Real-World Data on the Use of Follitropin Delta in a Dutch IVF Center.

From August 2017 onward, the majority of patients who underwent IVF or IVF‐ICSI at the EMC used follitropin delta for ovarian hyperstimulation. A total of 793 patients had a regular cycle and used follitropin delta in an antagonist protocol with the dose determined by the dosing algorithm, with the intention of fresh embryo transfer on day 5. The patient demographics and baseline characteristics are shown in Table  1 . The mean age was 34.1 ± 4.6 years, with 44.9% of the women being older than 35 years. Among the women in the follitropin delta arm of the ESTHER‐1 trial, age was 33.4 ± 3.9 years, with 40.7% of the women being older than 35 years. The body weight was 69 ± 11.3 kg. In the ESTHER‐1 trial, the body weight was 64.7 ± 10.7 kg. The duration of infertility was 34.2 ± 24.3 months, and the proportion of women with primary infertility was 56.2%. The indications for IVF included mainly male factor (63.7%) and fewer other factors: unexplained (19.9%), tubal factor (5.9%), endometriosis I/II (2%) and other factors (0.6%). A small proportion (7.8%) underwent stimulation for oocyte freezing for social indications. In the ESTHER‐1 trial, the most frequent indication was unexplained subfertility, and no social freezing cycles were included. Twenty percent of our patients had undergone a previous IVF or IVF‐ICSI cycle, whereas in the ESTHER‐1 trial, all women were naïve IVF patients. AMH was 22.1 ± 13.3 pmol/L. In the ESTHER‐1 trial AMH was 19.4 ± 14.6 pmol/L (not mentioned in the publication, data received from authors). Supplementary Table  S1 shows the differences in patient characteristics between the EMC and ESTHER‐1 study population. Demographic and baseline characteristics. Note: Data are described as the mean ± SD or proportions. Social freezing excluded n  = 62. Pregnancy outcomes are shown in Table  2 . The ongoing pregnancy rate was 30.8%. The ongoing implantation rate was 36.5%. In the ESTHER‐1 trial, the ongoing pregnancy rate was 30.7%, and the ongoing implantation rate was 35.2%. Among the EMC patients, 30% of the women had a live birth. One woman was lost to follow‐up between confirmation of ongoing pregnancy and assessment of live birth. In the ESTHER‐1 trial, the live birth rate was 29.8%. In our population, 93.7% had a single embryo transfer and 6.3% had two embryos transferred. In the ESTHER‐1 trial, the proportion of women having a single embryo transfer was 95.9% and 4.1% had a double transfer. Four twin pregnancies (1.8%) occurred, all of which were monozygotic twins after a single embryo transfer. These count as 2 (ongoing) implantations and 1 ongoing pregnancy and live birth. In the ESTHER‐1 trial, four multiple pregnancies were reported; however, the publication does not specify whether these were monozygotic or dizygotic multiples. Sixty‐five women (11%) underwent embryo transfer on day 3, and the remaining 526 embryo transfers were performed on day 5. In the ESTHER‐1 trial, all women had their embryo transfer on day 5. Clinical efficacy outcomes. Note: Data are described as proportions. Social freezing excluded. One patient lost to follow‐up between confirmation of ongoing pregnancy and assessment of live birth. All monozygotic after single embryo transfer. The ovarian response and embryology outcomes are shown in Table  3 . In the entire population, 10.3 ± 5.4 oocytes were retrieved. In the ESTHER‐1 trial, the number of oocytes retrieved was 10.0 ± 5.6. The proportion of women who reached the target ovarian response of 8–14 oocytes was 48.9%. In the ESTHER‐1 trial, this proportion was 43.3%. The