for fetal weight estimation. Follow-up of the pregnancy will be performed in accordance with current standard of care, with her attending obstetrician or midwife.

If labor does not spontaneously commence during follow-up, in the absence of maternal or fetal conditions requiring early delivery, women will be scheduled for induction of labor between 41 and 42 weeks of pregnancy, following local guidelines.

A minimal set of data regarding the outcomes of pregnancy will be collected from the clinical file once labor has occurred: type of delivery (vaginal vs. cesarean), indication for instrumental or cesarean birth, obstetric complications (Hypertension / Preeclampsia, chorioamnionitis, post-partum hemorrhage, 3rd or 4th degree perineal tear, post-partum infections, stillbirth or neonatal death, or others), and neonatal outcomes, such as weight, gender, Apgar scores and umbilical artery pH.

Study procedures

The study pathway for each participant is summarized in Figs 1 and 2. According to our data, we expect that approximately 60% of the participants will remain undelivered for the next consultation. The initial set of data will be collected in all women. However, potential predictors will be again determined in more than half of the participants, resulting in 686 evaluations for a total of 429 women.

Fig 1

Schedule of enrolment, interventions, and assessments.

w, weeks; Dlv, delivery; US, ultrasound.

Fig 2

Study procedures.

Scheme showing the different moments in which the potential predictors will be collected, as well as the outcomes and the planned analysis. A proportion of women will require IOL (or cesarean delivery) due to maternal or fetal indication and will be excluded from the logistic regression models (however considered as censored information for survival analysis). From the remaining cohort, some of them will go into spontaneous labor, while the others will be induced after 41 weeks of pregnancy due to gestational age. These last two groups will define the main outcome. As information will be also collected at 40w, a secondary analysis, stratified by gestational age, will be performed. IOL, induction of labor; w, weeks of pregnancy; GA, gestational age.

The participants may abandon the study at any time upon request. In this case, they will be asked to decide how the information that has already been collected may be used during the analysis, as described in the data management plan.

Data management plan

Data will be collected in a form specifically designed for this purpose containing a maximum number of closed questions, adequately codified and anonymized, to avoid the possibility of identification and association of sensitive data to specific participants. All the information will be confidentially handled and will remain digitalized in an informatized database, password-protected and only accessible by the main researchers. Data will be encoded for any kind of transport and all paper forms will be destroyed following current legislation.

All data will be entered to a REDCap® (Nashville, TN) database only by the researchers who were trained in its application, and under utmost confidentiality. One of the researchers -who will not be in charge of data recording- will evaluate data entry by aleatorily selecting 10% of the forms and verifying their correct entry into the database. Also, inadequate or missing values will be periodically assessed to evaluate data quality. This will be periodically performed at all recruiting centers.

If a woman chooses to abandon the study, she will be asked about the use of her information. If the participant refuses to allow the use of the data, the corresponding entrance will be removed from the database and all paper documentation regarding her participation will be destroyed. However, if she agrees to the utilization of data, the follow-up will be censored at the time of consent withdrawal.

In the case that participation should be discontinued due to a medical indication for elective cesarean delivery or induction of labor, censorship will be established from this point. The sample size calculation has been adjusted to compensate for situations of this kind. Regarding loss to follow-up, we consider that delivering outside the Hospital is an unlikely event, as the eligibility criteria specify that women plan to deliver within the participating centers.

Finally, missing data in the predictive variables will lead to the exclusion of the participant from the regression models. Hence, an increase in sample size has been estimated to compensate this issue.

Statistical analysis

The distribution of continuous or categorial variables will be compared using Student’s T test or Fischer’s exact test, respectively. Two-sided significance level was set to 0.05.

The main outcome will define two groups: women who spontaneously go into labor and those requiring a post-term IOL. A model of prediction of the binary outcome will be elaborated using stepwise backward and forward logistic regression analysis, including all analyzed features and the gestational age at data collection. To add or remove variables from the model, p-values of 0.05 or 0.10 will be used, respectively. Goodness-of-fit of the model will be evaluated using Hosmer and Lemeshow test and, if multiple models are achieved, the best one will be selected searching parsimony and following Akaike’s Information Criterion. Area under the Receiver-Operating Characteristics curve will be used to assess predictive ability of the model. This value will be also calculated using bootstrapping resampling methods (1000 repetitions) to internally validate the results. As only a subset of the sample will have the measurement of cervical stiffness using Pregnolia device (as this assessment was introduced after the start of recruitment), a secondary analysis (following the same principles of the main analysis) will be performed including this variable. A correlation analysis will be carried out comparing cervical consistency index evaluated by ultrasound with cervical stiffness assessed using the aspiration device, as both measurements evaluate the same biophysical characteristic of the cervix.

