Use of gonadotropins in ovarian stimulation in Spain: Delphi consensus

Figures & data

Table 1. Participating sites.

Autonomous Community region	Province	Site
Andalusia	Cádiz	Puerta del Mar University Hospital
	Córdoba	Reina Sofía University Hospital
	Granada	Virgen de las Nieves University Hospital
	Málaga	Gutenberg Centre
	Huelva	Juan Ramón Jiménez University Hospital
	Jaén	Jaén University Hospital
	Seville	Virgen del Rocío University Hospital
	Seville	IVI Clinic – Seville
Aragon	Zaragoza	Montpellier Reproduction Unit
Canaries	Santa Cruz, Tenerife	Canary Islands University Hospital
	Las Palmas	Canary Islands University Hospital
Cantabria	Santander	Marquis de Valdecilla University Hospital
Castile - La Mancha	Albacete	Bernabéu Institute
Castile and Leon	Valladolid	Valladolid Clinical University Hospital
Catalonia	Barcelona	CIRH
	Barcelona	Eugin Clinic
	Barcelona	Ginefiv - Barcelona
	Barcelona	Clinical University Hospital Barcelona
	Barcelona	Santa Creu i Sant Pau Hospital
	Barcelona	IVI - Barcelona
	Barcelona	Quirón Salud Hospital Barcelona
	Tarragona	Embryogyn
Madrid Community	Madrid	IVI Clinic - Madrid
	Madrid	Ginefiv - Madrid
	Madrid	San Carlos Clinical Hospital
	Madrid	Gregorio Marañón University Hospital
	Madrid	Bernabéu Institute
	Madrid	IVF Life
Chartered Community of Navarre	Pamplona	Assisted Reproduction Institute, Quirón Salud Pamplona
Valencia Community region	Alicante	UR Vistahermosa
	Valencia	IVI Clinic - Valencia
Extremadura	Badajoz	CERHA Extremadura Centre for Assisted Human Reproduction
Galicia	Pontevedra	IVI Clinic - Vigo
Balearic Islands	Majorca	Son Espases University Hospital - Reproduction Unit
	Majorca	Bernabéu Institute
	Majorca	IVI Clinic - Majorca
Basque Country	Guipuzkoa	Donostia University Hospital
	Biscay	Cruces University Hospital
Murcia	Murcia	IVI Clinic – Murcia
	Murcia	Virgen de la Arrixaca University Clinical Hospital

Figure 1. Delphi study flow chart.

Table 2. Final results from the Delphi study. Statements that did not reach consensus by the end of the study are marked in italics.