number of cleavage‐stage embryos was 6 ± 3.7, the number of cryopreserved embryos was 2.2 ± 2.3, and the proportion of women with cryopreserved embryos was 73.8%. The proportion of cycles canceled with an insufficient number of follicles was 8.6%, and an excessive response leading to cycle cancellation or final oocyte maturation triggered by a GnRH agonist occurred in 16.2% of cycles. Ovarian stimulation. Note: Data are described as the mean ± SD or proportions. In women who received triggering for final follicular maturation. For women whose oocytes were retrieved, minus social freezing. When potential poor responders and normal to high responders were analyzed separately, the results were as follows: 8.7 ± 4.3 oocytes were retrieved in women with AMH levels lower than 15 pmol/L, and the proportion of women with a poor response (< 4 oocytes) was 6.1%. In women with AMH levels of 15 pmol/L or higher, the number of oocytes retrieved was 11.1 ± 5.7. The proportion of excessive responders with more than 15 oocytes was 22.2%, and that with more than 20 oocytes was 8.6%. These numbers and proportions are all consistent with the previously reported data in the ESTHER‐1 trial. Owing to differences between the protocols used in the EMC and the ESTHER‐1 trial, the proportions of canceled cycles with hypo‐ and hyperresponses and the use of agonist trigger cannot be compared between the EMC patients and the ESTHER‐1 trial. For this reason, only the numbers and percentages in treatment cycles in the EMC are described below and the results from the ESTHER‐1 trial are not mentioned. In the entire EMC population, 3 cycles were canceled because of hyperresponse (0.4%). Among the 711 women who received a trigger for final oocyte maturation, 125 used an agonist trigger (15.8%). Twenty‐three of these had a freeze‐all strategy because of high risk of OHSS, 1 for other reasons and 4 because of preventive measures for COVID‐19. Of the 23 women who had a freeze‐all strategy for OHSS risk, 6 were classified as hyperresponders (for classification, see Figure  1 ). The remaining 90 women underwent fresh embryo transfer with intensive luteal support. One patient developed early mild OHSS (based on hemoconcentration). Two patients were classified as hyperresponders (see Figure  1 ). Among the 667 women in whom the hCG trigger was used, 6 had freeze‐all due to signs of early OHSS. Among these women, 1 developed early OHSS without significant comorbidities (see Figure  1 ). She was hospitalized for 3 days. Two patients were classified as hyperresponders. Because of hydrosalpinges or intrauterine pathology, 5 women did not receive a fresh transfer after hCG trigger. Five women had no fresh transfer because of preventive measures for COVID‐19. For one woman, embryo transfer was not possible because of a cesarean scar niche. Among the 596 women who underwent fresh embryo transfer after hCG trigger, 3 were classified as hyperresponders. Six women developed late OHSS. Five of these women were hospitalized for 3–13 days. In the follitropin delta arm of the ESTHER‐1 trial, 2 women were hospitalized because of OHSS. Ovarian hyperstimulation syndrome (OHSS) flow diagram for use in the clinical trial setting. † Exaggerated response, as defined by the World Health Organization criteria. ‡ Subjects to be screened for OHSS symptoms on the day of embryo transfer, the day of positive pregnancy test or at the time of complaint. Shaded shapes denote the required reporting of a group in the context of a clinical trial. LFT, liver function test; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma‐glutamyl transferase; Cr, creatinine.

