Progestogens safety in the treatment of infertility and during pregnancy: new data in 2023. Position of the Russian Society of Obstetricians and Gynecologists

The Plenum of the Russian Society of Obstetricians and Gynecologists (RSOG) and the XVI Regional scientific and educational forum “Mother and Child” were held in St. Petersburg. A discussion of current technologies in the treatment of infertility and miscarriage as part of the session “Modern Reproductive Medicine: High Technologies in Clinical Practice” on June 29th, 2023, took place. Particular attention was paid to new data on the efficacy and safety of progestogens in reproductive medicine.

The President of the RSOG, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor V.N. Serov noted the position of progestogens in the current clinical guidelines of the RSOG, where they are recommended for use in threatened and recurrent miscarriages, as well as in assisted reproductive technologies (ART) and, based on a thorough analysis of evidence-based medicine data, it is indicated that "the safety profile of dydrogesterone and progesterone in the recommended doses in early pregnancy is well studied and is favorable (no evidence of an increase in the incidence of adverse events on the part of the pregnant woman and the fetus compared with no therapy/placebo or direct comparison of these remedies)”[1–5]. When preparing RSOG clinical guidelines, the aspects of the effectiveness and safety of progestogens were evaluated by experts in strict accordance with international standards based on a comprehensive analysis of all available scientific evidence, taking into account the availability of the remedy in a particular country and its instructions for medical use [1–5]. Clinical guidelines have been developed and approved to improve the quality of medical care in Russia - at present there is no evidence- based need to revise them, while the profile section of the RSOG website [6] is open to accept proposals for changes to existing clinical guidelines in subsequent revisions, experts carefully study each incoming proposal in accordance with the methodological recommendations of the Ministry of Health of Russia on the development of clinical guidelines [7].

Director of the Institute of Reproductive Medicine of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Doctor of Medical Sciences, Professor T.A. Nazarenko presented new information about an international multicenter study IRIS, which evaluated the efficacy of dydrogesterone and its safety profile in relation to the fetus and newborns in the use of ART in 1150 patients in Russia and Kazakhstan in 2019–2022 [8, 9]. The preliminary results of the IRIS study correlate with previously known data on the safety of dydrogesterone during pregnancy: the frequency of congenital anomalies in newborns whose mothers have been taking dydrogesterone during pregnancy does not exceed the population average, which indicates a favorable safety profile of this progestogen [8, 9].

At the end of her report, Professor T.A. Nazarenko indicated that the issues of the use and personalized choice of progestogens are actively discussed around the world, and as an example she cited a discussion at the international congress ESHRE-2023 in Copenhagen. The expert drew attention to the fact that the echoes of this discussion were brought to the Russian-speaking space without a proper balanced scientific assessment and were presented not by experts at scientific events, but by blog- gers on social networks and instant messengers, which led to a serious distortion of information. Unfortunately, the information also came directly to the patients, which caused numerous questions for this vulnerable and sensi- tive category of women. The essence of the discussion is this: at the ESHRE conference on June 27, 2023, within one of the sessions, pharmacy resident A. Henry presented a report on behalf of a team of authors from France, declared as “Birth defects reporting and the use of oral dydrogesterone in assisted reproductive technol- ogy: a global pharmacovigilance study” [10]. Despite the impressive title, the audience had been presented a work that did not meet international requirements for epide- miological research. The content of the presentation dif- fered from that presented in the abstract, the quantitative data on the slides of the presentation did not correspond to each other, the limitations of this type of research were not properly described, and in general the applied meth- odology did not allow drawing any conclusions about the frequency of adverse events. Actual numerous data from well-conducted clinical studies, including compara- tive, as well as systematic reviews confirm the favorable safety profile of dydrogesterone during pregnancy for the woman and the fetus [11–13].

The presented report did not cite studies of the last 5 years and focused on outdated information (the sources presented on the slides are dated 1994–2017). In the text of the abstract itself dydrogesterone was originally designated by the authors as a "teratogenic drug", and all the justification from the literature data was built around this claim. The report raised a lot of questions from the listeners and moderators of the session in connection with the controversy of the statements presented and the conclusions drawn.