The probability of spontaneous onset of labor for each day after the analysis will be evaluated using survival regression models. The data will be described using Kaplan-Meier’s non-parametrical survival function and the predictive model will be estimated using stepwise backward and forward Cox’s regression (proportional hazards model). As mentioned before, data regarding women who have been induced for maternal or fetal indication (different from gestational age) or with prelabor rupture of membrane without spontaneous onset of labor after 12 hours of expectant management will be censored at the time of admission for these causes.

All statistical analysis will be performed using Stata 16.1 software (StataCorp, Texas, USA).

Any incidental finding during analysis will be carefully evaluated and only pondered in the conclusions as hypothesis-generator, considering the multiple biases introduced by the assumption of true findings after studies which were not designed for these purposes.

Safety considerations

Given that the nature of the study is non-experimental (observational) and that the safety of the interventions has been widely evaluated during pregnancy, women will be not exposed to any risk due to their participation in this research.

This research project will be conducted in accordance with the protocol, the Declaration of Helsinki [14], the principles of Good Clinical Practice, the Human Research Act (HRA) [15] and the Swiss Human Research Ordinance (HRO) [16], as well as other locally relevant regulations.

The project leader will be promptly notified (within 24 hours) if immediate safety and protective measures must be taken during the conduct of the research project. Also, if a serious event occurs, the research project will be interrupted, and the Ethics Committee notified on the circumstances within 7 days according to Swiss HRO.

The participation in the study will represent for women time effort and the need for one extra visit and one extra ultrasonographic exam. However, these have already demonstrated their lack of deleterious effect on the pregnancy, therefore no harm is expected over maternal or fetal health.

No radioactive sources will be used during the development of the research project. Ultrasound examination will be performed following ALARA (As Low As Reasonably Achievable) criteria.

Status and timeline

Geneva University Hospitals, as the coordinating center, has already started recruitment and about 200 participants have already been included. The two collaborating centers will start including women by the beginning of 2022. If the health situation due to the COVID crisis allows to maintain research activities, we expect to complete the expected sample size by the end of 2022.

Discussion

We designed this prospective, multicentric, observational study with the aim to identify those clinical, biochemical, biophysical and ultrasonographic factors that may lead to the prediction of spontaneous onset of labor at term.

Considering recent evidence showing no increase in maternal or neonatal morbidity with elective IOL from 39 weeks of pregnancy (even showing an improvement in some indicators, such a cesarean delivery rates) [5], the question regarding the interest of systematically proposing this procedure to all women has been increasingly rising among clinical practitioners in delivery wards. While it may seem reasonable to offer IOL at 39 weeks to women who will end up arriving to the post-term period, so as to reduce complications, it is less intuitive to systematically do so, as it is well-established that women going into labor spontaneously present the lowest cesarean section rates [1, 2]. Also, systematic IOL at 39 weeks would represent an additional medical intervention at term, which may be rejected by many women [11, 12], especially those with low-risk pregnancies.

Unfortunately, it is currently not possible to differentiate women who would benefit from expectant management (and spontaneously go into labor) from those who will end up requiring IOL. Many studies have tackled this idea by searching features or biomarkers able to identify this outcome, mainly evaluating three groups of variables: maternal characteristics (such as age [17, 18], body mass index [17-19], parity [17, 18, 20], ethnicity [17], or Bishop score [21]), ultrasonographic features (including cervical length [17, 20–25] or the presence of funneling [25]), or biochemical biomarkers (comprising the vaginal detection of fetal fibronectin [26, 27]). Most of these studies have been performed in pregnancies arriving at 41 weeks [17, 18, 20, 21], with few carried out at earlier gestational ages [22, 23, 25]. Among all the assessed variables, cervical length and body mass index were the most evaluated features and those that showed a higher association with spontaneous onset of labor [17-25]. Regarding fetal fibronectin, it has mostly been used in the context of preterm labor, and when used at term it failed to discriminate women among the two groups [27]. Placental Alpha Microglobulin-1 has not been used in the prediction of spontaneous term labor.