Our most important conclusion is that all ovarian response endpoints were comparable in range between the real‐world EMC patient population and the follitropin delta group in the ESTHER‐1 randomized controlled trial, despite differences in body weight, AMH, age, and reasons for infertility. Higher AMH could lead to a stronger ovarian response during stimulation, while a higher body weight might result in fewer oocytes being retrieved. Our results show that the use of the dosing algorithm that was developed for follitropin delta can effectively correct for this, as the number of oocytes retrieved is comparable between the EMC and the ESTHER‐1 study. Another important difference is that 20% of the EMC patients have previously undergone an IVF treatment, whereas the patients in the ESTHER‐1 trial have not. This may particularly affect the chance of pregnancy. Since most pregnancies occur during the first IVF treatment and chances to become pregnant in subsequent cycles decrease due to selection, the impact of the number of treatment cycles is of importance [ 15 , 16 ]. Among EMC patients, a higher proportion of couples presented with male factor infertility compared to those included in the ESTHER‐1 trial. This subgroup is prognostically favorable, as in most cases the female partner does not contribute to the subfertility apart from age‐related factors. A large prospective cohort study conducted in the Netherlands between 2002 and 2004 [ 17 ] demonstrated that the most important predictors of pregnancy following IVF and ICSI are female age and severe male factor subfertility necessitating ICSI. Notably, ICSI performed for severe oligospermia was associated with a significantly higher ongoing pregnancy rate compared to other indications for IVF. There are differences between the populations at EMC and in the ESTHER‐1 study that may contribute in various ways to a lower or higher likelihood of IVF treatment success. Ultimately, these factors appear to balance each other out, as the pregnancy rates in both groups are comparable. The number of twin pregnancies does not differ between the EMC population and the ESTHER‐1 study. In the EMC patients, these were all monozygotic twins, counted as 2 ongoing implantations and 1 ongoing pregnancy and live birth. In the ESTHER study, ongoing implantation was defined as the number of fetuses per transferred blastocyst. Therefore, the number of monozygotic and dizygotic multiples will affect the ongoing implantation rate. From the publication of the ESTHER‐1 study, it cannot be determined whether the reported twin pregnancies were monozygotic or dizygotic. Differences exist between the EMC protocols and those applied in the ESTHER‐1 study regarding the use of preventive interventions and cycle cancellation. In some studies, conventional dosing protocols are associated with an incidence of OHSS of up to 20%, and the rates of moderate to severe OHSS are approximately 14% [ 18 ]. In recent years, three phase 3 trials have been published comparing individual dosing of follitropin delta to conventional dosages of follitropin alpha and beta [ 12 , 19 , 20 ]. All three of these studies revealed a significant reduction in the incidence of early moderate/severe OHSS and/or preventive interventions for early OHSS when follitropin delta was used. In the EMC, according to the local protocol, GnRH agonist trigger could already be used if ≥ 14 follicles of 11 mm or larger were present. This protocol is based on several studies comparing safety and treatment outcomes using either the hCG or GnRH agonist trigger for final follicular maturation [ 21 ]. In the ESTHER‐1 trial, triggering final follicular maturation with a GnRH agonist was used when 25–35 follicles with a diameter of ≥ 12 mm were present. Therefore, preventive interventions such as the use of an agonist trigger were used more often in EMC patients than in patients in the ESTHER‐1 trial. A key limitation in comparing OHSS rates between our EMC cohort and the ESTHER‐1 trial is the use of different classification systems. ESTHER‐1 employed the Golan classification [ 22 ], which is based on subjective clinical symptoms and older criteria, while our center used the more objective and reproducible system proposed by Humaidan et al. [ 14 ]. The Humaidan system incorporates both timing and severity, with clear thresholds for hospitalization and organ dysfunction. As a result, direct comparison of OHSS rates and severity between studies should be interpreted with caution, as differences may reflect classification methodology rather than true clinical outcomes. We suggest that future studies adopt a consensus OHSS classification and encourage journals and professional societies to standardize safety endpoint definitions. Although there are differences in preventive measures taken between the ESTHER‐1 trial and EMC, the absolute values are still low compared with those associated with conventional dosing protocols. In our own clinic, we observed an improvement in the incidence of safety‐related events compared with the period prior to the use of follitropin delta. Safety outcomes should be interpreted with caution due to the differences in protocols. Harmonization of the protocols was not possible because of previously implemented protocols in the EMC regarding the use of agonist trigger for the prevention of OHSS. We consider the low‐threshold use of an agonist, with a possible subsequent embryo transfer with additional luteal support, a safe and effective option. This descriptive study shows the results of the use of follitropin delta in an antagonist protocol in daily practice in a cohort of patients with a regular ovulatory cycle. While real world data offer valuable insights into how a treatment performs in broader, routine clinical settings, it cannot