A randomized trial comparing oral misoprostol alone with oral misoprostol followed by oxytocin in women induced for hypertension of pregnancy

Every year around 30 000 women die from high blood pressure in pregnancy (pre-eclampsia). In South Asia alone it is responsible for 10 000 deaths annually. Many of these deaths are preventable with timely delivery of the baby, which is the only curative treatment. Vaginal delivery is safer than caesarean section (CS) but labour induction in preeclampsia presents additional challenges. It is more difficult as mothers are often preterm and in their first pregnancies, and more dangerous as babies can be growth restricted.

Induction of labour occurs in two stages; softening and opening of the neck of the womb (cervical ripening) followed by stimulation of contractions (augmentation). Our previous study established low dose oral misoprostol (LDOM) as the optimal method for cervical ripening in the low and middle-income country (LMIC) setting, and this is now strongly recommended by the World Health Organization. Standard practice in these settings is cervical ripening with LDOM followed by augmentation using intravenous oxytocin through a gravity drip infusion (M/Ox). However, gravity drip infusions have a high potential for human error and equipment faults, so constant monitoring and accurate titration of oxytocin are essential. Excessive contractions put mothers and babies at risk; whereas inadequate contractions lead to a failed induction. Both these mechanisms could explain the high CS rate (41%) seen in our previous labour induction study 'INFORM' in India. There is an urgent need to establish a safe and effective induction method that does not rely on oxytocin for augmentation.

Avoiding oxytocin and continuing LDOM into labour for augmentation, could have numerous clinical and logistic benefits:

- A cold-chain is not required for LDOM as it is heat stable (unlike oxytocin).
- The lack of an intravenous infusion means that women will be free to mobilise in labour.
- LDOM does not need to be actively monitored or titrated against contractions. It is therefore less work-intensive than an oxytocin infusion, giving health practitioners more time to care for other aspects of the women's labour.
- The simplicity of the protocol may allow task-shifting.
- In the absence of close monitoring, an unattended patient on oxytocin could receive hours of inappropriate stimulation. In contrast, LDOM does not need constant monitoring, the stimulation will cease unless there is drug administration every 2 hours.
- There will be significant health system savings by negating the need for IV infusion pumps and continuous presence of a health practitioner.

A misoprostol-only induction protocol has been successfully used in three randomized trials in South Africa. The trial participants that received a misoprostol-only (M/M) protocol required 40% less CSs compared with those using a standard (M/Ox) protocol (15 vs 26%). Despite promise, these rates cannot be directly compared as they occurred in different trials. Indeed, no published study has ever directly compared the two protocols.

We propose a randomized superiority trial in three large government hospitals in Nagpur, India. 1000 pregnant women with hypertensive disease will be randomly allocated to use the conventional (M/Ox) protocol or the misoprostol only (M/M) protocol. The primary objective is to investigate whether a misoprostol only labour induction (M/M) protocol, compared to the standard protocol (M/Ox), can reduce the rate of CS in women undergoing labour induction for pre-eclampsia in low-income settings. We also propose a qualitative study, a situational analysis and an economic evaluation to be conducted alongside the trial. The objectives of these studies are: to explore care providers' perspectives on the potential advantages, barriers and risks of each protocol; understand current knowledge, attitudes and practices concerning induction of labour; and compare the cost-effectiveness of the protocols.

Every year approximately 30 000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure.

Low dose oral misoprostol, a prostaglandin E1 analogue, is the optimal method for labour induction in low resource settings. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion (M/Ox). Some studies have shown that you can continue oral misoprostol into active labour (M/M protocol). In the Cochrane review on labour induction, those on the M/M protocol had 42% less CSs than those on the M/Ox protocol (15% vs 26%). This protocol may also be simpler, safer and more acceptable to women. However, these two protocol have never been directly compared.

