Planned delivery to improve postpartum cardiac function in women with preterm pre-eclampsia: the PHOEBE mechanisms of action study within the PHOENIX RCT

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Chapter 1 Introduction

Pre-eclampsia affects 3–5% of pregnancies, complicating approximately 35,000 pregnancies in the UK every year. Cardiovascular disease is the leading cause of mortality in women in the UK. 1 Hypertensive disorders of pregnancy, in particular preterm pre-eclampsia, have been shown to be associated with an increased risk of development of a wide range of cardiovascular diseases, with increases in incidences observed as soon as 1 year postpartum. 2 The absolute risk that a woman with pre-eclampsia would develop a cardiovascular event including hypertension, ischaemic heart disease, stroke or venous thromboembolism when she reaches the age of 50–59 years is estimated to be 17.8%, compared with 8.3% in those without pre-eclampsia. 3 The American Heart Association now recognises pre-eclampsia as an independent risk factor for future cardiovascular disease. 4 The economic burden of cardiovascular disease is substantial; the British Heart Foundation estimated that in 2006 cardiovascular disease cost the NHS £14.3B and the UK economy £30.6B,5 and the cost for EU health-care systems related to cardiovascular disease is estimated at €110B, approximately 10% of the total health-care expenditure across the EU. With an increasingly ageing population, costs are set to rise further.

To date, only case–control studies and small single-centre cohort studies exist to provide evidence of association between pre-eclampsia and persistent cardiovascular dysfunction. Although some women have pre-existing risk factors for pre-eclampsia that also predispose to cardiovascular disease and for whom pre-eclampsia may accelerate progression through adding a further stress, in others, pre-eclampsia occurs with no pre-existing factors and may be the first ‘hit’ in the pathway. The most likely explanation for the additional impact from pre-eclampsia is subclinical myocardial injury caused by the underlying pathophysiology. This proposed research seeks to elucidate the role and extent of myocardial stress in determining subsequent cardiac dysfunction.

The Pre-eclampsia in HOspital: Early iNductIon or eXpectant management (PHOENIX) study, a multicentre randomised controlled trial, recruited women with late preterm pre-eclampsia who were 34 weeks’ gestation to less than 37 weeks’ gestation and having a singleton or dichorionic diamniotic twin pregnancy. 6 It demonstrated that initiation of planned delivery within the subsequent 48 hours after randomisation reduced severe maternal adverse outcomes with no difference in neonatal morbidity (but there were more neonatal unit admissions) compared with the current practice of expectant management until 37 weeks’ gestation. This PHOENIX study provided a key opportunity to examine the mechanisms underlying cardiovascular dysfunction following a randomised intervention on timing of delivery. An associated editorial alongside the main trial publication questioned whether initiating delivery in late preterm pre-eclampsia rather than waiting until term might theoretically reduce the stress on the woman’s cardiovasculature. 7 The editorial advised evaluating whether or not a change to active delivery of women with late preterm pre-eclampsia would also benefit maternal cardiovascular health in the long term.

We conducted a follow-up cardiovascular assessment of women eligible for the PHOENIX study to examine the hypothesis that planned delivery in women with preterm pre-eclampsia, with attendant myocardial ischaemia, may decrease the risk of the development of cardiovascular dysfunction following pregnancy. The main aim of this mechanistic study was to examine the effects of shortening pregnancy complicated by pre-eclampsia on cardiovascular function at 6 months postpartum by studying women enrolled in a randomised controlled trial of planned delivery compared with those undergoing usual care (expectant management) who had late preterm pre-eclampsia.

Chapter 2 Methods

Chapter 3 Results

Between 27 April 2016 and 30 November 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited, across 28 maternity units in England and Wales. A total of 133 women were allocated to planned delivery, 137 women were allocated to expectant management and a further 150 received non-randomised expectant management (Figure 1).

FIGURE 1.

