Efficacy and Safety of Letrozole, Misoprostol and Their Combination in First Trimester Missed Miscarriage: A randomised clinical trial

TL;DR

This study found that combining letrozole and misoprostol is more effective for managing first trimester missed miscarriage than using either drug alone.

Contribution

The study introduces combination therapy of letrozole and misoprostol as a novel non-surgical approach for first trimester missed miscarriage.

Findings

Combination therapy (letrozole + misoprostol) had the highest complete miscarriage rate (76.0%) by day 7.

Letrozole-only had the fewest side effects and no surgical evacuations needed.

Combination therapy showed effectiveness across subgroups of age, BMI, and gestational age.

Abstract

This study evaluated the efficacy and safety of misoprostol, letrozole and their combination in first trimester missed miscarriage.

This single-blind, randomised controlled trial was conducted between March 2023 and August 2024 among women diagnosed with first trimester missed miscarriage at Kasr Al-Aini Hospital, Cairo, Egypt. Participants were randomly assigned to three groups: misoprostol-only (Group A), letrozole plus misoprostol (Group B) and letrozole-only (Group C). The primary outcome was the rate of complete miscarriage. Secondary outcomes included abortion timing, adverse effects, need for surgical evacuation and the effect of age, body mass index (BMI) and gestational age on success.

A total of 225 women were included in this study. Group B had the highest cumulative complete miscarriage rate by day 7 (76.0%) compared with Group A (53.5%) and Group C (62.5%) (P = 0.0005). Early abortion (by day 4) occurred in 68.4% (group B), 46.5% (group A) and 37.5% (group C). Group B also had the highest incidence of adverse effects, particularly bleeding (85.3%) and pain (92.0%), although severe events were rare. Letrozole-only (group C) had the fewest side effects (26.7%) and required no surgical evacuations. Combination therapy proved most effective across subgroups by age, BMI and gestational age.

Combining letrozole with misoprostol significantly improves complete miscarriage rates with tolerable safety. Letrozole alone is safer but less effective. Thus, combination therapy may offer an optimal non-surgical strategy for individualised management.

Tables

Table 1.. Bleeding occurrence and severity of participants with missed abortions on three different medication regimens (N = 75).

	%
Group	Bleeding present	Mild	Moderate	Severe	P value
A	70.7	77.3	16.9	5.6	0.01
B	85.3	81.2	12.5	6.2
C	68.0	90.2	9.8	0.0
Occurrence P value					0.03

Table 2.. Pain occurrence and severity of participants with missed abortions on three different medication regimens.

	%
Group	Pain present	Mild	Moderate	Severe	P value
A	70.6	64.2	24.5	11.3	0.0008
B	92.0	73.9	17.4	8.7
C	68.0	88.3	9.8	1.9
Occurrence P value					0.0005

Table 3.. Timing of events of abortion.

	Groups, %
Timing	Group A	Group B	Group C	P value
First bleeding				0.45
Day 1–2	7.6	9.3	7.8
Day 3–4	66.0	76.5	52.9
Day 5–6	26.4	14.0	39.2
First tissue passage				0.14
Day 1–2	0.0	0.0	0.0
Day 3–4	60.5	75.4	50.0
Day 5–6	39.5	24.5	50.0

Table 4.. Side effects, emergent evacuation and outcome success of abortion.

	Group, %
Parameter	Group A	Group B	Group C	P value
Side effects
Headache	14.7	17.3	9.3	–
Nausea	32.0	32.0	12.0	–
Vomiting	12.0	10.7	2.7	–
Diarrhoea	4.0	4.0	1.3	–
Fever	9.3	13.3	4.0	–
Chills	6.7	6.7	0.0	–
Hot flushes	0.0	0.0	1.3	–
Total with side effects	60.0	69.3	26.7	–
Emergent evacuation	4.0	5.3	0.0	0.0005

Table 5.. Complete abortion timing.

