Interpretation
There are no previous randomised trials comparing these two stimulation methods during labour induction, although the regimen has been previously described.9,14 There are also one randomised trial in which low dose oral misoprostol has been used for augmentation of spontaneous labour to accelerate slow progress.15 In that study the LDOM group had lower rates of tachysystole than the oxytocin – but there was no difference in any other maternal or neonatal outcome. On the basis of the small size of studies and the potential risks of misuse, WHO recommended that it should not be used for augmentation.16
This study supports the previous evidence that suggest that LDOM is a safe and effective method of ongoing stimulation after cervical preparation with LDOM, although the reduction in CS that had been anticipated was not achieved. Although this study was not powered for neonatal outcomes, the safety signals in special care baby unit admission and neonatal deaths are both in favour of LDOM. Safety of induction is especially important in settings where there are cases of undetected growth restriction. In this study, the three babies who died were all small (2.5kg, 1.7kg and 1.1kg) and would have been vulnerable to intrauterine hypoxia even in the absence of hyperstimulation. Given the historical concerns with misoprostol, the increased risk of this patient population, and the lack of previous studies on this method, it was important to provide close individual monitoring to detect and treat any hyperstimulation. It was not however detected in either arm. Induction with LDOM is recognised to have very low rates of hyperstimulation, equivalent to balloon catheter cervical preparation,4 so the absence of hyperstimulation in over 500 women undergoing labour induction is not surprising.
Ongoing induction with an oxytocin infusion is a complex process, and not only requires an infusion pump and intravenous set, but also close skilled supervision by an appropriately trained maternity care worker to monitor and titrate the dose. The opportunity to replace this whole process with a tablet that can be taken orally is attractive to clinical staff, labouring women and health service funders alike. Qualitative and health economic assessments to formally assess these issues have been conducted and will be published separately. However, the maternal satisfaction scales in this study suggest that replacing an intravenous infusion method with an oral tablet did not affect satisfaction rates. This mirrors the qualitative study which found that women prioritised the safety of their babies over any particular method of induction.
The simplicity of the LDOM protocol could also have adverse consequences if it encouraged labour induction or augmentation in the community or by unskilled birth attendants. There have been reports of adverse outcomes from unauthorised intrapartum use of both oxytocin and misoprostol in the community,17,18 and the rate of adverse events is likely to be worsened by the frequent confusion over dosage and routes for both agents. National health care regulators should ensure that the public and informal health care workers are informed about the risks of unregulated use of misoprostol in labour, so that woman and their babies are not put at risk.
Further research is needed to understand whether these positive results can be replicated in other settings. The simplified induction protocol using an oral medication combined with the very low rate of hyperstimulation makes use of LDOM particularly attractive for low resource settings where fetal monitoring and close intrapartum medical supervision cannot be guaranteed for monitoring and titration of the oxytocin dose. LDOM is also an attractive protocol for high resource settings where de-medicalisation of maternity care is valued by many and there are fewer concerns regarding its unregulated use by informal health care workers.
CONCLUSIONS
In this study of ongoing labour induction after cervical preparation with LDOM and membrane rupture, the use of LDOM as an alternative to oxytocin infusion did not reduce the need for caesarean section. No cases of uterine hyperstimulation were seen in either group and the maternal and neonatal outcomes were reassuring with LDOM. Satisfaction rates in both groups were high and comparable, even though the time to birth was, on average, 31 minutes longer with LDOM than with oxytocin. We conclude that ongoing labour induction with LDOM is a safe and effective option after cervical preparation with LDOM and membrane rupture.
ADDITIONAL INFORMATION
Contributors
The idea for the study evolved from the former INFORM study conducted by the same investigator group. ADW led the grant application, chaired the trial management group and wrote the first draft of the paper; he is the study guarantor. SM, HB, BF, TE, SL, MTu, ZA, BW and ADW wrote the grant application. SM was the lead investigator in India, whilst MTa, SP and PVS were the site principal investigators with local responsibility for study conduct and data collection. KL and HB (replaced in Jan 2021 by JD) were the trial managers. BF was the trial statistician and conducted the analysis. SM, KL, HB/JD, BF, BW and ADW formed the trial management committee. All authors had full access to all the data in the study and accept responsibility to submit for publication.
Data Sharing
The data from this study will be confidential until the database is closed at the end of the study. Following this the study investigators will have exclusive access to the data until the publication of the results in a journal. Once this has happened, the database will be open to other researchers upon request. Open access databases will also be sought so as to maximise the availability of our research data with as few restrictions as possible, in line with MRC and Wellcome Trust policy. The consent form included a clause for women to give their permission for anonymous data to be used for future research studies.
Declaration of Interests
Professor Weeks runs an information website called misoprostol.org on a voluntary basis which receives no income. He also acted as a scientific advisor to Norgine from 2021-2. In this role he received no personal remuneration other than travel expenses, but money was paid to the University of Liverpool for his time. The other authors declare that they have no competing interests.
Acknowledgements
Trial Steering Committee: A Shennan (Chair), L Marions, A Medina-Lara, U Sharma; Independent Data and Safety Monitoring Committee: D Elbourne (Chair), A Muthal-Rathore, J Vogel, C Sutton. We thank the MRC, Wellcome Trust, NIHR and UK government for providing funding for the study through the Joint Global Health Trials scheme.
