Comparative study for efficacy of termination in first trimester pregnancy using Misoprostol and Mifepristone

Background: The best method for medical abortion depends fundamentally on pregnancy duration and the fi nal result varies on medical stuff’s experience. The aim of this study pertained to investigate the effectiveness of medical abortion using misoprostol, mifepristone or the combination of them. Patients and methods: During the period April 2007 to December 2017, 200 women with pregnancy until 49 days after LMP (last menstrual period) underwent medical termination by using 600 mg mifepristone (RU 486) (Mifegyn) Group A1 per os vs 800 mcg misoprostol (Cytotec) A2 and in other 200 pregnant women, duration between 49-63 days was administrated using 600 mg mifepristone followed 48 hours later 800 mcg misoprostol B1 vaginaly vs. only misoprostol B2. All participants were consistent with surgical abortion if deemed necessary and a transvaginal ultrasound was performed to confi rm an intrauterine pregnancy before the medical administration. The indications for the abortion were as following: missed abortion, endometrial death, spontaneous and induced abortions. Results: According to our study, there was not a case needed to undergo surgical abortion. Common side effects like nausea, vomiting, pain and moderate vaginal bleeding were noticed without the need of hospitalization. Bleeding was occurred earlier in Group A1 compared to Group A2. In addition, abortion started about 3.5 hours earlier in Group A1 compared to Group A2. Similarly, time between administration and abortion was 50% shorter in Group A1 compared to Group A2. The duration of bleeding in Group B1 in Group B2 was similar in the two groups. Analgesia was not necessary for any participant, while repeat administration was more than 7 times more frequent in Group B2 compared to Group B1. Conclusion: The combination of mifepristone and misoprostol and the single administration of mifepristone are safe and effective for medical termination of pregnancy in early fi rst trimester. Research Article Comparative study for effi cacy of termination in fi rst trimester pregnancy using Misoprostol and Mifepristone Georgi Stanulov1, Xanthi Anthoulaki1, Dorelia Deuteraiou1, Anna Chalkidou1, Grigorios Trypsianis2, Werner Rath3, Roland Csorba3, Georgios Galazios1,4 and Panagiotis Tsikouras1* 1Department of Obstetrics and Gynecology, Democritus University of Thrace, Greece 2Department of medical statistic, Democritus University of Thrace, Greece 3Faculty of Medicine, Obstetrics and Gynecology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, D-24105 Kiel 4Department of Obstetrics and Gynecology, Clinicum Aschaffenburg, Teaching Hospital University of Würzburg, Germany Received: 24 July, 2018 Accepted: 21 August, 2018 Published: 22 August, 2018 *Corresponding author: Panagiotis Tsikouras, Associate Professor Obstetrics and Gynecology, Democritus University of Thrace, Greece, Email id:


Introduction
The induced abortion rate is associated to a variable reported incidence, lower in countries with satisfactory organized family planning services and higher in poor societies when social and economic pressures led the people to reach their fertility goals through the availability of natural family planning contraception's methods resulting unintended pregnancies [1,2]. The estimated abortion rate around the world referred average by 3.5% [3]. Epidemiological studies consulted to the confi rmation that the human reproductive system is fi nely tuned to produce a minimum optimum interval between pregnancies. If pregnancy occurs in this time interval due to not using contraception's methods is associated to improving infant and maternal mortality and morbidity [4].
The management of unwanted pregnancies and the subsequent contraception shas a great meaning for the concerning women especially the teenagers which should be educated regarding the contraception's options to protect their fertility. The major challenge in the present time remains to ensure the effective methods of inducing abortion widely and make available to majority of women in the world. The induced abortion rate beyond the 1 st trimester is less than 15% of all refer procedures in the world and especially in European area ranged between 2 and 10%. Unfortunately was estimated that about twenty two million unsafe abortions were performed every year and 98% appear in developing countries [5][6][7]. Unsafe abortion is defi ned as a pregnancy termination in which the women underwent lacking and not conform to minimal recommend medical standards [5,6]. As part of improving maternal health and international development goals and targets unsafe abort must be dealt to prevent maternal mortality and morbidity [7]. The health consequences of unsafe abortion are based on the method of abortion used, gestational age and fi nally skills of the abortion provider [8]. Although contraceptive use led to reduce the number of unintended pregnancies, however approximately 33 million contraceptive users report about accidental pregnancy. Approximately 85 million (41%) women from 208 million total which estimated to be pregnant each year worldwide were noticed as unintended [9][10][11]. The recommend medical method for induced abortion include mifepristone alone or in combination with misoprostol [12][13][14][15][16][17][18][19][20]. To investigate the effectiveness and safety of pregnancy termination as medical abortion based pharmacological procedure without hospital stay.