be directly or definitively compared with the outcomes of a controlled RCT such as ESTHER‐1. Any comparison must be interpreted cautiously. Nonetheless, the large population of this study using real world data provides better insights into the effectiveness of follitropin delta across various subgroups and complements RCT data. The introduction of a new drug into routine clinical practice can be challenging, often resulting in resistance, as translating clinical trial outcomes to everyday practice is not always straightforward. Because of the high number of patients treated with follitropin delta in the EMC, we were able to make an exploratory comparison of treatment results between the EMC patients and those included in the ESTHER‐1 trial. This study expands the available data on the clinical use of follitropin delta from selected trial subjects to a broader general population, which in the real world is most likely to be different from that in clinical trials. In conclusion, the use of follitropin delta in a real‐world clinical setting with a large and diverse patient population results in comparable favorable ovarian response outcomes as those reported in an RCT. Moreover, the safety profile appears more favorable than that of conventional dosing protocols. To further address the limitations identified in this study, we recommend ongoing efforts to harmonize protocols and safety reporting standards, encourage data sharing for more robust comparative analyses, and promote stratified and adjusted analyses to account for baseline differences and prior ART exposure. Future research should systematically report twin zygosity and adopt consensus definitions for OHSS and other safety endpoints. Additionally, we advocate for multicenter collaborations and improved follow‐up procedures to enhance the generalizability and completeness of real‐world evidence in reproductive medicine.

In IVF treatment, the use of gonadotropins for ovarian hyperstimulation is necessary to achieve the growth of multiple follicles within one treatment cycle. It is important to determine the optimal dose for individual patients, as the individual ovarian response to the same dose of gonadotropins is heterogeneous [ 1 ]. This reduces the risk of hyperresponse and ovarian hyperstimulation syndrome (OHSS), as well as disappointingly low responses. OHSS is an iatrogenic complication of ovarian stimulation that can require hospitalization in approximately 2%–3% of IVF patients [ 2 ]. It can cause considerable morbidity in the early luteal phase and early pregnancy after IVF treatment and is potentially life‐threatening. Large‐scale studies have shown a linear relationship between the number of oocytes obtained and live birth rates up to 15 oocytes [ 3 ]. Above this number, the risk of OHSS increases significantly without a concomitant increase in live births. Several patient characteristics, including age, weight, body mass index (BMI), early follicular phase FSH and inhibin B levels, and antral follicle count (AFC), are considered predictive factors for ovarian response. These ovarian reserve tests are able to predict poor ovarian reserve to a certain extent, but their ability to predict optimal ovarian response in daily practice is low [ 4 , 5 ]. Compared with the former ovarian reserve markers described above, anti‐Müllerian hormone (AMH) currently seems to be the best predictor of the ovarian response to controlled ovarian stimulation (COS) [ 6 , 7 ]. Indeed, after patients were stratified according to their serum AMH levels, the ovarian response was predictable [ 8 ]. Follitropin delta is a recombinant human FSH (rhFSH) expressed in a human cell line. Compared with existing rFSH preparations, rhFSH preparations have a lower clearance rate due to differences in glycosylation profiles and induce a higher ovarian response [ 9 ]. To tailor the individual response, a biomarker‐driven dosing strategy was developed based on the patient's body weight (BW), which influences drug exposure and availability, and pretreatment serum AMH levels, which can predict the ovarian response [ 10 , 11 ]. The unique dosing algorithm is specific for follitropin delta and is designed to reduce the risk of extreme ovarian responses, both hypo‐ and hyperresponse, while maintaining ongoing pregnancy rates compared with current dosing strategies [ 12 ]. To establish the advantages of such a dosing algorithm, a randomized controlled noninferiority trial (the ESTHER‐1 trial) was conducted to compare follitropin delta in a fixed algorithm‐determined dose with follitropin alfa using a standard adjustable dose regimen [ 12 ]. The results of this trial revealed that follitropin delta was noninferior in terms of ongoing implantation and ongoing pregnancy and live birth rates. However, fewer interventions to prevent OHSS, despite similar oocyte yields and similar blastocyst numbers, were needed. Hence, follitropin delta seems to be effective but safer to use when it is dosed by the algorithm. Clinical trials include patients on the basis of strict inclusion and exclusion criteria; hence, data retrieved from these studies are applicable to that specific study population. However, patient populations in real life are often much more diverse than those in clinical trials are, and there are no strict inclusion or exclusion criteria used for those who have an indication for assisted reproductive technology (ART). To determine whether follitropin delta performs similarly to clinical trials in daily practice, the present study reports our experience with 793 patients who underwent their first IVF or IVF–ICSI cycle with follitropin delta. This group included women who were undergoing their first IVF treatment, as well as women who had previously undergone IVF treatment with another FSH preparation.