A biomarker that is gathering interest is the evaluation of cervical consistency. Traditionally included as one of the parameters evaluated in Bishop score, it has never achieved relevance as a predictor neither of preterm delivery nor of spontaneous onset of labor by itself. One of its main flaws is its high subjectivity, which leads to a very low reproducibility. However, different authors have started to focus on cervical consistency as a marker of preterm delivery, assessed either by ultrasound (by means of the cervical consistency index [13]) or using aspiration devices, as the one developed in Switzerland and commercialized by Pregnolia® AG. Both techniques have shown that cervical consistency decreases with ongoing pregnancy [13, 28], and the ultrasonographic evaluation has also been shown to be a potential predictor of preterm delivery [29], but not of the result of induction of labor [30]). We decided to include the assessment of cervical stiffness with the Pregnolia® AG device later in the study and therefore only a set of women will have this measurement.

We hope this study will allow to integrate current knowledge -along with new collected information- in a single prediction tool to evaluate the chance of spontaneous onset of labor, which will help both pregnant women and their care providers in the decision-making process and in the tailoring of medical advice during the last weeks of pregnancy.

Ethical considerations

All participants will be adequately informed, orally and written, and the research team will remain at their discretion to answer any question that they may find necessary. Participants will also sign the informed consent form before the study visit and they will have the possibility to withdraw from the study at any point, without any impact on standard of medical care received.

Complications may be diagnosed earlier as each participant will have one extra visit and one additional ultrasound scan. Also, the study does not represent any risk to women, as the explorations that will be carried out are usually performed in current standard of care. All data will remain anonymized, with no risk for participant identification if unauthorized data access occurs.

Regarding the inclusion of vulnerable participants, the recruitment of pregnant women is mandatory for studying the situations involving delivery. The results of this research will help to guide management of pregnant women.

As any work including human subjects, the study has been approved by the Geneva cantonal of the Research Ethics Commission (CCER) (2019–00261).

Conclusion

This study aims to prospectively develop a model combining relevant clinical, biochemical, biophysical, and/or ultrasonographic variables to predict the spontaneous onset of labor, which will be useful in the decision-making process of the last stages of pregnancy.

Recommended items to address in a clinical trial protocol and related documents.

(PDF)

Click here for additional data file.

Specific exclusion criteria for Pregnolia® system according to the manufacturer’s recommendations.

(DOCX)

Click here for additional data file.

Protocol submitted to ethics committee.

(PDF)

Click here for additional data file.

13 Apr 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Guillaume Ducarme, MD, MSc, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf  and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

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

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

4. Thank you for stating the following in the Funding Section of your manuscript:

“The developers of fetal Fibronectin (Hologic®) will provide the assay kits, along with the analyzers, at no cost for the researchers. The supplies to assess the presence of Placental alpha macroglobulin 1 in vaginal secretions will also be offered by the developers (Qiaogen®) without any charge. “Pregnolia AG®” will provide the device for the measurement of cervical stiffness. One Pregnolia Control Unit, as well as the disposable Pregnolia Probes, will be provided free of charge for the conduct of the research.

All the enterprises have been informed that the study protocol will be published, as well as the conclusions of the research, whatever are the results. The design of the study, the data collection, analysis, and publication are an exclusive responsibility of the researchers and no interference from the enterprises is expected. Data will not be shared, and the companies will only know the results once the analysis has finished. All collaboration contracts have been submitted and approved by the Swiss Ethics Committee.

The researchers are workers at the institutions involved in the study and will not receive any compensation for participating in the study. Therefore, the investigators declare no conflict of interest”

We note that you have provided additional information within the Funding Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Funding section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

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:

“The study is financed by the Geneva University Hospitals. The material required for quantitative Fetal Fibronectin measurement, qualitative Placental Alfa Microglobulin 1 (PartoSure® test), and the cervical aspiration device were provided free of cost by Hologic, QIAGEN, and Pregnolia AC, respectively. These suppliers had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Neither the investigators nor our institution was directly or indirectly financed by these private enterprises. Consequently, the authors declare no conflict of interest.”