	n (%)*
Group	Complete abortion by day 4	Additional complete abortion between day 4–7	Cumulative complete abortion by day 7
A	35 (46.5)	5 (7.0)	40 (53.5)
B	39 (68.4)	18 (31.6)	57 (76.0)
C	27 (37.5)	19 (25.0)	46 (62.5)

Table 6.. Correlation of success rates for complete evacuation with age, body mass index and gestational age in treatment outcomes.

	n (%)
	Age in years		BMI in kg/m2				Gestational age in weeks
Group	<35	≥35	≤18	18–25	25–29	≥30	≤7	7–9
Group A
Yes	37 (58.7)	6 (66.7)	1 (100)	5 (71.4)	21 (63.6)	16 (51.6)	24 (66.7)	11 (61.1)
No	26 (41.3)	3 (33.3)	0 (0.0)	2 (28.6)	12 (36.4)	15 (48.4)	12 (33.3)	7 (38.9)
Group B
Yes	51 (82.3)	6 (66.7)	1 (100)	1 (100)	24 (75.0)	26 (81.3)	31 (86.1)	19 (70.4)
No	11 (17.7)	3 (33.3)	0 (0.0)	0 (0.0)	8 (25.0)	6 (18.8)	5 (13.9)	8 (29.6)
Group C
Yes	46 (65.7)	2 (40.0)	0 (0.0)	3 (37.5)	20 (66.7)	25 (67.6)	28 (84.9)	9 (47.4)
No	24 (34.3)	3 (60.0)	0 (0.0)	5 (62.5)	10 (33.3)	12 (32.4)	5 (15.2)	10 (52.6)

Full text

1. Introduction

A missed miscarriage is defined as the absence of fetal cardiac activity in pregnancies under 20 weeks of gestation or in fetuses weighing less than 500 g, as outlined in international guidelines.^1^ Missed miscarriages account for approximately 15–20% of all pregnancy losses, making it the most common type of miscarriage.^2^ Although surgical evacuation has a high success rate, interest in medical management is increasing due to its simplicity, lower cost, non-invasive nature and minimal impact on future fertility.^3^ However, it may involve longer treatment duration and carries a risk of requiring urgent surgical intervention.

The National Institute for Health and Care Excellence recommends that for missed miscarriage, the preferred regimen is to use 200 mg oral mifepristone, followed 48 hours later by 800 μg misoprostol (vaginal, oral or sublingual), unless the gestational sac has already passed.^4^ For incomplete miscarriage, a single dose of 600 μg misoprostol (vaginal, oral or sublingual) is recommended, with 800 μg as an acceptable alternative to align protocols.^4^ Misoprostol, a prostaglandin E1 analogue, promotes uterine contractions and cervical ripening.^5^ It is favoured for its affordability, ease of use and lower side effect profile compared to other prostaglandins. Success rates for misoprostol alone range from 37–85%, depending on the regimen and can increase to 95% when combined with mifepristone.^6^ However, mifepristone use is often limited by cost and availability.^7^

Letrozole is a third-generation non-steroidal aromatase inhibitor with a half-life of approximately 45 hours.^8^ It competitively inhibits oestrogen synthesis by binding to cytochrome P450, targeting aromatase activity in the placenta, ovary and peripheral tissues.^9^ Though primarily approved for ovulation induction and certain types of breast cancer, letrozole has demonstrated efficacy in managing first-trimester missed miscarriage.^10^ Clinical studies show that 10 mg of letrozole daily for 3 days followed by 600–800 μg of vaginal misoprostol achieves a complete abortion rate of up to 93%.^11^

This study aimed to compare the efficacy and safety of three medical regimens for first trimester missed miscarriage: misoprostol alone, letrozole alone and letrozole plus misoprostol.