ITEM		MEDIUM RANGE	PARTICIPANTS WITHIN RANGE OF AGREEMENT (7–9)	PARTICIPANTS IN AN INDIFFERENT RANGE (4–6)	PARTICIPANTS WITHIN RANGE OF DISAGREEMENT (7–9)	CONSENSUS
PARAMETERS TO STRATIFY PATIENTS WITH A LOW OVARIAN RESPONSE
Q01a	The baseline indicator for designing an ovarian stimulation protocol is the patient’s age.	7–9	26 (65%)	10 (25%)	4 (10%)	Discrepancy
Q01b	The ovarian stimulation protocol must be designed taking into account the patient’s age.	7–9	39 (97.5%)	1 (2.5%)	0 (0%)	Consensus
Q02	The result from the previous cycles carried out by the patient is fundamental in designing a new ovarian stimulation protocol.	7–9	39 (97.5%)	1 (2.5%)	0 (0%)	Consensus
Q03	In patients with previous stimulation cycles, the most important indicators to take into account on designing the ovarian stimulation protocol are the doses of gonadotropins used and the number of oocytes retrieved.	7–9	37 (92.5%)	2 (5%)	1 (2.5%)	Consensus
Q04	For patients with no previous cycles, the indicators to be considered on designing the ovarian stimulation protocol are the antral follicle count, anti-Müllerian hormone, age and body mass index.	7–9	40 (100%)	0 (0%)	0 (0%)	Unanimity
Q05	The indicators that can be used to predict ovarian response are the antral follicle count and the anti-Müllerian hormone value.	7–9	39 (97.5%)	1 (2.5%)	0 (0%)	Consensus
Q06a	Age alone is not a good predictor ovarian response.	7–9	26 (65%)	9 (22.5%)	5 (12.5%)	Discrepancy
Q06b	Age alone is not a good quantitative predictor of ovarian response.	7–9	26 (65%)	10 (25%)	4 (10%)	Discrepancy
Q07	The antral follicle count evaluation is a clinical practice recommended for all patients prior to stimulation, in each cycle.	7–9	39 (97.5%)	1 (2.5%)	0 (0%)	Consensus
Q08	Anti-Müllerian hormone testing is a recommended practice in all patients before the first cycle of treatment and if the patient’s clinical conditions vary.	7–9	34(85%)	5 (12.5%)	1 (2.5%)	Consensus
Q09	Body mass index is a recommended measurement parameter for all patients.	7–9	37 (92.5%)	3 (7.5%)	0 (0%)
GOALS OF OVARIAN STIMULATION TREATMENT
Q10	The appropriate number of oocytes that should be obtained in an ovarian stimulation cycle may vary depending on the patient’s age and clinical profile.	7–9	35 (87.5%)	3 (7.5%)	2 (5%)	Consensus
Q11	The main determining factors to achieve an adequate number of oocytes during ovarian stimulation are age and the number of antral follicles at the start of stimulation.	7–9	31 (77.5%)	8 (20%)	1 (2.5%)	Consensus
Q12	The goal of ovarian stimulation for patients with a diagnosis of low reserve is to obtain the maximum possible amount of oocytes compared to the number of antral follicles available before beginning stimulation.	7–9	40 (100%)	0 (0%)	0 (0%)	Unanimity
Q13	The goal of ovarian stimulation for normal-responding patients could be set at obtaining 10–15 oocytes.	7–9	36 (90%)	1 (2.5%)	3 (7.5%)	Consensus
Q14	For normal-responding patients, the optimum range of response is considered to be 9 or more oocytes.	7–9	38 (95%)	1 (2.5%)	1 (2.5%)	Consensus
Q15	Ovarian stimulation of more than 20 oocytes increases the risk of complications.	7–9	36 (90%)	3 (7.5%)	1 (2.5%)	Consensus
Q16	The increased risk of complications influences the number of oocytes to be obtained in an ovarian stimulation cycle in patients. The number of oocytes to be obtained must therefore be weighed against the risk of hyper-stimulation and the risk of haemoperitoneum.	7–9	33 (82.5%)	7 (17.5%)	0 (0%)	Consensus
OVARIAN STIMULATION PROTOCOLS: MONOTHERAPY (FSHr)
Q17	FSH monotherapy is the regimen commonly recommended for normal- or hyper-responding patients under 35 years of age.	7–9	38 (95%)	1 (2.5%)	1 (2.5%)	Consensus
Q18	The dose used in ovarian stimulation in monotherapy is from 150 to 300 IU depending on the clinical parameters defined at the start of stimulation.	7–9	39 (97.5%)	1 (2.5%)	0 (0%)	Consensus
Q19	In the event of a low previous response or low ovarian reserve, a dose of 300 IU is the most common.	7–9	32 (80%)	4 (10%)	4 (10%)	Consensus
Q20a	For hyper-responsive patients, the starting dose for FSH is usually 75 to 100 IU.	4–6	10 (25%)	11 (27,5%)	19 (47,5%)	Discrepancy
Q20b	For hyper-responsive patients, the starting dose for FSH is usually 75 to 150 IU.	7–9	32 (80%)	5 (12.5%)	3 (7.5%)	Consensus
Q21a	For patients with polycystic ovaries, the starting dose of FSH is usually 75 to 100 IU.	4-6	9 (22,5%)	12 (20%)	19 (47,5%)	Discrepancy
Q21b	For patients with polycystic ovaries, the starting dose of FSH is usually 75 to 150 IU.	7–9	30 (75%)	5 (12.5%)	5 (12.5%)	Consensus
Q22	FSH in monotherapy increases the patient’s comfort compared to using two different drugs in combination.	7–9	33 (82.5%)	5 (12.5%)	2 (5%)	Consensus
Q23a	FSH in monotherapy increases adherence to treatment compared to the use of two different drugs combined.	4-6	16 (40%)	14 (35%)	10 (25%)	Discrepancy
Q24	FSH in monotherapy reduces mistakes in handling the medication.	7–9	30 (75%)	8 (20%)	2 (5%)	Consensus
Q25	Stimulation can begin between day 2 and day 4, giving greater flexibility for the first monitoring	7–9	33 (82.5%)	4 (10%)	3 (7.7%)	Consensus
Q26a	Changes or variations in the dose used during ovarian stimulation gives no advantage in the final outcome	7–9	24 (60%)	6 (15%)	10 (25%)	Discrepancy
Q26b	There is no evidence that changes or variations in the dose used after ovarian stimulation has begun gives advantages in the final outcome.	7–9	29 (72.5%)	4 (10%)	7 (17.5%)	Consensus
OVARIAN STIMULATION PROTOCOLS: MONOTHERAPY (rFSH) VS. COMBINED THERAPY (rFSH + LH/HMG) WITH ANTAGONISTS
Q27	Combined ovarian stimulation treatment is only indicated for certain groups of patients.	7–9	29 (72.5%)	4 (10%)	7 (17.5%)	Consensus
Q28	The most common indications for receiving ovarian stimulation treatment combined with LH are an age of over 35 years and poor response in previous cycles.	7–9	35 (87.5%)	5 (12.5%)	0 (0%)	Consensus
Q29	It was unanimously accepted that other indications for adding LH-acting drugs are excessive pituitary LH suppression or a lack of response to FSH alone in previous cycles.	7–9	40 (100%)	0 (0%)	0 (0%)	Unanimity
Q30	Generally, normal-responding patients under 35 years of age do not benefit from ovarian stimulation treatment combined with drugs with a LH effect.	7–9	29 (72.5%)	11 (27.5%)	0 (0%)	Consensus
SAFETY/EFFICIENCY OF THE DEVICE
Q31	The type of device used by the patient influences the safety of ovarian stimulation treatment.	7–9	30 (75%)	7 (17.5%)	3 (7.5%)	Consensus
Q32	The type of device used by the patient influences the comfort of ovarian stimulation treatment.	7–9	40 (100%)	0 (0%)	0 (0%)	Unanimity
Q33	The device used must ensure as much as possible that the dose selected is the one administered by the patient.	7–9	38 (95%)	2 (5%)	0 (0%)	Consensus