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

5. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

6. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Please revise the following points:

line 57 delete second “labor”, change to “(labor spontaneously)”

line 58 please clarify the meaning of “lately” in this context? Do the authors refer to “recently” or the time point of IOL as in late induction of labor? This is not clear to the reader.

line 60 change “obstetrical” to “obstetric outcomes”

line 72 consider re-wording here “expectant management” (rather than attitude)

line 121 re-wording of heading “Eligibility criteria and obtaining informed consent”

lines 122/123 suggest re-wording to “participate in the study” (rather than join in …)

lines 139/140 suggest re-wording to “If the criteria are met, the study will be presented to the participant including a study information sheet and a copy of the informed consent.”

lines 142/143 suggest re-wording to “the first study visit will be scheduled. During this appointment, any study related questions will be answered and the two copies …”

line 150 “established” (typo)

line 156 maternal height/weight: will BMI be calculated and categorised accordingly?

line 175 rewording “from the posterior fornix”

line 182 change to 2 sentences. : … system device. The probe must be applied …”

lines 204/205 suggest re-wording “ (eg oligohydramnios or fetal malpresentation), change “obstetrical” to “obstetric”

line 210 suggest rewording “later when the woman will be re-examined in the same way, except …”

line 211 follow up of the pregnancy (typo)

line 213 suggest rewording “commence” (rather than start)

line 216 suggest rewording “the study pathway for each participant”

lines 218/219 needs re-wording; suggest “The initial set of data will be collected in all participants. Potential predictors will be again determined in more than half of the women resulting in around 686 evaluations for a total of 429 women.”

line 222 “destination of information”: do you mean storage or release or both? Not clear to the reader. Requires further clarification here.

line 228 suggest re-wording “specific” rather than “concrete”

lines 233/234 suggest re-wording “trained in its application” (rather than handle it), add “be” to change to “not be in charge”, change to “10 % of the forms” (rather than “a 10 % of …”)

line 239 change to “all paper documentation” (delete “the”)

lines 269/270 suggest re-wording “women who have been induced for …” (rather than “whose labors …”)

line 279 do you mean “safety” (not security)?

line 293 needs re-wording “Achievable” not “Acceptable” (ALARA)

line 316 Can you provide a reference for your statement that IOL at 39 weeks is increasing medical intervention at term?

lines 318+319 delete “an”

lines 326-328 this statement needs to be reworded to make it clear to the reader: is it low BMI and short CL which are associated with spontaneous onset of labour?

lines 329/330: suggest re-wording: “Placental alpha Microglobulin-1 has not been used …”

line 337: ad “in” Switzerland

lines 339/340: highlighted/commented statement needs to be re-visited

line 341: meaning of “lately” needs to be defined again here

line 342: suggest re-wording to “current knowledge”

line 349: change to “discretion” (rather than “disposal”), change “They” to “Participants will also sign …”

line 351: suggest re-wording to “ … impact on standard of medical care received”

line 352: suggest re-wording: “Complications might be diagnosed earlier as each participant will have one extra visit and one additional ultrasound scan.

lines 357/358: suggest re-wording: delete “the”, change to “involving delivery. The results of this research will help to guide management of pregnant women” (or something similar)

line 369: do you mean “companies” (enterprises)?

line 370: delete “whatever are the results”

lines 371/372: what do you mean by “interferences”? Needs re-wording. Please change to “companies” again.

line 373: consider re-wording “finalised” (rather than “finished”)

line 375: please change to “employed by the institutions involved in the study”.

The manuscript is written well but needs revision in relation to points raised above. Clinically highly relevant topic. Academically well-designed protocol. Clear inclusion and exclusion criteria.

Reviewer #2: The current manuscript is a research protocol designed to gather data that will then be used to develop a model to determine the prediction of spontaneous onset of labor at term.

The main rationale provided in the paper is that labor induction is associated with increased risk of caesarean delivery, but that the evidence for this was not comparing like for like. The manuscript provides some rationale for the proposed study protocol but would benefit with inclusion and discussion of additional more recently published studies. (please see suggested reference list for inclusion)

Overall, an important topic that could lead to additional information that would help inform management of pregnancy and labor. The authors aim to include biochemical, clinical, ultrasonographic and physiological measurements. The data will then be used to develop a prediction model to determine the participants that will develop spontaneous preterm labor.

The grammar, flow and details of the manuscript and protocol are not easy to follow, and a number of suggestions are included for improvement.

In Lines 77-81, the authors describe the importance of including the opinion of the participant and their perceptions, choices and points of view. But this does not seem to be included within the methods section.

