Human Reproduction, Vol.25, No.5 pp. 1219– 1224, 2010
Advanced Access publication on March 9, 2010 doi:10.1093/humrep/deq059
ORIGINAL ARTICLE Infertility
Avoidance of weekend oocyte
retrievals during GnRH antagonist
treatment by simple advancement or
delay of hCG administration does not
adversely affect IVF live birth outcomes
K.P. Tremellen 1,2,* and M. Lane 1,2
1
Repromed, 180 Fullarton Road, Dulwich, SA 5065, Australia 2Research Centre for Reproductive Health, Discipline of Obstetrics and
Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia
*Correspondence address. Fax: +61-8-83338188; E-mail: [email protected]
Submitted on November 5, 2009; resubmitted on February 5, 2010; accepted on February 12, 2010
background: The use of GnRH antagonists in IVF treatment has many advantages over agonist long down-regulation, yet its uptake has
been hampered by an inability to program the start date for gonadotrophin stimulation so as to minimize weekend oocyte retrievals (ORs). In
this study, we retrospectively analyzed whether conducting a strict Monday to Friday OR program impacts on IVF outcomes.
methods: A total of 1642 non-programmed IVF antagonist cycles were analyzed to determine if advancing or delaying the OR by 1 day
from ‘ideal’ to avoid Saturday or Sunday OR, respectively, had any impact on IVF outcomes. The IVF outcomes of Tuesday to Thursday
served as a control as no modification in OR timing was required on these days.
results: Advancing the OR by 1 day from the ideal resulted in a small but significant decrease in the number of oocytes collected and
embryos created. Delaying the OR by 1 day from ideal resulted in a small increase in the number of oocytes collected and embryos created.
However, deviation from the ideal day of OR had no significant effect on live birth rates.
conclusions: It is possible to safely avoid weekend ORs during GnRH antagonist cycles by simply advancing an ideal Saturday OR to
Friday, and delaying an ideal Sunday OR to Monday, without adversely impacting on IVF live birth outcomes.
Key words: GnRH antagonist / IVF programming / weekend oocyte retrieval
Introduction
The evolving view among leading fertility physicians is that GnRH
antagonist therapy provides a superior ‘patient friendly’ IVF experience
compared with the traditional long down-regulation agonist protocol,
whereas still maintaining excellent pregnancy rates (de Klerk et al.,
2006; Devroey et al., 2009). Despite this, many IVF units have been
slow to make the transit from GnRH agonist to antagonist treatment
protocols, primarily because GnRH agonist therapy has the advantage
of allowing effective programming of the gonadotrophin start date,
thereby allowing clinics to smooth work demand over the week
whereas minimizing the risk of weekend oocyte retrievals (ORs).
In 2006, our own IVF program began to move away from the traditional long down-regulation GnRH agonist protocol, with the transition to almost universal GnRH antagonist therapy being complete
by late 2007. Long down-regulation GnRH agonist therapy is now
only used for a few select indications such as oocyte donation, preimplantation genetic diagnosis cycles, and the medical management of
severe endometriosis. However, the avoidance of weekend ORs did
provide a challenge during this period of transition as our unit does
not have the capacity for weekend theatre access to conduct ORs.
Although we contemplated programming IVF treatment using the
Combined Oral Contraceptive Pill (COCP) to minimize the risk of
weekend ORs, we decided not to take this approach as it significantly
delays IVF treatment and may increase gonadotrophin dose requirements, whereas decreasing viable pregnancy rates (Kolibianakis
et al., 2006a, b; Griesinger et al., 2008). Furthermore, one study
reporting on the use of the COCP to avoid weekend ORs in IVF
antagonist cycles found that 22% of women still required a weekend
OR despite the use of the COCP (Barmat et al., 2005). As an alternative, we elected to avoid weekend OR’s by simply bringing forward the
day of hCG administration in ‘ideal’ Saturday ORs to allow for a Friday
& The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: [email protected]
1220
oocyte collection, while delaying ‘ideal’ Sunday ORs to the Monday. It
has already been established that delaying hCG administration by
1 day has no significant negative effect on GnRH agonist IVF outcomes
(Dimitry et al., 1991), although a 2-day delay has been reported to be
detrimental in GnRH antagonist IVF cycles (Kolibianakis et al., 2004).