2. Methods

This single-blind randomised clinical trial was conducted at the Obstetrics and Gynecology Department, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt, between March 2023 and August 2024. Pregnant women diagnosed with first trimester missed miscarriage, had a singleton pregnancy, aged 18 years or older and had a haemoglobin level of at least 10 g/dL were recruited from the hospital's outpatient clinic. Exclusion criteria included the need for emergency treatment such as excessive bleeding, severe pain or cervical dilation. Women were also excluded if they had a known allergy to misoprostol or letrozole, had previously attempted to terminate the current pregnancy or had a history of uterine surgery (e.g., caesarean section or myomectomy). Additional exclusion criteria included the presence of an intrauterine device, molar pregnancy, a history of coagulopathy or current use of anticoagulant therapy and the presence of severe uncontrolled medical conditions such as poorly controlled diabetes mellitus, hypertension or decompensated heart disease. A comprehensive medical history was obtained to confirm each patient's eligibility for the study. In addition, all participants underwent a complete blood count and Rhesus typing prior to the initiation of treatment.

According to the Society of Radiologists in Ultrasound guidelines for diagnosing early pregnancy loss, a missed miscarriage was confirmed using transvaginal ultrasound based on specific criteria. These included a crown-rump length of ≥7 mm without detectable cardiac activity on two separate scans at least 7 days apart, or a mean sac diameter of ≥25 mm without an embryo. Additional diagnostic criteria included the absence of an embryo with cardiac activity for ≥2 weeks following an ultrasound that showed a gestational sac without a yolk sac, or for ≥11 days after a scan showing a gestational sac with a yolk sac.^12^ All ultrasound examinations were performed by a single experienced sonographer using a Medison ultrasound machine equipped with a transvaginal probe operating at a frequency of 2 to 4 MHz.

Participants were evenly randomised (1:1:1 ratio) into three study arms (misoprostol-only [Group A], letrozole plus misoprostol [Group B] and letrozole-only [Group C]) using a computer-generated random sequence created in STATA (STATA Corporation, College Station, Texas, USA), Version 14.2. The sequence was prepared by an independent statistician and concealed using sequentially numbered, opaque, sealed envelopes. After providing written informed consent, participants were assigned to the next envelope in sequence. This was a single-blind design, whereby participants were blinded to their allocation, while the treating physicians were aware of the treatment assignment to ensure correct administration.

In the misoprostol-only (placebo; Group A) group, participants received 500 mg calcium carbonate orally once daily for 3 consecutive days to mimic the oral dosing schedule of letrozole used in the other arms. On the morning of day 3, the participant was admitted and administered 600 μg vaginal misoprostol every 4 hours for up to 4 doses, consistent with prior trials and international recommendations.^4131415^ Thus, calcium carbonate served as the oral placebo and this group functioned as the misoprostol-only control arm.

In the misoprostol plus letrozole (combination; Group B) group, participants received 10 mg letrozole orally once daily for 3 consecutive days. On the morning of day 3, they were admitted and administered 600 μg vaginal misoprostol every 4 hours for up to 4 doses, as described in previous studies.^4131415^

In the letrozole-only (Group C) group, participants received 10 mg letrozole orally once daily for 7 consecutive days as outpatients. This regimen was adapted from Yeung et al. which originally combined letrozole with misoprostol but this study intentionally excluded misoprostol in this arm to evaluate the efficacy of letrozole alone.^16^

All participants received structured instructions on how to record their experiences, including the timing of the first episode of vaginal bleeding, the timing of the first passage of tissue, the occurrence and severity of pain, the occurrence, severity and duration of bleeding and any side effects such as nausea, vomiting, fever or diarrhoea. They were educated on how to differentiate tissue passage from blood clots using verbal explanations and visual aids. Patients were also advised to return to the hospital in the event of severe bleeding.

On day 4 following the initiation of treatment, a follow-up transvaginal ultrasound was performed to assess the thickness of intrauterine remnants. A remnant thickness of less than 15 mm was considered indicative of complete abortion while remnants measuring 15 mm or more were classified as partial abortion or retained products of conception (RPOC).^17^ Patients with RPOC were scheduled for a second follow-up on day 7. After this period, those with persistent RPOC were offered additional misoprostol treatment or surgical evacuation as appropriate.

