Clinical Effectiveness and Cost-Effectiveness of Misoprostol in Comparison to Dilatation and Curettage for Treatment of First-Trimester Missed Abortion (Gestational Age ≤ 14 Weeks) in Iran

Saeed Husseini Barghazan: conceptualization, methodology, data curation, supervision, validation, writing – original draft, writing – review and editing. Aziz Rezapour: conceptualization, methodology, data curation, supervision, validation. Mohamad Hadian: conceptualization, methodology. Zahra Meshkani: methodology, writing – review and editing. Soheila Norouzi: investigation, validation, data curation. Setare Nassiri: conceptualization, methodology, investigation.

Ethical approval for this study was obtained from the “Iran's National Committee for Ethics in Biomedical Research” (Approval Number: IR.IUMS.REC.1399.068). The authors confirm that all methods were performed following the relevant guidelines and regulations, for example, the Declaration of Helsinki.

This was not a clinical study, although all participants in the study answered the questions voluntarily. The authors confirmed that informed consent was obtained from all subjects.

This was a prospective cost‐effectiveness analysis (CEA) conducted alongside a clinical trial, with a time horizon of 14 days. The study was carried out from August 1, 2021 to March 30, 2022, in three public hospitals in Iran; the clinical details have been described previously [ 22 ]. Medical and surgical interventions were defined as below. A. Hospital‐based misoprostol; starting with 400 mg, increasable up to 2000 mg/day in four divided doses, orally or vaginally depending on patient symptoms which was administered under the direct supervision of a physician in the hospital. B. Clinic‐based misoprostol; starting with 400 mg, increasable up to 2000 mg/day in four divided doses, orally or vaginally depending on patient symptoms, which was prescribed by a physician in the clinic, and the patient, returned home to continue the process of completing the abortion. Hospital‐based misoprostol; starting with 400 mg, increasable up to 2000 mg/day in four divided doses, orally or vaginally depending on patient symptoms which was administered under the direct supervision of a physician in the hospital. Clinic‐based misoprostol; starting with 400 mg, increasable up to 2000 mg/day in four divided doses, orally or vaginally depending on patient symptoms, which was prescribed by a physician in the clinic, and the patient, returned home to continue the process of completing the abortion. Dilation and curettage (D&C) was performed under general anesthesia in accordance with the relevant clinical guidelines. A total of 168 women aged 15–49 years, diagnosed with first‐trimester abortion (including medically necessary abortions, elective abortions, missed abortions, and threatened abortions up to 13 weeks of gestation), were consecutively recruited. Women with underlying chronic diseases were excluded. Written informed consent was obtained from all participants. Patients were asked to return 2 weeks after the first intervention to assess treatment success and adverse effects. After diagnosis, patients were counseled regarding the two available treatment options in routine practice: medical management with misoprostol or surgical management with dilatation and curettage (D&C). Allocation into groups was determined by patient preference in consultation with their physician, rather than random assignment, to reflect real‐world practice in Iran. The primary and secondary outcomes were defined. Pain and bleeding were assessed both during the procedure (intraoperative records) and after the procedure (postoperative recovery and follow‐up visits). Pain was measured immediately after the procedure and again at the 14‐day follow‐up. Estimated blood loss was recorded intraoperatively by the attending physician and reassessed at follow‐up if patients reported abnormal bleeding. Estimated blood loss, pain level, relative risk (RR), length of stay, acceptability of the intervention, pelvic infection, and the rate of complications (including bleeding, failed abortion, infection) or complete abortion were considered secondary outcomes. The Quality‐Adjusted Life Years (QALYs), based on the EQ‐5D‐3L questionnaire, was the primary outcome that estimated the utility score of the cases over 14 days [ 23 ]. It was assumed that the utility scores remained constant during the time horizon. The economic evaluation was conducted from a societal perspective, capturing both direct medical and indirect costs. Direct medical costs included hospital services, medications, diagnostic tests, and management of adverse clinical events. Unit costs were obtained from official hospital tariffs and Ministry of Health fee schedules for public hospitals in 2021. Indirect costs included the time spent by patients on treatment, transportation, and productivity losses. Productivity loss was estimated using the human capital approach, based on average daily wages in Iran. Lost workdays were calculated over a 14‐day period following treatment, reflecting the typical recovery and follow‐up duration observed in our study population. Transportation costs were estimated using average round‐trip fares reported by patients for hospital visits [ 24 , 25 ]. Direct medical costs included hospital services, medications, diagnostic tests, and management of adverse clinical events. Unit costs were obtained from official hospital tariffs and Ministry of Health fee schedules for public hospitals in 2021. Indirect costs included the time spent by patients on treatment, transportation, and productivity losses. Productivity loss was estimated using the human capital approach, based on average daily wages in Iran. Lost workdays were calculated over a 14‐day period following treatment, reflecting the typical recovery and follow‐up duration observed in our study population. Transportation costs were estimated using average round‐trip fares reported by patients for hospital visits [ 24 , 25 ]. The total costs and the costs per case were estimated. All costs were converted to US dollars using the average exchange rate of 2021 (1 USD = 254.860 Rials) [ 26 ]. A decision tree for surgical (D&C) and medical intervention (hospital and misoprostol in the clinic) for first‐trimester abortion was considered (Figure  1 ). To run the model, the probabilities of incidence of composite complications and the QALYs associated with each strategy were required, which were obtained from the patient's clinical processes at the time of follow‐up [ 22 ]. The decision tree for first‐trimester abortion. Explanation of the abbreviation used in the model, for example: (P_DC_Su = probability of successful treatment in D and C group)/or (P_DC_F_DC = probability of composite complication in D and C group need for repeated D and C). The incremental cost‐effectiveness ratio (ICER), defined as the ratio of the difference in mean costs to the difference in mean QALYs between the surgical and medical strategies over the 14‐day trial, was calculated and analyzed based on the WTP threshold, which, according to NICE, is set at $2756. Cost‐effectiveness acceptability curves were also constructed. A deterministic and probabilistic sensitivity analysis was conducted to assess the robustness of the analysis by focusing on key variables, including costs and utility. Data were analyzed using SPSS 18 and TreeAge Pro 2022.