However, it is presently unclear if advancement or delay of hCG
administration by 1 day has any negative consequences for GnRH
antagonist IVF outcomes (Devroey et al., 2009). Therefore, the
purpose of this retrospective study was to determine if advancing or
delaying hCG administration by 1 day from ‘ideal’ in order to avoid
weekend oocyte collections has any adverse impact on IVF treatment
outcomes in non-programmed GnRH antagonist cycles.
Materials and Methods
Tremellen and Lane
past ‘ideal’ to avoid Sunday oocyte collections or advanced 1 day from
‘ideal’ to avoid Saturday oocyte collections (‘non-ideal’ IVF cycle). Two
senior clinicians made all hCG timing decisions, allowing for a high
degree of consistency in scheduling decisions. Oocyte collections were
performed transvaginally under sedation 36 h following the administration
of the hCG trigger (5000 IU Pregnyl, Schering-Plough, Sydney, Australia;
250 mg Ovidrel, Serono, Sydney, Australia).
Luteal support was provided by a combination of nightly vaginal progesterone (Crinone 8%, Serono, Sydney, Australia) commencing on the
second day after oocyte collection and a single injection of 500 IU hCG
(Pregnyl, Schering-Plough, Sydney, Australia) on the sixth day of the
luteal phase. Luteal Pregnyl support was omitted in patients considered
at high risk of OHSS. Peripheral blood samples were taken for bHCG,
estradiol and progesterone measurements 16 days post-oocyte collection,
with progesterone luteal support ceasing at this point provided hormone
levels were adequate. First trimester pregnancy scans were conducted at
8 weeks gestation using a 7.5 MHz transvaginal scanner (Toshiba, Japan).
Study design
Couples undergoing IVF or ICSI treatment at our Adelaide site using GnRH
antagonist pituitary suppression during the 2008 calendar year were included
in this retrospective study. Patients using GnRH agonist therapy (long downregulation or ‘flare’ protocol) or those receiving COCP programming of their
GnRH antagonist cycle (irregular cycling or anovular women) were excluded
from the study. Furthermore, women aged 43 years or older were also
excluded because of their poor IVF treatment prognosis.
All patients involved in the study provided prospective written consent
for their medical records to be accessed for the purposes of quality assurance audits such as this study. Furthermore, local scientific advisory committee approval of the study protocol was undertaken. Full Institutional
Ethics Review Board approval was not required for this type of retrospective quality assurance audit, as per the Australian National Health and
Medical Research Guidelines (NHMRC) guidelines.
IVF clinical protocol
Gonadotrophin stimulation using recombinant FSH (Puregon, ScheringPlough, Sydney, Australia; Gonal F, Serono, Sydney, Australia) commenced
on Day 2 of the menstrual cycle, with a small fraction of patients starting on
Day 3. Dosage of rFSH was determined by patient age, prior IVF response
and ovarian reserve status assessed by antral follicle count and serum AntiMullerian Hormone measurement. Women aged ≤35 years were normally
commenced on 150 IU of rFSH per day, with 200 – 225 and 300 IU/day of
rFSH being used in the 36 – 39 and 40 – 42 year age groups, respectively.
The GnRH antagonist (250 mg Orgalutran, Schering-Plough, Sydney, Australia) was commenced on the seventh day of the menstrual cycle (sixth stimulation day) and continued until the day of hCG administration. A pelvic
ultrasound and blood collection was performed on Day 8 or 9 of the menstrual cycle to assess follicular and endometrial development. Patients at high
risk of OHSS or previous rapid follicle development during IVF treatment
also had a scan on Day 7 of the cycle (sixth day rFSH stimulation). Repeat
scans and blood tests were only performed if the lead follicle development
was under 14 mm on the Day 8/9 scan, consistent with the unit’s treating
philosophy of avoiding unnecessary medical investigations in order to
enhance the ‘patient friendliness’ of IVF treatment. The dosage of rFSH
stimulation was able to be modified following the Day 8/9 scan if the clinician
suspected a poor or excessive response to gonadotrophin stimulation.
