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.
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