What assessments or questionnaire will be provided to the participant, and how will this data be analysed and included in the final data set, either alone or alongside the biochemical and clinical measurements?

Line 53 – 58: please add citations that support this information.

The manuscript should be revisited and checked for typographical and spelling errors. I have noted a few below.

Line 58: should lately be later? Or other?

Line 101: should ‘would’ be ‘will’?

Line 150: change ‘stablished’ to established

Line 188: what is “XX 2021”

Line 216: “The path gone across by the participant has been summarised in Figure 1” As written this sentence is difficult to understand,

Line 232 – 245: rather than ‘she’ or ‘her’ suggest changing to ‘the participant’ where appropriate. The grammar and flow of this paragraph is difficult to understand.

Line 232: change ‘stablished’ to ‘established’.

Line 360: what is “XXXXXX” Based on this it is not clear if the study has been approved by the ethics committee or not. Please confirm.

The authors track changes and comments seem to still be in places throughout the document.

Additional references to be included and discussed:

Fonseca et al., 2020.

Does induction of labor at term increase the risk of cesarean section in advanced maternal age? A systematic review and meta-analysis.

Eur J Obstet Gynecol Reprod Biol 2020 Oct;253:213-219. DOI: 10.1016/j.ejogrb.2020.08.022

Erickson EN et al 2021

Induction of labor or expectant management? Birth outcomes for nulliparous individuals choosing midwifery care.

Birth. 2021 Dec;48(4):501-513.

Middleton P et al 2020.

Induction of labour at or beyond 37 weeks' gestation.

Cochrane Database Syst Rev. 2020 Jul 15;7(7):CD004945.

Elden H et al 2016

Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks.

BMC Pregnancy Childbirth. 2016 Mar 7;16:49.

Kortekaas JC, et al. 2014.

Effects of induction of labour versus expectant management in women with impending post-term pregnancies: the 41 week - 42 week dilemma.

BMC Pregnancy Childbirth. 2014 Oct 23;14:350.

Stock SJ et al 2012.

Outcomes of elective induction of labour compared with expectant management: population based study.

BMJ. 2012 May 10;344:e2838. doi: 10.1136/bmj.e2838.

Reviewer #3: Interesting abstract for the protocol.

The language could be phrased differently to be clearer, for example (line 52): "Induction of labor (IOL) has longtime been associated with" would read better as "It has been accepted that induction of labour has previously been associated with"

line 93: "will allow to predict" would be better as "will allow prediction of"

line 119" "finally needed" would be better as "recruited".

line 150 and 242: "stablished" - is this "established"?

line 188: "XX 2021" it is now 2022 - is the date known?

line 211: "or" should this be "of"?

line 215: after the patient goes into labour - do you collect the outcome of the labour - i.e. live birth, cesarean required, length of time from hospital arrival to birth or leaving the delivery suite? If you do collect these values, include them in the protocol, and state how they will be reported on.

line 216: "gone across" would be better as "experienced"

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

15 May 2022

Dear Editors and Reviewers,

You will find below these lines the corrections and observations regarding the revision process. It is my duty to thank you all for your comments and suggestions, which have surely improved our work.

Besides from the recommended amendments, I would like to point out that we have removed the Centre Hospitalier Universitaire Vaudois, in Lausanne, given that the collaboration has not finally fructified. Therefore, the study protocol will only be applied in two Swiss centers.

When pointing out the location of a certain modification in the manuscript, the lines indicated below refer to the ‘Revised manuscript with track changes’ version, so you can easily identify the rectification.

On behalf of all the authors, I would like to show our gratitude once again for the work performed by the Editors and the Reviewers, whose positive and constructive comments have enriched our manuscript. We look forward to receiving your feedback of the corrected version of our work.

We remain at your complete disposal for any further comment or clarification that you may find necessary to address to us

Yours faithfully,

Federico Migliorelli, MD, PhD,

Corresponding Author

Department of Pediatrics, Gynecology, and Obstetrics, Division of Obstetrics,

Geneva University Hospitals

30 Boulevard de la Cluse

1211 Geneva 14, Switzerland

E-Mail: femigliorelli@gmail.com

Editors and Reviewers Comments:

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Thank you very much for these remarks. We have reviewed the files and updated the file naming, as well as any deviation from your style requirements. We hope that the manuscript will fit your standards in its actual state.

