Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Comparative effectiveness of gonadotropins used

for ovarian stimulation during assisted
reproductive technologies (ART) in France:
A real-world observational study from the
French nationwide claims database (SNDS)
M. Grynberg a, b, *, I. Cedrin-Durnerin b, F. Raguideau c,
E. Herquelot c, L. Luciani d, 1, F. Porte e, 1, P. Verpillat f,
C. Helwig f, J.E. Schwarze f, S. Paillet g, 1, C. Castello-Bridoux g, 1,
Thomas D'Hooghe f, h, i, M. Benchaïb j
a ^
Hopital Antoine Becl
ere, Service de Medecine de La Reproduction et Pr eservation de La Fertilit
e, 92140,
Clamart, France
b ^
Hopital Jean Verdier, Service de Medecine de La Reproduction et Pr eservation de La Fertilit
e, 93140, Bondy,
France
c
HEVA, 69006 Lyon, France
d
Direction des Affaires Medicales e Real-World Evidence, Merck Sant e, 69008, Lyon, France
e
Direction des Affaires 
economiques - Market Access, Merck Sant e, 69008, Lyon, France
f
Merck Healthcare KGaA, Darmstadt, Germany
g
Direction des Affaires Medicales - Fertilit
e, Merck Sant
e, 69008, Lyon, France
h
Department of Development and Regeneration, Laboratory of Endometrium, Endometriosis & Reproductive
Medicine, KU Leuven, Herestraat 49 - Box 805 | B-3000, Leuven, Belgium
i
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University Medical School, New
Haven, CT, 06510, USA
j ^
Hopital Mere Enfant, Service de Medecine de La Reproduction et Pr eservation de La Fertilit
e, 69500, Bron,
France

* Corresponding author. Ho^pital Antoine Be

cle
re, Service de Me
decine de la Reproduction et Pre servation de la Fertilite
,
92140, Clamart, France.
E-mail addresses: michael.grynberg@aphp.fr (M. Grynberg), isabelle.cedrin-durnerin@aphp.fr (I. Cedrin-Durnerin), FRA-
GUIDEAU@hevaweb.com (F. Raguideau), eherquelot@hevaweb.com (E. Herquelot), laura.luciani@merckgroup.com (L. Luciani),
fanny.porte@merckgroup.com (F. Porte), patrice.verpillat@merckgroup.com (P. Verpillat), Christoph.Helwig@merckgroup.com
(C. Helwig), juan-enrique.schwarze@merckgroup.com (J.E. Schwarze), segolene.paillet@merckgroup.com (S. Paillet), claire.
castello-bridoux@merckgroup.com (C. Castello-Bridoux), thomas.dhooghe@merckgroup.com (T. D'Hooghe), mehdi.benchaib@
chu-lyon.fr (M. Benchaïb).
1
an affiliate of Merck KGaA, Darmstadt, Germany.

https://doi.org/10.1016/j.bpobgyn.2022.102308
1521-6934/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

a b s t r a c t
Keywords:
r-hFSH This comparative non-interventional study using data from the
HP-hMG French National Health Database (Syst eme National des Donnees de
Live birth Sante) investigated real-world (cumulative) live birth outcomes
Cumulative live birth following ovarian stimulation, leading to oocyte pickup with either
Real-world data originator recombinant human follicle-stimulating hormone (r-
France
hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries
including mainly HP-hMG (menotropins), and marginally u-hFSH-
HP (urofollitropin). Using data from 245,534 stimulations (153,600
women), biosimilars resulted in a 19% lower live birth (adjusted
odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76e0.86) and a
14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86,
95% CI 0.82e0.89); and urinaries resulted in a 7% lower live birth
(adjusted OR 0.93, 95% CI 0.90e0.96) and an 11% lower cumulative
live birth (adjusted HR 0.89, 95% CI 0.87e0.91) versus originator r-
hFSH alfa. Results were consistent across strata (age and ART
strategy), sensitivity analysis using propensity score matching, and
with r-hFSH alfa and beta as the reference group.
© 2023 The Authors. Published by Elsevier Ltd. This is an open
access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

Introduction

Urinary and recombinant gonadotropin products (recombinant human follicle stimulating hormone
(r-hFSH)) are routinely used for ovarian stimulation (OS) in assisted reproductive technologies (ART),
which is defined as all interventions that include the in vitro handling of human oocytes and sperm or
of embryos for the purpose of reproduction [1]. Owing to differences in their origin, production, and
purification methods, urinary-derived and r-hFSH products have different characteristics regarding
purity, degradation profile, and glycosylation profile [2]. For example, originator r-hFSH alfa (Gonal-f®,
Merck, Darmstadt, Germany) is a biochemically pure FSH preparation (
95%) with regard to r-hFSH
alfa protein content [3e5], and the manufacturing process results in high batch-to-batch consistency
with respect to isoform profile and glycan-species distribution [6,7]. Similarly, originator r-hFSH beta
(Puregon®, NV Organon, The Netherlands) is also biochemically pure with regard to r-hFSH beta
protein content and has a high batch-to-batch consistency with respect to isoform profile and glycan
species distribution [8]. By contrast, some urinary-derived gonadotropin-based products (human
menopausal gonadotropin (hMG) or highly purified urinary FSH (u-hFSH-HP)) contain a miscellanea of
gonadotropins (FSH, human chorionic gonadotropin (hCG), and luteinizing hormone (LH)), up to 20% of
non-gonadotropin proteins and up to 40% of oxidized forms [5,9,10]. Furthermore, the FSH content of r-
hFSH differs from that of highly purified hMG (HP-hMG) in terms of glycosylation pattern (including
sialylation) [7,11], whereby the glycosylation pattern of r-hFSH is similar to that observed at the
midpoint of the menstrual cycle, whereas urinary products have a glycosylation pattern similar to that
seen in menopausal women [7,11].
Such variations may affect the biological activity, metabolic clearance, and half-life of the various
gonadotropins, and this variability could potentially lead to differences in therapeutic effectiveness in
women undergoing ART [11]. In randomized controlled trials (RCTs), treatment with originator r-hFSH
alfa consistently resulted in a higher number of oocytes (þ2), shorter treatment duration (1 day), and
a lower daily and total dose (200 IU) compared with HP-hMG [12,13]. This can be explained by the
fact that, based on in vivo bio- and immune-assays and other biological tests, originator r-hFSH has
higher specific activity (biopotency/mg of proteins) and, as mentioned above, higher purity and lower
batch-to-batch variability than urinary products [5,6,10]. Importantly, treatment with originator r-
hFSH alfa is associated with an increased number of recovered oocytes, which is a well-known

