Pregnancy physiology pattern prediction study (4P study): protocol of an observational cohort study collecting vital sign information to inform the development of an accurate centile-based obstetric early warning score

Introduction Successive confidential enquiries into maternal deaths in the UK have identified an urgent need to develop a national early warning score (EWS) specifically for pregnant or recently pregnant women to aid more timely recognition, referral and treatment of women who are developing life-threatening complications in pregnancy or the puerperium. Although many local EWS are in use in obstetrics, most have been developed heuristically. No current obstetric EWS has defined the thresholds at which an alert should be triggered using evidence-based normal ranges, nor do they reflect the changing physiology that occurs with gestation during pregnancy. Methods and analysis An observational cohort study involving 1000 participants across three UK sites in Oxford, London and Newcastle. Pregnant women will be recruited at approximately 14 weeks’ gestation and have their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation and temperature) measured at 4 to 6-week intervals during pregnancy. Vital signs recorded during labour and delivery will be extracted from hospital records. After delivery, participants will measure and record their own vital signs daily for 2 weeks. During the antenatal and postnatal periods, vital signs will be recorded on an Android tablet computer through a custom software application and transferred via mobile internet connection to a secure database. The data collected will be used to define reference ranges of vital signs across normal pregnancy, labour and the immediate postnatal period. This will inform the design of an evidence-based obstetric EWS. Ethics and dissemination The study has been approved by the NRES committee South East Coast–Brighton and Sussex (14/LO/1312) and is registered with the ISRCTN (10838017). All participants will provide written informed consent and can withdraw from the study at any point. All data collected will be managed anonymously. The findings will be disseminated in international peer-reviewed journals and through research conferences.

I was confused by the protocols. It states the study will start in August 2012. This protocol is dated January 2017 and has 11 authors. There is also a second protocol dated 14 September 2015 with four of the 11 authors.
The last references are 2014 which may explain why the text appears a little dated and may explain the comment that current obstetric EWS do not reflect the physiological changes of pregnancy. This statement does not hold true for the obstetric EWS introduced nationally in both the north and south of Ireland. I accept however that there is scant literature historically on the measurements of vital signs as pregnancy advances. I am also puzzled by the decision to base normality and abnormality on centiles. What is the basis for this? Surely, the observations need also to be linked to different obstetric or medical complications.
Is there a risk that observations by a midwife may impact on the measurements? I am surprised there is not more discussion about wearable devices and I suspect there may have been significant developments since this protocol was first written. I also note that there is a plan to copy measurements retrospectively from the clinical records. This runs the risk of errors and of measurements being rounded up or down. Again, this could be overcome with the use of wearable devices that could be used as both inpatients and outpatients.

GENERAL COMMENTS
The idea of collecting vital sign data for pregnancy as noted is not new but the context of then using contemporary data to create data driven parameters for early warning criteria is novel and needed. The abstract is confusing as it states " we will start in august 2012" Is this an error ? Can the authors be more specific the position that the patient will be in when the various parameters are collected and how this may change during the course of the pregnancy. For BP measurements they state that they will only use the first measurement, this is frequently elevated and most recommend repeat --how will this be addressed?