The criterion used for ‘ideal’ timing of the hCG trigger administration
for collection of mature oocytes was the presence of two or more follicles
≥17 mm in diameter, with the majority of follicles being ≥14 mm. An
‘ideal’ IVF cycle was defined as one in which it was possible to administer
the hCG trigger on the exact day that follicle growth reached these maturity criteria. Conversely, trigger injections were routinely delayed for 1 day
Embryology protocol
Routine insemination of oocytes using density gradient purified sperm was
performed if good quality sperms were available. If the male partners
normal sperm morphology was ,10% (normal range in our laboratory
for normal morphology ≥15%) or if there were less than 1 × 106
motile sperm available, ICSI was used to achieve fertilization. Light microscopic examination was used to verify fertilization 16 h later. Embryos
were graded excellent (Grade 1), good (Grade 2), poor (Grade 3) and
very poor (Grade 4) according to the usual morphological criteria for
grading embryos (cell number, fragmentation, nuclear appearance for cleavage stage embryos; compaction and blastocyst cavity formation, cell
number in the inner cell mass and trophectoderm for Day 4/5 embryo
assessment). Grade 1 and 2 embryos were preferentially transferred and
only Grade 1 and 2 embryos were cryopreserved. Embryo transfer was
normally performed under ultrasound guidance on Day 4 or 5 after OR
(‘blastocyst’ transfer). Embryo transfers were only conducted on a
Monday to Saturday basis. Avoidance of transfers on Sundays was achieved
by transferring Day 4 embryos on the Saturday, rather than transferring
these embryos as blastocysts the following day. Previous published work
from our unit has shown that Day 4 and 5 embryo transfers have comparable pregnancy rates (Feil et al., 2008). When the number of fertilized
oocytes equaled the number of embryos allocated to be transferred, cleavage stage (Day 2/3) embryo transfers were performed.
Statistical analysis
The primary end-point for this study was live birth rate, which was defined
as the proportion of IVF cycles reaching OR that resulted in the birth of at
least one live born child. The reporting of pregnancy outcomes (live birth,
pregnancy complications and fetal abnormalities) is mandated by law in
South Australia, resulting in a 100% complete follow-up of all pregnancies.
The studies secondary pregnancy end-points included biochemical pregnancy rate (proportion of ORs that resulted in a day 16 luteal bHCG ≥
20 IU/l) and implantation rate (proportion of transferred embryos that
resulted in a gestation sac at 8 weeks gestation). Embryology secondary
outcomes included fertilization rate (proportion of collected oocytes
that developed two pronuclei) and the number of embryos of sufficient
quality to warrant cryo-preservation.
Data were analyzed using commercial software (GraphPad Prism Version
5.02, Graphpad Software Inc, La Jolla, CA, USA). Baseline demographic
and fertility-related variables between groups were analyzed using either the
one-way ANOVA or the Mann–Whitney U-test for continuous variables
and x2 for categorical variables. Differences in pregnancy outcomes were
1221
Avoiding weekend oocyte retrievals in antagonist cycles
analyzed by x2 analysis and also expressed as an odds ratio (95% confidence
interval). A P-value ≤0.05 was considered statistically significant.
Results
A total of 1642 IVF cycles are included in this study, with 472 ORs
(28.7%) occurring on a Monday (both on the ideal day and 1 day
after the ideal), 372 ORs (22.7%) on a Friday (both on the ideal day
and 1 day before the ideal) and the remaining 798 ORs (48.6%)
being performed from Tuesday to Thursday (Table I).
The results in Table I depict the various IVF prognostic variables for
each weekday OR group. No significant differences in patient’s age,
number of previous IVF cycles, etiology of infertility or ovarian
reserve status were noted between the groups. This would suggest
that the important patient covariants affecting IVF response and pregnancy outcome are equally distributed throughout the week, allowing
for meaningful non-biased comparisons between the groups.
The outcome of IVF stimulation is recorded in Table II. As
expected, a significant difference in the duration of gonadotrophin
stimulation was observed between the three groups. Advancement
of Saturday ORs to Friday resulted in a small reduction (0.59 days)
in the average duration of rFSH stimulation for the Friday OR group
compared with the control group. Conversely, avoidance of Sunday
ORs by delaying the OR until Monday resulted in a small but significant
increase (0.63 days) in the average duration of rFSH stimulation compared with the control group.