The primary outcomes included the incidence of complete miscarriage and the time from induction to complete abortion. Secondary outcomes consisted of the need for urgent surgical evacuation, the incidence of drug-related side effects (such as nausea, vomiting, fever, diarrhea, hot flushes, severe bleeding, and severe abdominal pain) and the relationship between the complete abortion rate and maternal factors including age, BMI and gestational age.

The sample size was calculated using STATA (STATA Corporation), Version 14.2. The calculation was based on an expected complete abortion rate of 80% with letrozole plus misoprostol compared to 51% with misoprostol alone, as reported by Elbareg et al.^18^ Assuming a two-sided significance level of 0.05, a 95% confidence interval and 80% power, and following the methodology outlined by Röhrig et al. the required sample size was estimated at 75 patients per group.^19^ As the study included three groups (misoprostol-only, letrozole + misoprostol and letrozole-only), this sample size was applied uniformly, yielding a total of 225 women (75 per group).

Data were analysed using Statistical Package for Social Sciences (SPSS) software, Version 25 (IBM Corp., Armonk, New York, USA). Basic descriptive statistics were calculated for demographic data. The normality of continuous measures was assessed by using Kolmogorov- Smirnov test. To compare differences between the three groups, ANOVA test was used for continuous variables and Chi-square test was used for categorical variables. The significance level was set at P <0.05.

3. Results

A total of 225 pregnant women were included in this study and were equally distributed among the three study arms (n = 75 each). There were no significant differences in age, BMI, or gestational age among the groups. For Groups A, B and C, the mean age was 29.5 ± 3.9, 29.8 ± 4.5 and 28.8 ± 3.4 years (P = 0.30); BMI was 29.1 ± 4.2, 29.0 ± 3.8 and 29.4 ± 4.3 kg/m^2^, respectively (P = 0.82); gestational age was 8.0 ± 2.2, 7.5 ± 1.9 and 8.1 ± 2.3 weeks, respectively (P = 0.15). Bleeding occurred in 70.7% (Group A), 85.3% (Group B) and 68.0% (Group C) (P = 0.03). Mild bleeding was most frequent (Group A = 77.3%, Group B = 81.2%, Group C = 90.2%). Severe bleeding occurred only in Groups A (5.6%) and B (6.2%) and severity differences were significant (P = 0.01) [Table 1].

Pain was reported to by 70.6% (Group A), 92.0% (Group B) and 68.0% (Group C) (P = 0.0005) of participants. Mild pain was most common (Group A = 64.2%, Group B = 73.9%, Group C = 88.3%). Severe pain was reported by 11.3% (Group A), 8.7% (Group B) and 1.9% (Group C) (P = 0.0008) [Table 2].

First bleeding occurred mainly on days 3–4 (Group A = 66.0%, Group B = 76.5%, Group C = 52.9%; P = 0.45). Tissue passage also peaked on days 3–4 (Group A = 60.5%, Group B 75.4%, Group C = 50.0%; P = 0.14) [Table 3].

Side effects were reported in 60.0%, 69.3% and 26.7% in Groups A, B and C, respectively. Nausea was most common (32.0% in Group A and Group B, 12.0% in Group C). Headache, vomiting, fever and chills were more frequent in Groups A and B than in C. Hot flushes were only reported in Group C (1.3%). In addition, emergent evacuation was required in 4.0% (Group A), 5.3% (Group B) and none in Group C (P = 0.0005) [Table 4].

By day 4, complete abortion occurred in 46.5% of women in Group A, 68.4% in Group B and 37.5% in Group C. Between days 4 and 7, an additional 7.0% of women in Group A, 31.6% in Group B and 25.0% in Group C achieved complete abortion. Thus, the cumulative rates by day 7 were 53.5% in Group A, 76.0% in Group B and 62.5% in Group C. These differences were not statistically significant (P = 0.14) [Table 5].

