The safety of hormone therapy during pregnancy. Joint statement by experts in reproductive medicine, obstetrics and gynecology, endocrinology, clinical pharmacology, neonatology and pediatrics

At present, comprehensive measures to improve the demographic situation are being developed on a national level. A significant contribution to the support and implementation of the national project “Demography” is made by the activity of the obstetric and gynecological service. Therefore, great expectations are placed on its potential and further development. In particular, measures to increase fertility include preserving reproductive health, overcoming infertility, and careful management of pregnancy, as every pregnancy is of great value today [1].

To improve the quality of medical care in Russia, clinical guidelines have been approved and are regularly updated [2–12]. When developing clinical guidelines, the experts of the Russian Society of Obstetricians and Gynecologists (RSOG) both consider the position of international professional communities (FIGO, ESHRE, NICE) [13–16] and reflect Russian approaches, taking into account the vast clinical experience and scientific base accumulated in our country. Approved by the Ministry of Health of the Russian Federation, the RSOG Clinical Recommendations regulate the provision of quality medical care, are mandatory [17], and reflect the current evidence base for each treatment method, including the safety of the drugs used [2, 3, 7].

Various types of hormonal support are used in assisted reproductive technology (ART) programs and in the management of pregnancies at high risk of fetal loss [2–7]. The most commonly used drug classes are gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, gonadotropins, ovulation triggers, estrogens, gestagens, and, when indicated, glucocorticoids (GCs), insulins, and thyroid hormones [2–7, 13–16, 18–21]. As a rule, recommended therapies are regulated by relevant guidelines based on the available evidence base and in accordance with instructions for medical use approved by the Ministry of Health of the Russian Federation. Drugs recommended for use during pregnancy have special requirements in terms of safety for both the mother and the fetus.

International electronic libraries have accumulated a large number of publications of varying methodological quality regarding the use of hormone therapy during pregnancy. Some of the studies and research are the scientific basis for the clinical guidelines and have a significant impact on practical obstetrics in terms of pregnancy management and outcomes. Unfortunately, there are occasionally published descriptions of clinical cases, results of experimental studies with insufficient number of participants, data from observational studies, registries, and non-specialized databases, which do not allow to interpret the results unambiguously or to establish a causal relationship between adverse events and the intake of a particular drug. Inaccurate or incorrect interpretation of data often doubts the rationale for prescribing drugs, even those with a long history of use and a well-studied safety profile. As a result, physicians and patients begin to avoid effective therapies. For example, although some articles have already been withdrawn because of publication errors and inaccuracies [22], groundless concerns about the safety of dydrogesterone in relation to fetal congenital anomalies continue to circulate [22–25]. It is important to note that retracted articles are no longer formally part of the scientific base and should not influence clinical decision-making [26].

It should be noted that the formation of abnormalities of embryo and fetus development inevitably occurs with a certain frequency in the population and depends on numerous factors: the state of the mother's health, her lifestyle during pregnancy and previous illnesses, the presence of chromosomal and genetic abnormalities of the fetus, the impact of various non-specific environmental factors, including some drugs with teratogenic effects. For this reason, studying the causal relationship between drug exposure and congenital malformations is challenging and must follow a rigorous methodology [27].

Estrogen use in assisted reproductive technology

Assisted reproductive technology (ART) programs with cryopreserved/frozen embryo transfer account for more than 40% of all in vitro fertilization (IVF) cycles [28]. Two main methods of preparation for the transfer of thawedembryos are used: natural menstrual cycle with progesterone support after ovulation or substitution cycle, when the phases of the menstrual cycle are formed by the administration of estrogens (follicular phase) and estrogens with progesterone (luteal phase) [4, 5]. Natural cycle has advantages in patients with regular menstrual cycle, stable ovulation, adequate transformation of the endometrium, in the absence of uterine pathology (endometrial polyp, intrauterine synechiae, malformations, uterine scar, uterine myoma, etc.). According to statistics, half of the patients do not meet these criteria. In these cases, hormone replacement therapy is prescribed to prepare the endometrium for embryo implantation. It is known that the effectiveness of cycles with cryopreserved/thawed embryo transfer is comparable to that of embryo transfer in a fresh cycle [29]. Moreover, there is evidence that perinatal outcomes of cryopreserved/thawed embryo transfer have advantages in terms of reduced incidence of low fetal weight for appropriate gestational age, preterm labor, placenta previa, placental detachment, and perinatal mortality compared to fresh embryo transfer [30, 31]. The use of hormonal support in the post-transfer period is often continued during the first trimester of pregnancy -,as patients in these IVF cycles lack their own corpus luteum [4, 5].

