Cocktail treatment by GnRH-antagonist, letrozole, and mifepristone for the prevention of ovarian hyperstimulation syndrome: a prospective randomized trial

Figures & data

Figure 1. Flow diagram for enrollment, randomization, follow-up, and analysis of study participants.

Table 1. Classification of OHSS.

	Clinical features	Laboratory results
Mild	Abdominal bloating Mild abdominal pain Mild nausea/vomiting	Enlarged ovaries (7–8 cm)
Moderate	Moderate abdominal pain Nausea/vomiting	HCT > 41% WBC > 15 × 10^9/L Hypoproteinemia (ALB < 30 g/L) Enlarged ovaries (8–12 cm)
Severe	Mild and moderate clinical feature Clinical ascites/hydrothorax Severe dyspnea Anuria/oliguria Weight gain (> 1 kg/24 h)	HCT > 55% WBC > 25 × 10^9/L Creatinine clearance < 50 ml/min Serum creatinine > 115 μM/L Na^+ < 135 mmol/L; K^+ > mmol/L ALT > 80 U/L and/or AST > 70 U/L Enlarged ovaries (>12 cm)
Critical	Thromboembolism Acute respiratory distress syndrome	Same as severe OHSS

WBC: white blood cell counts; HCT: hematocrit; ALT: alanine transaminase; AST: aspartate aminotransferase

Table 2. Basal characteristics of the participants.

	Combination (n = 78)	Mifepristone (n = 78)	p Value
Age (years)	29.7 ± 3.6	29.6 ± 3.2	.78
Duration of infertility (years)	3.9 ± 2.9	4.1 ± 3.2	.73
BMI (kg/m^2)	22.0 ± 3.3	21.90 ± 3.7	.56
AFC (n)	23.0 ± 6.5	23.0 ± 7.7	.85
Basal FSH (IU/L)	6.6 ± 1.6	6.4 ± 1.6	.40
Basal LH (IU/L)	6.0 ± 5.1	5.5 ± 4.0	.51
Basal E2 (pg/ml)	47.1 ± 36.1	43.3 ± 18.8	.86
Factors of infertility, n (%)
Tubal factor	33 (42.3)	29 (37.2)	.51
Anovulatory	8 (10.3)	16 (20.5)	.08
EMS^a	2 (2.6)	5 (6.4)	.44
Male factor	12 (15.4)	8 (10.3)	.34
Multiple factors	18 (23.1)	14 (17.9)	.43
Unexplained infertility	5 (6.4)	6 (7.7)	.75
COH protocol, n (%)
Luteal long GnRH-a protocol	34 (43.6)	28 (35.9)	.33
GnRH-ant protocol	20 (25.6)	22 (28.2)	.72
Follicular phase long protocol	24 (30.8)	28 (35.9)	.50
Total Gn (IU)	1689.2 ± 641.7	1824.5 ± 809.7	.63
Duration of Gn stimulating (days)	10.2 ± 2.1	10.4 ± 2.2	.40
Number of retrieved oocytes (n)	26.6 ± 6.2	25.7 ± 4.3	.29
Good-quality embryos (n)	11.5 ± 5.5	10.0 ± 4.8	.09

^aEMS: endometriosis

Table 3. Incidence of OHSS in two groups.

	Combination (n = 78)	Mifepristone (n = 78)	p Value
No OHSS (n, %)	15 (19.2)	12 (15.4)	.53
Mild (n, %)	47 (60.3)	43 (55.1)	.02
Moderate (n, %)	12 (15.4)	23 (29.5)	.04
Severe (n, %)	4 (5.1)	10 (12.8)	.09
Moderate and severe (n, %)	16 (20.5)	33 (42.3)	.003
No symptoms (n, %)	29 (37.2)	16 (20.5)	.03

Table 4. Incidence of moderate and severe OHSS in different COH protocols.

	Combination	Mifepristone	p Value
Luteal GnRH-a protocol	20.6 (7/34)^a	42.9 (12/28)^b	.096
GnRH-ant protocol	15.0 (3/20)^a	36.4 (8/22)^b	.116
Follicular phase GnRH-a protocol	25.0 (6/24)^a	46.4 (13/28)^b	.110

^aNo significant difference among long GnRH-a, GnRH-ant, and ultra-long protocols in combination group.

