PREGNANCY OUTCOME AND COST-EFFECTIVENESS COMPARISONS OF ARTIFICIAL CYCLE-

PREPARED FROZEN EMBRYO TRANSFER WITH OR WITHOUT GNRH AGONIST

PRETREATMENT FOR POLYCYSTIC OVARY SYNDROME:
A RANDOMISED CONTROLLED TRIAL

L Luo, M Chen, Y Wen, L Zhang, C Zhou, Q Wang

a
The Center of Reproductive Medicine, First Affiliated Hospital, Sun Yat-sen
University and Guangdong Provincial Key Laboratory of Reproductive
Medicine, Guangzhou, China

By: dr. Aditya Pratama Alamsyah

Introduction
Artificial cycle-prepared
frozen embryo transfer
with gnrh agonist
pretreatment for
polycystic ovary
syndrome
Frozen embryo transfer (FET) is widely used in assisted reproductive medicine as an alternative to fresh
cycle transfer as FET lowers the risk of ovarian hyperstimulation syndrome (OHSS) and can increase the
cumulative pregnancy rate per in vitro fertilisation (IVF) cycle.
Artificial cycle (AC) induction using consecutive estrogen and progesterone with or without
gonadotropin-releasing hormone agonist (GnRH-a) pretreatment is often used before FET for
anovulatory women to mimic the natural endometrium environment.

AC prepared-FET (AC-FET) with GnRH-a pretreatment was found to increase live birth rate among specific
patient subgroups such as women with endometriosis, possibly by transiently suppressing the
hypothalamic-pituitary-gonadal axis and inducing a hypo- estrogenic effect
Pregnancy Cost-
outcome effectiveness Downregulation of estrogen signalling not only reduces the risk of unexpected ovulation but also terminates
the ‘implantation window’ in advance.7 Further- more, it was also reported that GnRH expression in the
endometrium can directly inhibit inflammatory factors and increase endometrial adhesion molecules.

Therefore, we designed the present randomised controlled trial (RCT) to compare pregnancy
Objective outcomes and cost-efficiency of AC- FET with or without GnRH pretreatment for women with
PCOS.

To compare the live birth rate and cost effectiveness of artificial cycle-prepared frozen embryo transfer (AC-
FET) with or without GnRH agonist (GnRH-a) pretreatment for women with polycystic ovary syndrome
(PCOS)
 Materials & Methods
Subject
Design Randomized Control Trial

period Enrolment began in April 2017 and was Exposed group Control group
completed in November 2018
(n= 172) (n= 171)
• Study inclusion criteria included age 20–40 years • 172 patients • 171 patients
and previous PCOS diagnosis according to
Data sampling modified Rotterdam criteria as validated in the with GnRH-a without
Chinese population
pre treatment pretreatment
• chi-square test
Statistical analysis • Fish- er’s exact test
• Statistical Package for the Social Sciences

exclusio •
•
Uterus Anomali
Endometriosis
• Any con- traindication
to hormonal
• A FET cycle after pre-
implantation genetic

n • Uterus Adhesion
supplementation testing (PGT)
Results
Results
Discussion

In the present RCT, pretreatment with GnRH did not

improve live birth rate, clinical pregnancy rate or early
pregnancy loss rate following artificial cycle-prepared FET
for women with PCOS. However, GnRH agonist
pretreatment did significantly enhance the cost to PCOS
patients compared with those receiving the same AC-FET
protocol without GnRH pretreatment.
 Conclusion
For women with PCOS, an endometrial preparation using GnRH agonist
pretreatment prior to AC-FET does not improve live birth rate compared with the
standard AC- FET protocol without GnRH-a pretreatment, and the direct cost per
live birth is much higher.

Therefore, AC-FET without GnRH-a pretreatment appears to be the

better choice for women with PCOS; however, larger trials are required
for confirmation.
Critical Appraisal
• Women with Policystic Author(s) and L Luo, M Chen, Y Wen, L Zhang,
Patient Ovarii Syndrom C Zhou, Q Wang
Affiliation(s)
Pregnancy outcome and cost-effectiveness comparisons of

Title artificial cycle-prepared frozen embryo transfer with or without

GnRH agonist pretreatment for polycystic ovary syndrome: a
Intervention • GnRH Agonist Treatment randomised controlled trial

An Internasional Journal of
Journal obstetrics and gynaecology
• Women without GnRH
Comparison agonist treatment
Volume and
page numbers Early review
• Clinical Pregnancy
• Cost-Effectiveness
Outcome • Live Birth Rate Year of
2020
• Early Pregnancy Loss publication