According to the regulatory drug documentation, estrogens are not registered in the Russian Federation for use during pregnancy due to insufficient data; however, a number of studies show that their use in some cases (e.g., in cycles with cryopreserved/thawed embryo transfer) is justified and quite effective [32–34]. In off-label ART programs, estrogen preparations are used: estradiol valerate orally or estradiol hemihydrate as a transdermal gel [4, 5, 16, 35]. Concerns about estrogen use regarding fetal safety often arise, however, they are unfounded. According to experts, it can be assumed that since the concentrations of exogenous sex steroids are equivalent to the doses of hormones in the natural menstrual cycle, there are no adverse effects on the fetus [4, 5, 16]. Recent publications on the safety of estrogen use confirm the possibility of using this classof drugs up to 12 weeks of gestation [16, 35–38]. The use of estrogens is not an indication for termination of pregnancy. This suggests that to date, this classof drugs does not belong to absolute teratogens [39].

Use of gestagens in reproductive medicine

According to international and Russian guidelines, the use of gestagens to prevent miscarriage is proven to be pathogenetically reasonable, and the effectiveness of their use has been shown by numerous clinical studies [2, 3, 7, 13–15]. In reproductive medicine, dydrogesterone or progesterone are approved by the Ministry of Health of the Russian Federation and used to support the luteal phase in ART programs and to prevent threatened and reccurent miscarriage [2, 3, 7, 38, 40–44].

Exogenous progesterone used during pregnancy has a molecular structure similar to endogenous progesterone produced by the corpus luteum or placenta. Like all gestagens used in pregnancy, progesterone is produced from the plant raw material – wild yam [45, 46]. Bioidentical progesterone has a similar metabolism to endogenous progesterone and exerts its effects by binding to both progesterone receptors and receptors for other steroid hormones: androgens, glucocorticoids, and mineralocorticoids [46, 47]. Progesterone micronization technology has been available since 1980, and micronized progesterone has been used in obstetrics for 40 years [48]. Studies that have further evaluated the effects of micronized progesterone on the fetus have found no short-term safety problems associated with the therapy [49, 50].

Dydrogesterone is produced from the progesterone molecule by its optical modification and is an isomer with high bioavailability and selectivity having affinity only for progesterone receptors [45, 46, 51]. Therapy with dydrogesterone in early pregnancy does not increase the risk of gestational diabetes mellitus due to the absence of glucocorticoid activity. This excludes the possibility of altering carbohydrate metabolism by increasing the processes of gluconeogenesis and the development of peripheral insulin resistance [45, 46, 52, 53]. Moreover, based on the above, there is no substrate for genitourinary abnormalities in the fetus due to the lack of binding to androgen receptors [45, 46, 54].

Dydrogesterone has been used in clinical practice for more than 60 years [55]. During the period of the drug use, a significant evidence base on its safety during pregnancy has been accumulated. According to randomized clinical trials, dydrogesterone administration in the first trimester demonstrated a high safety profile and was not associated with an increase in adverse events both from the mother and the fetus [56–58]. It is important to note that this issue is especially relevant in IVF programs: the results of a large-scale study by Yang W. et al. (2023), which included 124,815 IVF cycles, showed no adverse fetal events with dydrogesterone in this cohort of patients [59]. To date, more than 60 studies have been published, including more than 50 for 2020–2024, with the use of dydrogesterone in ART programs, indicating high scientific interest and promising use of the molecule in terms of both efficacy and safety [60, 61]. A systematic review and meta-analysis of randomized clinical trials (RCTs) published in 2024 found no additional risk of congenital fetal anomalies with the use of dydrogesterone [62]. At the same time, the discussion on the drug's safety continues in the Human Reproduction journal within the work of Katalinic A. et al. (2024). It was confirmed that this systematic review and meta-analysis of RCTs represents the most comprehensive evidence to date on the issue of studying the incidence of congenital anomalies after the use of dydrogesterone in the first trimester, including after IVF programs [63, 64].