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

independent predictive factor of live birth in fresh transfers [14e21] and is significantly related to the
chance of cumulative live birth [15,22].
The European Medicines Agency (EMA) requires biosimilar products to have comparable structural,
physicochemical, pharmacological, pharmacokinetic, toxicological, efficacy, and safety profiles to
reference r-hFSH alfa, determined through comparability studies [23]. However, despite showing
comparability with respect to these parameters, r-hFSH alfa biosimilars are not considered to be exact
copies of reference r-hFSH alfa [24,25]. Furthermore, a number of publications have reported differ-
ences in the glycosylation profiles between reference r-hFSH alfa and r-hFSH alfa biosimilars
[11,26e29]. Such differences are relevant as the biological function and action of r-hFSH are finely
regulated by glycan structures, and the glycosylation profile is a crucial factor in the determination of
receptor affinity and the circulatory half-life of the gonadotropin [2]. In addition, although biosimilar r-
hFSH products have shown an equivalent number of recovered oocytes and a similar risk of ovarian
hyperstimulation syndrome (OHSS) compared with originator r-hFSH in registration RCTs [30e32],
recent meta-analyses of RCTs demonstrated a lower probability of clinical pregnancy [33,34] and
ongoing pregnancy and live birth [33] in women treated with biosimilar r-hFSH products compared
with those treated with the originator product.
Infertility RCTs are often too small to detect all treatment effects between the treatment arms that
are relevant from the patient or physician perspectives, or the reporting of these treatment effects may
be limited [35]. For example, the above-mentioned registration RCTs were neither designed nor
powered to detect differences in pregnancy or live birth outcomes [30,31]. To gain greater insight into
the reproductive outcomes reported in RCTs applied to clinical practice, studies using real-world data
have the benefit of larger sample sizes than RCTs to assess the comparability of available treatments
across all patient groups (e.g., regardless of age or predicted response) [36]. For example, while RCTs
were not powered to demonstrate superiority in terms of pregnancy/live birth outcomes between r-
hFSH and urinary products [37], large real-world observational studies and analyses of national reg-
istries demonstrated that the live birth rate and cumulative live birth rate were higher with originator
r-hFSH alfa than with HP-hMG [38e41]. Accordingly, real-world observational studies can complement
RCTs, to accumulate evidence on clinically relevant fertility outcomes, including cumulative pregnancy
and live birth, between gonadotropin products. Such studies are, however, contingent on identifying
large, high-quality real-world data sources (national clinical registries or reimbursement databases)
from which these real-world data can be obtained.
Several different gonadotropin products are currently reimbursed in France, including HP-hMG and
r-hFSH products. In 2019, there were a total of 157,593 ART attempts in France, and 27,180 children
were born following ART [42]. Therefore, we carried out a non-interventional study based on data from
the French National Health Database (Syst eme National des Donn ees de Sante [SNDS]) to describe the
ART pathway (in vitro fertilization [IVF] and/or intracytoplasmic sperm injection [ICSI] and fresh and
freezeethaw embryo transfers) in France and to compare the effectiveness (live birth following fresh
embryo transfer and cumulative live birth following fresh and/or frozen embryo transfers [FET]) of
commonly used gonadotropin products used for OS.

Materials and methods

Study design

This was a multi-cohort, comparative, non-interventional study based on secondary use of the SNDS
data. The SNDS, which has been described elsewhere [43,44], is the largest claims database in France. It
contains individual data linked anonymously to an individual's social security number (Num ero
d'Inscription au R
epertoire [NIR]) for all healthcare expenditures reimbursed by the French National
Health Insurance, including billing and reimbursement of outpatient healthcare consumption and data
from the national hospital discharge database, representing data on >99% of the French population.
Specifically, the SNDS contains socio-demographic data (age, sex, and region), information on all
healthcare expenses reimbursed by the national healthcare public system, including outpatient visits,

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

medication (including gonadotropins and ART-associated treatment), medical procedures, laboratory

tests, hospital admission and procedures (including hospital-based management of births, mis-
carriages, ectopic pregnancies, and OHSS), with their corresponding care dates and date of death, all
linked to create a longitudinal record of outpatient health encounters, hospital diagnoses, and drug
dispensing [43]. However, clinical and biological information (such as ovarian reserve or number of
oocytes retrieved) is not recorded and, therefore, could not be used in this study.
The comprehensive nature and the quasi-exhaustivity of the database make it a valuable resource
for a real-world observational study of globally important medicalescientific questions related to
fertility treatment outcomes d ART procedures in France are covered at 100% by health insurance (up
to a maximum of six artificial inseminations and four IVF attempts), after prior agreement from the
health insurance fund, in women up to the age of 43 years [45].

Study registration and ethics approval

This study is registered on the Health Data Hub website (T50770420190523). In accordance with
current regulations, the study protocol was submitted to the committee for research, studies, and
evaluations in the field of health (Comit
e d’Expertise pour les Recherches, les Etudes et les Evaluations dans
le domaine de la Sant e [CEREES]) for approval and was authorized by the French data protection au-
thority (Commission Nationale de l’Informatique et des Libert es [CNIL], which protects personal data,
supports innovation, and preserves individual liberties [CNIL authorization number MR:920,437]).

Study population

Study cohorts
Cohorts of stimulations were compared based on the type of gonadotropin dispensed in pharma-
cies. These cohorts comprised patients treated with originator r-hFSH alfa only (Gonal-f®, Merck KGaA,
Darmstadt, Germany); patients treated with r-hFSH originator preparations (originator r-hFSH alfa and
originator r-hFSH-beta [Puregon®, N.V. Organon, The Netherlands]); patients treated with urinaries
including mainly HP-hMG (menotropins [Menopur® Ferring Pharmaceuticals, Saint-Prex, Switzerland;
Fertistartkit® IBSA FARMACEUTICI SRL, Italy]), and marginally u-hFSH-HP (urofollitropin [Fosti-
monkit® IBSA FARMACEUTICI SRL, Italy]) and patients treated with r-hFSH alfa biosimilar preparations
(Ovaleap®, Theramex Ireland Ltd., Ireland; Bemfola®, Gedeon Richter PLC, Hungary). In this article, the
term “originator” is used to encompass the official European Medicines Agency terms “original similar
biological medicinal product or reference medicine or reference medicinal product or reference’ bio-
logical medicine” [24,46], and the official Food and Drug Administration term “reference product OR
original product” [47e49].