2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

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

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Following your recommendations, we have reviewed the data sharing and availability statements. As mentioned in the cover letter, given that our manuscript describes a research protocol, we are not able to provide any data at this moment, as it has not yet been generated. However, we share your views regarding this issue, and we are committed to publish the minimal underlying dataset to increase reproducibility and transparency once we publish the results of our investigation.

4. Thank you for stating the following in the Funding Section of your manuscript:

“The developers of fetal Fibronectin (Hologic®) will provide the assay kits, along with the analyzers, at no cost for the researchers. The supplies to assess the presence of Placental alpha macroglobulin 1 in vaginal secretions will also be offered by the developers (Qiaogen®) without any charge. “Pregnolia AG®” will provide the device for the measurement of cervical stiffness. One Pregnolia Control Unit, as well as the disposable Pregnolia Probes, will be provided free of charge for the conduct of the research.

All the enterprises have been informed that the study protocol will be published, as well as the conclusions of the research, whatever are the results. The design of the study, the data collection, analysis, and publication are an exclusive responsibility of the researchers and no interference from the enterprises is expected. Data will not be shared, and the companies will only know the results once the analysis has finished. All collaboration contracts have been submitted and approved by the Swiss Ethics Committee.

The researchers are workers at the institutions involved in the study and will not receive any compensation for participating in the study. Therefore, the investigators declare no conflict of interest”

We note that you have provided additional information within the Funding Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Funding section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

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:

“The study is financed by the Geneva University Hospitals. The material required for quantitative Fetal Fibronectin measurement, qualitative Placental Alfa Microglobulin 1 (PartoSure® test), and the cervical aspiration device were provided free of cost by Hologic, QIAGEN, and Pregnolia AC, respectively. These suppliers had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Neither the investigators nor our institution was directly or indirectly financed by these private enterprises. Consequently, the authors declare no conflict of interest.”

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

We apologize for the double input regarding the funding information. As asked, we removed the funding-related text from the manuscript, leaving only the Funding Statement on the cover page. Even if the paragraph in the text was much more developed, it essentially contains the same information, so we are keeping the Funding Statement without any further modification. Please let us know if this complies with your standards. We kept on the manuscript a brief sentence disclosing the conflict of interest, which is none for any of the authors.

5. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

I believe that there is a misunderstanding regarding the grant information. We did not receive any grant to carry on the research; the study was solely financed by the Department of Obstetrics of Geneva University Hospitals. As stated in the Funding Information, the industry (Hologic, QIAGEN and Pregnolia) supplied the material needed for the study, but neither economic nor financial support was received. I expect that with the abovementioned Funding Statement this issue will be clarified.

6. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

The full ethics statement can be found in the lines 418-439 of the manuscript. The letter of approval has been also submitted with the protocol. To clarify this issue, we have introduced the name of the subdivision of the Swiss Ethical Committee approving the protocol, which is the highest authority in this matter. If you believe that further development is necessary, please do not hesitate to ask for it, and we will happily inquire the Committee for any required documentation.

7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

We have added the caption for our Supporting Information at the end of the manuscript (before the references). We have also updated the in-text citations. You can find them in lines 482 and 139, respectively.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

6. Review Comments to the Author

Reviewer #1: Please revise the following points:

line 57 delete second “labor”, change to “(labor spontaneously)”

line 58 please clarify the meaning of “lately” in this context? Do the authors refer to “recently” or the time point of IOL as in late induction of labor? This is not clear to the reader.

line 60 change “obstetrical” to “obstetric outcomes”

line 72 consider re-wording here “expectant management” (rather than attitude)

line 121 re-wording of heading “Eligibility criteria and obtaining informed consent”

lines 122/123 suggest re-wording to “participate in the study” (rather than join in …)

lines 139/140 suggest re-wording to “If the criteria are met, the study will be presented to the participant including a study information sheet and a copy of the informed consent.”

lines 142/143 suggest re-wording to “the first study visit will be scheduled. During this appointment, any study related questions will be answered and the two copies …”

line 150 “established” (typo)

line 156 maternal height/weight: will BMI be calculated and categorised accordingly?

