Management of Medical Termination of Pregnancy (MToP) up until the 7^th week of gestation in the Czech Republic

Summary

Objective:
In the Czech Republic (CR), it is possible, to carry out Medical Termination of Pregnancy (MToP) in the 1^st trimester since June 2014, in case a woman submits a written request for it and in case the ultrasound examination confirms an intrauterine singleton prosperous pregnancy, between day 42 and 49 of gestation, crown-rump length (CRL) of the embryo 2–9 mm. The aim of the study is to analyze the management of MToP up until the 7^th week of gestation in five centres in the CR.

Design:
Multicenter cohort (prospective) study.

Setting:
Department of Obstetrics and Gynecology, Palacky University Olomouc, Faculty of Medicine and Dentistry, University Hospital Olomouc; The Institute for the Care of Mother and Child, Charles University in Prague, Third faculty of Medicine; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, General University Hospital in Prague; Department of Gynecology and Obstetrics, Charles University in Prague, First faculty of Medicine, Hospital Na Bulovce, Prague; Department of Gynecology and Obstetrics, Masaryk University, Faculty of Medicine, University Hospital Brno.

Methods:
In 2014–2016, a total of 1820 pregnant women requested MToP. The diagnosis of an intrauterine singleton prosperous pregnancy was set by transvaginal ultrasound, CRL 2–9 mm. MToP was carried out by combination of mifepristone (600 mg orally) and misoprostol (400 mcg orally) within 48 hours. MToP follow up (exclusion of ongoing pregnancy) after 2–3 weeks was carried out by transvaginal ultrasound as well.

Results:
In 11.0% of women (201/1820) who requested MToP, CRL > 9 mm, unprosperous, multiple or ectopic pregnancy was diagnosed. In the remaining 1619 women MToP was carried out, but in 221 cases (13.7%) at least one additional pre-first visit was needed before the diagnosis of intrauterine singleton prosperous pregnancy CRL 2–9 mm could be established, in 19 cases (1.2%) two pre-first visits and in 5 cases (0.3%) even three. Gestational age was 42–49 days (average 47.1, median 47), the women were 14–47 years of age (average 30.7, median 30). In 20.8% of women (336/1619) MToP follow up was missed and of the remaining 1283 women, ongoing pregnancy (MToP failure) was diagnosed in 1.6% (24/1283), incomplete abortion in 6.5% (83/1283) and complete abortion in 91.9% (1179/1283). A subsequent surgical intervention was carried out in 7.1 % of women (91/1283).

Conclusion:
A medical facility performing MToP in the 1^st trimester should develop its own methodology in accordance with the legislation in force, Summaries of Product Characteristics, and recommendations of professional associations. The methodology should also include a method of evaluation of the result and management. The subsequent surgical intervention should only be performed in indicated cases. The main goal of MToP follow up is to exclude ongoing pregnancy (MToP failure), and the patient should be informed in detail about the risks involved and possibilities of their solution, it is necessary to obtain an informed consent.

Keywords:
medical termination of pregnancy, first trimester

INTRODUCTION

In the Czech Republic (CR), it is possible to carry out Termination of Pregnancy (ToP) in the 1^st trimester in case a woman submits a written request for it and in accordance with the specific legislation [1, 2]. The procedure can be done by a pharmacological or a surgical method. At the moment, medicinal products for two pharmacological methods that can be used to terminate pregnancy in the 1^st trimester (until 49^th, or 63^th day of the secondary amenorrhea) are authorized for use in the CR [15, 16, 17, 18], however, authorized medicinal products for the second method (until 63^th day) [17] are not currently available in the CR. Medical products for the first method (until 49^th day) are available in the CR since June 2014 [5, 6, 11, 14, 15, 16].

The aim of the study is to analyze the management of Medical Termination of Pregnancy (MToP) up until the 7^th week of gestation in five centres in the CR.

MATERIALS AND METHODS

The multicenter cohort (prospective) study was carried out in five centres in the Czech Republic (University Hospital Olomouc, The Institute for the Care of Mother and Child in Prague, General University Hospital in Prague, Hospital na Bulovce in Prague, University Hospital Brno).