The largest age group of women was 25–34 years in both the Misoprostol group (54.8%) and the Dilation and Curettage (D&C) group (41.6%). About 35.7% of participants in the Misoprostol group and 38% in the D&C group had their second pregnancy resulting in termination. More significant differences between the two groups were observed in education levels, gestational age, and history of previous abortion. More details of the demographic characteristics are presented in Table  1 . Demographic characteristics of participants. In the trial, of the 42 women assigned to receive misoprostol in the hospital under the supervision of a physician, 76.2% experienced complete expulsion by Day 14. Overall, treatment failed in 23.8% of them. In the surgical D&C arm, 4.76% experienced treatment failure and required repeated treatment. The RR and the probability of experiencing a composite complication in hospital‐based misoprostol and clinic‐based misoprostol patients were 5 and 11.5 times higher than in the D&C group, respectively. The QALY scores differed between treatment groups. The average QALYs for the hospital‐based misoprostol, clinic‐based misoprostol, and D&C patient groups were estimated at 0.6891, 0.3947, and 0.6605, respectively. Procedure characteristics and details of persistent/late‐onset complications are shown in Table  2 . Procedure details and complications of the study participants. Average per‐patient costs from a societal perspective for hospital‐based misoprostol, clinic‐based misoprostol, and D&C patient groups were US$135.09, US$158.20, and US$138.36, respectively. The clinic‐based misoprostol strategy is associated with worse clinical outcomes on the one hand and higher overall costs on the other hand compared to the two other strategies. Table  3 summarizes the probabilities, costs, and QALYs for the three types of strategies for pregnancy termination. Probabilities, costs, and QALYs. From a societal perspective, the hospital‐based misoprostol strategy was cost‐effective compared to D&C and clinic‐based misoprostol, with an ICER of $195.79 per QALY. The ICER for the hospital‐based provision of misoprostol is below the maximum willingness‐to‐pay threshold of $2756 per QALY (Figure  2 ). The results suggest that hospital‐based misoprostol dominates the two other strategies studied (Table  4 ). Probabilistic sensitivity analysis indicated that hospital‐based misoprostol has a > 44%–49% chance of being more cost‐effective than both D&C and clinic‐based misoprostol (Figure  3 ). Cost‐effectiveness graph for three strategies. ICERs, cost per QALYs, and cost‐effectiveness results. Monte Carlo acceptability curve at expected threshold.

