Self-management of Postnatal Anti-hypertensive Treatment: a Trial Development Pilot Study

Hypertensive disorders of pregnancy (HDP) affect 3-15% of pregnancies. Gestational hypertension is new-onset blood pressure (BP) > 140/90mmHg after 20 weeks gestation. Pre-eclampsia is gestational hypertension with proteinuria (> 300mg / 24 hours). HDP are the second commonest direct cause of maternal death in the UK and USA, and the leading cause of maternal death in Latin America and the Caribbean.

HDP persist postpartum, and complications can occur during this time. Most women with HDP will be treatment-free by 3 months postpartum. This rapidly changing BP, with shifting medication requirement, poses a challenge in terms of how best to manage this down-titration. Both NICE guidelines and a Cochrane review highlight that few clinical studies have addressed the management of BP postpartum. In practice clinical care is to continue antepartum anti-hypertensive medication and monitor BP in the community with a focus on prevention of over-treatment.

Approximately 30% of eclamptic seizures occur postpartum: studies suggest that half occur more than 48 hours after birth. A case series of patients who sustained a stroke in association with HDP, showed that more than half occurred postpartum.

Severity of hypertension in later life may be predicted by BP during the first 6 weeks postpartum. Several retrospective cohort studies and a meta-analysis have suggested that HDP are associated with an increased risk of future cardiovascular disease (CVD) in the mother. The 2011 American Heart Association guidelines for the prevention of CVD in women cite a history of HDP as a major risk factor for CVD, and advocate enquiring about pregnancy complications during the evaluation of CVD risk.

Home BP readings have been shown to be more strongly related to indices of target organ damage and have better prognostic value in essential hypertension than office BP measurement. Voluntary home BP monitoring by patients with essential hypertension is becoming increasingly common. The European and American Societies of Hypertension now recommend home BP measurement in the routine diagnosis and monitoring of essential hypertension.

Self-monitoring and self-titration of anti-hypertensive medications in essential hypertension has been shown to be both feasible and more effective than usual care. Women with HDP would seem to be an ideal cohort in whom to apply these experiences: the disease has, in general, a limited time course meaning that intensive monitoring is more reasonable and more likely to be adhered to. Pregnant women are in a younger age group than the majority of those with essential hypertension, and may be more comfortable with the use of technology to assist in disease monitoring. Women might also be more empowered in the setting of a recent pregnancy to take greater responsibility for their health.

Evidence exists to support the accuracy of home BP recordings in hypertensive pregnant women. Studies to date in antenatal women suggest a low non-concordance rate and low rate of inaccurate recordings. Studies have also suggested: better correlation between home BP recordings and indication of the need for anti-hypertensive medication; reduced number of hospital admissions in women with mild HDP who undertook home BP monitoring.

If self-management in the postpartum period proves to be feasible, acceptable and successful, it could lead to a reduction in the length of inpatient stay, readmissions and the number of postpartum visits, with cost-saving implications. Furthermore as the importance of BP control in the immediate postpartum period has already been demonstrated to affect women's CVD risk up to 15 years after delivery, any strategy, which successfully increases women's adherence to an effective treatment regimen, has the potential to influence their healthcare needs well into the future.

The proposed trial aims to apply the research experience regarding self-management in essential hypertension to postpartum women with HDP where both high and low BPs can lead to adverse outcomes, and where detection of on-going hypertension is essential. This study is a pilot study: it has been set up in order to inform the planning of a large-scale multi-centre randomised controlled trial by testing the feasibility of methods and procedures for later use on a large scale. We want to increase our experience of applying this management approach in this subset of patients; to select the most appropriate primary outcome measure and to estimate the effect size of this intervention; to assess recruitment potential; and to evaluate the feasibility of coordinating this trial across several centres. The primary objective of the large-scale trial will be to determine whether the self-management approach can improve BP control in women with medicated HDP in the postnatal period.

The study is a non-blinded randomised controlled trial. To assist with recruitment numbers, and assess the feasibility of running a multi-centre trial, we are planning to run this study in several hospitals. Women who have developed HDP requiring medication will be approached during the antenatal period: they will complete an informed consent form and undertake a screening appointment. Following birth, whilst they remain in hospital, consent will be confirmed and a baseline appointment will take place. At this visit women will be randomised to one of two treatment arms: usual care, or self-management.

All women will be followed up at 10 days, 4 and 6 weeks, then 3 and 6 months postpartum and have their BP measured by one of the study team. All participants will be asked to complete the EQ-5D-5L Health Questionnaire to assess their quality of life at visits 1, 5 and 7.

