781 patients, 18–38 years of age with regular ovulatory menstrual cycles and normal uteri eligible for IVF/ICSI and infertility for over a year

MENOPUR^® 225–450 IU/day (n=373) rFSH alfa (Gonal-F) 225–450 IU/day (n=354)

Non-inferiority of ongoing-pregnancy rate (defined as clinical pregnancy confirmed by ultrasound at
10 weeks after ovum pickup following one IVF/ICSI cycle)

Number of follicles, number of oocytes retrieved and fertilised, number of embryos transferred, days of stimulation with gonadotrophin, oestradiol levels on the first and sixth day of gonadotrophin administration and at the time of hCG administration, and safety (including frequency and severity of AEs, miscarriage, and frequency of OHSS type 2 and type 3)

Long GnRH agonist protocol. After downregulation with a GnRH agonist, all patients received a fixed dose
of 225 IU/day of MENOPUR^® or rFSH; at Day 6, the dosage could be adjusted up to
450 IU/day depending on ovarian response

hCG (5000–10,000 IU)

Fresh only. One to three normally developed embryos were transferred at Visit 7

All patients that were included in the EISG study. See EISG study description. Patients were tabulated according to the method of fertilisation: IVF (n=233) or ICSI (n=458) or both (n=3)

Investigate LH activity influence on pregnancy outcomes of EISG study subjects with MENOPUR^® vs rFSH alfa in a long protocol

Serum E2 and LH levels were assessed on day 6 and on the day of hCG administration (or within 48 hours), and hCG levels were assessed on day 6 of stimulation (the day of first dose adjustment). The analyses were performed using ELISA methods

Number of follicles, number of oocytes retrieved and fertilised, number of embryos transferred, days of stimulation with gonadotrophin and oestradiol levels on the first and sixth day of gonadotrophin administration and at the time of hCG administration

The MENOPUR^® and rFSH groups were compared using t-tests or Wilcoxon rank tests for continuous data. Pregnancy rates were compared between groups with generalised linear models using a binomial distribution with the identity link function. Wald tests were used to test differences. Subgroups of categorical data were compared using the chi-square test or Fisher’s exact test. In each group, the association between the OPR and prognostic factors such as age, body mass index, duration of infertility, number of previous cycles, GnRH agonist administration (depot/daily), baseline and day 6 LH levels, day 6 hCG (only in the MENOPUR^® group) level, day 6 and day of hCG administration E2 levels and IVF/ICSI procedure was investigated using logistic regression models. Missing data were defaulted to a negative response (i.e., “no” for pregnancy)

See EISG study description

731 patients, 21–37 years of age with regular ovulatory menstrual cycles and presumed to be ovulatory, tubal or unexplained infertility for ≥1 year before randomisation

MENOPUR^® 225–450 IU/day (n=363) rFSH alfa (Gonal-F) 225–450 IU/day (n=368)

Ongoing-pregnancy rate per started cycle (defined as the presence of at least one viable foetus 10–11 weeks after embryo transfer, documented by transvaginal ultrasound)

Clinical-pregnancy rate, endometrial status, follicular development, oocytes retrieved, fertilisation rate, embryo quality, endocrine profile in serum and follicular fluid and treatment-emergent adverse events (onset after start of stimulation), moderate/severe OHSS and early pregnancy loss

Long GnRH agonist protocol. Patients were treated with 225 IU of MENOPUR^® or rFSH for 5 days, following which doses were adjusted individually by 75 IU and up to 450 IU/day according to the follicular response

hCG (250 µg)

Fresh only. One or two embryos were transferred on day 3 after oocyte retrieval

All patients that were included in the MERiT study. See MERiT study description

Investigate the endocrine status of MERiT study subjects during IVF with MENOPUR^® vs rFSH alfa (n=731)

Blood samples were obtained on Days 1 and 6 of stimulation, last stimulation day, and at oocyte retrieval. Follicular fluid was collected at retrieval from at least one follicle of ≥17 mm from which an oocyte had been retrieved

Embryo quality was assessed daily by local embryologists according to the number of blastomeres and the following morphology aspects: degree and localisation of fragmentation, blastomere uniformity, visual sign of multinucleation and cytoplasmic appearance

Long GnRH agonist protocol. See MERiT study description

All patients that were included in the MERiT study. See MERiT study description

Investigate embryological outcomes in MENOPUR^® vs rFSH alfa-treated patients (n=731)

