Cervical Pregnancy Clinical Trial
Official title:
Medical Management of Late Intrauterine Death Using a Therapeutic Combination of Isosorbide Dinitrate and Oxytocin.
The purpose of this study is to assess the therapeutic efficacy and safety of isosorbide dinitrate-oxytocin in combination in the management of late intrauterine foetal death.
A prospective, randomised, double-blind, controlled clinical trial (RCT) was conducted to
compare the efficacy and clinical safety of the induction of labour using the combination of
isosorbide dinitrate-oxytocin (experimental arm, X = 1) compared to misoprostol-oxytocin
(standard arm, X = 0). The main result of the study was the success rate of foetal expulsion
within 15 hours, while the average administration induction interval defined the secondary
result. A total of 60 women with pregnancies greater than 20 weeks gestation were referred
for foetal evacuation. We defined late intrauterine foetal death (IUFD) as babies without
signs of life in the uterus after 20 complete weeks of pregnancy. The approval to conduct
the study was obtained from the institutional board ethical committees of both hospitals.
All participants were informed about the objectives of the study, and informed consent was
required. Patients with the following characteristics were included: closed cervix without
evidence of cervical dilation or baseline uterine activity, A Bishop score of <5, having
intact membranes, gestation greater than or equal to 20 weeks established by the date of
menstruation or by fetometry and ultrasound-confirmed late IUFD. This study did not include
the medical management of multiple pregnancies, IUFD after late foeticide or the management
of specific medical conditions associated with an increase in the risk of IUFD or patients
with a history of hypertension, along with women with a history of unexplained antepartum
haemorrhage, pelvic dystocia or any another counter-indications where medications were used.
Patients were assigned through a computational random number generator to receive isosorbide
dinitrate or misoprostol. Allocation to groups was predetermined and arranged in numerical
order. All participants were given a vaginal exam by the same person, who was blinded to the
treatment allocation. The medications were administered in the posterior fornix, and
cervical activity was evaluated at baseline and every 3 hours to monitor any change based on
the Bishop score.
If the cervical conditions did not change after the treatment application, participants
received a new dose, without exceeding 4 doses, to facilitate cervical ripening. Once a
Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution
beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and
doubling the dose every 15 minutes. The labour induction time from the first application of
medication to the expulsion of the foetus was determined with a digital stopwatch. Each
woman's vital signs were verified to determine that she was in stable condition and
demonstrated haemodynamic stability as a requirement for the application of a new dose.
During this time, the data and medical information were collected on paper and were later
entered into a computational database. The participants remained at rest during the
evaluation of adverse effects, such as headache, abdominal pain, pelvic pain, lower back
pain, nausea, dizziness, and vomiting. The lack of cervical activity after 4 doses of
medication was considered treatment failure.
A base solution of isosorbide dinitrate and misoprostol was prepared to obtain a
concentration of 20 micrograms per milliliter (mcg/mL) in 10% lactose solution. Serial
dilutions were performed using known concentrations in mobile phase buffer solution (150 g
ammonium acetate and 11.5 mL glacial acetic acid to 1 L water), methanol and water in a
proportion of 350:100:550, respectively. The concentration of both drugs was determined
using a ultraviolet (UV) light spectrophotometer reading at lambda 220 nm and a reference
filter of lambda 278 nm. The mean absorbance for each set of standards, controls and samples
was calculated by a standard plot curve. Computer-based curve-fitting statistical software
was employed. Peak absorption and area under the curve were taken into account to determine
stability of the pharmacological integration. Known samples of isosorbide dinitrate and
misoprostol were added to 100% glycerin to prepare the gel solution. The reagents had final
concentrations of either 80 mg of isosorbide dinitrate in 1.5 ml of gel solution or 100
micrograms of misoprostol in the same presentation.
Both solutions were packed in syringes that had the same appearance for the purpose of
keeping the physician, patient and researcher blinded. The pharmacist was the only
participant who knew the contents of the syringes. Four syringes were placed in an opaque
and sealed envelope consecutively numbered with a unique study number. The envelopes were
opened by the physician who applied the contents of the syringe, repeating the
administration every 3 hours according to the prior selection and random allocation of
patients. The entire "stock" of reagents remained stable for a period of 20 days and was
maintained at room temperature (18-25° C) before using.
The calculation of the sample size was based on the Cox regression model using the risk
quotient (log Hazard Ratio) and a 95% confidence interval (95% CI).17 To reach a power
(superiority of the clinical trial) of 80% and an α value of 0.05, with a standard deviation
of 0.5 and under the assumption that 25% of all women will fail to induce labour, the
estimated sample size required for the trial was 60 patients (30 in each arm).
All continuous variables were summarised using histograms and the measures of central
tendency before conducting the statistical analyses. The statistical analyses were performed
using the Chi-Square test, Fisher's exact test and the Mantel-Haenszel test, and Student's t
test when appropriate. The Shapiro-Wilk test was used to verify the normality of the data.
To model the time-event of labour induction after IUFD, Cox regression was utilised,
controlling for the covariates maternal age, foetal size and weight, and weeks of gestation.
The proportional hazards assumption was evaluated using the two graphed lines, which
corresponded to the survival curves (absence of crossing) and the log-log plots in the
figure. Respiratory and cardiac rate, temperature (measured orally) and systolic and
diastolic blood pressures (recorded using sphygmomanometry) were determined at baseline and
every 3 hours until the trial ended. Relative risks (RRs) and 95% CIs were estimated
utilising bivariate analysis, including non-serious adverse events among the treatment
groups. Attributable risk was calculated to determine the probability of total risk of each
adverse effect observed with the use of isosorbide dinitrate or misoprostol. All of the
tests were two-tailed, and results that had values of p < 0.05 were considered statistically
significant.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment