Second trimester a abortion induction with misoprostol only versus misoprostol plus isosorbide mononitrate: a randomized controlled study

INTRODUCTION

In all recorded induced abortions second trimester abortion accounts for 10-15% and thought to be responsible for more than  70%  of all  abortion  recorded related complications. ¹

 In past, abortion surgical induction  methods  were often practiced for  pregnancy termination.  Fortunately nowadays with the availability of potent uterotonic drugs Like prostaglandins and its analogue e1 and e2 , medical termination of abortion is preferred. Misoprostol is commonly used for termination of second trimester abortion.² Drugs as mifepristone have been used with it to reduce the interval time for abortion  induction and   outcome improvement ³. Mifepristone has shown to be effective but it is  unavailable and expensive.

 Ripening of cervix is a very important milestone for successful termination of abortion . Nitric oxide(N.O) donors as isosorbide mononitrate(Effox_R) have been used for   ripening of cervix in first

trimester and  also for induction of  labour  at term for  a long time.⁴

Cervical ripening has been linked to an inflammatory response. During ripening there is an influx of inflammatory mediators into the cervical stroma. Pro-inflammatory cytokines (interleukin-1 and interleukin-8) are thought to play a key role on metabolism of extracellular matrix and ripening of cervix. ⁵

Nitric oxide donors thought to  induce matrix metalloproteinases production namely MMP-1 and MMP-9, which are essential for degradation of  collagen. ⁶ It also increases proinflammatory mediators as prostaglandins and cytokines . The previous agents  use for second trimester termination of pregnancies can shortens the induction time of  abortion . The study aims to complete  evaluation of  the efficacy of isosorbide mononitrate when combined with pg e1 anlogue  misoprostol in shortening the induction to abortion interval in termination of pregnancy in second trimester

The aim of this work is to compare the efficacy of the usage of misoprostol alone versus a combination of misoprostol and isosorbide mononitrate in cervical ripening and induction of abortion in second trimesteric missed abortion patients demonstrated by the change of cervical dilatation and effacement, decreased time required for complete expulsion of the abortus and to evaluate safety of both drugs and side effects.

PATIENTS AND METHODS

This study was a randomized clinical trial on the Second trimesters (13-26 weeks) missed abortion pregnant women who admitted for medical induction of abortion.

Inclusion criteria: Maternal Age 18-35years, Gestational age: Second trimester of pregnancy (between 13-26weeks), missed abortion confirmed by ultrasound, singleton pregnancy, unscarred uterus, normal uterus and cervix on clinical examination, uterine  cervix is not dilated, no bleeding from vagina .

Exclusion criteria: The patient with the following was excluded from the study,  evidences suggesting start of spontaneous abortion as previous trial to induce abortion, presence of uterine contraction or bleeding, multi-fetal pregnancy, septic abortion, history of Previous cervical surgery or any manipulation, uterine anomaly, presence of IUCD in situ, underlying medical diseases as cardiovascular diseases, history of allergy or adverse effects to vaginally administered medication e.g. isosorbide -5-mononitrate, those unwilling to participate in the trial and all patients were informed about the study and will be included in the study after their approval and will be subjected to

Consent: Written consent was obtained from the pregnant women who are included in the study after explanation of the study and its aims in addition to consent for performing surgical evacuation for any remnants if needed.

Full history taking: Name, Maternal Age, obstetric history (Gravidity and parity) First day of last menstrual period, gestational Age, medical and surgical history, previous laparotomies and their types, previous Pregnancy complications, history of smoking, pelvic pain.

Clinical examination: Height (in cm) and weight (in kg) measurements, BMI calculation Blood pressure measurement, obstetric Examinations (PV Examination) Previous scars analysis

Laboratory investigations: Preoperative and postoperative CBC, Coagulation profile, Kidney and liver functions

Investigation: All women underwent Trans-abdominal or Transvaginal Ultra-sonography during the Routine examination to confirm the inclusion criteria of the study (Gestational age and confirmation of the intrauterine fetal death

Randomization: Participants were randomly assigned to misoprostol alone or misoprostol+isosorbide-5-mononitrite using identical sealed envelopes technique. We prepared 200 identical envelops, half of them filled with a label identifying “misoprostol” group with all instruction details, while the other half filled with a label identifying the “misoprostol+isosorbide-5-mononitrite” group” with all instruction details. All envelops was prepared by the investigator and sealed before starting enrollment. After enrollment, each participant was allowed to choose one envelop to determine to which group she will be assigned.