Embryology outcomes did not appear to be significantly influenced
by the day on which OR occurred (Table II). No significant difference
was observed between the groups with regard to the numbers of
oocytes collected or embryos generated, nor fertilization rates. Furthermore, embryo quality, as assessed by morphological grading of
the lead embryo or the number of embryos of sufficient quality to
cryopreserve was not significantly different between the groups.
Finally, the number of embryos transferred, and the proportion
of embryos transferred at the blastocyst stage (overall 81.89%,
P ¼ 0.77) was not significantly different between the groups.
A total of 650 cycles of IVF resulted in biochemical evidence of
implantation, giving an overall biochemical pregnancy rate of 39.6%
Table I Baseline characteristics of patients according to the day of OR.
Control OR
(Tuesday –Thursday OR)
Monday OR
Friday OR
P-value
.............................................................................................................................................................................................
Number OR’s performed
798
472
372
–
Maternal Age (years)
35.3 + 4.6
35.1 + 4.8
35.2 + 4.8
0.762
Paternal age (years)
37.8 + 6.1
38.0 + 6.9
38.0 + 6.4
0.941
Number of prior IVF cycles
1.62 + 2.1
1.52 + 2.1
1.62 + 2.1
0.351
Tubal factor (%)
8.8%
11.4%
11.2%
0.755
Endometriosis (%)
5.7%
6.0%
5.7%
0.755
Male factor (%)
47.3%
47.4%
44.8%
0.755
Other (%)
25.1%
22.5%
25.4%
0.755
Unexplained (%)
13.1%
12.7%
12.9%
0.755
Maternal BMI
26.5 + 6.3
27.7 + 4.75
27.7 + 8.9
0.752
Serum AMH (pmol/l)
25.4 + 23.6
25.1 + 23.2
26.3 + 40.4
0.969
AFC (2–5 mm)
10.8 + 8.1
10.5 + 8.3
10.6 + 8.4
0.822
Friday OR
P-value
BMI, body mass index; AMH, Anti-Mullerian hormone; AFC, antral follicle count; OR, oocyte retrieval.
Table II IVF treatment outcomes according to the day of OR.
Control
(Tuesday–Thursday OR)
Monday OR
.............................................................................................................................................................................................
Days of rFSH stimulation
9.47 + 2.18
10.1 + 2.26
8.88 + 2.07
,0.0001
Number oocytes collected
8.82 + 5.51
8.90 + 5.67
8.60 + 5.63
0.6969
Number embryos produced
5.21 + 3.80
5.32 + 3.83
4.94 + 3.87
0.260
Fertilization rate (%)
58.66%
58.85%
57.40%
0.131
Number of embryos transferred
1.20 + 0.50
1.19 + 0.51
1.21 + 0.51
0.906
Number of embryos cryopreserved
1.15 + 1.86
1.30 + 1.96
1.06 + 1.95
0.143
Biochemical pregnancy rate per OR (%)
39.84% (318/798)
38.98% (184/472)
39.78% (148/372)
0.950
Implantation rate (%)
31.03% (296/954)
30.72% (173/563)
33.40% (150/449)
0.603
Live birth rate (%)
32.83% (262/798)
31.77% (150/472)
34.14% (127/372)
0.525
1222
Tremellen and Lane
per OR. No significant difference was observed in the biochemical
pregnancy or implantation rates between the various days of the
week (Table II). The overall live birth rate per OR conducted was
32.8%, with no significant difference in live birth rates being observed
over the various days of the week.
A subgroup analysis was then conducted in which ORs performed
on a Monday and Friday were classified as having been performed on
the ‘ideal’ or ‘non-ideal’ (delayed or advanced by 24 h) day. When
comparing IVF outcomes between ideal and non-ideal ORs conducted
on the same day (Table III), several differences that were not apparent
from the original analysis (Table II) were identified. As would be
expected, the differences in the numbers of days of gonadotrophin
stimulation between ideal and non-ideal ORs became more marked,
with approximately a day difference being observed in each group.
Bringing forward ideal Saturday ORs to Friday resulted in approximately one less oocyte being collected and as a result one less
embryo being created. Conversely, delaying ideal Sunday ORs to
Monday resulted in two extra oocytes being collected and one
additional embryo being created. In the non-ideal Friday OR group,
significantly less oocytes were collected and less embryo embryos
were generated, which meant that slightly fewer embryos on
average were transferred fresh or were available for cryopreservation.