Participant flow chart. a, 28 women did not receive initiation of planned delivery within 48 hours due to clinical decision (n = 2), labour ward being too busy (n = 15), a shortage of neonatal cots (n = 5), or other reasons (n = 6).

For the intention-to-treat analysis, data from 100 women in the planned delivery group and 107 women in the expectant management group were included. Follow-up to the 6-month postpartum assessments continued until 20 June 2019. Thirty-three (25%) women were lost to follow-up in the planned delivery group and 30 (22%) in the expectant management group (see Figure 1). Baseline characteristics appeared similar between the two groups, with groups well balanced on minimisation factors (Table 1).

The enrolment characteristics are shown in Table 2.

There were no differences between women in the planned delivery group compared with the expectant management group in the primary outcome using either the 200910 [risk ratio (RR) 1.06, 95% confidence interval (CI) 0.80 to 1.40] or the 2016 definition11 (RR 0.78, 95% CI 0.33 to 1.86), shown in Table 3. No between-group differences were observed in 2009 diastolic dysfunction grade 1 (RR 1.40, 95% CI 0.59 to 3.31), grade 2 (1.11, 95% CI 0.78 to 1.57) or grade 3 (1.18, 95% CI 0.08 to 18.43) diastolic dysfunction subclassification nor in 2016 diastolic dysfunction classification. Overall, 10% (31/321) of women had a left ventricular ejection fraction < 55% 6 months postpartum. Similarly, using the more recent 2016 classification for systolic and diastolic dysfunction, no differences were observed in systolic (RR 0.76, 95% CI 0.32 to 1.80) or any of the diastolic dysfunction parameters. Hypertension prevalence, defined as on antihypertensive treatment with or without systolic blood pressure > 140 mmHg and with or without diastolic blood pressure > 90 mmHg at 6 months postpartum, was similar between those managed with planned delivery and those expectantly managed (RR 1.01, 95% CI 0.85 to 1.20) but, overall, was present in 71% of the cohort. No significant differences were observed in any of the cardiac parameters including geometric and haemodynamic parameters, left ventricular global cardiac parameters, myocardial mechanics and left ventricular basal or apical parameters between those women with planned delivery and those who were expectantly managed (see Table 3). The high prevalence of systolic and/or diastolic dysfunction or persistent hypertension was not explained by pre-existing chronic hypertension because when these women were excluded (n = 37, 11%), systolic and/or diastolic dysfunction was evident in 49.5% of women and hypertension was evident in 68.7% of women.

Mean time from enrolment to delivery was 2.5 [standard deviation (SD) 1.9] days in the planned delivery group compared with 6.8 (SD 5.3) days in the expectant management group. No differences were observed between groups in cardiorespiratory outcomes prior to discharge from hospital nor in any systolic or diastolic blood pressure measurements (Table 4).

The only variables affecting development of systolic and/or diastolic dysfunction at 6 months postpartum (2009 definition)10 were maternal BMI [adjusted odds ratio (OR) 1.33 per 5 kg/m², 95% CI 1.12 to 1.59 per 5 kg/m²] and maternal age (adjusted OR 2.16, 95% CI 1.44 to 3.22 per 10 years) (Table 5). Interval from study enrolment to delivery was not associated with development of the primary outcome. There were no significant predictor variables for systolic and/or diastolic dysfunction at 6 months postpartum by the updated 2016 definition11 (Table 6). Inclusion of antenatal values of highly sensitive cardiac troponin-I did not alter the results. All women in the planned delivery group received the trial intervention, although this was not always initiated within 48 hours as intended. Of the women allocated to the planned delivery group, 105 out of 133 (79%) had delivery initiated within 48 hours (see Figure 1).

Overall, 8% (n = 25) of women had their clinical echocardiograms escalated by the trial cardiologist with clinical follow-up recommended. These were for a combination of structural (n = 8), valvular (n = 8), functional (n = 9) or combined (n = 2) findings. These clinical escalations accounted for 12% of those with the primary outcome, with 88% of those with systolic and/or diastolic dysfunction not requiring clinical escalation.