According to the position of the International Federation of Obstetricians and Gynecologists (FIGO), the safety profile of gestagens used (dydrogesterone, progesterone) is well-studied and favorable for mother and fetus. Since no causal relationship between the use of gestagens during pregnancy (oral /injectable/ vaginal/rectal administration, etc.) and the formation of fetal malformations has been identified, their use in the treatment of reccurentmiscarriage is not contraindicated [13].

When considering safety issues, the specifics of adherence to technology or good practice (GxP) in the manufacture of medicines are important, especially given the increasing number of generic registrations. Globally, there are known cases of withdrawal of a whole group of drugs due to the development of serious adverse reactions when taking generic analogs, associated with differences in the methods of synthesis of active substances, changes in manufacturingtechnology and changes in the composition of adjuvants [65]. Even minimal differences in the composition of excipients or impurities can cause significant, including unexpected, adverse reactions [66].

Dydrogesterone in the original preparation (“Duphaston”) has a high degree of safety, confirmed by preclinical studies of expanded scope and clinical studies of a high level of evidence [56–58]. The dydrogesterone substance in this preparation complies with strict pharmacopeia requirements. The quality is regularly monitored for the absence of impurities and is used as a reference standard in the European Pharmacopoeia (EP) and the US pharmacopoeia (USP) [67, 68].

It is essential to mention that the quality of the substance may play a significant role in the therapeutic effect: original drugs and generics show different results in comparative clinical trials [56–58, 69]. The safety and efficacy of dydrogesterone in the original preparation has been confirmed with a specific active compound, with specific adjuvants, in a specific dose range, for registered indications. The regulatory documentation of the “Duphaston” preparation approved by the Ministry of Health of the Russian Federation reflects a favorable safety profile in relation to the fetus [43].

Glucocorticoid use during pregnancy

In accordance with international and Russian guidelines, glucocorticoids may be used during pregnancy if indicated [14, 20]. Glucocorticoids have a favorable clinical effect in most autoimmune inflammatory diseases and can be used in women with reccurentmiscarriage and suspected immune etiology. A number of randomized placebo-controlled trials have shown some positive effects on specific immunological biomarkers in patients with reccurentmiscarriage [14].

Another condition that correlates with pregnancy lossand requires glucocorticoid treatment is a nonclassic congenital adrenal hyperplasia (NCAH) [20]. Although 68% of women with NCAHcan have spontaneous pregnancies without glucocorticoid treatment, early pregnancy lossare common in the absence of treatment [70, 71]. Therefore, it is necessary to consider glucocorticoid therapyprimarily during the pregnancy planning stage, especially in women with infertility or reccurentmiscarriage. It should be noted that glucocorticoid therapy (prednisolone, methyl-prednisolone) easily penetrate the placenta. Use of this classof drugs during pregnancy should be only on absolute indications [72, 73]. When deciding on glucocorticoid therapy, it is important to start it at the pregnancyplanning stage, as it is the implantation stage of glucocorticoid therapy that is most important for improving the prognosis of the pregnancy. Glucocorticoids in pregnancy are used only when the expected benefit for the mother outweighs the potential risk of adverse effects on the mother and fetus. The drugs should be used in the lowest effective doses. Treatment may be with prednisolone (2.5-7.5 mg for 1-2 doses) or methylprednisolone (2-6 mg at bedtime) in the I-II trimesters followed by withdrawal, or until delivery, depending on the course of the pregnancy [20]. The drug doses are usually not altered with the onset of pregnancy. An increase in dosage is indicated only if signs of adrenal insufficiency develop [20].