(type of the study) • Randomized Control Trial

1a. R- Was the assignment of patients to treatments
randomised ?
YES
1b. R- Were the groups similar at the start of the trial ?
YES
2a. A – Aside from the allocated treatment, were groups
treated equally ?
YES
2b. A – Were all patients who entered the trial accounted for ?
And were they analysed in the groups to which they were
randomised ? YES
 3. M - Were measures objective or were the patients and
clinicians kept “blind” to which treatment was being received ?
NOT BLIND, BUT THE MEASURES WERE OBJECTIVE
What were the results?
Intention-to-treat analyses of clinical pregnancy out- comes are summarised in
Table 3. The primary outcome, live birth rate (LBR) per intention-to-treat, did
not differ between the GnRH-a pretreatment and control group (85/ 172
[49.4%] versus 92/171 [53.8%], absolute rate differ- ence = 4.4%, 95% CI 10.8 to
2.0%, relative ratio (RR) = 0.92, 95% CI 0.65–1.33, P = 0.45). Similarly, inten-
tion-to-treat analyses of the secondary outcomes yielded no significant
differences in implantation rate (IR) (45/245 [59.2%] versus 127/214 [59.3%], RR
= 1.0, 95% CI 0.9– 1.2, P = 0.97), clinical pregnancy rate (CPR) (109/172 [63.4%]
versus 111/171 [64.9%], RR = 0.98, 95% CI 0.7– 1.4, P = 0.82) and early
pregnancy loss rate (EPLR) (16/ 109 [14.7%] versus 13/111 [11.7%], RR = 1.3,
95% CI: 0.6–2.5, P = 0.55). However, there were significant differ- ences in costs
between groups (Table 4). The median total direct cost for patients in the
pretreatment group was sig- nificantly higher than that in the control group
(7799.2 versus 4438.9 RMB, OR = 1.9, 95% CI 1.2–3.4, P < 0.001). Similarly,
median direct cost per live birth was significantly higher in the pretreatment
group (15663.1 versus 8189.9 RMB, OR = 1.9, 95% CI 1.2–3.8, P < 0.001).
Moreover, all primary and secondary outcome results also held for women who
complete the protocols (Table S2). Live birth rate comparisons between patients
from the first and the second FET cycle were also con- ducted (Table S3, Figure
S1).
How precise was the estimate of the treatment effect ?

However, there were significant differ- ences in costs between groups

(Table 4). The median total direct cost for patients in the pretreatment
group was sig- nificantly higher than that in the control group (7799.2
versus 4438.9 RMB, OR = 1.9, 95% CI 1.2–3.4, P < 0.001). Similarly,
median direct cost per live birth was significantly higher in the
pretreatment group (15663.1 versus 8189.9 RMB, OR = 1.9, 95% CI
1.2–3.8, P < 0.001).
Will the results help me in caring for my patient ?
(ExternalValidity/Applicability)
• Is my patient so different to those in the study that the results cannot
apply ? Probable No, Because my patient is Asian race too
• Is the treatment feasible in my setting ? No, Because the facility in my
setting dosn’t Support
• Will the potential benefits of treatment outweigh the potential harms
of treatment for my patient? No, because the direct cost per live birth
is much higher
 • Gonadotropin Releasing Hormone Duration of follow
Intervention
Agonist Pre-treatment AC-FET up
• 2 Years
• In this study, The Authors calculated with alpha 0.05 and 80%
Design • Randomized Control Trial Number considered power that 155 FET cycles were required in each group to
demonstrate an absolute difference of 13% in the live birth rate
for enrollment between study groups. We increased the number to 170 patients
per group to allow for a dropout rate of 10%.
Outcome • Yes
ascertained • Control group: 171
Number enrolled • Intervention group :172
Main source of • 348 Women with Polycystic
subjects Ovarian Syndrome (PCOS)
Number included in • Control group: 171
• woman 20–40 years old analysis • Intervention group :172
Inclusion criteria • previous PCOS diagnosis according to modified Rotterdam criteria as
validated in the Chinese population

• Congenital or Acquired Uterine Anomalies

• Intrauterine Adhesions Statistical method • Chi square/fisher exact
Exclusion criteria • Endometriosis
• Pregnancy Woman
• This was a single-centre, open-label, randomised controlled trial
Other relevant
Main source of data
registered at the Chinese trial registry (ChiCTR-IOR- 17010729) and
approved by the Medical Ethics Committee of the First Affiliated
Hospital, Sun Yat-sen University, and by the institutional review boards information
• None
of the participating cen- tres

Author’s key result • For women with PCOS, an endometrial preparation using GnRH agonist pretreatment prior to AC-FET does not improve live birth rate compared with the standard AC-
FET protocol without GnRH-a pretreatment, and the direct cost per live birth is much higher.
• Intention-to-treat analyses of clinical pregnancy out- comes are summarised in Table 3. The primary outcome, live birth rate (LBR) per intention-to-treat, did not differ
between the GnRH-a pretreatment and control group (85/ 172 [49.4%] versus 92/171 [53.8%], absolute rate differ- ence = 4.4%, 95% CI 10.8 to 2.0%, relative ratio

& conclusion
(RR) = 0.92, 95% CI 0.65–1.33, P = 0.45).
• owever, there were significant differ- ences in costs between groups (Table 4). The median total direct cost for patients in the pretreatment group was sig- nificantly
higher than that in the control group (7799.2 versus 4438.9 RMB, OR = 1.9, 95% CI 1.2–3.4, P < 0.001).
Conclusion
• Randomized Control Trial
• Adequate number of subjects
Scientific merit • good
• Provide control group to be compared
Strength of with
• Appropriate Statistical analysis
paper • Appropriate type of study
• Outcomes measured adequately
Clinical relevance • relevant

Type of study • RCT

• This study is single • Double blind RCT to minimize bias

recommendation
center study
• This study is open
weakness
label Any referenced • No
to be criticized