Patients and Methods
All participants were consistent with surgical abortion if deemed necessary and a transvaginal ultrasound was performed to confi rm an intrauterine pregnancy before the medical administration. In the upper described protocol fi rst trimester pregnancies until 9 weeks or 63 days gestational age since the 1 st day of the last menstrual period are included, for medical termination.
The indications for the abortion were as following: missed abortion, embryonic demise, spontaneous and induced abortions. We obtained approval by the institutional ethics committee and all eligible patients gave their written consent after receiving relevant information including the potential adverse effects of medical pregnancy termination. Four hundred eligible participants were selected from the hospital medical records total seven hundred young pregnant women, who visited the family planning centre Democritus University of Thrace, Greece for abortion induction in the study time. Data were extracted by chart review that included patient information. All patients had signed a written consent after detailed information about abortions induction modus. Pregnant women were arranged in two groups. The group A includes pregnant women until 49 days after LMP in which pregnancy termination will be performed either with four tablets (800 mcg) Misoprostol placed in the posterior vaginal fornix or three tablets (600mg) Mifepristone administrated orally. In the group B were enrolled pregnant women with gestational age between 49 until 63 days in which the pregnancy termination procedure was performed using either the combination of Mifepristone and Misoprostol or Misoprostol alone ( Figure 1). In cases of medical combination three tablets Mifepristone (600mg) were taken orally on fi rst day and 48 hours following ingestion of Mifepristone, 800 mg Misoprostol were placed vaginally in the participants ( Figure  1). To investigate the effectiveness of the two medical methods of pregnancy termination in fi rst trimester were examined and evaluated the following control parameters like as: Start bleeding in the two main groups, start the abortion in the two main groups, completion of abortion in major groups certifi ed after seven days with transvaginal ultrasound, necessity of surgical abrasion or aspiration after drug abortion due to fetal remnants, recording of side effects (fever, major bleeding, vomiting, nausea, blood transfusion) in the two main groups, effect on the menstrual cycle for three months after the medical abortion certifi ed with a questionnaire and ultrasound checks once a month at the Outpatient Clinic of the Family Planning of the DUTH. Exclusions criteria were the following:

Statistical analysis
Statistical Package for the Social Sciences (SPSS), version 19.0 (IBM) was used for statistical analysis. The normality of quantitative variables was examined with Kolmogorov-Smirnov test. All quantitative variables were determined as the mean ± standard deviation (SD). Categorical variables were determined as frequencies (and percentage). Student's t test and chi-square test were used to determine differences between two groups of patients. Odds ratios (OR) and their 95% confi dence interval (CI) were estimated by mean of logistic regression models as a measure of association between categorical variables. All assays were two tailed and statistical signifi cance was considered for p values less than 0.05.   The two groups were also similar in terms of height (p=0.975) and weight (p=0.893) ( Table 1). The vast majority of women in both groups were primipara (Group A1: 74.2%%; Group A2: 82.0%) and null gravidity and parity (Group A1: 87.6%; Group A2: 93.7%). There were no statistically signifi cant differences in the number of previous pregnancies (p=0.270), the number of previous deliveries (p=0.137) and the prevalence of missed abortion (p=0.137) between the two groups of women (Table 1).

Sample
Finally, the distribution of women according to education level and to social status was similar in both groups (p=0.669 and p=0.445, respectively) while the majority of women in both groups were smokers (Group A1: 59.6% vs Group A2: 58.6%, p=0.887).

Discussion
Medical abortion has been investigated as an option for premature termination of undesirable pregnancy and avoidance the risk of anesthesia, surgical injuries of cervix, uterus, other organs as well as the cases of uterine perforation (0.12-1.98%), blood transfusion (0.5%), necessity of repeating   surgical intervention (1%) and ongoing pregnancy due to failure of surgical intervention (0.2%) [19][20][21][22]. Also, the risk of adhesions of the uterus in both the endometrial cavity and the minor pelvis near the uterus is avoided by drug abortion.
Disadvantages of this method are close medical monitoring, frequent control with ultrasound and biochemical parameters, prolongation of vaginal bleeding and pelvic pain.