Evidence from the 2024 systematic review suggests that antenatal use of low-dose prednisolone (up to 10 mg) may be associated with lower fetal gestational age but is not associated with miscarriage and stillbirth, congenital anomalies, differences in blood pressure or low blood glucose at birth, and low bone mass, high blood pressure in the prepubertal period [74].

Use of thyroid hormones during pregnancy

Studies have shown that manifest hypothyroidism during pregnancy is associated with adverse pregnancy outcomes for both the mother (increased risk of miscarriage, preterm labor, low birth weight) and the fetus (negative impact on neurocognitive development) [14, 75]. In accordance with international and Russian recommendations, levothyroxine therapy is the only currently established treatment for hypothyroidism in women, including those with pregnancy loss[14, 21, 76].

During pregnancy, immediately after the diagnosis of hypothyroidism in women it is necessary to prescribe a full dose of replacement therapy with levothyroxine sodium preparations if the level of serum TSH in the blood exceeds 10 mU/L [21]. The goal of replacement therapy is to maintain low-normal thyroid stimulating hormone (TSH) and high-normal free thyroxine levels (Т4). According to the regulatory documents approved by the Ministry of Health of the Russian Federation, the use of drugs of this class during pregnancy is not contraindicated and should be carried out according to the indications, in the recommended doses and under the supervision of a doctor [77]. Use in combination with thyrostatic agents in pregnancy is contraindicated due to the increased risk of hypothyroidism in the fetus.

Subclinical hypothyroidism is a relatively common complication, occurring in approximately 3% of pregnant women, and is also associated with adverse pregnancy outcomes including miscarriage, gestational diabetes, preterm labor, pre-eclampsia and small for gestational age fetal size [78, 79]. In subclinical hypothyroidism (elevated TSH and free T4 levels within normal limits) during pregnancy, therapy with levothyroxine sodium is recommended for women with TPOAb (+) and TSH >4 mU/l and <10 mU/l, and may be recommended for women with TPOAb (+) and TSH >2.5 and <4 mU/l, as well as in the absence of TPOAb but with TSH >4.0 and <10 mU/l [21].

No adverse effects of levothyroxine in hypothyroidism on the pregnant woman or the fetus have been reported in studies. Systematic reviews have shown that levothyroxine increases live births in women with hypothyroidism and reccurentmiscarriage [80] and may reduce the risk of preterm labor and amniotic fluid abnormalities [81].

Use of insulin therapy during pregnancy

Pregnancy with diabetes mellitus (DM) is associated with risks to maternal and fetal health. Planning pregnancy and maintaining physiological glucose levels in pregnant women with diabetes can reduce the incidence of complications in the course and outcome of pregnancy [82]. Effective glycemic control with maintenance of physiological or near physiological blood glucose levels before and during pregnancy reduces many of these risks to levels seen in the general population.

In patients with type 1 diabetes mellitus (T1D) during pregnancy, intensified insulin therapy with multiple injections of short-acting insulin (fast-acting insulin, rapid-acting insulin) and basal insulin or pump insulin therapy is recommended to maintain target glycaemic control during pregnancy [18, 82]. To reduce the risk of adverse maternal and fetal outcomes, patients with T1D during pregnancy should maintain target glycemic levels (fasting/pre-meal/overnight/night plasma glucose level 3.9–5.3 mmol/l; plasma glucose level 1 h after a meal 6.1-7.8 mmol/l or 2 h after a meal 5.6–6.7 mmol/l; HbA1c<6.0%) [18, 82]. An interdisciplinary approach between obstetrician-gynecologist, endocrinologist, and general practitioner is needed to ensure comprehensive management and prevention of adverse pregnancy outcomes in patients with T1D [18].