Chapter 4 Discussion

In this randomised controlled trial of women with late preterm pre-eclampsia, planned delivery did not reduce cardiovascular dysfunction at 6 months postpartum. The adverse cardiovascular sequelae of preterm pre-eclampsia are substantial; 10% of women with preterm pre-eclampsia had a left ventricular ejection fraction < 55%, 71% remained hypertensive and 49% of women had evidence of impaired diastolic dysfunction of undetermined long-term clinical importance 6 months postpartum. Women in the planned delivery group had a median shortening of pregnancy from enrolment to delivery of 4 days, but this did not result in decreased hypertension or cardiovascular dysfunction compared with those managed with usual care by expectant management. Only elevated BMI and higher age at enrolment predicted the occurrence of postpartum systolic and/or diastolic dysfunction.

Previous systematic reviews and meta-analyses describe an association between pregnancies complicated by pre-eclampsia and long-term adverse cardiovascular morbidity and mortality including hypertension, myocardial infarction (13-fold increase), major cardiovascular events (13-fold increase), heart failure (eightfold increase), stroke (14-fold increase) and death (sixfold increase). We are unaware of any published randomised controlled trials evaluating the impact of timing of delivery on subsequent maternal cardiovascular function. This large, multicentre trial represents contemporaneous management of women with late preterm pre-eclampsia followed up by detailed standardised blood pressure and echocardiography assessment at 6 months postpartum. Our cohort sample size (321 women) is, to our knowledge, considerably larger than that of any other postpartum cardiovascular study previously performed, and the involvement of 28 centres throughout the UK makes this representative of the UK pregnant population. The randomised design allowed us a unique opportunity to explore the impact of timing of delivery on postpartum cardiovascular function.

The strengths of this study include a sufficiently large sample of women with late preterm pre-eclampsia from 28 centres throughout the UK completing a detailed 6-month postpartum cardiovascular assessment to describe the burden of cardiovascular disease in this population, linking pre-eclampsia with longer-term cardiovascular disease. The trial was conducted to rigorous standards, with a prespecified protocol without changes. The findings are likely to be generalisable to similar health-care settings because it was undertaken in a large number of maternity units across England and Wales, with a diverse representation of women in terms of both demography and disease spectrum. More than half of the eligible women who were approached agreed to participate in the trial, which indicated agreement of equipoise in this scenario. Echocardiography was performed by multiple echocardiographers throughout England and Wales, representative of cardiology units throughout the NHS. We have reported all prespecified secondary outcomes, interpreting them cautiously.

The limitations of the trial include a change in the international definition of systolic and/or diastolic dysfunction, such that interpretation of the findings needs to be undertaken in the light of the prespecified 2009 definition10 and the later 2016 definition. 11 Our results reflect systolic and diastolic definitions used first in 2009 and which were then updated in 2016. We acknowledge that there is an interim group with a left ventricular ejection fraction between 50% and 55% and further prospective follow-up would help our understanding of the implications of this impairment in women following pregnancy. We, a priori, utilised the independent definition of systolic and/or diastolic dysfunction for this particular patient group as defined by Melchiorre et al. ,24 adapted from recommendations of the European Association of Echocardiography and American Society of Echocardiography10 with adjustments for age, the higher circulating volume in pregnancy and the acute nature of pre-eclampsia in an otherwise previously normal cardiovascular system. 24 Newer non-pregnant specific definitions (ASE/EACVI guidelines 2016)11 result in lower prevalence of diastolic dysfunction if applied, but cardiovascular morbidity is still evident and prevalent. There was a relatively short difference of a median 4 days in those managed with planned delivery than in those managed expectantly, and it is likely that this difference may not have been sufficiently long to result in detectable differences in cardiovascular function at 6 months postpartum. Approximately one-third of the women recruited for this study had declined participation in the PHOENIX study and as a result were included as a non-randomised expectant management (usual-care) group. Results across all groups were very similar. We did not recruit women with a healthy pregnancy, as our primary research question was whether or not shortening of pregnancy after diagnosis of preterm pre-eclampsia altered the prevalence of cardiovascular dysfunction at 6 months postpartum.