Despite these differences in IVF stimulation outcomes between ideal
and non-ideal OR groups, they did not translate into any differences
in biochemical pregnancy rates, implantation rates or live birth rates.
The odds ratio (95% confidence intervals) for live births when comparing ideal Friday with ideal Saturday ORs was 1.17 (0.76– 1.81)
and the corresponding values when comparing ideal Monday with
ideal Sunday ORs was 0.90 (0.71– 1.23).
Discussion
The results of this study suggest that avoidance of weekend ORs in
GnRH antagonist IVF cycles can be successfully achieved by simply
advancing ideal Saturday OR’s to Friday, while delaying ideal Sunday
ORs to Monday, without any detrimental effect on IVF pregnancy outcomes. Therefore, in the interests of ‘patient friendly’ IVF, the use of
the COCP for programming the start date of gonadotrophin
stimulation in order to minimize the risk of weekend ORs should be
abandoned for women with regular menstrual cycles, especially as
the COCP may increase gonadotrophin dose requirements and may
reduce viable pregnancy rates (Kolibianakis et al., 2006a, b; Griesinger
et al., 2008). Furthermore, even with the use of COCP programming,
it is impossible to predict an individual patient’s response rate to gonadotrophin stimulation with absolute certainty, still placing them at risk
of requiring a weekend OR (Barmat et al., 2005).
On first principles one could anticipate three potential problems
related to our technique of advancement of hCG scheduling. First,
advancement of ideal Saturday ORs to Friday could be expected to
lead to the collection of fewer oocytes, with an increase in the proportion of oocytes that are immature, and could possibly result in
inadequate endometrial development. We did observe a small
reduction in the number of oocytes collected and fertilized, equating
to just less than one embryo per IVF cycle. The absence of any significant
effect of advancing the OR by 1 day on live birth rates, however,
suggests that embryo number and inadequate endometrial development is not a significant issue. It is possible that the small non-significant
trend toward a reduction in the number of embryos available for cryopreservation observed in the Saturday ideal OR group may translate
into a significant reduction in overall pregnancies once frozen embryo
transfer pregnancies are analyzed. The outcome for all the frozen
embryos generated in this study is unlikely to be known for several
years, making such an analysis impossible to conduct at this point.
Delaying a Sunday oocyte collection to Monday could theoretically
harm IVF outcomes by leading to the ‘post mature’ loss of oocyte
quality in the lead follicles. However, any potential loss of lead follicles
is more than likely to be offset by the development of more mature
follicles from the previously borderline mature cohort. Our observation of a small increase in the number of oocytes collected and comparable fertilization rate on ideal Sunday ORs compared with ideal
Monday ORs suggests that delaying the OR by 1 day has no negative
impact on oocyte quality or quantity. Furthermore, pregnancy and live
birth rates were not significantly different between the ideal and nonideal Monday ORs, suggesting that there was no clinically significant
negative affect on embryo quality or endometrial development
brought about by delaying the OR by 1 day. This is consistent with
Table III IVF outcomes for ORs conducted on the ideal day of scheduling compared with those advanced or delayed by
1 day from ideal.
Monday OR
.................................................
Ideal Monday
OR (n 5 221)
P-value
Ideal Sunday
OR (n 5 251)
Friday OR
.................................................
Ideal Friday
OR (n 5 207)
P-value
Ideal Saturday
OR (n 5 165)
.............................................................................................................................................................................................
Number of days rFSH stimulation
9.66 + 2.5
10.48 + 1.9
,0.0001
9.30 + 2.1
8.35 + 1.9
,0.0001
Number of oocytes
7.78 + 5.5
9.88 + 5.6
,0.0001
9.04 + 5.7
7.95 + 5.4
0.0241
Number of embryos
4.78 + 3.6
5.78 + 3.9
,0.004
5.32 + 4.1
4.45 + 3.5
0.010
Fertilization rate (%)
60.0%
58.0%
0.187
58.01%
55.0%
0.093
Embryos transferred
1.15 + 0.50
1.23 + 0.51
0.128
1.27 + 0.5
1.13 + 0.5
0.006
Embryos cryopreserved
1.07 + 1.7
1.51 + 2.1
0.675
1.19 + 2.1
0.91 + 1.7
0.142
Biochemical pregnancy rate (%)
38.91% (86/221)
39.04% (98/251)
0.977
40.0% (83/207)
35.8% (59/165)
0.391
Implantation rate (%)
32.15% (82/255)
29.54% (91/308)
0.503
34.60% (91/263)
31.72% (59/186)
0.523
Live birth rate (%)
30.76% (68/221)
33.06% (83/251)
0.621
35.74% (74/207)
32.12% (53/165)
0.463
1223
Avoiding weekend oocyte retrievals in antagonist cycles
previous reports suggesting that delaying the hCG trigger by 24 h has
no detrimental effect on GnRH agonist IVF pregnancy outcomes
(Dimitry et al., 1991).