^bNo significant difference among long GnRH-a, GnRH-ant, and ultra-long protocols in mifepristone group.

Figure 2. Alterations of serum E₂, P, and VEGF level between the combination and mifepristone groups. (A) Comparison of serum E₂ level on hCG + 0, +3, and +5. (B) Comparison of serum P level on hCG + 0, +3, and +5.

Figure 3. Comparison of serum VEGF level between the combination and mifepristone groups. (A) Comparison of serum VEGF level on hCG + 3 and +5. (B) The relationship between serum VEGF level on hCG + 3 and the severity of OHSS. (C) The relationship between serum VEGF level on hCG + 5 and the severity of OHSS.

Table 5. Clinical and laboratory features between combination and mifepristone groups.

	Combination (n = 78)	Mifepristone (n = 78)	p Value
Ovarian diameter on hCG + 5 (cm)	8.7 ± 1.1	9.1 ± 1.5	.021
Ascites index	7.1 ± 3.2	7.58 ± 4.04	.460
Luteal phase (days)	7.5 ± 2.6	9.6 ± 1.8	<.001
Luteal phase < 5 d (n, %)	15 (19.2)	1 (1.3)	<.001
Puncture and drainage (n, %)	2 (2.6)	5 (6.4)	.442
WBC on hCG + 3 (10^9/L)	7.6 ± 2.0	9.6 ± 2.4	<.001
HCT on hCG + 3 (%)	36.5 ± 3.5	36.8 ± 3.5	.528
Hemoconcentration (n, %)^a	3 (3.9)	10 (12.8)	.043
D-D on hCG + 3	1.8 ± 2.8	2.1 ± 3.1	.621
ALT on hCG + 5 (g/L)	59.6 ± 39.4	74.2 ± 41.9	.026
AST on hCG + 5 (g/L)	62.8 ± 48.8	72.7 ± 42.9	.183
ALB on hCG + 5 (g/L)	34.3 ± 3.5	32.4 ± 3.5	.001

^aHemoconcentration: HCT > 41%

Table 6. Ordinal multinomial logistic regression analysis.

Variables	OR^a	95% CI	p Value
Age	0.98	0.88 − 1.09	.65
AFC	1.00	0.97 − 1.08	.41
Duration of Gn	1.07	0.86 − 1.33	.55
Gn dosage	1.00		.20
Number of oocyte retrieved	1.09	1.00 − 1.19	.05
Intervention
Combination	0.31	0.15 − 0.63	.001
Mifepristone	–	–	–
Serum E2 on hCG + 0	1.00	1.00 − 1.00	.03
Serum VEGF on hCG + 5	1.03	1.02 − 1.04	< .001
Ovarian diameter on hCG + 5	3.63	2.35 − 5.60	< .001

^aOR: odds ratio

Table 7. Cumulative pregnancy outcomes after freeze-all cycle and all subsequent frozen embryo transfer cycles between combination and mifepristone groups.

	Combination (n = 78)	Mifepristone (n = 78)	p Value
Total cycles of FET with transfer	98	106	.62
1st cycle of FET	71	72	–
2nd cycle of FET	21	28	–
3rd cycle of FET	6	5	–
4th cycle of FET	0	1	–
Cleavage embryo transfer cycles	32	45	.15
Blastocyst transfer cycles	66	61	–
Embryo transfer number	1.59 ± 0.49	1.62 ± 0.49	.621
CPR per FET, n (%)	65/98 (66.3)	66/106 (62.3)	.55
Implantation rate, n (%)	74/159 (46.5)	79/172 (45.9)	.91
Abortion rate per FET, n (%)	7/65 (10.8)	6/66 (9.1)	.75
LBR per FET, n (%)	58/98 (59.2)	60/106 (56.6)	.71
CCPR per randomized, n (%)	65/78 (83.3%)	66/78 (84.6%)	.83
CLBR per randomized, n (%)	58/78 (74.4)	60/78 (76.9)	.71

FET: frozen embryo transfer; CPR: clinical pregnancy rate; CCPR: cumulative clinical pregnancy rate; LBR: live birth rate; CLBR: cumulative live birth rate

Availability of data and materials

Not applicable.