FSH: follicle-stimulating hormone; LH: luteinising hormone. a: Statements that did not reach consensus in first round; b: statements revised for 2º round *statement eliminated.

Table 3. Recommendations to optimise the use of gonadotropins in IVF, both conventionally and in IVF-ICSI.

Stratification of patients with a low ovarian response

The ovarian stimulation protocol must be designed taking into account the patient’s age. The result from the previous cycles carried out by the patient is fundamental in designing a new ovarian stimulation protocol. For patients with previous stimulation cycles, the most important indicators to take into account on designing the ovarian stimulation protocol are the doses of gonadotropins used and the number of oocytes retrieved. For patients with no previous cycles, the indicators to be considered on designing the ovarian stimulation protocol are the antral follicle count, anti-Müllerian hormone, age and body mass index. The indicators that can be used to predict ovarian response are the antral follicle count and the anti-Müllerian hormone value. The antral follicle count evaluation is a clinical practice recommended for all patients prior to stimulation, in each cycle.

Ovarian stimulation protocols: monotherapy (rFSH)

FSH monotherapy is the regimen commonly recommended for normal- or hyper-responding patients under 35 years of age. The dose used in ovarian stimulation in monotherapy is from 150 to 300 IU depending on the clinical parameters defined at the start of stimulation. In the event of a low previous response or low ovarian reserve, a dose of 300 IU is the most common. For hyper-responsive patients, the starting dose for FSH is usually 75 to 150 IU. For patients with polycystic ovaries, the starting dose of FSH is usually 75 to 150 IU. FSH in monotherapy increases the patient’s comfort compared to using two different drugs in combination. FSH in monotherapy reduces mistakes in handling the medication. Stimulation can begin between day 2 and day 4, giving greater flexibility for the first control. There is no evidence that changes or variations in the dose used after ovarian stimulation has begun gives advantages in the final outcome.

Ovarian stimulation protocols: monotherapy (rFSH) vs. combined therapy (rFSH + LH/HMG) with antagonists

Combined ovarian stimulation treatment is only indicated for certain groups of patients. The most common indications for receiving ovarian stimulation treatment combined with LH are an age of over 35 years and poor response in previous cycles. Other indications for adding LH-acting drugs are excessive pituitary LH suppression or a lack of response to FSH alone in previous cycles. Generally, normal-responding patients under 35 years of age do not benefit from ovarian stimulation treatment combined with drugs with a LH effect.

Safety/efficiency of the device

The type of device used by the patient influences the safety of ovarian stimulation treatment. The type of device used by the patient influences the comfort of ovarian stimulation treatment.