The Saeed Husseini Barghazan affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This study was conducted in conjunction with a nonrandomized controlled trial, which revealed a significant difference in the rate of composite complications between hospital‐based and clinic‐based misoprostol patient groups. Patients who received misoprostol in clinics and self‐administered the medication at home demonstrated the poorest clinical outcomes and exhibited a pronounced deficiency in essential self‐management skills. This finding may be attributed to insufficient patient counseling and education services related to abortion care within the settings examined. Comprehensive counseling and education services are strongly correlated with higher rates of complete miscarriage, improved clinical outcomes, and increased patient satisfaction, reflecting the critical role of patients in determining pregnancy‐related outcomes [ 27 , 28 , 29 , 30 ]. In contrast, a recently published Cochrane review concluded that early medical abortion procedures are effective regardless of whether the medication is self‐administered or provided by a healthcare professional. Nevertheless, the authors acknowledged a lack of sufficient evidence to robustly evaluate the safety of self‐administration in comparison to administration under medical supervision [ 31 ]. Furthermore, both medical abortion subgroups demonstrated certain limitations compared to surgical abortion with respect to complete abortion rates and composite complications. Recent meta‐analyses of clinical trials have concluded that patients undergoing medical abortion are more likely than those undergoing surgical abortion to experience composite complications, including bleeding, nausea, vomiting, pain, and fever. Nevertheless, levels of satisfaction and acceptance reported for medical abortion are generally higher than those for the surgical method. Although medical methods—particularly those involving prostaglandin alone—have several disadvantages compared to combined regimens and surgical approaches, they may represent a suitable option for women experiencing fear or anxiety related to surgical procedures [ 11 , 32 ]. The analysis revealed that the clinic‐based misoprostol strategy was associated not only with poorer clinical outcomes but also with higher overall costs compared to the other two strategies. Although this approach incurred lower direct medical expenses, it resulted in greater productivity loss costs. Nonetheless, the estimated costs among the strategies were relatively similar, particularly between patients receiving clinic‐based misoprostol and those undergoing dilation and curettage (D&C). This study compared both the costs and outcomes of alternative methods for therapeutic management of first‐trimester pregnancy termination (≤ 14 weeks) in the context of Iran, a developing country. Cost data were collected prospectively from a societal perspective, encompassing health system costs, out‐of‐pocket payments, productivity losses, and nonmedical expenses. As anticipated, the medical method was found to be less expensive than the surgical method, with an ICER indicating cost‐effectiveness. The findings demonstrated that hospital‐based medical management using misoprostol yields relatively acceptable clinical outcomes within 2 weeks and is associated with lower overall societal costs compared to dilation and curettage (D&C) for early abortion. Our results align with a recently published cost‐minimization study reporting that medical treatment of first‐trimester spontaneous abortion with prostaglandins was approximately five times less costly than D&C within Spain's National Health System (SNS). The authors estimated that medical treatment saves an average of €1576.80/patient. Furthermore, they recommended prioritizing medical treatment over evacuation curettage due to acceptable success rates, minor side effects, manageable complications, and higher patient satisfaction [ 17 ]. These positive clinical outcomes have been corroborated by another economic evaluation conducted in Spain, which reported that uterine curettage significantly increases costs compared to misoprostol for patients with missed abortion [ 33 ]. A cost‐effectiveness study based on a randomized controlled trial (RCT) comparing medical and surgical methods for managing incomplete miscarriages in low‐resource Nigerian settings reported a higher failure rate in the misoprostol group compared to Manual Vacuum Aspiration (MVA), although the difference in complete evacuations was not statistically significant. Nevertheless, the study demonstrated higher patient acceptance and satisfaction rates in the misoprostol group and concluded that misoprostol was more cost‐effective than the MVA method [ 34 ]. The findings of the present study suggest that hospital‐based medical treatment using misoprostol could be considered a relatively acceptable strategy alongside dilation and curettage (D&C) for well‐motivated women undergoing first‐trimester pregnancy termination and management of abortion‐related complications. To our knowledge, this economic evaluation represents the first effort to assess the economic aspects of pregnancy termination care in Iran, utilizing prospectively collected effectiveness and economic data from a locally designed clinical trial conducted from a societal perspective. However, this study has certain limitations. First, it relied on national tariff payments and reimbursements to estimate direct medical costs, without performing a comprehensive bottom‐up costing of all resource items during the trial. Second, the study employed a nonrandomized clinical trial design, which inherently reduces the strength of evidence compared to RCTs. These factors should be carefully considered when interpreting the study's findings.

The CEA indicates that hospital‐based administration of misoprostol for first‐trimester induced abortion is associated with lower societal costs and improved quality of life compared to both dilation and curettage (D&C) and clinic‐based misoprostol. This suggests that hospital‐based misoprostol may be a more advantageous option in terms of both economic and health outcomes for patients undergoing this procedure.

