Resolution of the Advisory Board on the subject: Multicenter Open-Label Observational Program to Research on Predictors of Pregnancy Rate in Assisted Reproductive Technology in the Russian Population According to Actual International and National Guidelines (IRIS study)

On 26 September 2019, in Moscow, within the framework of the XХ Anniversary All-Russian research and educational forum “Mother and Child-2019”, the Expert Board meeting on the use of progestogens in reproductive medicine took place.

The participant list of the meeting included: G.Т. Sukhikh, L.V. Adamyan, V.N. Serov, E.N. Andreeva, I.I. Baranov, N.V. Bashmakova, V.F. Bezhenar, E.Anat. Kalinina, E.Andr. Kalinina, D.P. Kamilova, E.V. Kvashnina, I.Yu. Kogan, I.E. Korneeva, V.S. Korsak, A.I. Malyshkina, I.V. Molchanova, T.A. Nazarenko, Ya.I. Olofsson, T.I. Pestova, N.M. Podzolkova, N.V. Protopopova, N.F. Prokhorenko, V.E. Radzinsky, N.I. Tapilskaya, M.A. Shakhova, E.V. Shikh, M.I. Yarmolinskaya.

Meeting participants noted that in spite of rampant development of diagnostic and treatment methods, at the present time, management of patients with a personal history of miscarriages and infertility still remains one of the most topical medical issues [1, 2].

In the last few years, owing to a host of reasons, there has been a dramatic decline in fertility rate in Russia. Different measures toward normalization of the demographic situation have been undertaken at the state level. High hopes are placed on the abilities of obstetrics and gynecology services in our country. Specifically, such measures include preserving reproductive potential and careful management of pregnancy, as nowadays every case of pregnancy is highly valuable. In this connection, drugs pharmaceuticals belonging to the pharmacological class of progestogens are of a considerable interest [4, 5, 26, 38].

Progestogens form a large and non-uniform class of drugs which are widely used in gynecology and reproductive medicine. Only a few progestogens are used in pregnant women, and they differ across the group in their method of administration, chemical structure, range of registered therapeutic indications and effectiveness when used in different clinical situations. In Russia, micronized progesterone and dydrogesterone are allowed to be used and often applied in pregnancy; progesterone injections are rather less common [1, 2, 38, 39].

The existing evidence base allows us to make conclusions about the effectiveness of progestogens in reducing the risk of threatened miscarriage and recurrent pregnancy loss. In this connection, this class of pharmaceuticals, the progestogens mentioned above, are recommended in Russia for the prevention of recurrent pregnancy loss [2, 5, 6]. According to results of the largest appropriate randomized clinical trials with progestogens: the rate of live births in threatened miscarriage is 88% with dydrogesterone comparing with 72% without progestogen (ОR = 1.22; p < 0.05) [13], and in recurrent miscarriage 93% with dydrogesterone comparing with 83% with placebo (ОR = 1.12; p < 0.05) [12, 23]; in threatened miscarriage the live birth rate with vaginal bioidentical progesterone was 75% comparing with 72% in the placebo group (ОR = 1.03; p = 0.08) [15, 17], and in recurrent miscarriage such figures were 66% and 63%, respectively (ОR = 1.04; p =0.45) [14]. Numerous meta-analyses [18–23], as well as current European and Russian guidelines, confirm positive results with using progestogens in terms of prevention of pregnancy loss [5, 9, 10, 11, 24, 39, 45].

Micronized progesterone is registered in Russia and used for prevention of preterm labor after 22 weeks of pregnancy, as in several studies and meta-analyses it has demonstrated effectiveness by reducing risk of preterm labor at up to 34 weeks of pregnancy, whereas studies with dydrogesterone for the same therapeutic indication are scarce to it is not therefore possible to make definite recommendations at present. [17, 24, 39].

Progestogens are widely used in pregnancy indications and treatment of infertility caused by luteal phase deficiency in different diseases [1, 27, 38]. Dydrogesterone has also demonstrated effectiveness in the treatment of endometriosis-associated infertility, and allowing treatment of pain associated with endometriosis without suppression of ovulation, thereby possibly allowing pregnancy to occur even during the course of treatment [38, 43, 44, 51].

In the last 40 years the treatment options for infertility significantly widened, which is primarily due to the implementation of assisted reproductive technologies (ART) and, specifically, in vitro fertilization (IVF). Thanks to the ART programs, it can be inferred more than 10 000 000 IVF babies have been born worldwide to date. Although the effect of ART on Russian demographic parameters is not very pronounced, its contribution grows on an ongoing basis, and, according to the Russian Association for Human Reproduction (RAHR), approximately 2% of children, i.e. every fiftieth child, is born in Russia with the aid of ART [3, 4, 26, 52, 53].