Indeed, maternal BMI will be calculated. However, we expect to include it as a continuous variable in the model. We may only present the categorization to describe the characteristics of the sample.

line 175 rewording “from the posterior fornix”

line 182 change to 2 sentences. : … system device. The probe must be applied …”

lines 204/205 suggest re-wording “ (eg oligohydramnios or fetal malpresentation), change “obstetrical” to “obstetric”

line 210 suggest rewording “later when the woman will be re-examined in the same way, except …”

line 211 follow up of the pregnancy (typo)

line 213 suggest rewording “commence” (rather than start)

line 216 suggest rewording “the study pathway for each participant”

lines 218/219 needs re-wording; suggest “The initial set of data will be collected in all participants. Potential predictors will be again determined in more than half of the women resulting in around 686 evaluations for a total of 429 women.”

line 222 “destination of information”: do you mean storage or release or both? Not clear to the reader. Requires further clarification here.

line 228 suggest re-wording “specific” rather than “concrete”

lines 233/234 suggest re-wording “trained in its application” (rather than handle it), add “be” to change to “not be in charge”, change to “10 % of the forms” (rather than “a 10 % of …”)

line 239 change to “all paper documentation” (delete “the”)

lines 269/270 suggest re-wording “women who have been induced for …” (rather than “whose labors …”)

line 279 do you mean “safety” (not security)?

line 293 needs re-wording “Achievable” not “Acceptable” (ALARA)

line 316 Can you provide a reference for your statement that IOL at 39 weeks is increasing medical intervention at term?

lines 318+319 delete “an”

lines 326-328 this statement needs to be reworded to make it clear to the reader: is it low BMI and short CL which are associated with spontaneous onset of labour?

lines 329/330: suggest re-wording: “Placental alpha Microglobulin-1 has not been used …”

line 337: ad “in” Switzerland

lines 339/340: highlighted/commented statement needs to be re-visited

line 341: meaning of “lately” needs to be defined again here

line 342: suggest re-wording to “current knowledge”

line 349: change to “discretion” (rather than “disposal”), change “They” to “Participants will also sign …”

line 351: suggest re-wording to “ … impact on standard of medical care received”

line 352: suggest re-wording: “Complications might be diagnosed earlier as each participant will have one extra visit and one additional ultrasound scan.

lines 357/358: suggest re-wording: delete “the”, change to “involving delivery. The results of this research will help to guide management of pregnant women” (or something similar)

line 369: do you mean “companies” (enterprises)?

line 370: delete “whatever are the results”

lines 371/372: what do you mean by “interferences”? Needs re-wording. Please change to “companies” again.

line 373: consider re-wording “finalised” (rather than “finished”)

line 375: please change to “employed by the institutions involved in the study”.

Thank you very much for all your comments and suggestions. We have thoroughly revised the manuscript and corrected the mistakes and sentences as you suggested. We have also rephrased those statements which were not clear for better understanding. We hope that this new version will satisfy the reviewer.

The manuscript is written well but needs revision in relation to points raised above. Clinically highly relevant topic. Academically well-designed protocol. Clear inclusion and exclusion criteria.

Thank you for your comments. This encourages us to keep on working.

Reviewer #2: The current manuscript is a research protocol designed to gather data that will then be used to develop a model to determine the prediction of spontaneous onset of labor at term.

The main rationale provided in the paper is that labor induction is associated with increased risk of caesarean delivery, but that the evidence for this was not comparing like for like. The manuscript provides some rationale for the proposed study protocol but would benefit with inclusion and discussion of additional more recently published studies. (please see suggested reference list for inclusion)

Thank you very much for your proposal. We have included your suggestions appropriately throughout the paper.

Overall, an important topic that could lead to additional information that would help inform management of pregnancy and labor. The authors aim to include biochemical, clinical, ultrasonographic and physiological measurements. The data will then be used to develop a prediction model to determine the participants that will develop spontaneous preterm labor.

The grammar, flow and details of the manuscript and protocol are not easy to follow, and a number of suggestions are included for improvement.

Thank you very much for your careful reading and your comments. We have corrected the manuscript following your recommendations. We believe that it has been very much improved with your collaboration.

In Lines 77-81, the authors describe the importance of including the opinion of the participant and their perceptions, choices and points of view. But this does not seem to be included within the methods section.

What assessments or questionnaire will be provided to the participant, and how will this data be analysed and included in the final data set, either alone or alongside the biochemical and clinical measurements?