In 2014–2016, a total of 1820 pregnant women requested MToP up until the 7^th week of gestation (Table 1).

The diagnosis of an intrauterine singleton prosperous pregnancy was set by transvaginal ultrasound, and the dating of pregnancy was carried out according to the crown-rump length (CRL) of the embryo. At CRL = 2 mm it is possible to prove a prosperous pregnancy (presence of blood circulation pulsation), and CRL = 9 mm corresponds to the 49^th day of secondary amenorrhea (Scheme 1).

MToP was carried out by administering the first medicinal product containing the active substance mifepristone 600 mg (Mifegyne^® 3 tablets of 200 mg each) in a single oral dose followed 36 to 48 hours later by the administration of the second medicinal product containing the active substance misoprostol 400 mcg (Mispregnol^® 1 tablet of 400 mcg) orally. After 14 to 21 days following the administration of the medicinal product with the active substance mifepristone (Mifegyne^®), a follow up transvaginal ultrasound examination was carried out to exclude ongoing pregnancy (Scheme 2).

Evaluation of the result

1. „Ongoing pregnancy“ – a medical abortion has failed, if the pregnancy continues,
2. „Incomplete abortion“ – presence of a non-vital embryo / fetus in the uterine cavity; another abnormal ultrasound finding in the area of uterine cavity or cervical canal, and simultaneously presence of clinical symtoms; persistent value of human chorionic gonadotropin (hCG) in serum of more than 1000 IU/l (positive low sensitivity urine hCG test),
3. „Complete abortion“ – a medical abortion is successful when the expulsion has occured without the need of any other observation (Expectant management) or additional treatment (misoprostol alone or Surgery).

Management

1. „Ongoing pregnancy“ – repetition of the pharmacological method – MToP (up until the 9^th week of gestation, CRL ≤ 25 mm), or surgical method – SToP (up until the 12^th week of gestation, CRL ≤ 55 mm); continuing the pregnancy – Prenatal care,
2. „Incomplete abortion“ – Expectant management or additional misoprostol or Surgery.

RESULTS

Out of the total of 1820 pregnant women who requested MToP up until the 7^th week of gestation, 8 women (0.4%) were diagnosed with a biochemical pregnancy of unknown location unprosperous, 147 women (8.1%) were diagnosed with a clinical intrauterine singleton prosperous pregnancy, but with CRL > 9 mm, 27 women (1.5%) were diagnosed with a clinical intrauterine singleton unprosperous pregnancy, 10 women (0.5%) with a clinical intrauterine multiple prosperous pregnancy, and 9 (0.5%) women with a clinical ectopic pregnancy (unprosperous). Therefore, in a total of 11.0% women (201/1820), it was not possible to carry out the procedure, and they were excluded from the study (Table 1).

In 1619 women a clinical intrauterine singleton prosperous pregnancy, CRL 2–9 mm, was diagnosed, and MToP was carried out, but in 221 cases (13.7%) at least one additional pre-first visit was needed before the diagnosis could be established, in 19 cases (1.2%) two pre-first visits and in 5 cases (0.3%) even free. Gestational age was 42–49 days (average 47.1, median 47), the women were 14–47 years of age (average 30.7, median 30), of them, 171 women were at an age of 40 and more (10.6%) (Table 1).

A total of 20.8% of women (336/1619) did not attend the follow up ultrasound examination to exclude ongoing pregnancy, and the result thus could be evaluated in 1283 women only. Ongoing pregnancy (MToP failure) was diagnosed in 1.6% (24/1283), Incomplete abortion in 6.5% (83/1283) and Complete abortion in 91.9% (1179/1283). A subsequent surgical intervention was carried out in 7.1 % of women (91/1283) (Table 1).