P. Boom has received consultancy fees and travel support (European Society of Human Reproduction and Embryology) from Ferring. JSE Laven has received unrestricted research grants from Ansh Labs, Ferring, Merck Serono and Roche Diagnostics. He also received consultancy fees from Ansh Labs, Titus Healthcare, Roche Diagnostics and Gedeon Richter, honoraria from Ferring (European Society of Human Reproduction and Embryology and LIFE meeting) and Roche Diagnostics; travel support from Ferring (European Society of Human Reproduction and Embryology and LIFE meeting) and Roche Diagnostics; and data safety monitoring for LOCI Trial UK outside the submitted work.

This is a descriptive analysis of real‐world data obtained from the Erasmus University Medical Centre (EMC). Between March 2019 and August 2023, 913 women started IVF treatment with an intended embryo transfer on day 5 after ovum pickup. They had a regular ovulatory cycle and used a GnRH antagonist protocol. The study was reviewed by the local medical ethics review committee (study number MEC‐2023‐0747). A waiver was issued by the committee stating no informed consent was required since this is a retrospective analysis. Data from patients who objected to the use of their data were not included. Of the 913 potential subjects, 120 did not give permission for their data to be used, so they were excluded. The remaining 793 patients were included in this analysis. The starting dose of follitropin delta was determined by the dosing algorithm on the basis of the patient's BW and AMH. Serum AMH levels were measured using the automated Elecsys AMH plus immunoassay (Roche Diagnostics International, Rothkreutz, Switzerland) or the Lumipulse G AMH assay (Fujirebio, Tokyo, Japan). Outcome data were restricted to the first IVF cycle with follitropin delta. The results of the first IVF treatment of these 793 patients using follitropin delta, following the same protocol and dosed according to the algorithm from the ESTHER‐1 trial, are reported in this paper. Women aged 20–44 years who were undergoing their first IVF or IVF–ICSI treatment with follitropin delta were included. Indications include male factor infertility, tubal factor infertility, uterine factor infertility, stage I/II endometriosis, or combinations of these four indications. Moreover, unexplained infertility and oocyte freezing on social grounds were also included. A proportion of these women had a previous IVF attempt, either successful or unsuccessful, so not all participants were treatment‐naïve patients. The latter group received a dose of follitropin delta determined by the dosing algorithm independent of the type or dose of follitropin used in previous treatment(s) or their response. Women with AMH levels below 7.14 pmol/L (1.0 μg/L) received a different protocol or dose and were not included in this study. Women were given a fixed dose of follitropin delta, as calculated with the algorithm. Ovarian stimulation was started on day 2 of the menstrual cycle; from cycle day 6, the GnRH antagonist (Ganirelix, Fyremadel, Ferring, St. Prex, Switzerland) was added. Final follicular maturation was triggered the same day or the next day as soon as at least 1 follicle had reached 17 mm in diameter, with the majority of the follicles being at least 14 mm. If fewer than three follicles ≥ 14 mm in total were present, the stimulation was canceled. Triggering was performed with 10 000 IU of u‐hCG (Pregnyl, Merck Sharp & Dohme, Oss, The Netherlands) or 250 μg of r‐hCG (Ovitrelle, Merck, Amsterdam, The Netherlands) if fewer than 14 follicles ≥ 11 mm were present. When more than 14 follicles ≥ 11 mm were present, either hCG or a GnRH agonist (0.2 mg Decapeptyl, Ferring, St. Prex, Switzerland) was used, depending on clinical manifestations such as increased OHSS risk (abdominal pain or distension, free fluid visible on transvaginal ultrasound) or patient characteristics such as young age, low BMI and/or high AMH or OHSS after a previous IVF treatment. Oocyte retrieval