The effect of delaying hCG administration on endometrial development is still under debate. As we have shown that delaying the hCG
trigger by 24 h does not reduce pregnancy rates in IVF treatment,
one can assume that any negative effect on the endometrium is not clinically significant. However, studies have shown that delaying the hCG
trigger by 2 days may alter endometrial development and have a detrimental effect on pregnancy rates (Kolibianakis et al., 2004). In one study,
endometrial biopsies were taken on the day of OR in women administered hCG either as per normal protocol or with a 48 h delay. Endometrial development was normal in the ‘per protocol’ group but
advanced by up to 3 days in the delayed hCG group (Kolibianakis
et al., 2005). In this study, progesterone levels taken 24 h after the
hCG trigger were increased by 100% in the delayed hCG group, probably related to the fact that more mature follicles were present. Since
elevated early luteal progesterone levels have been associated with
accelerated glandular development (Develioglu et al., 1999), the
authors proposed that delaying the hCG trigger by 2 days may cause
an early closure of the implantation window and therefore decrease
pregnancy rates. Our interpretation of these reports in the context of
our results is that it would appear to be safer to advance an ideal Saturday OR to Friday, rather than to delay it by 2 days to a Monday.
The link between premature luteinization, advanced endometrial
development and pregnancy outcome is still not clear. A recent
meta-analysis of five studies examining the influence of elevated progesterone concentration on the day of hCG administration on pregnancy outcome failed to identify any significant association (Venetis
et al., 2007). Similarly, another study has suggested that while 18.2%
of women undergoing an IVF antagonist cycle have evidence of premature luteinization (late follicular phase progesterone .1.5 ng/ml or
5.5 nmol/l), this premature exposure of the endometrium to progesterone only negatively impacts cleavage stage embryo implantation
but not blastocyst implantation (Papanikolaou et al., 2009). In our
study in excess of 80% of transfers were conducted at the blastocyst
stage, thus possibly extending the implantation window even if serum
progesterone levels were prematurely increased by delaying the hCG
trigger. We would therefore advocate a preference for blastocyst over
cleavage stage embryo transfer when the oocyte collection is delayed
from ‘ideal’, or when there is a premature increase in late follicular
phase progesterone concentration.
The physiologically ideal criteria for administration of hCG in GnRH
antagonist IVF cycles has not been conclusively determined. In most
studies, hCG is administered when ≥3 follicles ≥17 mm are present
(Borm and Mannaerts, 2000; Fluker et al., 2001; Kolibianakis et al.,
2002), although other studies have successfully used the criteria of ≥3
follicles with a maximum diameter 18 mm (Garcia-Velasco et al.,
2001) or at least 1 follicle of 18 mm and 3 follicles ≥15 mm (de Jong
et al., 2001). It would therefore appear that follicles between 15 and
18 mm in diameter have good reproductive potential. If we assume follicles grow at 2 mm per day, the 3-mm span in good follicle development
should allow for a grace period of at least 24 h in scheduling the hCG
trigger injection. Our observation of no significance difference in pregnancy outcomes with advancement or delay of the hCG injection by
one day supports this conclusion. Furthermore, studies have suggested
that considerable observer error exists for ultrasound measurement of
follicular diameter (Prins and Vogelzang, 1984, Forman et al., 1991). It is
likely that many hCG scheduling decisions based on ideal follicle dimensions are actually only occurring within 1 –2 days of ideal size due to the
margins of error experienced in follicle measurement. It is our view that
human follicular physiology appears to be much more forgiving than
many reproductive physicians would believe.