We considered sources of possible bias for our trial. Selection bias into the trial was unlikely because of the randomisation process, which included robust allocation sequence concealment such that determining the next allocation was not possible. Performance and detection bias were possible because it was not possible to mask the participating clinicians, the participating women or the data collectors because the timing of delivery was contained within maternity records where morbidity was recorded. However, the trial echocardiographer was masked to randomisation groups and each echocardiogram was therefore read independent of the knowledge of trial allocation.

There was expected attrition to the 6-month follow-up of around 20% in both groups, but data completeness of pregnancy outcomes was high (> 99%). The study was originally powered for an analysis of 322 women (161 women in two treatment groups). However, it became apparent that a group of eligible women chose not to consent to the main randomised comparison in the PHOENIX study but would consent for the observational PHOEBE study, with all women in this group following usual care, which was expectant management. The aims of the PHOEBE study were primarily to explore the mechanism behind the effect of the intervention (timing of delivery) and to provide an understanding of postpartum cardiovascular dysfunction after preterm pre-eclampsia. We acknowledge that this study was underpowered for examining the effect of the intervention. The primary outcome event rate was also lower than expected by both 200910 and 2016 guidelines. 11 For the evaluation of the effect of the intervention, the two randomised groups were compared. As there was no signal of a significant effect in the secondary outcomes that would suggest that we had missed an important difference in the primary outcome (likely to be related to the much shorter separation in time between randomisation and initiation of delivery between the two groups than anticipated), we also combined all women recruited to provide an overall cohort of 321 women in which to complete the prognostic assessment (see Table 5) and to present a detailed cardiovascular assessment on a large prospective cohort of women with preterm pre-eclampsia.

A recent systematic review summarised 36 studies of maternal cardiovascular function involving 815 women at time of disease with pre-eclampsia. This study demonstrated that increased vascular resistance and left ventricular mass were the most consistent findings in pre-eclampsia. 38 Differentiating features of a pregnancy complicated by pre-eclampsia from normal pregnancy include left ventricular wall thickness of ≥ 1.0 cm, exaggerated reduction in early diastole/atrial contraction and lateral e′ of < 14 cm/second, which are the markers of diastolic dysfunction. Reduced stroke volume, diastolic dysfunction and left ventricular remodelling are most marked in severe and early-onset pre-eclampsia. 24,35,39 Our finding of cardiovascular dysfunction and persistent hypertension in the majority of women following preterm pre-eclampsia is in keeping with other single-centre observational studies. 40–49 However, none was multicentre nor designed to examine different maternal delivery strategies. Our finding of 71% of women with preterm pre-eclampsia remaining hypertensive 6 months postpartum is higher than reported in larger population-based cohorts, highlighting high levels of presumed undiagnosed hypertension. 50 As the PHOENIX study has now reported, it is unlikely that the opportunity will arise for other investigators to examine whether or not timing of delivery has an impact on cardiovascular function using such a randomised approach. Developing accurate validated prognostic tools to best identify those at highest risk of cardiovascular dysfunction remains challenging, and postpartum intervention strategies must now be explored to reduce this cardiovascular burden of disease.

We have demonstrated that the burden of postpartum cardiovascular dysfunction following preterm pre-eclampsia in these women, not otherwise identified as having morbidity, is high. In low-resource health-care settings and developing countries where underdetected comorbidities including chronic hypertension are high and cases of fulminant eclampsia prevalent (incidence 1.4%),51 the burden of cardiovascular morbidity is likely much higher. Recent US data suggest stagnation in the improvements in incidence and mortality of cardiovascular disease, specifically among younger women. 52 It is imperative that we understand the mechanisms that contribute to worsening risk factor profiles in young women to reduce future cardiovascular morbidity and mortality. This is acknowledged in the 2030 Agenda for Sustainable Development,53 which aims to reduce by one-third premature mortality from non-communicable diseases, with cardiovascular disease being the leading cause of death from such diseases.