In the combination therapy group, high rates of complete evacuation were consistently observed across most subgroups, including women aged <35 years (82.3%), those with BMI ≥30 kg/m^2^ (81.3%) and those with gestational age ≤7 weeks (86.1%). In contrast, misoprostol-only and letrozole-only groups demonstrated lower success rates in women with higher BMI and later gestational age [Table 6].

4. Discussion

In this randomised study of 225 women with first-trimester missed miscarriage, three protocols were compared (misoprostol only, letrozole only and their combination). No significant differences were found among the groups in baseline characteristics (P >0.05).

Complete abortion was highest in the combination group (76.0%) compared with misoprostol alone (53.5%) and letrozole alone (62.5%). Partial abortion was lowest in the combination group (7.0%) and the ‘no change’ rate was also lowest (12.7%), indicating superior efficacy. These findings align with Torky et al., who reported 78% complete abortion with letrozole + misoprostol versus 39% with misoprostol alone (P <0.05).^20^ Javanmanesh et al. similarly found significantly higher complete abortion rates in the combination group (P <0.001).^21^ Naghshineh et al. observed 76.6% complete abortion in the letrozole + misoprostol group versus 42.6% with misoprostol + placebo (P <0.05).^22^ Elbareg and Fathi reported 80% versus 51.8% success (P <0.05).^18^ Behroozi-Lak et al. found a significant difference of 76.9% versus 41.03% in favour of letrozole (P = 0.001).^23^ Lee et al. also reported 86.9% in the letrozole group versus 72.6% with misoprostol (P = 0.03).^24^

Regarding abortion timing, complete abortion by day 4 occurred in 46.5% of women in the misoprostol group, 68.4% in the combination group and 37.5% in the letrozole group. The cumulative rates by day 7 were 53.5%, 76.0% and 62.5%, respectively (P = 0.14). The combination group also showed earlier onset of vaginal bleeding (76.6%) and tissue passage (75.4%) by day 3–4, compared to 66.0% and 60.5% in misoprostol, and 52.9% and 50% in letrozole groups. Naghshineh et al. reported shorter induction-to-abortion intervals with letrozole (5.1 ± 1.7 h versus 8.9 ± 2 h; P <0.001).^22^ However, Zhuo et al. and Nash et al. found no significant differences in abortion timing (P = 0.3).^2526^

Treatment-related symptoms varied among groups. Bleeding (85.3%) and pain (92%) were most frequently observed in the combination group (Group B), reflecting the expected pharmacological action of misoprostol. In contrast, adverse drug effects such as nausea, vomiting, fever and diarrhoea were also more frequent in this group (69.3%). Additionally, 5.3% of women required emergent evacuation (P = 0.0005). The misoprostol group (Group A) had moderate rates of bleeding (70.7%), pain (70.6%), side effects (60.0%) and requiring evacuation (4%). The letrozole group (Group C) had the lowest adverse effect profile of bleeding (68.0%), pain (68.0%), side effects (26.7%) with no emergency evacuations. Severe bleeding occurred in 5.6% (Group A), 6.2% (Group B) and 0% (Group C), and severe pain in 11.3% (A), 8.7% (B), and 1.9% (C) (P = 0.01 for bleeding severity; P = 0.0008 for pain severity).

Success rates also varied by maternal characteristics. In women <35 years, the combination group showed the highest efficacy (82.3%), while letrozole was least effective among women ≥35 years (40.0%). By BMI, the combination group had the highest success rates across all categories, notably 100% (BMI ≤18), 100% (18–24), 75% (25–29) and 81.3% (≥30), outperforming misoprostol-only and letrozole-only regimens. Gestational age impacted outcomes; the combination group (Group B) maintained high rates at all gestational ages (≤7 weeks: 86.1%, >9 weeks: 87.5%), while misoprostol-only and letrozole-only success rates declined with increasing gestation.