This large study is the first of its kind to clearly show that in a typical
clinical population, avoidance of weekend oocyte collections during
GnRH antagonist treatment can be achieved by simply advancing or
delaying ideal weekend ORs by one day without negatively impacting
on IVF pregnancy outcomes. Our pragmatic approach to IVF treatment works very well provided the IVF unit has sufficient medical/
scientific manpower and theatre access to cope with the increased
work loads generated on Mondays and Fridays. We acknowledge
that smaller IVF units with less staff and theater flexibility may not
be able to accommodate these increased workloads. For these
units, the use of COCP programming may still be required even
though it is perceived as being less ‘patient friendly’. Simply delaying
the start date for gonadotrophin stimulation from day two to five in
an attempt to smooth demand is not a viable alternative as this has
been shown to result in a very significant increase in cycle cancellation
due to insufficient response (Hohmann et al., 2003).
In conclusion, the results of this study indicate that follicular and
endometrial development during GnRH antagonist IVF cycles is
quite robust and can withstand advancement or delay in hCG administration by 1 day without adversely impacting on IVF live birth success.
However, we acknowledge that retrospective studies such as ours are
prone to bias and require confirmation by randomized controlled trials
(RCTs) before any definitive conclusions on the efficacy of week day
that only GnRH antagonist IVF treatment can be made. However,
based on the very small non-significant differences in pregnancy outcomes observed between ideal and non-ideal ORs in our study, the
sample size for such equivalence RCTs would be prohibitively large.
It is hoped that by showing that GnRH antagonist IVF cycles can be
conducted on a week day-only basis without compromising live
birth rates, more IVF units will make the transition to the ‘patient
friendly’ GnRH antagonist approach.
Authors’ roles
K.T. was responsible for the study design, data analysis and writing of
the manuscript M.L. was involved in data collection and review of the
manuscript.
Acknowledgements
The authors wish to thank Deb Tippins for her assistance in data collection and Dr Christine Kirby for her helpful review of this manuscript.
Conflict of interest: K.T. has previously received honoraria from
Schering-Plough, manufactureres of the GnRH antagonist Ganarelix.
Funding
This study was supported by Schering-Plough Australia as part of a
quality assurance grant.
1224
References
Barmat LI, Chantilis SJ, Hurst BS, Dickey RP. A randomized prospective
trial comparing gonadotropin-releasing hormone (GnRH) antagonist/
recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/
rFSH in women pretreated with oral contraceptives before in vitro
fertilization. Fertil Steril 2005;83:321–330.
Borm G, Mannaerts B. The European Orgalutran Study Group. Treatment
with the gonadotrophin-releasing hormone antagonist ganirelix in women
undergoing ovarian stimulation with recombinant follicle stimulating
hormone is effective, safe and convenient: results of a controlled,
randomized, multicentre trial. Hum Reprod 2000;15:1490– 1498.
de Jong D, Macklon NS, Eijkemans MJ, Mannaerts BM, Coelingh Bennink HJ,
Fauser BC, Ganirelix Dose-Finding Study Group. Dynamics of the
development of multiple follicles during ovarian stimulation for in vitro
fertilization using recombinant follicle-stimulating hormone (Puregon) and
various doses of the gonadotropin-releasing hormone antagonist
ganirelix (Orgalutran/Antagon). Fertil Steril 2001;75:688–693.
de Klerk C, Heijnen EM, Macklon NS, Duivenvoorden HJ, Fauser BC,
Passchier J, Hunfeld JA. The psychological impact of mild ovarian
stimulation combined with single embryo transfer compared with
conventional IVF. Hum Reprod 2006;21:721 –727.
Develioglu OH, Hsiu JG, Nikas G, Toner JP, Oehninger S, Jones HW Jr.
Endometrial estrogen and progesterone receptor and pinopode
expression in stimulated cycles of oocyte donors. Fertil Steril 1999;
71:1040 – 1047.
Devroey P, Aboulghar M, Garcia-Velasco J, Griesinger G, Humaidan P,
Kolibianakis E et al. Improving the patient’s experience of IVF/ICSI: a
proposal for an ovarian stimulation protocol with GnRH antagonist
co-treatment. Hum Reprod 2009;24:764 – 774.