Different factors influence the performance of the IVF programs [3, 8, 38], such as:

Uncontrollable factors, which cannot be changed for a given patient (age, ovarian reserve, presence of somatic and gynecologic pathology);

Controllable factors which can be influenced by providing sensible care solutions including physician’s qualification, stimulation protocols and drug dosage, endometrial condition, psychological and other preparation, options for luteal phase support, assisted reproduction laboratory manuals.

One of the recognized factors toward improving the IVF success rate is the luteal phase support [30]. In 2019, the new international (ESHRE) and Russian (Russian Society of Obstetricians and Gynecologists, RSOG) ART clinical guidelines have been published which recognized the necessity of prescription of effective progesterone preparations such as bioidentical progesterone (injections or micronized intravaginal progesterone) or dydrogesterone [3, 8].

Comparative studies of these progestogens were carried out using different dosages and treatment regimens [30, 33]. It was found that the use of dydrogesterone at a dose of 30 mg/day in IVF cycles can be associated with higher rates of pregnancy [29]. In this connection a large research LOTUS program was conducted which included two randomized clinical trials with recruitment of more than 2000 patients in 12 countries [31, 32, 34]. Within the framework of these studies the data were obtained which were required for drug registration by therapeutic indication “luteal phase support in ART” [37, 42].

Based on the meta-analysis of Individual Participant Data of the LOTUS clinical program (LOTUS I and LOTUS II studies), the pregnancy rate was 38.1% for dydrogesterone and 34.1% for vaginal micronized progesterone (ОR = 1.32; 95% CI = 1.08–1.61; p = 0.0075), and live birth rate was 34.5% and 31.2%, respectively (ОR = 1.28; 95% CI = 1.04–1.57; p = 0.0214) [34, 35]. It is important to notice, that some patients may prefer the convenience of orally taken dydrogesterone administration to intravaginal progesterone use, which may also significantly affect the choice of the drug [8,45].

Today much attention is paid to the safety of the drugs used during pregnancy [3, 8, 9]. Some retrospective cohort studies have reported about possible risks associated with the use of different progesterone formulations during pregnancy [46–49]. That is why in modern randomized clinical trials, prospective studies and meta-analyses, as well as in clinical recommendations, thorough evaluations of the safety aspects were carried out with a high methodological level according to international standards: there was no statistically significant difference in occurrence of negative effects found in children born to mothers who received bioidentical progesterone or dydrogesterone during pregnancy when comparing to each other or with active drug and placebo/no treatment [2, 8, 11–15, 18–23, 33, 34, 36, 37, 50].

According to the data from a large-scale study of Russian demographic situation, owing to its high clinical effectiveness dydrogesterone use in all women with miscarriage indications and in the IVF procedures may yield a demographic effect in the form of additional birth of 23 thousand children each year [40, 41].

The manufacturing of Duphaston® in Russia started in 2018 in Belgorod. A new production line to localize the full-cycle manufacturing of the drug compliant with the international quality standards and requirements of good manufacturing practice of Abbott [43], which is an obvious positive factor in increasing drug availability for Russian patients. Dydrogesterone has been included on Russia’s list of vital and essential drugs (VED), and its price is subject to strict state regulation [42, 43].

Dydrogesterone has been used in clinical practice worldwide for more than 60 years, and the experience with its use rests on results obtained in more than 113 million women including more than 20 million women receiving treatment during pregnancy [32, 37]. Dydrogesterone is used to decrease the risk of pregnancy loss in threatened and recurrent miscarriage, as well as in infertility caused by luteal phase deficiency, also, for luteal phase support in IVF cycles both in Russia and abroad [24, 37, 42]. The experience with dydrogesterone use by Russian physicians as the component of treatment regimens employed in IVF cycles, is limited [45].

In this context, Abbott has initiated a multicenter, open-label, observational clinical study to evaluate the probability of pregnancy in IVF cycles using dydrogesterone in accordance with the instruction for luteal phase support and international and Russian clinical guidelines [3, 8, 42]. This study is aimed to enable development of a model for prediction of a positive pregnancy results after IVF and successful live birth as a function of different controllable and uncontrollable factors. Also, the data on tolerability of, and adherence to dydrogesterone therapy will be obtained in all kind of patients undergoing “fresh” IVF cycles, which can be seen in the real-world clinical practice. The Experts discussed and proposed suggestions, and approved with amendments, the concept of the IRIS study protocol which will be further submitted for coordinated approval to regulatory bodies and published on ClinicalTrials.gov. The study is scheduled to be conducted in 2020–2021 with subsequent publication of its results.

The study results will further allow us to obtain additional important data on ART aiming at further improvement of infertility treatment.