Abstract
BackgroundPre-eclampsia is a progressive and unpredictable complication of pregnancy and is a leading cause of maternal and perinatal death globally. The majority of these deaths occur in low and lower-middle income countries, particularly countries in Sub-Saharan Africa and South Asia. Delivery of the fetus and placenta is currently the only curative treatment option for pre-eclampsia. The timing of delivery must be carefully balanced in order to optimise both maternal and perinatal outcomes. Too early, and complications associated with early preterm birth may lead to adverse neonatal outcomes. Too late, and the disease may progress, causing serious complications such as maternal death, stroke, eclampsia, placental abruption, fetal growth restriction, and stillbirth. Accurately detecting pre-eclampsia and predicting the onset of complications is challenging, particularly in settings where resources are limited. There is a lack of evidence to guide clinicians regarding the optimal time of delivery for late preterm pre-eclampsia (between 34+0 and 36+6 weeks’ gestation), and an urgent need to evaluate interventions in regions where the main disease burden lies, rather than high income countries where fatal and serious outcomes are rare.
Methods
In this thesis, I evaluate the impact of planned delivery for pre-eclampsia between 34+0 and 36+6 weeks’ gestation on pregnancy outcomes in a low and lower-middle income setting. Prior to this, I conducted a systematic review and individual participant data meta-analysis of the current available evidence on planned delivery for late preterm pre-eclampsia, and evaluated the longer-term infant outcomes from a trial in the UK comparing planned delivery to expectant management for late preterm pre-eclampsia. I assessed the feasibility of conducting a timing of delivery trial across sites in India and Zambia, via a mixed-methods feasibility and acceptability study, and explored the language barriers to informed consent in Zambia via a qualitative study. I designed a protocol for a randomised controlled trial (CRADLE-4), comparing planned delivery to expectant management, in women with pre-eclampsia without severe features between 34+0 and 36+6 weeks’ gestation, across nine sites in India and Zambia. I coordinated the interventional phase of this trial between December 2019 and March 2022. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 hours, with a non-inferiority hypothesis (margin of 10% difference). I analysed maternal and perinatal short-term clinical outcomes between the two management groups, by intention to treat, with an additional per-protocol analysis for the perinatal outcome.
Results
The systematic review identified six randomised controlled trials, all conducted in high income countries. These were included in the individual participant data meta-analysis which demonstrated that, in high income settings, planned delivery from 34 weeks onwards, for pre-eclampsia without severe features, significantly reduces the risk of a composite maternal outcome of maternal morbidity or mortality. Planned delivery was also found to reduce the risk of an infant being born small for gestational age. However, short-term perinatal respiratory morbidity was increased by planned delivery. Two-year follow-up of infants in the largest timing of delivery trial to date (901 women across 46 maternity units in England and Wales) found a small difference in neurodevelopmental scores between the two management groups; however, the average score for infants in both groups was within the normal range.
As part of the CRADLE-4 feasibility study, I explored the disease burden associated with pre-eclampsia across four proposed trial sites in India and Zambia, alongside current management of pre-eclampsia and the acceptability of late preterm delivery to women, their families, and healthcare providers. The high prevalence of pre-eclampsia related complications observed in these settings established a need to evaluate the proposed intervention (planned delivery). I identified several barriers and facilitators to implementing the interventional phase of the trial which informed design of the main trial protocol. The CRADLE-4 Trial enrolled 565 women with late preterm pre-eclampsia across nine sites in India and Zambia. 284 women were allocated to planned delivery and 281 women were allocated to expectant management. Planned delivery was associated with a non-significant reduction in the composite maternal outcome (adjusted risk ratio 0·91, 95% CI 0·79 to 1·05). In the planned delivery group, the incidence of the primary perinatal outcome was 58 (19%) compared to 67 (22%) in the expectant management group. The adjusted risk difference for non-inferiority was -3·39% (90% CI -8·67 to +1·90; p=<0·0001 [non-inferiority]). I was therefore able to demonstrate non-inferiority of planned delivery compared to expectant management. Planned delivery was associated with a significant reduction in severe maternal hypertension (aRR 0.83, 95% CI 0.70 to 0.99) and stillbirth (aRR 0.25, 95% CI 0.07 to 0.87).
Conclusion
This thesis provides new evidence to demonstrate that planned delivery for late preterm pre-eclampsia, at sites in India and Zambia, is safe, and reduces the risk of stillbirth by 75%. Although planned delivery was not associated with a statistically significant reduction in the composite outcome of maternal mortality or morbidity, individual components were all in the direction favouring planned delivery, and a significant reduction in the incidence of severe maternal hypertension was observed. This is consistent with the synthesis of evidence from trials conducted in high income countries, which demonstrated clear maternal benefit associated with planned delivery. The pragmatic trial design, preceded by a thorough assessment of the context and community, means that the findings are likely to be generalisable to other similar settings. However, the impact of planned delivery in a broader range of settings, including more rural areas, will be important to understand prior to implementation on a wide scale. The insights gained during the feasibility and acceptability study highlight the need for continued community engagement, in order to improve awareness and understanding around pre-eclampsia and address the wider social determinants of maternal and infant health. Overall, these findings demonstrate that planned delivery for pre-eclampsia from 34 weeks onwards is an intervention that has the potential to substantially reduce perinatal mortality and maternal morbidity, in the regions of the world where improvements in maternal and infant health are most urgently required.
| Date of Award | 1 Oct 2023 |
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| Original language | English |
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| Supervisor | Andrew Shennan (Supervisor) & Lucy Chappell (Supervisor) |