Dimitry ES, Oskarsson T, Conaghan J, Margara R, Winston RM. Beneficial
effects of a 24 h delay in human chorionic gonadotrophin administration
during in-vitro fertilization treatment cycles. Hum Reprod 1991;
6:944 – 946.
Feil D, Henshaw RC, Lane M. Day 4 embryo selection is equal to day 5
using a new embryo scoring system validated in single embryo
transfers. Hum Reprod 2008;23:1505 – 1510.
Fluker M, Grifo J, Leader A, Levy M, Meldrum D, Muasher SJ, Rinehart J,
Rosenwaks Z, Scott RT Jr, Schoolcraft W et al. North American
Ganirelix Study Group. Efficacy and safety of ganirelix acetate versus
leuprolide acetate in women undergoing controlled ovarian
hyperstimulation. Fertil Steril 2001;75:38 – 45.
Forman RG, Robinson J, Yudkin P, Egan D, Reynolds K, Barlow DH. What
is the true follicular diameter: an assessment of the reproducibility of
transvaginal ultrasound monitoring in stimulated cycles. Fertil Steril
1991;56:989 – 992.
Garcia-Velasco JA, Isaza V, Vidal C, Landazábal A, Remohı́ J, Simón C,
Pellicer A. Human ovarian steroid secretion in vivo: effects of GnRH
agonist versus antagonist (cetrorelix). Hum Reprod 2001;16:2533– 2539.
Tremellen and Lane
Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC,
Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian
stimulation with GnRH antagonists for IVF: a systematic review and
meta-analysis. Fertil Steril 2008;90:1055 – 1063.
Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two
ovarian stimulation protocols with gonadotropin-releasing hormone
(GnRH) antagonist cotreatment for in vitro fertilization commencing
recombinant follicle-stimulating hormone on cycle day 2 or 5 with the
standard long GnRH agonist protocol. J Clin Endocrinol Metab 2003;
88:166 – 173.
Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J,
Van Steirteghem A, Devroey P. Effect of ovarian stimulation with
recombinant follicle-stimulating hormone, gonadotropin releasing
hormone antagonists, and human chorionic gonadotropin on
endometrial maturation on the day of oocyte pick-up. Fertil Steril
2002;78:1025 – 1029.
Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC,
Devroey P. Prolongation of the follicular phase in in vitro fertilization
results in a lower ongoing pregnancy rate in cycles stimulated with
recombinant follicle-stimulating hormone and gonadotropin-releasing
hormone antagonists. Fertil Steril 2004;82:102 –107.
Kolibianakis EM, Bourgain C, Papanikolaou EG, Camus M, Tournaye H,
Van Steirteghem AC, Devroey P. Prolongation of follicular phase by
delaying hCG administration results in a higher incidence of
endometrial advancement on the day of oocyte retrieval in GnRH
antagonist cycles. Hum Reprod 2005;20:2453 – 2456.
Kolibianakis EM, Papanikolaou EG, Camus M, Tournaye H, Van
Steirteghem AC, Devroey P. Effect of oral contraceptive pill
pretreatment on ongoing pregnancy rates in patients stimulated with
GnRH antagonists and recombinant FSH for IVF. A randomized
controlled trial. Hum Reprod 2006a;21:352 – 357.
Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K,
Griesinger G. Among patients treated for IVF with gonadotrophins
and GnRH analogues, is the probability of live birth dependent on the
type of analogue used? A systematic review and meta-analysis. Hum
Reprod Update 2006b;12:651– 671.
Papanikolaou EG, Kolibianakis EM, Pozzobon C, Tank P, Tournaye H,
Bourgain C, Van Steirteghem A, Devroey P. Progesterone rise on the
day of human chorionic gonadotropin administration impairs
pregnancy outcome in day 3 single-embryo transfer, while has no
effect on day 5 single blastocyst transfer. Fertil Steril 2009;91:949– 952.
Prins GS, Vogelzang RL. Inherent sources of ultrasound variability in
relation to follicular measurements. J In Vitro Fert Embryo Transf 1984;
1:221 – 225.
Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P,
Tarlatzis BC. Is progesterone elevation on the day of human chorionic
gonadotrophin administration associated with the probability of
pregnancy in in vitro fertilization? A systematic review and
meta-analysis. Hum Reprod Update 2007;13:343– 355.