Overall, the combination of misoprostol and letrozole demonstrated the most favourable profile in terms of efficacy, timing and broad applicability across age, BMI and gestational subgroups. While letrozole alone had the safest profile, its efficacy was lower. These results support adopting combination therapy in clinical practice to maximise outcomes in medical management of missed miscarriage.

This study has several notable strengths. It is the first randomised trial to compare letrozole alone with misoprostol and their combination in the treatment of first trimester missed miscarriage, providing novel insights into therapeutic options. It also evaluated the impact of maternal age, BMI and gestational age on complete abortion rates, allowing for personalised treatment considerations. The randomised design ensures reduced bias and strengthens internal validity. Furthermore, this study addressed a common clinical problem, enhancing its practical relevance and potential to influence clinical guidelines.

However, some limitations should be considered. The relatively small sample size may limit generalisability. Serum oestradiol and calcium levels were not measured, which could have provided additional insights into hormonal and physiological mechanisms. The cost of extended letrozole regimens may also restrict accessibility in some settings. Because the letrozole-only group did not require admission on day 3, complete blinding of patients and physicians was not feasible. This limitation is inherent to trials comparing oral outpatient regimens with inpatient misoprostol administration. Although participants were instructed on how to distinguish tissue passage from blood clots, some misclassification cannot be fully excluded. Nevertheless, this limitation was mitigated by structured counselling, the use of visual aids and the objective confirmation of uterine evacuation by ultrasound. These limitations underscore the need for larger, multicentre studies with comprehensive biochemical monitoring and cost-effectiveness analysis.

5. Conclusion

This study demonstrated that combining misoprostol with letrozole offers superior efficacy in complete abortion rates and timing, especially in women under 35 years and those with higher BMI, with side effects comparable to misoprostol alone. The findings highlight the importance of individualised treatment based on maternal age, BMI and gestational age. While combination therapy showed the highest success, the letrozole-only regimen may serve as a safer alternative for select patients, despite its longer time to abortion, particularly when rapid completion is not essential.

Authors' Contribution

Mohamed Fikry Yousef: Conceptualization, Methodology, Investigation, Supervision. Mamdouh Abdelfatah Sheeba: Methodology, Investigation, Data curation. Hany Saad Amin Mohamed: Investigation, Data curation, Formal analysis. Abdelrahman Adel Abdelmonem Salama: Radiological assessment, Validation, Resources. Ahmed Hassan (Columbia University): Formal analysis, Writing – Review & Editing. Marwan Taghian: Writing – Review & Editing, Validation. Mahmoud Mostafa Hassan Ali: Investigation, Resources. Ahmed Ragab Ebrahim Ragab: Data curation, Visualization. Ahmed Hassan (Cairo University, Corresponding Author): Conceptualization, Investigation, Data curation, Supervision, Formal analysis, Writing – Review & Editing, Writing – Original Draft & Editing. Amira Alasmer: Investigation, Data curation. Mohamed Ramadan Mohamed: Methodology, Project administration.

Acknowledgement

The authors would like to acknowledge Mahmoud M. Ali (ANCOVA for Clinical Research Solutions – ANCOVA Research Center, Mansoura City, Egypt - Jazan, Saudi Arabia) for providing writing, proofreading and editorial support during the preparation of this manuscript.

Ethics Statement

Ethical approval for this study was obtained from the Cairo University Institutional Review Board (Cairo IRB), Faculty of Medicine, Cairo University, Cairo, Egypt (approval code: MD-390-2022). Participants provided written informed consent prior to inclusion in the study. This clinical trial was registered on the Open Science Framework (code: Ayj5p, https://doi.org/10.17605/OSF.IO/AYJ5P).

Conflict of Interest

The authors declare no conflicts of interest.

Funding

No funding was received for this study.

Data Availability

Data is available upon reasonable request from the corresponding author.