Pregnancy And Neonatal Outcomes Of hMG Stimulation With Or Without Letrozole In Endometrial Preparation For Frozen–Thawed Embryo Transfer In Ovulatory Women: A Large Retrospective Cohort Study

Figures & data

Table 1 Baseline Characteristics At Cycle Level

Characteristic	Letrozole (n=1569)	HMG (n=1827)	Letrozole + HMG (n=2505)	P-Value^a	P-Value^b	P-Value^c
Maternal age (year)	35.03±3.88	34.46±4.24	35.48±4.59	0.002	<0.001	0.048
Duration of infertility (years)	3.73±2.85	3.62±2.87	3.69±2.82	0.846	0.693	0.865
BMI of women	23.51±4.21	23.39±4.83	23.67±4.93	0.529	0.167	0.873
Day 3 FSH (mIU/mL)	4.09(0.17–9.97)	4.13(0.84–9.98)	4.17(0.32–9.99)	0.482	0.851	0.186
Day 3 LH (mIU/mL)	4.98(0.11–18.94)	4.92(0.17–19.01)	4.96(0.94–17.32)	0.239	0.694	0.481
Day 3 E2 (pg/mL)	34.00(10.00–85.00)	33.00(10.00–90.00)	33.00(10.00–99.00)	0.461	0.861	0.336
Day 3 P (ng/mL)	0.30(0.10–0.80)	0.30(0.10–0.90)	0.30(0.10–0.90)	0.151	0.197	0.751
Infertility causes, n (%)
Male factor	193(12.28%)	215(11.75%)	309(12.35%)	0.206	0.455	0.799
Tubal factor	736(46.89%)	825(45.15%)	1145(45.69%)
Endometriosis	18(1.17%)	36(1.99%)	39(1.56%)
Mixed	577(36.80%)	685(37.48%)	942(37.61%)
Unexplained	45(2.86%)	66(3.63%)	70(2.79%)
Fertilization method
IVF (%)	1007(64.18%)	1104(60.43%)	1487(59.36%)	0.077	0.183	0.023
ICSI (%)	377(24.03%)	480(26.27%)	715(28.54%)
Half IVF +half ICSI (%)	185(11.79%)	243(13.30%)	303(12.10%)
Year of treatment (%)
2007–2010	50(3.19%)	76(4.16%)	72(2.87%)	<0.001	<0.001	<0.001
2011–2012	228(14.53%)	247(13.52%)	290(11.58%)
2013–2014	645(41.11%)	1044(57.14%)	918(36.65%)
2015–2016	646(41.17%)	460(25.18%)	1225(48.90%)

Notes: ^aLetrozole vs HMG; ^bHMG vs letrozole+HMG; ^cLetrozole vs letrozole+HMG. Bold values represent statistical significance.

Figure 1 Diagram of inclusion criteria.

Table 2 Ovarian Stimulation Characteristics And Hormonal Data On The Trigger Day In FET Cycle

Characteristics	Letrozole (n=1569)	HMG (n=1827)	Letrozole+HMG (n=2505)	P-Value^a	P-Value^b	P-Value^c
Hormones at time of hCG injection
FSH (mIU/mL)	8.47(1.67–26.17)	9.98(1.52–28.39)	9.30(1.03–30.86)	<0.001	<0.001	<0.001
LH (mIU/mL)	19.05(0.72–74.64)	17.99(0.42–77.75)	18.64(0.89–80.76)	0.054	0.091	0.658
E2 (pg/mL)	284.00(135.00–1058.00)	483.00(128.00–2811.00)	327.00(101.00–2443.00)	<0.001	<0.001	<0.001
P (ng/mL)	0.60(0.10–3.40)	0.40(0.10–3.90)	0.60(0.10–4.1)	<0.001	<0.001	0.396
Hormones on day of transfer
E2 (pg/mL)	107.00(10.00–403.00)	298.00(25.00–849.00)	122.00(12.00–772.00)	<0.001	<0.001	0.026
P (ng/mL)	18.30(1.80–56.20)	15.00(0.50–57.50)	19.00(0.90–60.70)	<0.001	<0.001	0.008
Endometrial thickness (mm)	11.07±2.11	11.15±2.02	11.12±2.45	0.099	0.991	0.929

Notes: ^aLetrozole vs HMG; ^bHMG vs letrozole+HMGL; ^cLetrozole vs letrozole+HMG. Bold values represent statistical significance.

Table 3 Reproductive Outcomes After FET According To The Type Of Endometrial Preparation Treatments

