PIVET rFSH dosing algorithms for individualized controlled ovarian stimulation enables optimized pregnancy productivity rates and avoidance of ovarian hyperstimulation syndrome

Figures & data

Figure 1 First PIVET rFSH algorithm designed for ~8.3 IU increments suited to the Puregon Pen.

Note: Modified to set maximal rFSH dosage at 450 IU. *Antral Follicle Count based on number of antral follicles <10 mm.
Abbreviation: rFSH, recombinant follicle stimulating hormone.

Figure 2 Second PIVET rFSH algorithm designed for 12.5 IU increments suited to Gonal-F Pen.

Notes: Modified to set maximal rFSH dosage at 450 IU. *Antral Follicle Count based on number of antral follicles <10 mm.
Abbreviation: rFSH, recombinant follicle stimulating hormone.

Figure 3 Derivation of 2,822 cases of IVF initiated over a 6-year period at PIVET Medical Centre applying PIVET algorithms.

Abbreviations: AFC, antral follicle count; BMI, body mass index; IVF, in vitro fertilization.

Table 1 Patient demographics and treatment flow for women initiating rFSH stimulation under PIVET algorithms

Cycle information (01/04/2008 to 30/04/2014)
Cycles initiated, n	2,822
TVOA, n	2,646
Cancellation before oocyte retrieval, n (%)	176 (6.2)
No of embryo transfer, n (% of retrievals)	2,211 (83.6)
Single embryo transfer, n (% of embryo transfers)	1,588 (71.8)
Increased monitoring program, n (% of retrievals)	483 (18.3)
Cases admitted to hospital, n (% of started cycle)	31 (1.1)
Paracentesis, n (% severe OHSS)	9 (0.3)
Freeze all for OHSS (% of retrievals)	55 (2.1)
Age groups
<30 years, n (%)	324 (11.5)
30–34 years, n (%)	704 (24.9)
35–39 years, n (%)	952 (33.7)
40–44 years, n (%)	758 (26.9)
≥45 years, n (%)	84 (3.0)
Mean age (±SD), years	36.16 (±5.27)
Stimulation protocols
Antagonist, n (%)	1,619 (57.4)
Flare agonist, n (%)	850 (30.1)
AACEP, n (%)	204 (7.2)
Long agonist, n (%)	107 (3.8)
Variants, n (%)	42 (1.5)

Abbreviations: AACEP, agonist antagonist conversion with estrogen priming; OHSS, ovarian hyperstimulation syndrome; SD, standard deviation; TVOA, transvaginal oocyte aspiration.

Table 2 Oocytes recovered and embryo/oocyte utilization rates for all women having a TVOA procedure categorized by age groups

	Age group
	<30 years	30–34 years	35–39 years	40–44 years	≥45 years
Mean oocytes retrieved (±SD)	11.02 (±6.21)	10.20 (±5.93)	9.10 (±5.48)	6.18 (±4.38)	4.07 (±4.11)
Oocyte utilization rate (%)	27.8	29.5	28.3	31.2	35.0
Embryo utilization rate (%)	50.3	50.4	49.8	60.5	64.7

Abbreviations: SD, standard deviation; TVOA, transvaginal oocyte aspiration.

Table 3 Oocytes recovered for all women having a TVOA procedure categorized according to AFC rating

AFC group	Mean oocytes retrieved (±SD)
A++ (≥40 follicles)	12.35 (±6.85)
A+ (30–39 follicles)	11.82 (±5.85)
A (20–29 follicles)	12.26 (±6.16)
B (13–19 follicles)	9.98 (±4.62)
C (9–12 follicles)	8.33 (±4.41)
D (5–8 follicles)	5.32 (±3.70)
E (<4 follicles)	4.90 (±4.53)

Abbreviations: AFC, antral follicle count; SD, standard deviation; TVOA, transvaginal oocyte aspiration.

Table 4 Clinical pregnancy and live birth outcomes for all women having a TVOA procedure and categorized according to age group

	Age group
	<30 years	30–34 years	35–39 years	40–44 years	≥45 years
Clinical pregnancy rate per embryo transfer (%)	43.4	39.9	28.6	11.7	0.0
Live birth rate per embryo transfer (%)	36.4	33.5	22.4	7.5	0.0
Live birth rate per initiated cycle (%)	29	27.7	18	5.5	0.0
Freezing rate per initiated cycle (%)	64.2	64.6	51.3	28.4	9.5
Live birth productivity rate, per initiated cycle (%)	57.1	51.7	33.2	8.4	0.0

Abbreviation: TVOA, transvaginal oocyte aspiration.

Figure 4 The proportion of patients in each rFSH starting dose category, who responded adequately to the starting dose of FSH and required no adjustment (elevation) to achieve at least four follicles (for the high AFC groups) and eight to twelve follicles for the remainder.

Note: Where adjustments were made, this was mostly one or occasionally two dose increments.
Abbreviations: AFC, antral follicle count; rFSH, recombinant follicle stimulating hormone.