was performed 35 h after triggering final follicular maturation. Women who had received an hCG trigger started micronized progesterone (Utrogestan vaginal capsules, Besins Healthcare, Belgium) 200 mg 3 times/day on the day after oocyte retrieval for a total of 15 days. For women who had received a GnRH agonist trigger, a visit to the clinic was planned on the intended day of embryo transfer to assess the risk of developing OHSS. Patient well‐being (abdominal pain, nausea, shortness of breath, increased body weight, and abdominal distension) was assessed, and blood was drawn to check for hemoconcentration. A subsequent transvaginal ultrasound was performed to assess the size of the ovaries and the presence of ascites. If there were no signs of early OHSS, a fresh embryo transfer was performed with the intensive luteal support explained below. If signs of OHSS were present, particularly hemoconcentration and/or ascites, all suitable embryos were cryopreserved. Intensive luteal support is crucial if fresh embryo transfer is performed after agonist triggering because of luteal phase insufficiency after agonist triggering [ 13 ]. The use of 1500 IU hCG on the day of oocyte retrieval after agonist trigger reduces the risk of developing OHSS without affecting the ongoing pregnancy rate [ 13 ]. Patients who used an agonist trigger all received 1500 IU of hCG on the day of oocyte retrieval and started with micronized progesterone (Utrogestan vaginal capsules, Besins Healthcare) 200 mg 3 times/day plus estradiol (Progynova, Bayer, Weimar, Germany) 2 mg 2 times/day on the same day until 15 days after oocyte retrieval if embryo transfer was performed. Women < 38 years of age underwent a single embryo transfer if it was their first or second IVF treatment. Women ≥ 38 years without medical contraindications received a single or a double embryo transfer, and women < 38 years when starting their 3rd, 4th or 5th cycle could opt for a dual embryo transfer. The decision of whether one or two embryos were transferred was left to the patient after counseling them about the risks accompanying a possible twin pregnancy. Embryo development was assessed on day 3 after ovum pickup. When multiple high‐quality embryos were present, reassessment and embryo selection for transfer were performed on day 5. If only one (in the case of preferred single embryo transfer) or two (in the case of double embryo transfer) good‐quality embryos were present on day 3, embryo transfer was performed on day 3. Patients performed a urinary pregnancy test at home 16 days after oocyte retrieval and reported the result to the clinic. Ultrasound was performed 5 weeks after oocyte retrieval and was repeated between 9 and 10 weeks after oocyte retrieval to confirm clinical and ongoing pregnancy. The endpoints that were assessed included ongoing pregnancy rate, defined by at least one intrauterine viable fetus 10–11 weeks after transfer, and ongoing implantation, defined as the number of intrauterine viable fetuses 10–11 weeks after transfer divided by the number of blastocysts transferred. The secondary endpoints include the live birth rate (defined as the birth of at least one live‐born neonate), targeted ovarian response (8–14 oocytes) and extreme ovarian response (< 4, ≥ 15, or ≥ 20 oocytes), embryology and safety. The safety endpoints included the number of women hospitalized with OHSS [ 14 ] and/or preventive interventions for early OHSS (freeze all strategies and/or trigger with a GnRH agonist in women with more than 14–22 follicles). As this is a descriptive analysis, only the mean and standard deviation were determined. The full dataset of the ESTHER‐1 trial was not available for our analysis; therefore, the results described in the published article of the ESTHER‐1 trial were used for comparison. All the statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS), version 25 (SPSS Inc., Chicago, Illinois).

Table S1: Comparison of baseline characteristics between EMC and ESTHER‐1 study population.