Two decades of research have documented an association between pre-eclampsia and major cardiovascular disorders in later life. 2,3,54,55 Despite this body of evidence, usual practice after a pregnancy complicated by preterm pre-eclampsia is no specific follow-up. It is recognised by the Joint British Societies, which includes the British Cardiac Society, Heart UK and the British Hypertension Society, that pregnancy and infancy are good opportunities for education and intervention. 56 Furthermore, they endorse intensive risk factor lowering in individuals with high risk factors that cause cardiovascular disease. Women with preterm pre-eclampsia are at increased risk of cardiovascular disease later in life compared with those without preterm pre-eclampsia. In addition, compared with women without hypertension in pregnancy, women who have had one or more pregnancies affected by pre-eclampsia have been shown to have an increased hazard ratio of 1.9 (95% CI 1.53 to 2.35) for any stroke, 1.67 (95% CI 1.54 to 1.81) for cardiac atherosclerotic events, 1.82 (95% CI 1.34 to 2.46) for peripheral events, 2.13 (95% CI 1.64 to 2.76) for heart failure, 1.73 (95% CI 1.38 to 2.16) for atrial fibrillation, 2.12 (95% CI 1.49 to 2.99) for cardiovascular deaths and 4.47 (95% CI 4.32 to 4.62) for chronic hypertension. 2 This study has provided mechanistic information on how subsequent clinical cardiovascular events may be mediated through impaired cardiac function identifiable at 6 months after preterm pre-eclampsia and highlights the postpartum period as an opportunity for early intervention prior to sustained and irreversible damage. There is increasing interest in the role of lifestyle and therapeutic interventions (e.g. with angiotensin-converting enzyme inhibitors) to reduce subsequent cardiovascular risk. This study provides a body of evidence for postpartum cardiac functional impairment and demonstrates the need for further research into early intervention, particularly relating to novel therapeutic pathways.

In conclusion, our study confirms that late preterm pre-eclampsia is associated with substantial postpartum cardiovascular dysfunction. The relatively short delay in those expectantly managed (compared with planned delivery) does not worsen this cardiovascular dysfunction. Ten per cent of women with preterm pre-eclampsia had a left ventricular ejection fraction < 55%, 71% remained hypertensive and 49% of women had evidence of impaired diastolic dysfunction of undetermined long-term clinical importance 6 months postpartum. Further follow-up would be useful to understand the longer-term cardiovascular implications of these findings and whether these parameters relate to hypertension, age or increased BMI. Pre-eclampsia should not be considered a self-limiting disease of pregnancy alone. This research improves our understanding of the mechanistic processes linking pre-eclampsia with maternal cardiovascular impairment. The evidence suggests that expectant management of preterm pre-eclampsia does not worsen postpartum cardiovascular dysfunction, and women can be reassured that prolongation of a pregnancy affected by preterm pre-eclampsia will not further worsen their cardiovascular health. The study informs counselling of women with pre-eclampsia around future risks and also identifies the postpartum period as a critical area to target in future intervention studies.

Acknowledgements

We thank Ursula Bowler and Pauline Rushby (University of Oxford); Eleanor Hendy and Emma Green (King’s College London); Linda Arnold (University of Oxford); and all the participating women, site research midwives and doctors for their contribution to the study.

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List of abbreviations

BMI

body mass index

CI

confidence interval

cTnI

highly sensitive cardiac troponin-I

FiO2

fraction of inspired oxygen

HTA

Health Technology Assessment

NIHR

National Institute for Health Research

OR

odds ratio

PHOENIX

Pre-eclampsia in HOspital: Early iNductIon or eXpectant management

RR

risk ratio

SD

standard deviation

SpO2

oxygen saturation

TDI

tissue Doppler imaging