DISCUSSION

„Unwanted Pregnancy“ – diagnosis

In 11% of pregnant women who requested MToP, it was not possible to carry out the procedure: 8% of women were diagnosed with an intrauterine singleton prosperous pregnancy, but according to the dating, the pregnancy corresponded to more than 49^th day of secondary amenorrhea, and it was not possible to carry out the procedure by pharmacological method anymore (the available medicinal products are authorized for administration until the 49^th day of secondary amenorrhea – the so-called „on-label use“, afterwards, the intervention can only be performed by a surgical method) [15, 16]; 2% of women were diagnosed with an unprosperous pregnancy, and the procedure should therefore be reimbursed from the public health insurance funds (medical reasons are present – the so-called „medical indication“, however, there is no reimbursement mechanism determined for the pharmacological method) [3, 4]; 1% of women were diagnosed with an intrauterine multiple prosperous pregnancy (medicinal products are not authorized for use in multiple pregnancy – the so-called „off-label use“) [15, 16]. From the medical point of view, the pharmacological method can be used in all the above mentioned cases with the exception of ectopic pregnancy, however, organizational, legal and economic aspects pose a problem [1, 2, 3, 4, 5, 7, 8, 9, 10, 14, 18, 19, 20, 21].

An intrauterine singleton prosperous pregnancy can only be diagnosed by ultrasound, and at the earliest, from the 42^nd day of the secondary amenorrhea (presence of blood circulation pulsation in the embryo, CRL = 2 mm). The pharmacological method can therefore be offered to a pregnant woman only from the 42^nd to 49^th day of secondary amenorrhea (CRL 2–9 mm). From the organizational point of view, if the patent comes earlier, at least one more clinical visit is necessary (10–28% of cases in the individual centres), on the other hand, if she comes later, the pharmacological method cannot be carried out (5–11% of cases in the individual centres). In the case of an „unwanted pregnancy“ it is thus very important for a woman to come to the health facility carrying out the pharmacological method as soon as she finds out that she is pregnant. From the medical point of view however, it is not necessary to confirm a prosperous pregnancy, and the pregnancy can also be terminated by the pharmacological method in the 1^st trimester even after the 49^th day of secondary amenorrhea. However, this means using the authorized medicinal product in a manner that is not in accordance with the Summary of Product Characteristics, i.e. the so-called „off-label use“, and in case there are no medical reasons for it, this procedure means an unnecessary risk for the doctor from the legal point of view. On the other hand, in case there are medical reasons – the so-called „medical indication“ and the intervention should be reimbursed from the public health insurance funds, there is no reimbursement mechanism determined for the pharmacological method. The gynecologic and obstetric „medical indications“ for the ToP at a request of the patient in case the pregnancy does not exceed 12 weeks include e.g. a conception after the 40^th year of age (6–13% of cases in the individual centres), a conception after two previous cesarean deliveries, or a failure of intrauterine contraception [1, 2].

MToP follow up examination after 2–3 weeks – evaluation of the result and management

A total of 21% of women (7–26% in individual centres) did not attend the follow up ultrasound examination, and the result thus could not be evaluated.

An ultrasound examination can reliably diagnose/exclude ongoing pregnancy or presence of a non-vital embryo/fetus in the uterine cavity. What poses a danger, however, is the high false positivity rate in the evaluation of abnormal ultrasound finding in the area of uterine cavity or cervical canal. The surgical intervention should only be indicated if clinical symptoms are present (mainly heavy or persisting bleeding), not on the basis of an abnormal ultrasound finding.

The value of serum hCG of more than 1000 IU/l (positive low sensitivity urine hCG test) cannot reliably diagnose/exclude ongoing pregnancy, or presence of a non-vital embryo/fetus in the uterine cavity, and consequently it is always necessary to perform an ultrasound examination. Moreover, the serum hCG value of more than 1000 IU/l can be expected in MToP follow up in approximately 10% of women even in the case of a „Complete abortion“. However, the value of serum hCG of less than 1000 IU/l (negative low sensitivity urine hCG test) can reliably exclude the ongoing pregnancy [Slunska et al., unpublished results].

The low sensitivity urine hCG test thus seems to be the most effective for the purposes of MToP follow up, because it is positive only at the serum hCG value of more than 1000 IU/l. A woman can perform the test herself, it is cheap and the negative result reliably excludes ongoing pregnancy. In the case of a positive result (approx. 10% of cases), or presence of clinical symptoms, it is possible to perform an ultrasound examination.