We propose a pragmatic, open-label, randomised trial to compare an M/M labour induction protocol with the standard M/Ox protocol. We will recruit 1000 women with hypertensive disease of pregnancy over 24 months in 3 Indian government hospitals. After informed consent, the treatment will be allocated using sequentially numbered, sealed envelopes. The M/M group will be induced using oral misoprostol tablets (25 mcg) every 2 hours for a maximum of 12 doses, with artificial rupture of membranes (ARM) once in active labour. In the M/Ox arm, the misoprostol will be replaced with an intravenous oxytocin infusion following ARM if a good contraction pattern hasn't established.

The primary outcome will be caesarean section. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and the relative cost-effectiveness. The Mother-Generated Index will be used to assess satisfaction alongside individual in-depth interviews with staff and patients. A situational analysis will explore health providers' knowledge, attitudes and practices regarding the use of uterotonics in labour in two districts adjacent to Nagpur.

Who might benefit from this research?

This research to establish the optimal induction labour method in LMIC is critical to preventing morbidity and mortality from pre-eclampsia. Approximately 30,000 women die every year from preeclampsia, and many more suffer complications or stillbirth. Virtually all these deaths take place in LMICs, and could be prevented with prompt delivery, the only cure for the disease. This depends on having a safe, effective induction protocol that is acceptable to women, cost-effective and widely available.

Research has previously focussed on the higher cost prostaglandins. However it is clear that the global burden of pre-eclampsia cannot be reduced unless low-cost solutions are developed to assist those who cannot afford expensive medications. Misoprostol is an effective low cost solution to this problem, but has not been available in a suitable form. Recently, however, a low cost, high quality oral misoprostol 25mcg tablet has been produced (Cipla, Mumbai) for labour induction, making effective induction methods available to vast numbers of poorer Indian women. If we can demonstrate the effectiveness of an 'all oral misoprostol' induction regimen, it will allow labour induction to be conducted at a lower level of health facilities. In this way it could reach the very poorest in society, those most vulnerable to the complications of pre-eclampsia.

The large numbers in the study and the use of intravenous infusion pumps for the oxytocin in the M/Ox arm will make the results generalisable beyond LMICs. If effective, it will also benefit women in richer settings who, understandably, would prefer a method of induction in which vaginal drug administration, intravenous cannulation and restrictive infusion sets are avoided. The results will also be of great interest to those who fund health services, as an effective, low cost induction method would be welcomed worldwide.

How might they benefit from this research?

This research has the potential to save the lives of many mothers and babies around the world. Moreover, with the centrality of women to family life throughout the world, the impact of a maternal life saved spreads far beyond that woman to her children, family and community. Developing strategies to prevent maternal death is therefore highly cost effective as a public health intervention.

Caesarean section in LMIC settings carries high risks of morbidity and mortality, especially so in pre-eclampsia when mothers can already be critically unwell. Any intervention that reduces caesarean section will benefit mothers by averting complications such as sepsis, haemorrhage, anaesthetic complications, and risks in future pregnancies.

Intrapartum oxytocin infusions are recognised to be associated with poor fetal outcomes [18]. This is related to the need for constant titration against effect, as well as the potential for overdose unless carefully monitored. Low dose oral misoprostol (LDOM) has the potential to be far safer for these vulnerable, often growth restricted fetuses, thus reducing rates of both stillbirth and cerebral palsy that can result from intrapartum hypoxia.

Oral dosing and the freedom to mobilize in labour are additional benefits to women themselves. A LDOM protocol may be less work-intensive, giving health practitioners more time to care for other aspects of the women's condition. The implementation of a misoprostol-only protocol has logistical advantages: no cold chain is required, and there are greater opportunities for task-shifting within facilities. This could increase access to this key intervention. Health systems could make significant savings by negating the need for intravenous infusion pumps, the continual presence of a highly trained health practitioner and reduced resources required for caesarean sections. If so, then it will also release resources for other health care interventions and other parts of the health system.