Embryos were assessed locally; digital images of each embryo at Days 1, 2 and 3 were also sent for assessment to a panel of central embryologists, who were blinded to each other’s evaluations as well as to local embryologists’ evaluations and treatment allocations. Top-quality embryo defined as four or five blastomeres on day 2, seven or more blastomeres on day 3, equal-sized blastomeres and ≤20% fragmentation on day 3, and no multinucleation. Minimum-quality embryo (lowest quality allowed for transfer) was defined as four or more blastomeres on day 3 with no cleavage arrest and ≤20% fragmentation

Logistic regression models were applied for binary data, while continuous data were analysed using ANOVA models. All analyses were adjusted for age (<35 and ≥35 years). Oocytes with three or more pronuclei were regarded as having fertilisation failure and were excluded from all analyses of embryo quality. The individual embryo quality parameters (number of blastomeres and morphology) and the overall embryo classification were displayed for both the local and central embryologists. Embryo end-points on a patient level (e.g., oocytes retrieved, top-quality embryos) were presented descriptively among patients with oocyte retrieval. The analysis of ratios (e.g., top-quality embryos of oocytes retrieved) was based on patients with oocyte retrieval, while the difference between treatments in terms of other end-points was based on all patients in the intent to treat population. Live birth, ongoing pregnancy and ongoing implantation were presented according to overall embryo classification for the consolidated score. The differences between treatments in live-birth rate and ongoing-pregnancy rate were estimated using a logistic regression model, while ongoing implantation was investigated using a generalised estimation equation method to account for the possible correlation between embryos from the same patients. Ongoing-implantation rates by overall embryo classification were calculated for patients with 0 or 100% ongoing implantation rate after single- or double-embryo transfer. Mean blastomere survival rate was calculated based on the survival rate for each thawed embryo. Cryosurvival data were analysed using a logistic regression model adjusting for age.

See MERiT study description

Patients that were included in the EISG and MERiT studies. All randomised subjects who received at least one dose of gonadotrophin in an IVF cycle (MENOPUR^®, n=491; rFSH, n=495) were included in the analysis. Subjects who underwent intracytoplasmic sperm injection cycles were excluded

Compare the live birth rates resulting from ovarian stimulation with MENOPUR^® or rFSH in women undergoing IVF cycles

The superiority of one gonadotrophin preparation over the other was tested using the likelihood ratio test in a logistic regression analysis

See EISG and MERiT study descriptions

280 patients undergoing their first IVF/ICSI treatment were randomised. Inclusion criteria: women with good physical and mental health, aged 18–37 years; regular menstrual cycles; BMI <30 kg/m²; normal basal serum FSH (≤10 IU/L) and estradiol (E2) (≤75 pg/mL) levels; no uterine, ovarian or adnexa abnormalities. The exclusion criteria: patients with a history of recurrent pregnancy loss; any significant systemic disease, endocrine or metabolic disorder; concomitant medication interfering with the study; patients who have received any ovulation induction drug within 1 month before their inclusion in the study

MENOPUR^® (HP-hMG) 150–300 IU/day (n=140) rFSH alfa 150–300 IU/day (n=140). MENOPUR^® and rFSH alfa starting dose was 225 IU for the first two days of stimulation

Ongoing-pregnancy rate per randomised patient (intention-to-treat analysis, ITT). The ongoing pregnancy rate was defined as the presence of at least one viable foetus beyond Week 20 of pregnancy on ultrasound. A started cycle was considered when patients had their first injection of gonadotropins. Delivery rate was also recorded

Clinical-pregnancy rate defined as the presence of a gestational sac with a positive heartbeat 4–5 weeks after embryo transfer, pregnancy loss (including biochemical pregnancies, miscarriages, and ectopic pregnancies), implantation rate and ovarian hyperstimulation syndrome (OHSS) rate.
Secondary clinical endpoints were the number of cumulus–oocyte complexes (COCs) retrieved, the number of metaphase II oocytes obtained (ICSI cycles), fertilisation rate, and serum E2 and progesterone levels on the day of hCG administration

Antagonist protocol. The starting dose for MENOPUR^® and rFSH was 225 IU/day for the first 2 days of stimulation. If required, individual adjustments were made: if E2 was <100 pg/mL, the dose was increased to 300 IU/day; if E2 was between 100 and 200 pg/mL, then the dose was maintained at 225 IU/day; if E2 was >200 pg/ml, the dose was lowered to 150 IU/day. These adjustments were performed equally for both groups of patients for the following 3 days

rhCG ∝ 250 µg

Fresh only. A maximum of three embryos were transferred on Day 3 of the cleavage state