Inclusion criteria
The study population comprised women who had an oocyte pickup (OPU) between 01/01/2013 and
31/12/2018, identified using the codes listed in Supplementary Table 1, and an OS performed with one of
the gonadotropins of interest that was dispensed within the 6-month period prior to the OPU. This
contingency was included because there is potentially a delay of up to 6 months in routine clinical practice
between a consultation for ART with simultaneous prescription of treatment (e.g., gonadotropins can be
dispensed several months before the beginning of ART) and the actual date of OPU. Women were included
in the study at the index date, which was the date of the start of an OS cycle, and was defined as the date
occurring 30 days before a recorded OPU and occurring within 6 months after the dispensing of
gonadotropin, to account for any delay between prescribing/dispensing and starting treatment.
Each stimulation was followed from the index date until either the date of the next stimulation (at
least 30 days apart), date of death, date of the first live birth (for the time-to-event analysis for the first
event) or 31/12/2019 (end of follow-up), whichever occurred first. OS leading to OPU was followed up
from 01/01/2013 to 31/12/2019, to allow at least 1 year of follow-up after the cut-off date based on the
data available at the time of the study. As “an ovarian stimulation leading to OPU” was the unit of
investigation in this study, a woman who had several ovarian stimulations leading to OPU could be
included several times in the study, and potentially in different cohorts.

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Exclusion criteria
Women who had OS for ART treatment under the following scenarios were excluded: as part of
oocyte donation (stimulations with a hospital stay for oocyte donation within 60 days after index date);
for chemotherapy for oncology or autoimmune diseases (delivered within 7 months after the index
date); using Elonva® (Corifollitropin alfa; N. V. Organon, The Netherlands [50]) in addition to one of the
gonadotropins of interest (6 months before and/or 30 days after the index date); using two different
international non-proprietary name (INN) gonadotropins (including recombinant) during the same
cycle (6 months before and/or 30 days after the index date) except hCG for triggering; women <18
years old or >43 years; women with no reimbursement record in the SNDS database for at least 18
months during the study period (as information on women who are lost to follow-up is not recorded in
the database); in adult women who are themselves twins or triplets (in this scenario, it is not possible
to link the health record to the patient owing to the potential evolution of pseudo-NIR numbers for
twin/triplet patients throughout their lifetime); and women with fictive identifiers, as linking the
health record to the patient was not possible.

Outcomes

Primary outcome
The primary outcome of the study was live birth, which was identified by a stay in hospital for
childbirth (identified using the specific International Classification of Diseases (ICD)-10 codes reported
in Supplementary Table 2) that was linked to the last stimulation leading to OPU before the live birth. A
live birth was considered linked to an ovarian stimulation leading to OPU if the following two con-
ditions were met: the OPU was the last observed before a live birth (without condition of time) and the
live birth was preceded by an embryo transfer within the 9-month period before the date of a live birth.
All reimbursed stimulation cycles during the study period were collected. In case of multifetal preg-
nancies, only one live birth was counted; if two hospital admissions for a live birth for the same woman
occurred <30 weeks apart, only the first was considered a live birth.
The primary outcome was reported as the live birth rate and as the cumulative live birth rate. The
live birth rate per ovarian stimulation leading to OPU was defined as the sum of live births only after a
fresh embryo transfer with each product, divided by the sum of non-freeze-all ovarian stimulations
with the same product. A fresh embryo transfer was defined as a transfer occurring within <7 days
after OPU and identified by the corresponding codes (Supplementary Table 2). The cumulative live
births resulting from ovarian stimulation cycles leading to OPU included all live births following fresh
and/or FET with each treatment, divided by the total number of treatments with the same product. A
FET was identified by thawing and/or transfer
7 days after the day of OPU, according to the corre-
sponding code (Supplementary Table 2).

Secondary outcomes
The adverse events leading to hospitalization were assessed by the presence of specific ICD-10
codes during predefined time windows, ranging from 1 week to 1 year (Supplementary Table 2)
after the index date. Depending on the time window after the index date, the analysis was done ac-
cording to the ovarian stimulations with prespecified follow-up to identify the considered outcome;
consequently, the number of stimulations varied according to the adverse event considered.

Statistical analysis

Covariates
As the study was based on real-world data and was not designed as an RCT, no random assignment of
treatment was performed. In this context, causal inference from a comparative non-interventional study
may be biased because it is not possible to determine whether the potential differences in outcomes
observed between the different treatment cohorts are really due to the treatment effect or due (at least
partially) to differences between patients or other measured and unmeasured characteristics. To control
for this possible source of bias, confounding baseline variables are incorporated into statistical models
[51]. Traditionally, confounders are identified from a set of variables. Each variable in the set is classified as

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

either a confounder or not, based on expert knowledge/assumptions of the underlying data-generating

mechanism [52]. For our study, the relevant covariates included in the statistical models were chosen
by the clinician co-authors, based firstly on variables that have been reported/validated to predict either
live birth or cumulative live birth after ovarian stimulation for ART treatment [53e55] and secondly on the
data that were routinely available in the SNDS database, either before or at the index date.
The predefined covariates (Supplementary Table 3) were age, center type (i.e., private or public),
pretreatment (contraceptives, estrogen, and progesterone), number of previous intrauterine in-
seminations, number of previous OPU, year of OPU, presence of previous miscarriages linked to hos-
pitalization, presence of previous evolutive pregnancies, and presence of previous childbirth. Data on
the use of a gonadotropin-releasing hormone (GnRH) analog to avoid premature ovulation, ovulation
trigger, and luteal phase support were extracted but not included as covariates in the main analyses
because this was not reported for a substantial number of cases in the SNDS; however, a sensitivity
analysis, including the use of a GnRH analog to avoid premature ovulation as a covariate in the
adjustment model, was also performed on stimulations with available information on GnRH analog use.

Stimulations
All analyses were performed per ovarian stimulation leading to OPU as the unit of analysis.
Continuous variables were summarized using descriptive statistical measures (mean, standard devia-
tion [SD], median, minimum, maximum, and interquartile range [Q1, Q3]). All statistical tests were two-
sided and used a 5% significance level. All confidence intervals represent the 95% limits and are two-
sided. The statistical analyses were performed with SAS software (SAS Institute, NC, USA; version 9.4).

Primary outcome
Live birth rates were compared using a logistic regression analysis adjusting for the predefined
covariates and are presented as odds ratios (OR) including all cycles with non-missing predefined
covariates. Cumulative live birth rates were compared using an AnderseneGill model [56] adjusting for
the predefined covariates and including all cycles with non-missing predefined covariates. The
AnderseneGill model is a survival model that generalizes the semiparametric Cox model for recurrent
time-to-event data. The time scale specified was the time since the start of stimulation leading to OPU.
The results of the AnderseneGill model are presented as the hazard ratio (HR) of having one or several
births for each ovarian stimulation leading to OPU. As the ovarian stimulations are not independent
(i.e., several ovarian stimulations for a woman are expected to be correlated), the robust sandwich
estimate of the covariance matrix was computed at the level of women in the AnderseneGill model.

Secondary outcomes
The adverse events leading to hospitalization that were linked or not linked with pregnancy are
reported as the number and proportion of the ovarian stimulations leading to OPU with each of the
products of interest.

