The retrospective questionnaire indicated that product availability and accepted clinical practice dictate different standards of care in each country. The following comparators were designated by the clinical experts:
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1.
Austria: DVI, Dtab, oxytocin;
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Poland: Dgel, oxytocin, Foley catheter;
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3.
Romania: oxytocin;
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4.
Russia: Dgel; oxytocin;
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Slovakia: Dtab; Dgel.
In all countries except Romania, prostaglandins were considered the SOC in the IOL. Oxytocin was used in almost all cases of IOL in Romania as first line therapy (without prior prostaglandins use). Despite the limitations of oxytocin, it was still used by obstetricians in Austria, Poland, Russia and Romania. In the latter, oxytocin was the only option considered for IOL before the launch of MVI.
Results of the Literature Review
From the literature search, 11 RCTs out of 26 studies were included in the literature review and data synthesis (Wing [9], Facchinetti [10], [11], Marconi [12], Stewart [13], Strobelt [14], Rabl [15], Cromi [16], [17], Edwards [18], Jóźwiak [19]) (Table 1). Although Cromi [16] concerned a double balloon catheter, the study was included, since it was shown that there were no significant differences in effectiveness or safety of ripening with a double balloon catheter when compared to Foley catheter [20, 21]. Further details on literature review search strategy can be found in supplementary material (S1).
Table 1 Evaluation of studies homogeneity included to literature review
For time-to-event end-points, only trials reporting both time to delivery and time to active labor/labor onset were included in the data synthesis and statistical calculations. This approach ensured reliability of the results. Therefore, trials which assessed only one of the end-points were excluded from the calculations because of the risk of potential bias on the model results. The following trials were eligible for statistical analysis: Wing [9], Facchinetti [11], Rabl [15], Cromi [16] and [17]. Since there were observed differences in the end points definitions, random effect model was used to perform a statistical analysis.
Results of head-to-head trials showed that for time to delivery and time to active labor, MVI was statistically significantly better than DVI (Wing [9]), DVI was statistically significantly better than Dgel (Facchinetti [11]), DVI was comparable to Dtab (Rabl [15]) and Foley (meta-analysis of Cromi [14] and [17]). Detailed results are presented in Table 2.
Table 2 Results of analysis of clinical data
To reflect resource utilization of MVI versus the comparator, outcomes based on time-to-event end-points were recalculated as a reduction/increase, presented as the percentage of time (in hours) in the comparator arm. According to the calculations performed, use of MVI was related to a reduction both in time from induction to labor onset and time of labor.
On the basis of RR parameters (Table 3), MVI seems to have similar performance on effectiveness and safety, since the differences in most of the outcomes did not reach statistical significance. Nevertheless, it was shown that MVI was related to significantly lower oxytocin use versus all comparators. Vaginal delivery was observed more often in MVI arm versus DVI, Dgel, and Dtab. Only in case of Foley frequency of vaginal delivery was lower in the MVI group, although this result was not statistically significant.
Table 3 Percentage of patients with vaginal delivery, with oxytocin administration and with adverse events
Unfortunately, adverse events were not widely reported in the trials. Only for one trial, Wing [9], it was possible to present a broad spectrum of the safety profile. When compared to DVI, use of MVI was related to significantly higher risk of uterine tachysystole, tocolytic administration and meconium in amniotic fluid. No difference in postpartum hemorrhage was observed. Occurrence of chorioamnionitis was significantly lower for MVI. For Dgel, an indirect comparison was possible to perform only for postpartum hemorrhage. The result was not statistically significant; nevertheless, the direction of the result was in favor of MVI. It was impossible to assess MVI safety when compared to Dtab because of lack of data in Rabl [15]. For MVI versus Foley no differences in risk of meconium in amniotic fluid, chorioamnionitis and postpartum hemorrhage were observed; however, the direction of outcomes indicated lower risk of these events in the MVI arm. For uterine tachysystole the outcome was unfavorable for MVI, with statistical significance achieved.
To calculate the risk of particular end-point occurrence for MVI arm, calculated RR and risk of the events in the comparator arms were used. As a basic outcome the numerical value of assessed parameters was considered, while statistical significance of the outcome was considered as conservative assumption (Tables 2, 3). This approach was reasonable, since the main purpose of the project was to estimate anticipated costs related to MVI use in place of alternative technologies in clinical practice in IOL. Therefore, the direction of the outcome, even if not statistically significant, was relevant to reflect differences in costs.
Results of the Retrospective Questionnaire
Market shares of interventions used in IOL in 5 countries of interest revealed a lack of one most commonly chosen option across countries. Prostaglandins were used in the vast majority of cases of IOL in Austria and Slovakia. In Poland only 2 % of IOL was supported by one of the prostaglandins (Dgel). Oxytocin was used in almost all cases of IOL in Romania and often used in Poland and Russia. Balloon catheter was used most often in Poland (Table 4).
Table 4 Economic parameters used in the analysis
Costs applied in the economic model are presented in Table 4.
The hourly cost of stay in wards varied both between countries and ward types. Generally, the most expensive was the labor ward with higher hourly rate for cesarean than vaginal delivery. The cost of stay on antenatal ward was the lowest one (with exception of Austria). On average, Austria and Slovakia had the highest hourly rates whereas Russia had the lowest (Table 4).
The length of patient stay on the hospital wards was connected with the local clinical practice. In general, the patient’s stay on the postnatal ward was the longest one. In all countries except for Romania, cesarean delivery was related to a longer length of stay than vaginal delivery (the difference was between 4.75 and 74.50 h). In Russia, patient stayed about 11.92 and 16.67 h in total on hospital wards (for vaginal and cesarean delivery, respectively); whereas, at the other end the scale, is Slovakia with 130 and 168.75 h (Fig. 2).
Time spent by medical staff per patient was reported separately for each specialist. The differences in time devoted by medical staff across countries were noticeable, as it varied from 30 to a maximum of 560 min per nurse (Austria–Romania) and from 155 to 840 min per obstetrician-gynecologist (Austria–Russia) (Fig. 3).
Results of the Cost–Consequences Model
Results of the cost–consequences model were calculated as cost differences per single patient, separately for two variants of clinical data implementation: (1) numerical and (2) statistically significant values. The results of the model are presented in Table 5.
Table 5 Results of cost–consequences model for comparisons: misoprostol vaginal insert vs standard of care
Use of MVI in most scenarios was related to a reduction in time consumed by hospital staff, mostly for midwives and obstetrician-gynecologists, and a reduction in the length of patients’ stay in hospital wards, especially for the phase between induction and labor and during labor itself (Table 5).
Using MVI in place of prostaglandin E2 was less costly in almost all comparisons. The highest cost difference was observed in Austria, where MVI generated savings between €575.15 and €713.42 per patient. Both numerical and statistically significant scenarios showed savings. The exception was Russia, where the total healthcare cost derived from using Dgel was a slightly lower than for MVI in the model variant with statistically significant values. However, the difference was small (€5.36 per patient in favor of Dgel). For Poland, the introduction of MVI in IOL generated additional savings in comparison to Dgel, while the comparison to Foley was related to extra costs, due mostly to the very low cost of the Foley catheter.