Women’s opinion on matters that affect their pregnancies is always interesting, and that is the reason why we included this description in the rationale for the study. However, this work does not intend to collect information regarding this subject (in fact, we are only collecting variables that may influence on spontaneous onset of labor, but we will not be performing any intervention). In this way, it is out of the scope of this study to assess women’s perceptions of the last weeks of pregnancy. Nevertheless, if we succeed in creating a predictive model of spontaneous onset of labor, its application within a research project and an ulterior clinical protocol could be the matter of an interesting research, focusing on women’s experiences with this tool and the alternatives presented to her to decide on the final stages of pregnancy.

Line 53 – 58: please add citations that support this information.

Thanks for the comment. We thought that this statement was supported by the ulterior references, but we added citations to this paragraph to increase understanding.

The manuscript should be revisited and checked for typographical and spelling errors. I have noted a few below.

Line 58: should lately be later? Or other?

Line 101: should ‘would’ be ‘will’?

Line 150: change ‘stablished’ to established

Line 188: what is “XX 2021”

Line 216: “The path gone across by the participant has been summarised in Figure 1” As written this sentence is difficult to understand,

Line 232 – 245: rather than ‘she’ or ‘her’ suggest changing to ‘the participant’ where appropriate. The grammar and flow of this paragraph is difficult to understand.

Line 232: change ‘stablished’ to ‘established’.

Line 360: what is “XXXXXX” Based on this it is not clear if the study has been approved by the ethics committee or not. Please confirm.

The authors track changes and comments seem to still be in places throughout the document.

Additional references to be included and discussed:

Fonseca et al., 2020. Does induction of labor at term increase the risk of cesarean section in advanced maternal age? A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2020 Oct;253:213-219. DOI: 10.1016/j.ejogrb.2020.08.022

Erickson EN et al 2021. Induction of labor or expectant management? Birth outcomes for nulliparous individuals choosing midwifery care. Birth. 2021 Dec;48(4):501-513.

Middleton P et al 2020. Induction of labour at or beyond 37 weeks' gestation. Cochrane Database Syst Rev. 2020 Jul 15;7(7):CD004945.

Elden H et al 2016. Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks. BMC Pregnancy Childbirth. 2016 Mar 7;16:49.

Kortekaas JC, et al. 2014. Effects of induction of labour versus expectant management in women with impending post-term pregnancies: the 41 week - 42 week dilemma. BMC Pregnancy Childbirth. 2014 Oct 23;14:350.

Stock SJ et al 2012. Outcomes of elective induction of labour compared with expectant management: population based study. BMJ. 2012 May 10;344:e2838. doi: 10.1136/bmj.e2838.

Thank you very much for all your comments and contributions. We hope that in its current form, the manuscript is more understandable, and that the methodology section is as clear as necessary to allow replication.

Reviewer #3: Interesting abstract for the protocol.

The language could be phrased differently to be clearer, for example (line 52): "Induction of labor (IOL) has longtime been associated with" would read better as "It has been accepted that induction of labour has previously been associated with"

line 93: "will allow to predict" would be better as "will allow prediction of"

line 119" "finally needed" would be better as "recruited".

line 150 and 242: "stablished" - is this "established"?

line 188: "XX 2021" it is now 2022 - is the date known?

line 211: "or" should this be "of"?

line 215: after the patient goes into labour - do you collect the outcome of the labour - i.e. live birth, cesarean required, length of time from hospital arrival to birth or leaving the delivery suite? If you do collect these values, include them in the protocol, and state how they will be reported on.

Indeed, we will be collecting the labor outcomes once they have occurred, by reviewing clinical files. We have added this information in the protocol, and you may find it in the lines 237-242.

line 216: "gone across" would be better as "experienced"

Thank you very much for all your comments and suggestions. We have included them in our manuscript as we believe that they will increase its quality.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

23 Jun 2022

Prediction of spontaneous onset of labor at term (PREDICT Study): Research protocol

PONE-D-21-40209R1

Dear Dr. Migliorelli,

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,

Guillaume Ducarme, MD, MSc, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional): All comments and modifications have been addressed

Reviewers' comments:

1 Jul 2022

PONE-D-21-40209R1

Prediction of spontaneous onset of labor at term (PREDICT Study): Research protocol

Dear Dr. Migliorelli:

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.

If we can help with anything else, please email us at plosone@plos.org.

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Guillaume Ducarme

Academic Editor

PLOS ONE