It is a good alternative and involves avoiding surgical interruption of pregnancy by cervical dilation and vaginal scarring. It is estimated that over 50% of pregnancies in humans will not develop further and will not get the character of clinically apparent pregnancy [23]. It is also estimated that 15% of pregnancies will develop clinically but will result in what is called "spontaneous abortion" [24]. In recent years, Clinical judgement is required in cases using corticosteroid for a long time [26]. For selection of the medical abortion as most appropriate method is important the following points: determination of pregnancy length, confi rmation of intrauterine pregnancy, the exclusion of ectopic pregnancy (occurrence 1,5-2% of pregnancies). In suspicious cases like previous ectopic pregnancy, pelvic infl ammatory disease and pregnancy in the presence of an intrauterine device, further examinations as vaginal ultrasound and serial human chorionic gonadotropin measurements are necessary [26,27].
To avoid failed termination of pregnancy is of great importance not the procedure undertaken at a very early gestation age.
Otherwise the decidua only be evacuated and the conceptus be not dislodged [26,27]. The active metabolite from misoprostol is misoprostol acid that induces contractions of the uterus and cervical ripening, opening which led to expulsion of pregnancy. Oxytocin increases the contractility of the uterus but is not in itself capable of to lead to cervical maturation. Oxytocin receptors are found in myometrium and out of pregnancy, however, receptor protein mRNA begins to be detected at 13 weeks of gestation and increases during pregnancy reaching levels 300 times higher than out-of-pregnancy levels [32].
Oxytocin and secure medicines needed in a healthcare system and was the fi rst drug which was used to stop a gestation [37][38][39].
A safe option to surgical miscarriages is the misoprostol that can be applied alone or in combination with other drugs (such as mifepristone). Medical abortion has the benefi t of being less invasive, better accepted by women and more discreet. It is desirable for some, because the drugs usually cause miscarriage and surgical intervention is rarely required. The World Health Organization provides clear and easily accessible guidelines about how to use, the benefi ts compared to other methods, and the potential risks of misoprostol when used to induce abortion. There are also local guidelines that differ and are tailored to different needs depending on the country [40][41][42]. As will be shown in this paper, misoprostol is more effective when used in combination with mifepristone than used as a monotherapy, that's why there are several protocols for the combination of the two drugs. 1% of women who undergo medical abortion with misoprostol may present severe haemorrhage requiring medical care or hospitalization [40][41][42]. Some women may have an ectopic pregnancy that could be diagnosed prior to treatment. There are pregnancies that continue after misoprostol administration as a failure of the method. 12% of these embryos are more likely to have congenital abnormalities. For this reason, a more effective abortion method usually follows, such as uterine curettage. So, it is necessary to inform the woman, that although complete abortion is not certain, stopping pregnancy after the application is recommended [40][41][42]. Misoprostol can also be used to prepare the cervix, before the surgical abortion. There are indications that the all procedure is facilitated, while later complications from cervical trauma such as premature births are reducing. Especially effective is when misoprostol is applied in the second trimester, where it can be combined with cervical dilation such as Lamicel or Dilapan. In any case, we have to think about the possibility of next pregnancy and to protect in every way the woman's genital system [40][41][42].
Nowadays, misoprostol's role is so important that is included into the World Health Organization's List of Essential Medicines [43][44]. In the 1990s, a gestation discontinuation with misoprostol combined with abortion drugs took place successfully in approximately three million women. Many authors report that the simultaneous administration of misoprostol with either methotrexate or mifepristone has high effi cacy for the fi rst trimester termination of pregnancy, with results ranging from 83% to 96% for the combination of methotrexate and misoprostol and 92% to 96% for the combination of misoprostol and mifepristone [45][46][47][48].
Mifepristone is an antagonist of progesterone receptors and is administered at a 600 mg oral dose or another 200 mg oral combination in combination after 36 hours of two doses of misoprostol 400 micrograms per dose transvaginal [45][46][47][48]. According to another study, 200 mg mifepristone was administered oral in combination with 800 mcg/ml subcutaneously or transvaginal. Studies on the metabolism of mifepristone concluded that no signifi cant differences in blood concentrations within 48 h of administration with oral doses ranging from 100 to 800 mg without any infl uence to the safety and effi cacy [49][50][51][52].Induced abortions were performed in pregnancies of less than 49, 50-56, 57-63 days or <9 weeks [53][54].