Gestational diabetes mellitus (GDM), that is, diabetes first diagnosed during pregnancy, can also adversely affect the health of the fetus and newborn as well as the mother, and is associated with a significantly higher risk of hypertensive disorders, caesarean section, and metabolic disorders in the future. Studies have shown that both pregestational DM and GDM are associated with the development of macrosomia, which, in turn, can lead to fetal death, prematurity, birth trauma, and respiratory distress syndrome (RDS) [83]. Newborns of mothers with GDM are more likely to have metabolic disorders: increased risk of obesity, hyperbilirubinaemia, polycythemia, hypomagnesaemia, and hypocalcaemia. To reduce the risk of adverse maternal and fetal outcomes, patients with GDM should maintain target glycemic levels (fasting/fasting/overnight/night plasma glucose <5.1 mmol/l; plasma glucose 1 h after meals <7.0 mmol/l; additional glycemic control 2 h after the start of meals may be recommended in the following cases: gastropathy, high-fat and high-protein meals, use of short-acting insulin, evidence of macrosomia with normal fasting and 1 h after the start of meals, morbid obesity. Target glycemic level at 2 h from the start of a meal is <6.7 mmol/l) [82].

In Russia, the use of oral sugar-lowering drugs in pregnant women with GDM is currently not permitted due to concerns about adverse effects of these drugs on the fetus; therefore, insulin therapy remains the only approved medication option for controlling hyperglycemia during pregnancy [18, 19, 82–84]. As insulin resistance is different in all pregnant women, insulin requirements are also different, and insulin doses are individualized. It is common practice to start insulin therapy with low doses and further titration until target glycemic levels are achieved [18]. The use of biosimilar insulin preparations that have not undergone the full procedure of drug registration and pre-registration clinical trials in pregnant women is prohibited during pregnancy [18]. At the same time, there are several insulins registered by the Ministry of Health of the Russian Federation for use during pregnancy [85, 86]. Regardless of the type of diabetes, continuous and quality control of glycaemia is essential. The use of continuous glucose monitoring in pregnancy withT1D, T2D, and GDM can improve glycemic control of the mother and reduce the risk of adverse pregnancy outcomes, both maternal and fetal [87–91].

Monitoring of children's health status

Neonatal outcomes in children exposed antenatally to hormone therapy are comparable to the Russian Statistics Agency data on fetal abnormalities [56–58, 92] and the global report on the background risk of fetal abnormalities due to environmental and genetic factors [56–58, 92, 93]. Follow-up of newborns and children up to 12 months of age born to mothers who had received hormonal supplementation during pregnancy showed no additional risk for either major or minor fetal congenital malformations [94, 95].

There is currently a lack of studies on long-term follow-up of children exposed antenatally to hormone therapy due to the insufficient evidence base, including bioidentical progesterone and dydrogesterone [16].

The Russian experience of monitoring children up to 7–9 years of age, whose antenatal development was accompanied by hormonal treatment with gestagens, estrogens, and glucocorticoids, has not shown any additional risk of congenitalmalformations. According to the results of these observations, the majority of children had normal sexual development, age and gender identification was formed according to age and without peculiarities, elements of sexual dysontogenesis - were observed in single cases and did not differ from the control group (mothers who did not receive hormone therapy) in terms of incidence rate. Abnormalities were more common in girls whose mothers were taking estrogens and gestagens and in boys whose mothers were receiving glucocorticoids, however, the proportion of these children was not statistically significantly different from the proportion of children in the group of women not receiving hormone therapy [96].

It is worth emphasizing that the drugs (progesterone, dydrogesterone, insulin, prednisolone, levothyroxine) authorized for medical use on the territory of the Russian Federation are included in the relevant RSOG guidelines [2, 4, 6, 7, 18, 19, 21] and in the list of VED, and the instructions for their use and circulation in Russia are duly regulated by the Ministry of Health of the Russian Federation. All these facts give doctors and patients confidence in the high quality of medical care provided in accordance with Federal Law No. 323-FZ ‘On the Fundamentals of Health Protection of Citizens in the Russian Federation’ [17, 97].

Doctors and patients should be more cautious, trust and follow reliable sources of information and clinical guidelines to rationally apply all available treatment options.

This document will help to strengthen clinical approaches to the management of pregnancies at high risk of fetal loss. This, in turn, will contribute to the preservation of reproductive potential, careful management of pregnancy, timely and quality care for successful pregnancy and live births, women's positive experiences of pregnancy, and interaction with the health care system.