Abortion refers to the termination of a pregnancy through the removal or expulsion of its products from the uterus before the fetus reaches viability—typically defined as weighing < 500 g or measuring under 25 cm in length. While the precise incidence of spontaneous abortion remains uncertain, it is estimated that ~15% of clinically confirmed pregnancies and up to 60% of biochemically confirmed pregnancies end in miscarriage. Notably, around 80% of these spontaneous abortions occur within the first 12 weeks of gestation [ 1 ]. On a global scale, an estimated 73 million abortions are performed annually, representing roughly 29% of all pregnancies. Alarmingly, nearly 45% of these procedures are classified as unsafe, with the vast majority occurring in developing countries where access to reproductive healthcare is limited [ 2 ]. In Iran, abortion is legally permitted only under narrowly defined medical circumstances, such as severe fetal abnormalities or threats to the mother's life. Despite these restrictions, the issue remains significant: recent data indicate that ~450,000 abortions occur each year, equating to a rate of 10.7/1000 women aged 15–44. Most of these procedures are conducted illegally and under unsafe conditions, highlighting the disconnect between policy and the reproductive realities faced by many Iranian women [ 3 ]. The clinical outcomes and the healthcare costs are important to focus in pregnancy and to reach, the safe method was recommended in the studies [ 4 , 5 ]. According to a review by Bridwell and colleagues, the mortality rates for unsafe and safe abortions are between 4.7% and 13.2% and < 0.2%, respectively [ 6 ]. Hospitals have admitted ~5 million cases to treat complications resulting from unsafe abortions, which impose a significant burden on health systems due to illness or death. A lack of skills among care providers, as well as environments without established medical standards, contribute to unsafe abortions [ 7 ]. The rate of unsafe abortions in developed countries is 3%, while it is 55% in developing countries. This disparity is attributed to unmet needs, social stigma, and criminalization [ 8 ]. Complications of unsafe abortions include retained products of conception, bleeding, uterine perforation, misoprostol toxicity, embolism, endometritis, retained cervical dilators, and amniotic fluid introduction [ 6 ]. To reduce the risks and complications of abortions, it is recommended to perform these services according to high standards based on acceptable guidelines within healthcare systems [ 9 ]. International guidelines describe different approaches to the management of first‐trimester missed abortion depending on gestational age. For pregnancies < 7 weeks, medical abortion is commonly described, while for those between 7 and 14 weeks, vacuum aspiration is outlined as a standard option. Medical abortion is also discussed for pregnancies beyond 12 weeks of gestation [ 9 ]. Surgical procedures such as dilatation and curettage (D&C), suction curettage, and dilation and evacuation (D&E) are recognized alternatives to medical abortion [ 10 ]. However, in Iran, the actual clinical practice differs from these international recommendations. For first‐trimester missed abortion (≤ 14 weeks), the two main approaches used in hospitals are medical management with misoprostol and surgical management with D&C. Other procedures such as vacuum aspiration or D&E, although described in guidelines, are not routinely performed. Accordingly, our study population consisted of women with missed abortion up to 14 weeks of gestation who were treated with either misoprostol or D&C, reflecting the practices in this setting. According to Zhang and colleagues, medications such as misoprostol, letrozole with prostaglandins, and mifepristone with or without prostaglandins are frequently used for abortion [ 11 ]. Based on a systematic review by Abubeker and colleagues, a combination of misoprostol and mifepristone or misoprostol alone is considered safe, effective, and acceptable for medical termination [ 12 ]. Based on Bridwell and colleagues, the introduction of misoprostol in regions with restrictive legislation made clandestine abortions less unsafe [ 6 ]. The immediate complications were the most important factor that researchers focused on when comparing medical and surgical interventions. The results showed advantages of dilation and curettage in some studies and no differences in others [ 13 ]. Vacuum curettage and medical abortion (misoprostol or its combination with mifepristone) for first‐trimester abortion are recommended by WHO [ 14 ]. Although surgical methods have efficacy and complication rates of 95%–100% and < 1%, respectively [ 15 ], medical methods have gained popularity since 1988 and have been used in recent years because of their effectiveness, safety, postabortion care, and acceptability [ 16 ]. One of the most important advantages of medical abortion is that it does not require anesthesia and can be performed on an outpatient basis [ 17 ] which leads to cost savings compared to surgical methods [ 15 , 16 ]. Clearly, to help policymakers choose between interventions, their costs and effectiveness should be assessed in parallel, which requires cost‐effectiveness studies, especially in developing countries [ 18 , 19 ]. There has been a recent decline in the fertility rate in Iran, and the lack of access to legal abortions leads to a high number of clandestine and unsafe abortions. There is no official data on unsafe abortions in Iran; however, according to an updated meta‐analysis in Iran by Sayehmiri and colleagues, more than a quarter of pregnancies among Iranian women are unintended, with a prevalence of 26% between 2012 and 2018, leading to illegal and unsafe abortions [ 20 ]. These are attributed to social and religious beliefs and impose a burden on the health system, affecting women's quality of life [ 21 ]. One of the challenges for Iranian policymakers is how to educate women to prevent unintended pregnancies and to identify cost‐effective interventions that incur lower costs while maintaining higher effectiveness. Therefore, the present study aims to assess the cost‐effectiveness of misoprostol (hospital or clinic‐based misoprostol) compared with dilation and curettage (D&C) for first‐trimester pregnancy termination up to 13 weeks of gestation in Iran to support decision‐making.

The authors declare no conflicts of interest.