All randomised, controlled trials reporting data comparing clinical outcomes for women undergoing IVF/ICSI cycles and using recombinant FSH in comparison with HMG or highly purified HMG, purified urinary FSH (FSH‐P), and highly purified urinary FSH (FSH‐HP) for ovarian hyperstimulation in IVF or ICSI cycles were included. 42 studies/9,606 couples: rFSH vs P-FSH; rFSH vs HP-FSH and rFSH vs hMG

To compare the effectiveness of recombinant gonadotrophin (rFSH) with the three main types of urinary gonadotrophins (i.e., hMG, FSH‐P and FSH‐HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles

An extended search was done according to Cochrane guidelines including the Menstrual Disorders & Subfertility Group’s Specialised Register of controlled trials (up to May 2010), The Cochrane Central Register of Controlled Trials (up to May 2010), MEDLINE (1966 to May 2010), EMBASE (1980 to May 2010), CINAHL (1982 to May 2010), National Research Register, and Current Controlled Trials (up to May 2010)

Data selected by three reviewers. Data extraction and risk assessment done by four reviewers.
Primary outcome measure was live-birth rate and OHSS per randomised woman. Binary outcomes were analysed using odds ratios and also reported in absolute terms. Grouped analyses were carried out for all outcomes to explore whether relative effects differed due to key features of the trials

749 patients, 21–34 years of age with regular ovulatory menstrual cycles and presumed to be ovulatory, infertile for ≥ 12 months before randomisation

MENOPUR^® 150–375 IU/day (n=374) rFSH beta (Puregon) 150–375 IU/day (n=375)

Ongoing-pregnancy rate per started cycle (defined as presence of at least one intrauterine pregnancy with a viable foetus 10–11 weeks after embryo transfer in the fresh cycle)

Positive ß-hCG rate and clinical-pregnancy rate (transvaginal ultrasound showing at least one intrauterine gestational sac with foetal heart beat 5–6 weeks after transfer), follicular development, endocrine profile, oocytes retrieved, fertilisation rate, embryo quality, endometrial profile, the incidence of treatment-emergent adverse events (onset after start of stimulation), OHSS, pregnancy loss and patient self-assessed local tolerability

GnRH antagonist: Patients were treated with 150 IU of gonadotrophin for 5 days, following which the stimulation could be adjusted by 75 IU per adjustment and no more than 375 IU daily according to individual response

hCG (250 µg)

Fresh and frozen. A fresh, single blastocyst transfer was performed on Day 5 after oocyte retrieval. Patients with no ongoing pregnancy by trial end and with a surplus of vitrified blastocysts could undergo replacement cycles with compulsory single blastocyst transfer within 1 year of randomisation

Medline, Embase and CINAHL databases up to July 2018
Search terms used were identical to the 2011 Cochrane review by Van Wely M, et al.

28 studies met the selection criteria, with 7,553 women included in the total

• The search identified seven studies comparing HP-hMG with rFSH alfa or beta (n=3,397) and all provided data on the amount of gonadotrophin used – all seven studies administered MENOPUR^® as their HP-hMG
• In total, 3,220 women (95%) started gonadotrophin treatment
• All seven trials (MENOPUR^® versus rFSH) had data on clinical-pregnancy and live-birth rate and three trials (N=2,109) had data on cumulative live births following fresh and frozen embryo transfers

619 ITT patients, 21–35 years of age, regular menstrual cycles, infertility for ≥ 1 year and serum AMH ≥5 mg/mL at screening

MENOPUR^® 150-225 IU/day (n=310) rFSH alfa 150-225 IU/day (n=309). The maximum daily dose was 300 IU/day

Ongoing pregnancy rate per started cycle (defined by the presence of ≥1 intrauterine pregnancy with a detectable foetal heartbeat at 10–11 weeks of gestation)

Cumulative ongoing pregnancy, early pregnancy loss, OHSS frequency, follicular development, endocrine profile, endometrial development, number of oocytes retrieved and blastocyst quality

GnRH antagonist: Patients were treated with 150 IU daily gonadotrophin for 5 days, following which doses could be adjusted by 75 IU according to patient response

hCG (250 µg)

Fresh and frozen. A fresh single blastocyst transfer was performed on Day 5 after oocyte retrieval. Patients with no ongoing pregnancy after the fresh cycle could undergo single frozen blastocyst transfers within 6 months of the date of randomisation