Mifepristone combined with a prostaglandin analogue (misoprostol or gemeprost) is a treating option extensively used for medical abortions. During the years, this combination has been proven to be safe and effective. Guidelines from Royal College of Obstetricians and Gynecologists characterize this treatment option as an effective and proper method of terminating pregnancy. In contrary, the monotherapy with mifepristone is less effective, resulting in abortion only in 8% to 46% of pregnancies within 1-2 weeks. This is the cause it is almost always used in combination with misoprostol [55]. Mifepristone in combination with other drugs, is also used as treatment of hyperglycaemia caused by high levels of cortisol in adults with endogenous Cushing's syndrome who have diabetes mellitus type 2 or glucose intolerance and have failed to surgery or cannot undergo surgery [56]. Mifepristone can also be used for emergency contraception, although its use is not widespread [57].
Abdominal pain, uterine cramps and vaginal bleeding for nine to sixteen days are referred by almost all women who used the mifepristone/misoprostol regimen. Up to 8% of women have showed some kind of bleeding for 30 or more days. Among the less common side effects are referred nausea, vomiting or tendency to vomit, diarrhoea, dizziness, fatigue and fever [58][59][60]. Pelvic infl ammatory disease is a serious but not very often complication. Massive bleeding and inadequate emptying of uterine cavity require further management (such as endometrial ablation surgery) and sometimes hospitalization. Mifepristone is clearly contraindicated in ectopic pregnancy, adrenal insuffi ciency, bleeding disorders, hereditary porphyria, and long-term corticosteroid therapy [61,62]. Always some pregnancies have been undesirable. Many times, either because of rape, career, or economic reasons, women or their families considers this pregnancy unwanted [61,62]. Historically there have been several ways for an unwanted pregnancy to end. Some of them unfortunately were dangerous to the health and life of the pregnant woman [61,62]. Clearly the best treatment for unwanted pregnancy is to avoid it. With the advancement of family planning and contraception, the greatest number of unwanted pregnancies should be avoided. Unfortunately this is not always feasible. However, we must emphasize that every euro given to prevention dramatically reduces health care costs for complications and the treatment of infertility [61,62].
There were ways of limiting the woman, who wants to end a pregnancy. The prohibition of abortion, apart from the fact that it is considered a limitation of women's rights, is associated with an increase in illegal abortions. This increase hides major dangers for women's health and life, such as septicemia and peritonitis. Damage to society is, on the one hand, the immediate need to cover hospitalization, on the other hand, clearly greater and longer-term health cover in the event of disability or death [63,64]. In most Islamic countries abortion is forbidden and there are very severe penalties (up to death penalty) for any woman trying to end an unwanted pregnancy. The problem is more than doubled and the fact that not all methods of contraception are acceptable to the Koran.
With the rise of Muslims in Europe, it is increasingly necessary for doctors of European countries to deal with cases that were considered outdated decades ago [63,64]. There are Catholic countries in both Latin America and Europe, where there is a total or partial ban on abortion.
In some countries in Europe, such as Ireland and Malta, abortion is forbidden even when the embryo has abnormalities, even in cases of rape or incest. In most European countries abortion is permitted in some cases (embryo abnormalities, maternal disability, social reasons, as well as rape and incest).
In some countries such as Greece, Bulgaria, Denmark, France, Germany, Austria, the Czech Republic, Slovenia, Slovakia, Sweden, Spain, Portugal, Estonia, Latvia, Lithuania and Luxembourg mother abortions are also permitted. In Italy, Poland, Hungary, the Netherlands and Belgium abortion is prohibited [63,64].
With advances in medicine over the last decades, endometrial abortion was predominantly a method of ending unwanted pregnancies. Unfortunately, although it's pretty safe, neither is this method perfect. Some of its disadvantages are that it requires in-patient care, sometimes hospitalization, and increased costs. As a surgical operation, curettage also carries the risk of uterine and endometrial injury. There are only a few cases that women have infertility problems after scraping [63,64]. Medical termination of pregnancy is a relatively safe procedure associated to low overall mortality less than 2 per 100000 and low morbidity [63,64]. Early complications include retained products of conception (04%-2.9%), hemorrhage, and long term following medical procedure as following: pelvic infl ammatory disease and subfertility subsequent light for dates infants, ectopic pregnancy due to infl ammation, psychiatric squeal [63,64]. In our collective were noticed only simple complications without necessity of hospital stay. To Pregnant women who are contemplating abortion should be adequate informed, counseling from a competent trained professional health care in family planning centers with great experience and comprehensive knowledge relate to various methods of abortion. The family planning centers must be provided information to each woman regardless from age religion or circumstances in a way that she understand to allow the adequate choice and decision about the whether to have abortion and the suitable method. Information, counseling and abortion procedures should be provided as promptly as possible without undue delay due to greater safety at earlier gestational ages.