Ethics approval and consent to participate
This trial underwent peer review as part of the funding process. It is sponsored by the University of Liverpool (Brownlow Hill, Liverpool L69 7ZX, UK; UoL001374) which oversees the study quality and has final responsibility for the study conduct. The study was approved by the Institutional Ethics Committees at Government Medical College Nagpur (1724 EC/Pharmac/GMC/NGP), Spandan Heart Institute and Research Center (MOLI Study), the Mahatma Gandhi Institute of Medical Sciences (MGIMS/IEC/OBGY/96/2020) and the University of Liverpool (UoL001374). The study is insured by the sponsor (for harm arising from protocol design) and by the recruiting sites (for clinical negligence). The study is registered with ClinicalTrials.gov (NCT03749902) and Clinical Trial Registry, India (CTRI/2019/04/018827). All women enrolled in the trial provided informed written consent.
REFERENCES
1. World Health Organization, United Nations Children’s Fund (UNICEF) & United Nations Population Fund. (2023). Improving maternal and newborn health and survival and reducing stillbirth: progress report 2023. World Health Organization.
2. World Health Organization. WHO recommendations for induction of labour. Geneva: World Health Organization; 2011.
3. National Institute of Clinical and Care Excellence (NICE). Inducing Labour (NICE Guideline NG207). NICE, November 2021.
4. Kerr RS, Kumar N, Williams MJ, Cuthbert A, Aflaifel N, Haas DM, Weeks AD. Low-dose oral misoprostol for induction of labour. Cochrane Database of Systematic Reviews. 2021 Jun 22;6(6):CD014484.
5. Alfirevic Z, Keeney E, Dowswell T, Welton NJ, Dias S, Jones LV, Navaratnam K, Caldwell DM. Labour induction with prostaglandins: a systematic review and network meta-analysis. BMJ. 2015 Feb 5;350:h217.
6. World Health Organization. Reproductive Health. Managing complications in pregnancy and childbirth: a guide for midwives and doctors. 2nd edition. World Health Organization; 2017.
7. Dujardin B, Boutsen M, De Schampheleire I, Kulker R, Manshande JP, Bailey J, Wollast E, Buekens P. Oxytocics in developing countries. International Journal of Gynecology & Obstetrics. 1995 Sep 30;50(3):243-51.
8. Lovold A, Stanton C, Armbruster D. How to avoid iatrogenic morbidity and mortality while increasing availability of oxytocin and misoprostol for PPH prevention? International Journal of Gynaecology & Obstetrics. 2008 Dec;103(3):276-82.
9. Hofmeyr GJ, Alfirevic Z, Matonhodze B, Brocklehurst P, Campbell E, Nikodem VC. Titrated oral misoprostol solution for induction of labour: a multi‐centre, randomised trial. BJOG: An International Journal of Gynaecology & Obstetrics. 2001 Sep 1;108(9):952-9.
10. Bracken, H., Lightly, K., Mundle, S., Kerr, R., Faragher, B., Easterling, T., Leigh, S., Turner, M., Alfirevic, Z., Winikoff, B., & Weeks, A. (2021). Oral Misoprostol alone versus oral misoprostol followed by oxytocin for labour induction in women with hypertension in pregnancy (MOLI): protocol for a randomised controlled trial. BMC Pregnancy and Childbirth, 21(1), 537.
11. Hofmeyr, GJ, et al. Methods for cervical ripening and labour induction in late pregnancy: generic protocol. The Cochrane Library (2009).
12. Dos Santos F, Drymiotou S, Antequera Martin A, Mol BW, Gale C, Devane D, Van’t Hooft J, Johnson MJ, Hogg M, Thangaratinam S. Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study. BJOG: An International Journal of Obstetrics & Gynaecology. 2018;125(13):1673-1680.
13. O’Brien, PC, Fleming, TR. A Multiple Testing Procedure for Clinical Trials. Biometrics. 1979 35 (3): 549–556.
14. Dallenbach P, Boulvain M, Viardot C, Irion O. Oral misoprostol or vaginal dinoprostone for labor induction: a randomized controlled trial. American Journal of Obstetrics and Gynecology 2003;188(1):162-7.
15. Ho M, Cheng SY, Li TC. Titrated oral misoprostol solution compared with intravenous oxytocin for labor augmentation: a randomized controlled trial. Obstetrics and Gynecology. 2010 Sep;116(3):612-618.
16. World Health Organization. WHO recommendations for augmentation of labour. Geneva: World Health Organization; 2014.
17. Forna F, Titulaer P, Sesay S, Conteh S, Muoghalu S, Kanu P, Moses F, Kenneh S, Kayita J. Prevalence of use of highly concentrated oxytocin or ”pepper injection” in labor among clinicians undergoing emergency obstetric training in Sierra Leone. International Journal of Gynecology & Obstetrics. 2020 Dec;151(3):450-455.
18. Kujabi ML, Mikkelsen E, Housseine N, Obel J, D’Mello BS, Meyrowitsch DW, Hussein K, Schroll JB, Konradsen F, van Roosmalen J, van den Akker T, Maaløe N. Labor augmentation with oxytocin in low- and lower-middle-income countries: a systematic review and meta-analysis. American Journal of Obstetrics and Gynecology Global Reports. 2022 Oct 21;2(4):100123.