Stratified analyses
The stratified analyses were conducted by age categories (18e29 years, 30e34 years, 35e37 years,
38e40 years, and 41e43 years) and by freeze-all status (yes or no) (Supplementary Table 2).

Sensitivity analyses
A sensitivity analysis was performed on a subgroup of women undergoing their first ART cycle
within the study period (naïve stimulation from rank 1) using 1:1 propensity score matching. The
covariates were then individually assessed for the selection into the propensity score using a logistic
regression model, and a greedy algorithm with caliper (defined at 0.2 of variance of the logit of the
propensity score) without replacement was applied. We considered covariates to be balanced if the
absolute value of the standardized mean difference was <0.1 [57,58]. Only cumulative live birth rates
were calculated and compared in this analysis.
A sensitivity analysis was also performed for cumulative live birth on a subgroup of stimulations
leading to OPU (full population) for which data on GnRH analog use were recorded. These sensitivity
analyses were performed using the AnderseneGill model, with a robust sandwich estimate of the

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

covariance matrix at the woman level and adjusted with predefined covariates and the GnRH analog
used to prevent premature ovulation.

Results

A graphical representation of the main results has also been provided by the authors (Infographic
abstract).
A visual summary of the results of this study has been provided by the authors (Video Summary).

Details of women and stimulations included in the analysis

After successive application of the inclusion and exclusion criteria, 153,600 women who underwent
245,534 stimulations leading to OPU were included in the study (Fig. 1). 65.07% (159,772) of stimulations
were performed with either r-hFSH originators alfa or beta (leading to 44.99% (110,439) when only
originator r-hFSH alfa is considered), 29.92% with urinaries (65,654 with HP-hMG and 7,821 with u-
hFSH-HP), and 5.00% (12,287) with biosimilars. The mean age was 34.07 (SD 4.77) years at the time of
stimulation, and most women were treated in public hospitals (55.38%) (Table 1). The freeze-all popu-
lation represented 9.58% of stimulations (Table 1). The mean number of previous intrauterine in-
seminations was 0.55 (SD 1.27), and the mean number of previous ovarian stimulations leading to OPU in
the 2 years before the index date was 0.69 (SD 0.97) (Table 1). Descriptions of stimulations leading to
OPU at the index date are described in Table 1. A reimbursement record for pretreatment (contraceptives,
estrogen, and progesterone) was recorded for 93.06% of stimulations, pituitary downregulation for
74.96% of stimulations, an ovulation trigger for 99.26% of stimulations, and treatment for luteal phase
support for 90.20% of stimulations (Table 1).

Description of ART pathway

The mean number of stimulations per woman ranged from 1.20 to 1.45 (Table 2); the majority (61%)
of women had only one stimulation leading to OPU (Fig. 2).

Primary outcomes

Live birth
The unadjusted overall live birth rate was 15.57% (95% CI 15.41%e15.73%). Unadjusted live birth
rates according to each treatment are reported in Supplementary Fig. 1.
Using logistic regression analysis adjusting for all predefined covariates, including a total of
213,787 cycles, we observed a 19% lower chance of live birth with biosimilars (adjusted OR 0.81, 95%
CI 0.76e0.86) and a 7% lower chance of live birth with urinaries (adjusted OR 0.93, 95% CI
0.90e0.96) compared with r-hFSH alfa originator (p < 0.0001 for both versus r-hFSH alfa originator)
(Fig. 3). Using the same method, we observed an 18% lower chance of live birth with biosimilars
(adjusted OR 0.82, 95% CI 0.77e0.87) and a 7% lower chance of live birth with urinaries (adjusted OR
0.93, 95% CI 0.91e0.96) compared with r-hFSH originators (p < 0.0001 for both versus r-hFSH
originators) (Fig. 3).

Cumulative live birth

The unadjusted overall cumulative live birth rate was 21.39% (21.21%e21.57%). The unadjusted
cumulative live birth rates per treatment are reported in Supplementary Fig. 2.
Using an AnderseneGill model, with a random effect at the woman level and adjusted for the
predefined covariates, including a total of 236,386 cycles, we observed a 14% lower probability of
cumulative live birth with biosimilars (adjusted HR 0.86, 95% CI 0.82e0.89) and an 11% lower chance of
cumulative live birth with urinaries (adjusted HR 0.89, 95% CI 0.87e0.91) compared with r-hFSH alfa
originator (Fig. 4). Using the same methodology, we observed a 13% lower chance of cumulative live
birth with biosimilars (adjusted HR 0.87, 95% CI 0.83e0.91) and a 10% lower chance of cumulative

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Fig. 1. Flowchart of inclusion and exclusion criteria of cycles selected for the analysis.

live birth with urinaries (adjusted HR 0.90, 95% CI 0.89e0.92) compared with r-hFSH originators
(p < 0.0001 for both versus r-hFSH originators) (Fig. 4).

Secondary outcomes

The main reported adverse event leading to hospitalization and not linked to pregnancy was OHSS
for all treatment groups (ranging from 0.97% to 1.94%) (Table 3). Other adverse events leading to
hospitalization and not linked to pregnancy were ovarian cysts, ovarian torsion, hemorrhage, and

8
 Table 1

M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al.

Patient characteristics, descriptions of stimulations leading to OPU at the index date, and description of associated treatments for each stimulation leading to OPU at the index date.

Total (245,534) r-hFSH originators Originator r-hFSH r-hFSH biosimilars Urinaries*

(r-hFSH alfa and alfa (110,439) (12,287) (73,475)
r-hFSH beta)
(159,772)

Patient characteristics
Age (years) Mean (±SD) 34.07 (±4.77) 33.66 (±4.73) 33.68 (±4.75) 33.99 (±4.80) 34.98 (±4.73)
Min; Max 18.00; 43.00 18.00; 43.00 18.00; 43.00 18.00; 43.00 18.00; 43.00
Median 34.00 34.00 34.00 34.00 35.00
Age (in categories) 18e29 44,780 (18.24%) 32,237 (20.18%) 22,317 (20.21%) 2326 (18.93%) 10,217 (13.91%)
30e34 83,719 (34.10%) 57,208 (35.81%) 39,266 (35.55%) 4068 (33.11%) 22,443 (30.55%)
35e37 35,752 (14.56%) 22,992 (14.39%) 15,845 (14.35%) 1892 (15.40%) 10,868 (14.79%)
38e40 44,804 (18.25%) 27,398 (17.15%) 19,023 (17.22%) 2237 (18.21%) 15,169 (20.65%)
41e43 36,479 (14.86%) 19,937 (12.48%) 13,988 (12.67%) 1764 (14.36%) 14,778 (20.11%)
CMUc No 224,268 (91.34%) 146,515 (91.70%) 101,328 (91.75%) 11,081 (90.18%) 66,672 (90.74%)
Dispensed cumulative dose of Mean (±SD) 3976.68 (±2411.83) 3657.51 (±2123.98) 3689.50 (±2172.67) 4112.40 (±2460.06) 4648.02 (±2818.08)
gonadotropin (IU)

Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308
Type of center Private 108,660 (44.25%) 70,835 (44.34%) 51,226 (46.38%) 4759 (38.73%) 33,066 (45.00%)
Public 135,971 (55.38%) 88,306 (55.27%) 58,738 (53.19%) 7522 (61.22%) 40,143 (54.63%)
Unknown 903 (0.37%) 631 (0.39%) 475 (0.43%) 6 (0.05%) 266 (0.36%)
Freeze-all No 222,023 (90.42%) 143,495 (89.81%) 99,146 (89.77%) 10,705 (87.12%) 67,823 (92.31%)
9

Yes 23,511 (9.58%) 16,277 (10.19%) 11,293 (10.23%) 1582 (12.88%) 5652 (7.69%)
Descriptions of stimulations leading to OPU at the index date
a
Number of previous intrauterine insemination N 236,386 153,742 106,186 11,729 70,915
Mean (±SD) 0.55 (±1.27) 0.63 (±1.35) 0.65 (±1.36) 0.33 (±0.97) 0.42 (±1.10)
Number of previous stimulationsa N 236,386 153,742 106,186 11,729 70,915
Mean (±SD) 0.69 (±0.97) 0.58 (±0.88) 0.58 (±0.88) 0.51 (±0.88) 0.95 (±1.10)
Presence of previous childbirthsb No 182,884 (74.48%) 119,313 (74.68%) 83,518 (75.62%) 9439 (76.82%) 54,132 (73.67%)
Yes 62,650 (25.52%) 40,459 (25.32%) 26,921 (24.38%) 2848 (23.18%) 19,343 (26.33%)
b
Number of previous childbirths N 245,534 159,772 110,439 12,287 73,475
Mean (±SD) 0.28 (±0.52) 0.28 (±0.51) 0.27 (±0.51) 0.27 (±0.54) 0.29 (±0.52)
b
Presence of previous hospitalized miscarriages No 228,366 (93.01%) 149,037 (93.28%) 102,890 (93.16%) 11,601 (94.42%) 67,728 (92.18%)
Yes 17,168 (6.99%) 10,735 (6.72%) 7549 (6.84%) 686 (5.58%) 5747 (7.82%)
Number of previous hospitalized miscarriagesb N 245,534 159,772 110,439 12,287 73,475
Mean (±SD) 0.08 (±0.32) 0.08 (±0.31) 0.08 (±0.31) 0.06 (±0.29) 0.09 (±0.35)
Presence of previous evolutive pregnanciesb No 175,613 (71.52%) 114,773 (71.84%) 80,391 (72.79%) 9165 (74.59%) 51,675 (70.33%)
Yes 69,921 (28.48%) 44,999 (28.16%) 30,048 (27.21%) 3122 (25.41%) 21,800 (29.67%)
b
Number of previous evolutive pregnancies N 245,534 159,772 110,439 12,287 73,475
Mean (±SD) 1.11 (±2.06) 1.09 (±2.04) 1.06 (±2.01) 1.03 (±2.11) 1.15 (±2.08)
Description of associated treatments for each stimulation leading to OPU at index date
N total 244,342 159,008 109,886 12,217 73,117
(continued on next page)
 Table 1 (continued )

M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al.

Total (245,534) r-hFSH originators Originator r-hFSH r-hFSH biosimilars Urinaries*
(r-hFSH alfa and alfa (110,439) (12,287) (73,475)
r-hFSH beta)
(159,772)

Pretreatment (contraceptives, estrogen, N recorded 227,375 (93.06%) 148,368 (93.31%) 102,404 (93.19%) 11,138 (91.17%) 67,869 (92.82%)
progesterone)
Pituitary downregulation (GnRH agonists/ N total 244,342 159,008 109,886 12,217 73,117
antagonists) N recorded 183,166 (74.96%) 122,731 (77.19%) 86,145 (78.39%) 10,039 (82.17%) 50,396 (68.93%)
Ovulation trigger (choriogonadotropin alfa, N total 244,342 159,008 109,886 12,217 73,117
chorionic gonadotropin) N recorded 242,523 (99.26%) 157,829 (99.26%) 109,076 (99.26%) 12,133 (99.31%) 72,561 (99.24%)
Luteal phase support (progesterone, N total 244,342 159,008 109,886 12,217 73,117
dydrogesterone) N recorded 220,399 (90.20%) 144,015 (90.57%) 99,724 (90.75%) 10,623 (86.95%) 65,761 (89.94%)

N total: the denominator is the number of stimulations with non-missing information. Data are considered missing if the follow-up is less than 6 months. N recorded: the numerator is the
number of stimulations recorded for the variable of interest.
CMUc: Couverture Me dicale Universelle Comple
mentaire (free access to healthcare for people with an annual income <50% of the poverty threshold). SD: standard deviation.
a
Previous 2 years.

Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308
b
During follow-up period.
*
Urinaries include mainly HP-hMG (65,654 stimulations), and marginally u-hFSH-HP (7,821 stimulations).
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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Table 2
Distribution of the number of stimulations per woman.

r-hFSH originators Originator r-hFSH r-hFSH Urinaries (50,738)*

(r-hFSH alfa and alfa (77,092) biosimilars
r-hFSH beta) (112,868) (10,205)

Mean number of stimulations 1.42 (±0.75) 1.43 (±0.77) 1.20 (±0.51) 1.45 (±0.80)
leading to OPU (±SD)
Min; max 1.00; 11.00 1.00; 10.00 1.00; 7.00 1.00; 16.00

Max, maximum; Min, minimum; OPU, oocyte pickup; r-hFSH, recombinant human follicle-stimulating hormone; SD, standard
deviation.
*
Urinaries include mainly HP-hMG, and marginally u-FSH-HP.

Fig. 2. Sankey diagram of stimulation trajectories after the first stimulation. Up to rank 4 stimulations included. A Sankey diagram is
a visualization used to depict a flow from one set of values to another; for example, to show multiple paths through a set of stages. In
this example, the Sankey diagram shows the flow for four outcomes in the SDNS database (live birth, ongoing pregnancy without
live birth, no pregnancy, and no other stimulation) for up to four sequential stimulation cycles leading to OPU, as reported in the
SNDS. The majority (61.0% [N ¼ 93,706]) of the women had only one stimulation leading to OPU; 39.0% (N ¼ 59,894) had at least two
stimulations leading to OPU; 14% (N ¼ 21,975) had three stimulations leading to OPU; and 5% (N ¼ 7279) had four stimulations
leading to OPU. OPU, oocyte pickup; SNDS, Syste me National des Donne es de Sante .

infection, each of which occurred in <1% of cycles leading to OPU (Table 3). For all treatment groups, the
main reported adverse events leading to hospitalization and linked to a pregnancy were multifetal
pregnancies (ranging from 1.52% to 3.05%) and hospitalized miscarriage (ranging from 0.72% to 1.20%)
(Table 4). The other adverse events leading to hospitalization and linked to a pregnancy were termi-
nation of pregnancy and ectopic pregnancy, each of which occurred in <1% of cycles leading to OPU
(Table 4).