Group A (n=80) received combined Isosorbide-5-mononitrate 20mg (Effox 20mg ) once vaginal with Misoprostol 400mcg (2 tablets Cytotec ) at first then one tablet every 4-6 hours to a maximum of four doses or until reaching cervical ripening.

Group B (n=80) received only vaginal Misoprostol 400mcg (2 tablets Cytotec 200mcg) at first then one tablet every 4-6 hours to a maximum of four doses or until reaching cervical ripening.(The doses of Misoprostol will follow the New FIGO Guidelines for Misoprostol use 2017)

Study outcomes

Primary outcomes: The Efficacy in form of “induction abortion interval”: the Duration interval between the beginning of the induction and the complete expulsion of the abortus and also the number of misoprostol doses needed for complete expulsion when prostaglandins used alone and when prostaglandins and a nitric oxide donor used together.

Secondary outcomes: Association between Adverse symptoms that increased or newly discovered when prostaglandins and a nitric oxide donor used together such as severe bleeding, headache, abdominal pain, pelvic pain, severe hypotension, backache, fever, nausea and vomiting.

Statistical analysis of the collected data: Data were analyzed statistically  in terms of mean±standard deviation (±SD), median and range, or frequencies (cases number ) and percentages when appropriate. Numerical variables comparison  between the study  two groups was done using Student t test for independent samples. For categorical data comparing , Chisquare (χ²) test was performed. Exact test was used instead when the expected frequency is less than 5. Two sidedp values less than 0.05 was considered statistically significant. All statistical calculations were done using computer program IBM SPSS (Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) release 22 for Microsoft Windows

RESULTS

This study was a randomized clinical trial at el Hussein university hospital during time interval from June 2021 till December 2022 in which 160 Second trimester (13-26weeks) missed abortion pregnant women admitted for medical induction of abortion.

Patient characteristics: Age, Parity, Gestational age were summarized in Table 1.The above table shows the mean age, parity and gestational age of the studied patients. The study contained 200 women divided into 2 groups. One group received misoprostol and isosorbide mononitrate (nitrate group) and the other group received misoprostol only (misoprostol group).

Table 1: Demographic features and obstetric parameters of the studied patients

The age of the participating female ranged from 19 to 33years. The mean age of misoprostol group was 25.1(SD=3.5) years while it was 23.4(SD=3.2) years in nitrate group. The difference was not statistically significant.

There was no significant statistical difference between both groups regarding parity and gestational age.

Table 2: Success of abortion at the end of 24 hours

The above table shows the difference in success of induction of abortion in both groups within 24 hours. It was 91.3% in nitrate group and 77.5% in misoprostol group.

The difference between both group was statistically significant (P value=0.028) indicating that isosorbide mononitrate when added to misoprostol increase the chance of success of abortion. This table shows number of doses given for both groups. The statistical difference is significant indicating that the number of given doses in nitrate group was much less than in misoprostol group (P value>0.001).

Table 3: Comparison between the two groups regarding number of received doses for the whole group

Table 4: Comparison between the two groups regarding the number of received doses for the success of abortion.

This table shows number of doses needed till abortion occurs. In nitrate group 16 women received single dose, 45 women received two doses and 12 women received three or more doses. In misoprostol group only 7 women aborted by single dose, 11 women aborted by two doses and 44 women needed three or more doses for abortion to occur.

The difference between both groups was highly significant indicating that isosorbide mono nitrate decreases the number of doses of misoprostol needed for second trimesrter abortion (P value>0.001).

Table 5: Mean time of induction of abortion in both groups

This table shows the mean time of induction needed.

The mean time needed for abortion in Nitrate group was 10.72 hours, while it was 20.87 hours for misoprostol group.

There is a statistically significance difference indicating that the second trimester induction of abortion using isosorbide mononitrate with misoprostol takes much shorter time than misoprostol alone. The selected side effects were recorded positive when the patient needed medications to relieve her complaint. Among the reported side effects only headache showed significant difference with higher proportion among nitrate group (38.6%) compared to misoprostol group (8.8%).

Table 6: Proportion of selected side effects occurring in both groups

This table shows the adverse symptoms of both drugs