This discussion was instantly broadcast in Russia in the form of blogging "posts" not only to the medical community, but also addressed to patients. Wherein, the materials of this report were presented as a scientifically established fact, which led to a negative perception by several readers of the current Russian clinical guidelines. Due to the fact that Russian doctors had doubts about the validity of using the remedy in ART programs and during pregnancy, T.A. Nazarenko considered it necessary to discuss this issue within the profile session of the “Mother and Child” forum. There was a discrepancy of the results of the Henry A. study, both from scientifical and clinical point of view, to the previously established favorable safety profile of dydrogesterone.

Leading Researcher of the Reproduction Department, Research Institute of Obstetrics, Gynecology and Reproduction named after D.O. Ott, Doctor of Medical Sciences, Professor of the Department of Obstetrics and Gynecology, St. Petersburg State Pediatric Medical University of the Ministry of Health of Russia (St. Petersburg) N.I. Tapilskaya emphasized in her report that modern clinical data of good quality and many years of successful international experience in the use of dydrogesterone during pregnancy confirm its favorable safety profile. In this regard, she cited a profile meta- analysis by Prof. Katalinic A. et al. (2022), where the world's leading experts conducted a thorough search of all available information and summarized the data on the safety of dydrogesterone [12]. Professor Tapilskaya N.I. cited the conclusions of this study on the absence of a causal relationship between fetal malformations and the use of dydrogesterone in the first trimester of pregnancy: “We are confident in the validity of the use of dydrogesterone in threatened miscarriage or recurrent miscarriage and believe that the favorable safety profile of dydrogesterone allows its use during assisted reproductive technologies” [12].

Head of the Department of Pregnancy Loss Prevention and Therapy, of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov, Doctor of Medical Sciences, associate Professor Tetruashvili N.K. shared the data of her own studies and publications confirming the efficacy and safety of dydrogesterone in the treatment of patients with threatened and recurrent miscarriage [14, 15]. Good Practice Recommendations were presented by the world’s leading specialized organization FIGO (International Federation of Gynecology and Obstetrics) [16]. According to these recommendations, today there is no clear evidence of safety problems or fetal abnormalities associated with the use of oral progestogen (dydrogesterone) and vaginal progesterone during pregnancy, therefore their appointment on an empirical basis or within scientific studies is not contraindicated [16].

Leading expert in the area of clinical pharmacology, Head of the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases of the Institute of Clinical Medicine named after N.V. Sklifosovsky, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University) (Moscow), Doctor of Medical Sciences, Professor E.V. Shikh has commented on the safety of dydrogesterone. She drew attention to the fact that the staff of her department, along with the Department of Pediatrics, Sechenov University, were among the first in the country to conduct studies on the safety of progestogens during pregnancy and confirmed the safety of dydrogesterone for offspring [17]. The absence of a causal relationship with fetal malformations is due to the fact that dydrogesterone is a highly selective progestogen, during the metabolism of which an active metabolite with progestogenic activity is formed, which contributes to the preservation of pregnancy in the absence of activation of other steroid receptors (estrogen, androgenic, glucocorticoid). Emphasis was placed on the fact that there is no pharmacological substrate for the teratogenic effect of this molecule [8, 12, 14, 16, 17].

In conclusion, the President of the RSOG, Academician of the Russian Academy of Sciences V.N. Serov noted that the progestogens recommended during pregnancy fully meet international and Russian requirements on safety for the pregnant woman and the fetus. The absence of a negative effect on children born to women who received dydrogesterone or micronized progesterone during pregnancy has been proven. These remedies are included in the relevant clinical recommendations of the RSOG [1-5] and the List of Vital and Essential Drugs, and the instructions for their use and circulation in the country are properly regulated by the Russian Ministry of Health. All these facts allow doctors and patients to be confident in the high quality of medical care in accordance with Federal Law No. 323- FZ “On the fundamentals of protection of the public health” [18]. A constructive discussion of professional issues within scientific congresses and other specialized platforms is welcome, including the preparation of proposals for inclusion in clinical guidelines and sending them in the prescribed manner through the RSOG website [6]. At the same time, healthcare professionals should refrain from unbalanced and unethical provision of unverified information, especially directly to patients. Obstetrician-gynecologists should be guided in their clinical routine activities with clinical guidelines, official regulatory and methodological documents, as well as high-quality scientific publications in peer-reviewed journals.