Stratified analyses
The magnitude of the effect was maintained regardless of age or the ART strategy. A lower prob-
ability of cumulative live birth rate with biosimilars or urinaries compared with r-hFSH alfa originator
was observed in the age categories 18e29, 30e34, 35e37, 38e40, and 41e43 years (Fig. 5). When
stratified by ART strategy, we also observed a lower probability of cumulative live birth with biosimilars

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Fig. 3. Live birth after fresh embryo transfer according to gonadotropin (A) originator r-hFSH alfa and (B) r-hFSH originators (logistic
regression analysis adjusting for covariates listed in the footnote). The odds ratios were calculated using a logistic regression model.
The covariates used for the adjustment were age, center type (i.e., private or public), pretreatment (contraceptives, estrogen, and
progesterone), number of previous intrauterine inseminations, number of previous OPU, year of OPU, presence of previous mis-
carriages linked to hospitalization, presence of previous evolutive pregnancies, and presence of previous childbirth. Freeze-all
stimulations were excluded from this analysis. r-hFSH originators include originator r-hFSH alfa and originator r-hFSH beta. Uri-
naries include mainly HP-hMG, and marginally u-hFSH-HP. CI, confidence interval; OPU, oocyte pickup; OR, odds ratio; r-hFSH,
recombinant human follicle-stimulating hormone.

and urinaries compared with r-hFSH alfa originator in cycles with or without a freeze-all strategy
(Fig. 5).
Using the same methodology, we observed a lower probability of cumulative live birth with bio-
similars or urinaries compared with r-hFSH originators in the age categories 18e29, 30e34, 35e37,
38e40, and 41e43 years (Fig. 6). We also observed a lower probability of cumulative live birth with
biosimilars and urinaries compared with r-hFSH originators in cycles with or without a freeze-all
strategy (Fig. 6).

Sensitivity analyses
The propensity scores showed good overlap between treatment groups; the distributions of ab-
solute standardized differences between treatment groups before and after matching are summarized
in Supplementary Figs. 3e6. After 1:1 propensity score matching, we observed a lower effect of bio-
similars versus r-hFSH alfa originator (13% lower chance of cumulative live birth; adjusted HR 0.87, 95%
CI 0.81e0.93) (Supplementary Table 4) and a lower effect of urinaries versus r-hFSH alfa originator (8%
lower chance of cumulative live birth; adjusted HR 0.92, 95% CI 0.89e0.96) (Supplementary Table 5).

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Fig. 4. Cumulative live birth after fresh and/or frozen embryo transfer according to gonadotropin versus (A) originator r-hFSH alfa
and (B) combined group of r-hFSH originators alfa and beta (AnderseneGill model analysis adjusted for covariates listed in the
footnote). Hazard ratios were calculated using the AnderseneGill model using time from stimulation. The covariates used for the
adjustment were age, center type (i.e., private or public), pretreatment (contraceptives, estrogen, and progesterone), number of
previous intrauterine inseminations, number of previous OPU, year of OPU, presence of previous miscarriages linked to hospitali-
zation, presence of previous evolutive pregnancies, and presence of previous childbirth. r-hFSH originators include r-hFSH alfa and
rhFSH beta. Urinaries include mainly HP-hMG, and marginally u-hFSH-HP. CI, confidence interval; HR, hazard ratio; OPU, oocyte
pickup; r-hFSH, recombinant human follicle-stimulating hormone.

Furthermore, a lower effect of biosimilars versus r-hFSH originators was observed (16% lower chance of
cumulative live birth; adjusted HR 0.84, 95% CI 0.78e0.90) (Supplementary Table 6) and a lower effect
of urinaries versus r-hFSH originators (8% lower chance of cumulative live birth; adjusted HR 0.92, 95%
CI 0.88e0.95) (Supplementary Table 7). The propensity score models gave consistent results to those
from the AnderseneGill model (Supplementary Tables 4e7).
When the analysis was restricted to cycles with information on GnRH analogs and included the
GnRH analog used to prevent premature ovulation as an additional covariate, we observed a lower
effect of biosimilars and urinaries versus originator r-hFSH alfa (Supplementary Tables 8 and 9).

Discussion

In 153,600 women who underwent 245,534 OS leading to OPU between 01/01/2013 and 31/12/
2018, we found that, compared with r-hFSH alfa originator, OS with biosimilars resulted in a 19% lower
chance of live birth (adjusted OR 0.81, 95% CI 0.76e0.86) and a 14% lower probability of cumulative live

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Table 3
Number and proportion of all stimulations leading to oocyte pickup during which adverse events leading to hospitalization
developed.

Variable Indicator r-hFSH originators Originator r-hFSH Urinaries*

(r-hFSH alfa r-hFSH alfa biosimilars
and r-hFSH beta)

At least one adverse event (ovarian N total 157,665 108,869 12,034 72,347
cysts, OHSS, thromboembolism, N recorded 3704 (2.35%) 2541 (2.33%) 302 (2.51%) 1152 (1.59%)
infections, ovarian torsion,
hemorrhage)
Ovary related
OHSS N total 157,665 108,869 12,034 72,347
N recorded 2913 (1.85%) 2026 (1.85%) 234 (1.94%) 699 (0.97%)
Ovarian cysts N total 159,772 110,439 12,287 73,475
N recorded 632 (0.40%) 394 (0.36%) 64 (0.52%) 388 (0.53%)
Ovarian torsion N total 157,665 108,869 12,034 72,347
N recorded 100 (0.06%) 70 (0.06%) 2 (0.02%) 44 (0.06%)
Oocyte pickup related
Hemorrhage N total 159,651 110,344 12,273 73,391
N recorded 86 (0.05%) 71 (0.06%) 5 (0.04%) 29 (0.04%)
Infection N total 159,772 110,439 12,287 73,475
N recorded 1 (0.00%) 1 (0.00%) 0 (0.00%) 0 (0.00%)
General
Thromboembolic event N total 157,665 108,869 12,034 72,347
N recorded 3 (0.00%) 3 (0.00%) 0 (0.00%) 2 (0.00%)

N total: denominator ¼ number of stimulations with non-missing information. N recorded: numerator ¼ number of stimulations
recorded for the variable of interest. OHSS, ovarian hyperstimulation syndrome; r-hFSH, recombinant human follicle-
stimulating hormone.
*
Urinaries include mainly HP-hMG, and marginally u-FSH-HP.