Moreover, it is apparent from our results that although it is always recommended to women to undergo the follow up ultrasound examination, many of them do not come for it at all. It is therefore very important that a woman is informed in detail about the importance of MToP follow up, and her informed consent is necessary.

MToP failure „Ongoing pregnancy“ – informed consent and management

The main goal of MToP follow up is to exclude ongoing pregnancy, because in case the pregnancy continues, it is possible to proceed, depending on the actual gestational age and the patient‘s wish, in the following way: 1) repetition of the pharmacological method – MToP (up until the 9^th week of gestation, CRL ≤ 25 mm), 2) surgical method – SToP (up until the 12^th week of gestation, CRL ≤ 55 mm), [13], 3) in case the patient decides to continue the pregnancy, it is necessary to inform the patient in detail about the potential risk of abnormal fetus development (approx. 1% of cases, damage to central nervous system and/or extremities have been reported) [12], it is necessary to obtain the informed consent from the patient, it is recommended to make a detailed fetal anomaly scan by ultrasound [15, 16] (Scheme 1).

MToP failure „Ongoing pregnancy“ was diagnosed in 2% of women (1–3% in the individual centres). In one case the pharmacological method was repeated, however, without success, and the pregnancy was subsequently terminated by the surgical method. In one case the patient decided to continue the pregnancy and gave birth to a healthy child. In the other cases, the pregnancy was terminated by the surgical method. The Summary of Product Characteristics (SmPC) reports a total of approximately 1–2% of cases, and subsequently, the surgical method should be preferred, because the pharmacological method probably fails due to an individual non–responsiveness to the active substances [15, 16].

„Incomplete abortion“ – diagnosis and management

„Incomplete abortion“ was diagnosed in a total of 7% of women (2–11% in the individual centres). SmPC reports a total of approximately 2–3% of cases [15, 16]. This includes the following subunits: 1) presence of a non-vital embryo/fetus in the uterine cavity was diagnosed in 2% of women (1–3% in the individual centres) and in most cases, a subsequent surgical intervention was performed, SmPC reports approximately 1–2% of cases, and the Expectant management or administration of additional misoprostol should be preferred (according to the recommendations of WHO and/or FIGO, however, this is the use of a medicinal product that is not in accordance with the SPmC, the so-called „off-label use“) [7, 8, 9, 16, 19, 20, 21], 2) another abnormal ultrasound finding in the area of uterine cavity or cervical canal, and simultaneously presence of clinical symptoms were diagnosed in 5% of women (1–10% in the individual centres), and in most cases, a subsequent surgical intervention was performed, which however was indicated only on the basis of an abnormal ultrasound finding without presence of clinical symptoms, SmPC reports approximately 1–2% of cases and the surgical intervention should be indicated only if clinical symptoms are present (mainly heavy or persisting bleeding) [15, 16], 3) persistent value of serum hCG of more than 1000 IU/l (positive low sensitivity urine hCG test) were not evaluated in the study in the MToP follow up.

Subsequent surgical intervention

After MToP up until the 7^th week of gestation, the subsequent surgical intervention was performed in a total of 7% of women (4–12% in the individual centres). SmPC reports a total of approximately 5% of cases [15, 16].

CONCLUSION

A medical facility performing MToP in the 1^st trimester should develop its own methodology in accordance with the legislation in force, Summaries of Product Characteristics, and recommendations of professional associations. The methodology should also include a method of evaluation of the result and management. The subsequent surgical intervention should only be performed in indicated cases. The main goal of MToP follow up is to exclude ongoing pregnancy (MToP failure), and the patient should be informed in detail about the risks involved and possibilities of their solution, it is necessary to obtain an informed consent.

Petra Slunska, MD

Department of Obstetrics and Gynecology

University Hospital Olomouc

I. P. Pavlova 6,

775 20 Olomouc,

Czech Republic

E-mail: strasilova.petra@seznam.cz

corresponding author

Professor Marek Lubusky, MD, PhD, MHA

Department of Obstetrics and Gynecology

University Hospital Olomouc

I. P. Pavlova 6,

775 20 Olomouc, Czech Republic

E-mail: marek@lubusky.com