Characteristics	Letrozole (n=1569)	HMG (n=1827)	Letrozole+HMG (n=2505)	P-Value^a	P-Value^b	P-Value^c
Number of FET	1569	1827	2505
Number of thawed embryos	3022	3476	4715
Number of viable embryos after thawed	2986	3441	4687
Developmental stage at cryopreservation
Cleavage stage (Day 3 or 4)	2619(87.71%)	3043(88.42%)	2203(87.93%)	0.196	0.295	0.412
Blastocyst stage (Day 5)	367(12.29%)	398(11.58%)	302(12.07%)
Embryo quality
Grade I	649(21.73%)	690(20.06%)	523(20.86%)	0.245	0.076	0.091
Grade II	2332(78.09%)	2746(79.79%)	1970(78.66%)
Grade III	5(0.18%)	5(0.15%)	12(0.48%)
Number of embryos transferred
1	194(6.49%)	221(6.42%)	285(6.08%)	0.472	0.279	0.246
2	2792(93.51%)	3220(93.58)	4402(99.92%)
Clinical pregnancy rate per transfer (%)	52.07% (817/1569)	47.02% (859/1827)	52.26% (1309/2505)	0.047	0.037	0.486
Implantation rate (%)	34.36% (1026/2986)	31.76% (1086/3441)	34.24% (1605/4687)	0.048	0.036	0.481
Miscarriage rate (%)	10.53% (86/817)	14.78% (127/859)	14.13% (185/1309)	0.013	0.381	0.018
Multiple pregnancy rate (%)	25.58% (209/817)	26.43% (227/859)	22.61% (296/1309)	0.402	0.063	0.121
Ectopic pregnancy rate (%)	0.97% (5/833)	1.83% (16/875)	1.58% (21/1330)	0.018	0.392	0.031
Intrauterine and ectopic pregnancy rate (%)	0.36% (3/833)	0.80%(7/875)	0.38% (5/1330)	0.194	0.161	0.629
Ongoing pregnant rate per transfer (%)	47.61% (747/1569)	41.32%(755/1827)	47.27% (1184/2505)	0.012	0.009	0.461
Live birth rate (%)	46.59% (731/1569)	39.96%(730/1827)	44.87% (1124/2505)	0.008	0.022	0.265

Notes: ^aLetrozole vs HMG; ^bHMG vs letrozole+HMG; ^cLetrozole vs letrozole+HMG. Bold values represent statistical significance.

Table 4 Neonatal Outcomes After FET According To The Type Of Endometrial Preparation Treatments

Characteristics	Letrozole (n=931)		HMG (n=952)		Letrozole+HMG (n=1363)		P-Value^a	P-Value^b	P-Value^c	P-Vlue^d	P-Value^e	P-Value^f
	Singleton Births (n=531)	Multiple Births (n=400)	Singleton Births (n=508)	Multiple Births (n=444)	Singleton Births (n=885)	Multiple Births (n=478)
Stillborn- no (%)	0(0)	2(0)	0(0)	0(0)	1(0.11)	0(0)
Live born- no (%)	531(100)	398(99.5)	508(100)	444(100)	884(0.89)	478(0100)
Gestational weeks at delivery (weeks)
<32	6(1.12%)	4(2.00%)	6(1.18%)	8(1.80%)	5(0.56%)	10(2.09%)	0.892	0.346	0.491	0.341	0.056	0.925
32–36	33(6.22%)	92(46.00%)	28(5.51%)	232(52.25%)	58(6.55%)	212(44.35%)
≥37	492(92.66%)	104(52.00%)	474(93.31%)	204(45.95%)	822(92.89%)	256(53.56%)
Birth weight (g)
<1500	5(0.94%)	8(2.00%)	5(0.98%)	6(1.35%)	4(0.45%)	8(1.67%)	0.831	0.108	0.291	0.154	0.857	0.086
1500–2499	22(4.14%)	115(28.75%)	25(4.92%)	154(34.68%)	27(3.05%)	171(35.77%)
≥2500	504(94.92%)	277(69.25%)	478(94.10%)	284(63.97%)	853(96.38%)	299(62.56%)
Sex of neonates
Male	258(48.59%)	208(52.00%)	253(49.81%)	231(52.03%)	438(49.49%)	236(49.37%)	0.371	0.478	0.392	0.524	0.231	0.241
Female	273(51.41%)	192(48.00%)	255(50.19%)	213(47.97%)	447(50.51%)	242(50.63%)
Mode of delivery
Vaginal	122(22.98%)	14(3.50%)	134(26.38%)	10(2.26%)	243(27.46%)	14(2.93%)	0.115	0.355	0.069	0.189	0.332	0.386
Cesarean section	409(77.02%)	386(96.50%)	374(73.62%)	434(97.74%)	642(72.54%)	464(97.07%)

Notes: ^aLetrozole singleton births vs HMG singleton births; ^bHMG singleton births vs letrozole+HMG singleton births. ^cLetrozole singleton births vs letrozole+HMG singleton births; ^dLetrozole multiple births vs HMG multiple births. ^eHMG multiple births vs letrozole+HMG multiple births. ^fLetrozole multiple births vs letrozole+HMG multiple births.

Table 5 Logistic Regression Of Pregnancy Outcome In FET Cycles

Baseline Parameter	Category	aOR (95% CI)	P-Value
Age (years)	per year increased	0.83(0.71–0.93)	<0.001
BMI (kg/m^Citation2)	per kg/m^Citation2 increased	0.75(0.22–2.26)	0.61
Number of previous attempts	per time increased	0.79(0.67–0.96)	<0.001
Hormones at time of hCG injection
FSH (IU/L)	per IU/L increased	0.97(0.82–1.83)	0.63
LH (IU/L)	per IU/L increased	1.01(0.83–1.79)	0.56
E2 (pg/mL)	per pg/mL increased	0.72(0.45–0.82)	0.03
Progesterone (ng/mL)	per ng/mL increased	0.97(0.78–1.54)	0.94
Endometrial thickness (mm)	per mm increased	1.12(1.03–1.16)	<0.001
Type of stimulation protocol
	letrozole vs HMG	1.56(1.21–2.02)	<0.001
	HMG vs letrozole+HMG	1.42(1.24–1.62)	<0.001
	letrozole vs letrozole+HMG	1.16(0.83–1.34)	0.45

Notes: Analyses were adjusted for maternal age, maternal BMI, infertility causes, fertilization method, number of embryo transferred, and embryo quality. Bold values represent statistical significance.

Abbreviation: aOR, adjusted odd ratio

Roque M, Lattes K, Serra S, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril. 2013;99:156–162. doi:10.1016/j.fertnstert.2012.09.00323040524

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