Table 4
Number and proportion of stimulations leading to oocyte pickup and linked to pregnancy with adverse events leading to
hospitalization.

Variable Indicator r-hFSH originators Originator r-hFSH Urinaries*

(r-hFSH alfa r-hFSH alfa biosimilars
and r-hFSH beta)

At least one adverse event (multiple N Total 54,315 37,363 4068 22,880
pregnancy, miscarriage, termination N recorded 2726 (5.02%) 1834 (4.91%) 134 (3.29%) 1089 (4.76%)
of pregnancy, and ectopic pregnancy)
Multifetal pregnancies N Total 54,315 37,363 4068 22,880
N recorded 1658 (3.05%) 1112 (2.98%) 62 (1.52%) 641 (2.80%)
Hospitalized miscarriage N Total 65,154 44,462 4577 28,096
N recorded 762 (1.17%) 534 (1.20%) 33 (0.72%) 319 (1.14%)
Termination of pregnancy N Total 54,315 37,363 4068 22,880
N recorded 331 (0.61%) 220 (0.59%) 27 (0.66%) 171 (0.75%)
Ectopic pregnancy N Total 65,154 44,462 4577 28,096
N recorded 283 (0.43%) 184 (0.41%) 22 (0.48%) 97 (0.35%)

N total: denominator ¼ number of stimulations leading to an OPU resulting in a pregnancy without missing information. Ovarian
stimulations were followed up from 01/01/2013 to 31/12/2019, to allow for at least 1 year of follow-up after the cut-off date
based on the data available at the time of the study. N recorded: numerator ¼ number of stimulations leading to an OPU resulting
in a pregnancy that was positive for the variable of interest.
*
Urinaries include mainly HP-hMG, and marginally u-FSH-HP.

birth (adjusted HR 0.86, 95% CI 0.82e0.89); and OS with urinaries resulted in a 7% lower chance of live
birth (adjusted OR 0.93, 95% CI 0.90e0.96) and an 11% lower chance of cumulative live birth (adjusted
HR 0.89, 95% CI 0.87e0.91). These results were consistent with stratified analyses according to age or
ART strategy (with or without freeze-all) and in sensitivity analysis using propensity score matching.
The findings of this study are consistent with the known safety profile of originator r-hFSH alfa [59] and
the risks inherent to infertile women undergoing assisted reproductive technique and previously re-
ported literature findings [60e65].

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Fig. 5. Cumulative live birth rate according to stratified analyses: age categories and ART strategy (with or without freeze-all). (A)
Biosimilars versus originator r-hFSH alfa. (B) Urinaries versus originator r-hFSH alfa (AnderseneGill model analysis adjusting for
covariates listed in the footnote). Interaction test age and type of gonadotropin, p ¼ 0.0487; interaction test freeze-all and type of
gonadotropin, p ¼ 0.13. HR were calculated using the AnderseneGill model using time from stimulation. The covariates used for the
adjustment were age, center type (i.e., private or public), pretreatment (contraceptives, estrogen, and progesterone), number of
previous intrauterine inseminations, number of previous OPU, year of OPU, presence of previous miscarriages linked to hospitali-
zation, presence of previous evolutive pregnancies, and presence of previous childbirth. Urinaries include mainly HP-hMG, and
marginally u-hFSH-HP. ART, assisted reporductive technologies; CI, confidence interval; HR, hazard ratio; OPU, oocyte pickup; r-
hFSH, recombinant human follicle-stimulating hormone.

This is the first study to assess the effectiveness of gonadotropins in France, in a nationwide claims
database, reflecting the real-world routine national clinical practice. A particular strength of this study
is that it used the SNDS database as the data source. The SNDS database contains individual data used
for billing and reimbursement of outpatient healthcare consumption and data from the national
hospital discharge database, covering 99% of the French population. Thus, owing to the comprehen-
siveness of the coverage of the SNDS, it provides a valuable opportunity for a real-world study of this
globally important medicalescientific question by providing representative data on the overall routine
clinical care for ART in France in both the private and public hospital settings during the period
2013e2018 (and follow-up to 2019). By using this national database, there are no sampling issues and

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

Fig. 6. Cumulative live birth rate according to stratified analyses: age categories and ART strategy (with or without freeze-all). (A)
Biosimilars versus combined r-hFSH originators alfa and beta. (B) Urinaries versus combined r-hFSH originators alfa and beta
(AnderseneGill model analysis adjusting for covariates listed in the footnote). Interaction test freeze-all and type of gonadotropin,
p ¼ 0.0499; interaction test age and type of gonadotropin, p ¼ 0.034. HR were calculated using the AnderseneGill model using time
from stimulation. The covariates used for the adjustment were age, center type (i.e., private or public), pretreatment (contraceptives,
estrogen, and progesterone), number of previous intrauterine inseminations, number of previous OPU, year of OPU, presence of
previous miscarriages linked to hospitalization, presence of previous evolutive pregnancies, and presence of previous childbirth.ART,
assisted reproductive technologies; r-hFSH originators include r-hFSH alfa and r-hFSH beta. Urinaries include mainly HP-hMG, and
marginally u-hFSH-HP. CI, confidence interval; HR, hazard ratio; OPU, oocyte pickup; r-hFSH, recombinant human follicle-
stimulating hormone.

no selection bias, and our results are representative of reproductive outcomes during the study period.
Furthermore, because the data were routinely collected for reimbursement purposes, and not specif-
ically for this study, the events used as outcomes were not influenced by the study objectives, and there
was no risk of outcome misclassification.
The results of the main analysis are supported by those from the sensitivity analysis, whereby
similar results were reported using the AnderseneGill and the 1:1 propensity score matching models
in a population of women undergoing their first ART cycle. The stimulations in which a GnRH analog to
prevent premature ovulation was reported showed similar results to the main analysis, and there was
consistency in the magnitude of the estimated treatment effect for all stratified analyses defined by age