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 Professor Michael Turner Professor of Obstetrics and Gynaecology Director UCD Centre for Human Reproduction Coombe Women and Infants University Hospital Please state any competing interests or state "None declared": None declared This is an important and topical issue in contemporary maternity care.
I was confused by the protocols. It states the study will start in August 2012. This protocol is dated January 2017 and has 11 authors. There is also a second protocol dated 14 September 2015 with four of the 11 authors.
We apologise for causing confusion. The first stage of the 4P study occurred as a substudy of the Interbio 21-st study, commencing 1 August 2012. The second stage allowed the study to expand to two other sites, and allowed the first site (Oxford) to continue after the InterBio-21st study completed. As a result the first stage was done under an ethics amendment to the InterBio-21st study, the second with a separate ethics application and protocol. We have clarified this both in the text (Methods and analysisstudy design) and in appendix 8study timelinesas suggested by the editors. Since the study began it has become accepted good practice to publish the protocol before data analysis begins. This is what we wish to do. The protocol submitted for publication in BMJ open encompasses the whole 4P study, including patients recruited as a subset of Interbio-21st. We originally attached the latest version of the protocol submitted for ethical approval for stage 2 to our original submission. In retrospect this was both confusing for the reader and an over-interpretation of BMJ open guidance. We have therefore removed this from the current submission.
The last references are 2014 which may explain why the text appears a little dated and may explain the comment that current obstetric EWS do not reflect the physiological changes of pregnancy. This statement does not hold true for the obstetric EWS introduced nationally in both the north and south of Ireland. I accept however that there is scant literature historically on the measurements of vital signs as pregnancy advances.
We believe it is important to explain the basis for doing the 4P study, so we have not updated references beyond those relevant when we commenced stage 2.
Our abstract states: "nor do they reflect the changing physiology that occurs with gestation during pregnancy". We note that the I-MEWS (introduced in Ireland) makes no alteration for different gestations.
I am also puzzled by the decision to base normality and abnormality on centiles. What is the basis for this? Surely, the observations need also to be linked to different obstetric or medical complications.
We have addressed this issue in paragraph 4 of the introduction and referenced our (both highly cited and used in clinical practice) paper using the centile-based approach. The approach is particularly suited to pregnancy, where event rates are low. Further explanation of the benefits of this approach is contained within this paper.
Is there a risk that observations by a midwife may impact on the measurements?
Vital signs as taken by healthcare professionals such as midwives are those used for early warning. Normal ranges obtained by midwives are therefore what is required. The reviewer is correct that this may mean the vital signs taken by participants in the post-partum period may require adjustment. It is for this reason that midwife measurements will also be taken post-partum.
I am surprised there is not more discussion about wearable devices and I suspect there may have been significant developments since this protocol was first written.
The aim of the 4P study is to provide evidence-based early warning using the vital signs taken in normal practice, using normal equipment. We have undertaken studies involving wearable devices over many years ( . We chose the devices for women in to use in the home in light of this expertise. We think it will be some time before wearable devices are in routine use in pregnant women.
I also note that there is a plan to copy measurements retrospectively from the clinical records. This runs the risk of errors and of measurements being rounded up or down. Again, this could be overcome with the use of wearable devices that could be used as both inpatients and outpatients.
We have developed electronic systems to minimize the risk of data entry errorsexamples of these are included in the current submission (appendix 3). We have developed these systems in light of our experience in previous studies with wearable monitoring (Clifton DA, BMJ Open 2015;5:e00737, Jeffs E, J Adv Nurs. 2016 Aug;72(8):1851-62).We will also double data enter at least 10% of entries to check for accuracy. We will present the results of this analysis in the paper. We have clarified this in the protocol (data quality para 3).
Reviewer: 2 Laurence Shields, MD Dignity Health Please state any competing interests or state "None declared": None Declared The idea of collecting vital sign data for pregnancy as noted is not new but the context of then using contemporary data to create data driven parameters for early warning criteria is novel and needed. The abstract is confusing as it states " we will start in august 2012" Is this an error ?
We have changed the tense to say that the study commenced in 2012again this is a function of us nearing study completion but wishing to publish the protocol before it is possible to commence data analysisas is now considered good practice.
Can the authors be more specific the position that the patient will be in when the various parameters are collected and how this may change during the course of the pregnancy.
These are contained within Appendix 7standard operating procedures.
For BP measurements they state that they will only use the first measurement, this is frequently elevated and most recommend repeat --how will this be addressed?
We need to establish the range of blood pressures found in normal practice on first measurementnot what the blood pressure may adjust to on repeat However, our methods will allow us to estimate any effect of repeated measurement (see data quality para 1).