Figure 5 The distribution of oocytes recovered, indicating that almost 90% of women had fewer than 16 oocytes and under 4% had more than 20 recovered; most resulting from breaches of the described protocols.

Table S1 Clinical outcomes for all patients undergoing rFSH stimulation using either Gonal-f or Puregon

	Gonal-f (±SD)	Puregon (±SD)	P-value
Mean age (years)	35.9 (±5.2)	36.4 (±5.4)	0.012*
Mean BMI (kg/m^2)	24.4 (±4.4)	24.9 (±4.5)	0.003**
Mean eggs collected	9.1 (±5.7)	8.3 (±5.7)	0.0003***
Mean 2PN generated	5.1 (±4.0)	4.7 (±3.9)	0.009**
Mean oocyte utilization (%)	33.3 (±23.6)	34.0 (±24.3)	0.453
Mean embryo utilization (%)	55.3 (±32.4)	57.8 (±36.7)	0.063
Clinical pregnancy rate per fresh ET (%)	28.2	28.4	0.945
Live birth rate per fresh ET (%)	22.8	22.4	0.838
Miscarriage rate per pregnancy (%)	19.0	21.2	0.551

Notes: No significant differences were observed for pregnancy, birth, or miscarriage rates. However, the populations were slightly but significantly different in terms of mean age, mean BMI, and the number of oocytes and embryos with 2PN retrieved.

* P<0.05,

** P<0.01,

*** P<0.001.

Abbreviations: 2PN, two pronuclei; BMI, body mass index; ET, embryo transfer; rFSH, recombinant follicle stimulating hormone; SD, standard deviation.

Table S2 Clinical outcomes in younger women (<40 years), with AMH values <25 pmol/L, receiving rFSH stimulation using either Gonal-f or Puregon

	Gonal-f (±SD)	Puregon (±SD)	P-value
Mean age (years)	34.1 (±4.0)	34.6 (±3.7)	0.115
Mean BMI (kg/m^2)	24.7 (±4.5)	25.2 (±4.9)	0.196
Mean eggs collected	10.1 (±5.4)	8.0 (±5.1)	<0.0001****
Mean 2PN generated	5.7 (±4.0)	4.6 (±3.7)	0.0007***
Mean oocyte utilization (%)	30.1 (±21.5)	31.8 (±22.6)	0.357
Mean embryo utilization (%)	50.1 (±29.8)	53.6 (±36.1)	0.204
Clinical pregnancy rate per fresh ET (%)	32.8	34.9	0.693
Live birth rate per fresh ET (%)	27.1	28.4	0.815
Miscarriage rate per pregnancy (%)	17.4	18.5	0.984

Note: Only significant differences between number of oocytes collected and number of embryos with 2PN were observed.

*** P<0.001,

**** P<0.0001.

Abbreviations: 2PN, two pronuclei; AMH, anti-Müllerian hormone; BMI, body mass index; ET, embryo transfer; rFSH, recombinant follicle stimulating hormone; SD, standard deviation.

Table S3 Clinical outcomes for all patients undergoing rFSH stimulation using either Gonal-f or Puregon and analyzed according to treatment cycle type

	Antagonist cycles		Flare agonist cycles
	Gonal-f (±SD)	Puregon (±SD)	Gonal-f (±SD)	Puregon (±SD)
Mean age (years)	34.3 (±4.8)	35.2 (±5.4)**	37.7 (±4.5)	37.7 (±4.9)^NS
Mean BMI (kg/m^2)	24.6 (±4.6)	25.0 (±4.6)****	24.2 (±4.2)	24.8 (±4.3)^NS
Mean eggs collected	10.4 (±5.8)	9.4 (±5.6)**	7.2 (±4.6)	7.1 (±5.3)^NS
Mean 2PN generated	6.0 (±4.2)	5.3 (±4.0)**	3.9 (±3.2)	3.8 (±3.6)^NS
Mean oocyte utilization (%)	30.5 (±20.6)	33.1 (±21.9)^NS	35.5 (±24.6)	34.1 (±26.2)^NS
Mean embryo utilization (%)	50.7 (±29.6)	56.4 (±31.8)**	60.7 (±34.1)	59.7 (±43.2)^NS
Clinical pregnancy rate per fresh ET (%)	32.8	30.5^NS	22.7	25.7^NS
Live birth rate per fresh ET (%)	26.2	24.7^NS	19.2	19.7^NS
Miscarriage rate per pregnancy (%)	20.0	19.0^NS	15.4	23.2^NS

Notes: No significant differences were observed for all parameters using the flare agonist stimulation regimen. For antagonist cycles, the populations were slightly but significantly different in terms of mean age, mean BMI, number of oocytes, and embryos with 2PN retrieved and the embryo utilization rate. However, pregnancy, birth, and miscarriage rates between the two rFSH agents for antagonist cycles were not significantly different. Asterisk indicates significant difference between rFSH drugs in the same cycle type. NS indicates no significant difference between rFSH drugs in the same cycle type.

Abbreviations: 2PN, two pronuclei; BMI, body mass index; ET, embryo transfer; rFSH, recombinant follicle stimulating hormone; SD, standard deviation.