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

or ART strategy (with or without freeze-all). The results reported here are also consistent with the
recently published literature. A German non-interventional study with a similar design reported on live
birth rates recorded between 01/01/2007 and 31/12/2012 in 71 German fertility centers (58% of all
German IVF centers at the time of the study). In this study of 28,641 women (48,437 cycles), 61.9%
initiated a first treatment cycle with r-hFSH alfa originator and 38.1% with urinaries, and a lower cu-
mulative live birth rate was reported after OS with HP-hMG versus r-hFSH alfa originator [40].
Furthermore, in a meta-analysis of RCTs, a significantly lower live birth rate per initiated OS cycle was
reported with biosimilars compared with originator r-hFSH alfa (relative risk 0.83, 95% CI 0.71e0.97)
[33]. Finally, our study is the first to show that the cumulative live birth is lower after ovarian stim-
ulation with biosimilars compared with originator r-hFSH alfa or the combined group of originators r-
hFSH alfa and r-hFSH beta. When reporting cumulative live birth, we included all live births following
fresh and/or FET, related to the same OS. Cumulative live birth is increasingly reported when assessing
reproductive outcome after ART treatment as it also includes the outcomes of FET cycles associated
with OS leading to OPU; furthermore, FET cycles increasingly contribute to cumulative live birth
outcomes after ART treatment in light of the advancements in vitrification/warming technology [66].
In addition to the strengths of this study, we also acknowledge some limitations. However, as these
limitations are applicable to all cohorts, we do not anticipate them to have a differential effect on the
results of the study. Firstly, although we highlight the benefits of using real-world evidence, this study
was not an RCT, and the results might still be subject to unmeasured confounding or other biases. To
mitigate the effect of this, the analyses were adjusted for covariates that are known to affect live birth
outcomes, which were identified from the published literature and were available in the SNDS data-
base (as explained in the '“Materials and methods” section). Furthermore, matching with 1:1 pro-
pensity score analyses minimized the risk of biased associations when comparing treatment outcomes.
Secondly, as mentioned already, there is a lack of detailed clinical and biological information in the
SNDS (such as ovarian reserve or number of oocytes retrieved), and some medical data are either
underreported or not reported (e.g., the number and morphology of transferred embryos or causes of
infertility, which aredin combination with agedstrongly related to ART outcomes). A third limitation
of using the SNDS is that it records the date when the medication was dispensed, rather than the date
when the medication was administered: in practice, a gonadotropin medication could be dispensed
several months before a woman starts ART. Coding inconsistencies on the use of tests for ovulation
control and induction of ovulation prevented the accurate estimation of the exact gonadotropin start
dates (or exposure dates) or of the dosage actually injected. Accordingly, the most reliable data to
estimate the start date of an OS was OPU; however, by using OPU to define the index date, we were not
able to study canceled cycles. Furthermore, because the duration of time from stimulation to birth was
considered continuous (AnderseneGill model), we are unable to determine the probability of preg-
nancy after each cycle. However, as the average number of cycles undertaken in this study was rela-
tively low, this model was appropriate.
As the study methodology only allowed us to identify adverse events leading to hospitalization in
the SNDS database, the totality of adverse events was probably underestimated. Furthermore, because
only OHSS leading to hospitalization was recorded, it was not possible to differentiate between the
occurrence of moderate and severe OHSS.

Conclusions

We report the results of a comparative non-interventional study using data from the French Na-
tional Health Database (SNDS) on real-world live birth outcomes following OS leading to OPU. After
adjustment for potential confounding variables that have been reported/validated to affect clinical
outcomes after OS for ART treatment, compared with r-hFSH alfa originator treatment with biosimilars
resulted in a 19% lower chance of live birth (adjusted OR 0.81, 95% CI 0.76e0.86) and a 14% lower
probability of cumulative live birth (adjusted HR 0.86, 95% CI 0.82e0.89), whereas treatment with
urinaries (mainly HP-hMG) resulted in a 7% lower chance of live birth (adjusted OR 0.93, 95% CI
0.90e0.96) and an 11% lower chance of cumulative live birth (adjusted HR 0.89, 95% CI 0.87e0.91). This
effect was confirmed when the combined group of r-hFSH originatorsdr-hFSH alfa and r-hFSH
betadwere used as the reference group. This effect was also observed regardless of age or ART strategy

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

(with or without freeze-all) and was confirmed in the sensitivity analysis using 1:1 propensity score
matching. This is the first French nationwide study to compare live birth and cumulative live birth
outcomes among the different gonadotropin products.

Practice Points

 This study provides representative data on the overall routine clinical care for ART in France
in both the private and public hospital settings during the period 2013e2018.

Research agenda

 Because the combinations of gonadotropin products were excluded from this study, addi-
tional studies may investigate the potential and the efficacy in women who have received two
gonadotropin products during the same cycle.
 It will be of interest to extend this analysis to investigate the medical management strategy in
a different source with more fertility-related clinical parameters.

Funding

This study was funded by Merck (CrossRef Funder ID: 10.13039/100009945). Merck KGaA (Darm-
stadt, Germany) designed and approved the study, took part in data collection and data analysis, and
contributed to the data interpretation and final draft of the manuscript.

Authors’ contributions

All authors contributed to the conception and design of the analysis, as well as the interpretation of
data and critical review of this manuscript. All authors approved the manuscript for submission to the
journal.

Data availability

Any requests for data by qualified scientific and medical researchers for legitimate research pur-
poses will be subjected to Merck's Data Sharing Policy. All requests should be submitted in writing to
Merck's data-sharing portal https://www.merckgroup.com/en/research/our-approach-to-research-
and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html. When
Merck has a co-research, co-development, or co-marketing or co-promotion agreement, or when
the product has been outlicensed, the responsibility for disclosure might be dependent on the
agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to
share data in response to requests.

Declaration of competing interest

MG has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for
this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter,
Theramex, General Electric, Novartis, Besins Healthcare.

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M. Grynberg, I. Cedrin-Durnerin, F. Raguideau et al. Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102308

I-CD has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for
this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter,
and Theramex.
FR and EH are employees of HEVA, Lyon, France.
LL, FP, SP, and CC-B are employees of Merck Sante , Lyon, France, an affiliate of Merck KGaA,
Darmstadt, Germany.
PV, JES, and TDH are employees of Merck Healthcare KGaA, Darmstadt Germany.
CH is an employee of Merck KGaA, Darmstadt Germany.
MB has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for
this study, and lecture fees from Merck KGaA, Darmstadt, Germany.

Acknowledgments

The authors thank Professor Nicholas Moore Bordeaux PharmacoEpi, Inserm CIC 1401, University of
Bordeaux, for his advice on the methodology for the analyses in this study. The authors also like to
thank the Direction de la Strate 
gie, des Etudes partement Acce
et des Statistiques (DSES), De s, Traite-
ment et Analyse de la Donne e (DATAD), and Cellule de la CNAM en Charge de l'accompagnement des
Demandes D'extraction (DEMEX) teams at the Caisse Nationale de l'Assurance maladie (CNAM) for the
data extraction. The authors would also like to thank Steven Goodrick, inScience Communications,
Springer Healthcare Ltd., for providing medical writing support in the preparation of this article. This
work was funded by Merck KGaA, Darmstadt, Germany.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bpobgyn.2022.

102308.

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