At visits 2, 6 and 7 women will be weighed using a standardised set of scales in order to evaluate whether the extent and speed of return to booking weight correlates with resolution of gestational hypertension.

To follow on from the work that suggests that those with above-average BP at six weeks postpartum have an approximately 30% increase in aortic stiffness, we are planning to conduct a sub-study to analyse markers of vascular risk in women from both groups. As it may be assumed that the baseline characteristics of the two groups are then similar, if we demonstrate a treatment effect from the intervention, then it will allow us to analyse the relationship between BP control in the postnatal period and markers of vascular risk to help determine if it is the severity of pathology or effectiveness of control that determines long term outcome. Women will consent to an optional extended visit at baseline and 3 months where measures of arterial stiffness and microvascular changes will be taken (cardio-ankle vascular index, radial arterial tonometry and capillaroscopy). We will take a blood sample to measure circulating biomarkers relevant to cardiovascular health and pre-eclampsia. We aim to recruit a minimum of 15 women from each group.

We plan to run a second embedded sub-study to examine participants' health experiences. We aim to recruit a minimum of 50% of participants in each group. We will conduct structured interviews with participants in both arms, who consent to participate in the qualitative sub-study, to assess their experience of either usual care or self-management of BP in the postnatal period, and to identify and explore factors related to the successful (or unsuccessful) implementation of the intervention. This study will provide data regarding the views of patients as to the acceptability of self-monitoring in the routine management of gestational hypertension and pre-eclampsia after birth once they have been discharged from hospital. Baseline data (5 questions) will be collected at visit 1. The structured interviews will be done at visits 4 and 7, and will take 10-15 minutes on each occasion. There will be 5 questions for both groups, and an additional 5 questions for the intervention group. Structured responses will be entered on to a pre-coded scoring sheet. Free text responses will be audio-recorded.

Safety reporting will be from baseline to the 26 week follow up visit. Adverse events may be recorded by the participant using the trial telephone number, email, or via the text message service or smart phone app. Participants will be directly asked about adverse events at each study visit. All serious adverse events, whether 'expected' or 'unexpected', need to be reported. All serious adverse event (SAE) information will be recorded on the Primary Care Clinical Trials Unit (PC-CTU) SAE report form by the site or the Chief Investigator (CI) and faxed to the PC-CTU dedicated fax line. SAEs will be reported to the PC-CTU as soon as possible, preferably within 24 hours. The PC-CTU will perform an initial check of the report, request any additional information from the reporting clinician and ensure that the CI or safety delegator reviews and evaluates the report for expectedness and relatedness. All SAE reports will also be reviewed routinely by the Independent Safety Review Committee. All SAEs will be followed up until resolution or the end of the study period.

A SAE occurring to a participant should be reported to the REC and Sponsor where in the opinion of the Chief Investigator the event was 'related' (resulted from administration of any of the research procedures) and 'unexpected' in relation to those procedures. Reports of related and unexpected SAEs should be submitted within 15 working days of the CI becoming aware of the event.

A formal sample size calculation is not required for this pilot study. The analysis will be carried out on the basis of intention-to-treat. The analyses for this pilot study will be primarily descriptive and will not include any hypothesis testing or presentation of P-values for group comparisons. Continuous variables will be reported as means with standard deviations (or medians with Interquartile ranges if skewed). Categorical variables will be reported as counts and percentages. Differences between groups will be calculated and described with 95% confidence intervals only and will not include significance tests with P-values.

The delivery of the intervention will involve patient home visits. To facilitate these visits the study team will require access to patient identifiable data. The consent from will clearly list the data to be collected and for what purpose. The identifiable data will be held securely at the PC-CTU, separately from other trial data, with access to this data restricted to appropriate members of the study team identified on the delegation log. Identifiable data will be anonymised as soon as no longer required.

All study data required for analysis will be recorded on paper Case Report Forms (CRFs) and returned to the study team for data entry. CRFs will be held securely in locked filing cabinets, located within office space with restricted entry. All data points will be transferred from paper CRFs to a secure database management system (CDMS) hosted by the PC-CTU. Within the CDMS patients will be identified solely by a unique study identification number. No patient identifiable data will be held within the CDMS. At the conclusion of the trial, following database lock and final analysis all documents will be appropriately archived for at least five years.

The CI will ensure the study is conducted in accordance with the current approved protocol, PC-CTU SOPs and all applicable local and national guidelines and regulations. The PC-CTU has conducted a risk assessment prior to study commencement, which will inform the level and nature of monitoring required for this study. Direct access will be granted to authorised representatives from the Sponsor or host institution for monitoring and/or audit of the study to ensure compliance with regulations.

A Trial Management Group will be established to support the CI in overseeing the progress and conduct of the study.