Misoprostol versus Letrozol with Misoprostol in Management of First Trimesteric Missed Miscarriage

INTRODUCTION

Abortion is the gestation terminations earlier to a fetus can potentially live outside the uterus, it is a mutual complication of gestation occurring either spontaneously (miscarriage) or on purpose (induced abortion).¹ A missed miscarriage happens in 10 to 20% of the clinical recognized gestations.² Between 1990 and 1994, it was estimated that about 50 million induced abortions occurred per year worldwide while, this number increased to 56 million per year during the period from 2010 to 2014.³ Also, it was estimated that about 50% of abortions are not safe and could cause considerable maternal deaths therefore, successful management of abortion is a crucial matter in gynecology.⁴

Vacuum aspiration surgery was the selected method for terminating pregnancy in 1960s, then persuading

abortions using medications is vastly utilized in worldwide levels via mifepristone manufacture.⁵ Persuading abortions via medications is a substitute for surgical treatment, which has economy profits with lower side-effects and its success rate is 60 to 95%.⁶ Several medications can be utilized to persuade abortions and counting limitations in access to mifepristone medications and its high price, it isn’t available in the majority of the republics and substitute medications are utilized to persuade abortions.⁷ One of these medications is misoprostol which is prostaglandin E1 analogue.

Misoprostol is a prostaglandin that reasons myometrial cervical softening, contractions, and dilatations and it is utilized to persuade abortions and labour and to manage atonic postpartum hemorrhage and peptic ulcers.⁴ It has the benefit of being economic and steady with a low rate of side-effects, which has result in it has been comprised in the WHO list of important medications.⁶ In addition, misoprostol is could be kept in room temperature, it is affordable and efficient, doesn’t need special care during use and usually used with different routes of administration "vaginally, orally and sublingual".¹ Also, misoprostol is well tolerated by cases and significantly decreases treatments prices in addition, it considerably reduces curettage and the need for surgical intervention.⁵

Letrozole is a key aromatase inhibitor, that is utilized to excite ovulations in non-fertile females suffered from ovulatory dysfunctions, it has a comparatively short 45-h half-life and it is active orally and inhibits aromatase enzymes oppositely.⁸ Letrozole can have a function in abortions therapies by constraining estrogen synthesis that causes rise endogenous gonadotropin and lastly excites the growing of ovaria’s follicles.⁹ As well, it has been reported that Letrozole is also used for the treatment of breast cancer related to estrogen and it can replace mifepristone "which is expensive and not available in many countries".¹⁰

Some researchers propose prescriptions of aromatase inhibitors before the usage of major medication "such as misoprostol or mifepristone" for persuading medication abortions rises effectiveness of management regimens and also decreases the necessity for surgery.⁹ A success rate of 86.9% was achieved when letrozole was managed for 3-days trailed by misoprostol.¹¹ In another study, letrozole protocol has been utilized for 7-days and attained 95 % rate of success.⁹ While, letrozole and mifepristone were managed before misoprostol and accomplished a rate of complete abortion 98%.¹⁰ Many studies evaluated the impact of misoprostol with letrozole in management of missed miscarriage, but reaching firm results need further studies. The objective of this work was to match the safety and effectiveness of two treatment modalities (Misoprostol versus Letrozol with Misoprostol) in medical treatment of the 1^st trimesteric missed miscarriages.

PATIENTS AND METHODS

This is an interventional randomized case-control research that has been performed at the outpatient antenatal care clinic of Luxor General Hospital during the period from February to December 2017. The study included a number of 200-cases who were randomly classified to 2 equal groups: Group-I "Misoprostol" which included 100 cases received 800-mg of misoprostol at once of diagnosis vaginally and group-II "Letrozol + Misoprostol" which included 100 cases received 10-mg letrozol 2 times a day for 3 days as pretreatment then 800-mg of vaginal misoprostol. All females with 1^st trimester missed miscarriages and closed cervix and no conceptions of products in the cervical duct were included in this work. Exclusion criteria were; preceding attempts for termination of pregnancy, IUCD in utero, uterine tumors such as fibroids or malformations in addition to medical disorders such as heart disease, renal, liver disease and hemorrhage or blood disease.

All included cases have been exposed to the following full history taking counting personal history, complaint and present history, menstrual history, family history, history of medical disorders and full obstetric history. In addition, general, pelvic, abdominal and ultrasonographic examinations were done. Some investigations were done especially, ABO and Rh, sure diagnosis of missed miscarriage and gestational age by ultrasonography if there is a difference between amenorrhea and gestational age by ultrasound gestational age is recorded.

The first group (Misoprostol group) received 800-mg misoprostol (Misotac, Tab. 200 mcg Sigma ®, Egypt) vaginally at the first day of enrollment in the study and the second group (Letrozol + Misoprostol group) taken 10-mg letrozole (Femara Tab. 2.5-mg, Novarts ®, Egypt) 2 times a day for 3-days then 800-mg vaginal misoprostol. Patients were advised to document the following; date of 1^st vagina blood loss, date of 1^st passing of tissues parts, occurrence of pains and its strength (mild, moderate or severe) occurrence of bleeding and its strength (mild, moderate or severe) and its period, occurrence of side effects (nausea, vomiting, hyperpyrexia, shivering, colics etc…). Also, they were recommended to come back to the clinic if there were severe pains and blood loss, intolerable side-effect and at 3^rd and 7^th day after misoprostol dose. At the 3^rd day, ultrasound was done for the detection of incomplete abortion complete and second dose of misoprostol was given if missed or incomplete miscarriage. At the 7^th day, ultrasound was done and evacuation was done of missed or incomplete miscarriage. The patient was considered to have incomplete abortion if the remnant inside the uterus 2 cm or more. Regarding the taken outcome measures, primary outcome measures include full abortions rate and inductions to abortions period. While, the secondary result measures are duration of bleeding, occurrence of side-effects and the need of emergency evacuation.

Statistical analyzing have been done via SPSS-20 program (IBM, NY, USA).¹² Data are presented as means ± SD for quantitative data and by No. (%) for qualitative data. Comparison among groups have been done using Student’s t testing for parametric data and using Mann Whitney testing for nonparametric data. Chi-Square testing was utilized to examine the significance among studied groups concerning qualitative data or Fisher exact testing when needed. Probability value (P-value) was supposed significant if

RESULTS

The present results showed that nonsignificant changes were found among groups regarding ages (P-value=0.48), BMI (P-value=0.62), gestational age (P=0.32), gravidity (P=0.84) and previous CSs (P=0.83), (Table, 1). Misoprostol alone group (group, I) had significantly higher time passed after 1^st misoprostol dose till the start of vaginal spotting compared to group-II (53.9 ± 14.2 vs. 33.4 ± 7.4 hrs., P-value<0.01). Also, group-I had a significantly higher duration of vaginal bleeding after the 1^st misoprostol dose and time passed after 1^st misoprostol dose till the 1^st passage of POC in comparison with group-II, (P

T testing and Chi-square tests have been utilized to compare between groups.               NS     Not significant.

Table 1: Comparison between groups as regard demographic and baseline data.

**   Significance at (P-value≤0.01)

Table 2: Comparison between groups as regard clinical findings.

**   Significant (P≤0.01)

Table 3: Comparison between groups as regard follow-up.

**   Significant (P≤0.01)

Table 4: Comparison between groups as regard side effects.

Table 5: Comparison between groups as regard outcome and induction to abortion interval.