No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies
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Human Reproduction, Vol.35, No.5, pp. 1082–1089, 2020
Advance Access Publication on April 29, 2020 doi:10.1093/humrep/deaa028
ORIGINAL ARTICLE Infertility
No effect of ovarian stimulation and
oocyte yield on euploidy and live birth
rates: an analysis of 12 298
trophectoderm biopsies
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M. Irani1,*, C. Canon2 , A. Robles2 , B. Maddy3 , V. Gunnala1 , X. Qin1 ,
C. Zhang1 , K. Xu1 , and Z. Rosenwaks1
1
The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA,
2
Obstetrics and Gynecology, New York Presbyterian/Weill Cornell Medicine, New York, NY 10021, USA, 3 Weill Cornell Medicine,
New York, NY 10021, USA
*Correspondence address. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine 1305
York Avenue, 6th floor, New York, NY 10021, USA. Tel: 1-646-962-3413; Fax: 646-962-0392; E-mail: mohamad.irani@hotmail.com
Submitted on December 21, 2019; resubmitted on January 22, 2020; editorial decision on February 9, 2020
STUDY QUESTION: Does ovarian stimulation affect embryo euploidy rates or live birth rates (LBRs) after transfer of euploid embryos?
SUMMARY ANSWER Euploidy rates and LBRs after transfer of euploid embryos are not significantly influenced by gonadotropin
dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger or number of oocytes retrieved, regardless of a
woman’s age.
WHAT IS KNOWN ALREADY: Aneuploidy rates increase steadily with age, reaching >80% in women >42 years old. The goal of ovarian
stimulation is to overcome this high aneuploidy rate through the recruitment of several follicles, which increases the likelihood of obtaining
a euploid embryo that results in a healthy conceptus. However, several studies have suggested that a high response to stimulation might be
embryotoxic and/or increase aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis. Furthermore, a recent
study demonstrated a remarkable difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors in 42 fertility centres,
potentially suggesting an iatrogenic etiology resulting from different stimulation methods.
STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study that included 2230 in vitro fertilisation (IVF) with preimplantation
genetic testing for aneuploidy (PGT-A) cycles and 930 frozen-thawed single euploid embryo transfer (FET) cycles, performed in our centre
between 2013 and 2017.
PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 12 298 embryos were analysed for ploidy status. Women were divided
into five age groups (42 years old). Outcomes were compared between different durations of stimulation
(
Ovarian stimulation and blastocyst viability 1083
LIMITATIONS, REASONS FOR CAUTION: Although this large study (2230 IVF/PGT-A cycles, 12 298 embryos and 930 single FET cycles)
demonstrates the safety of ovarian stimulation in terms of aneuploidy and implantation potential of euploid embryos, a multi-centre study may
help to prove the generalisability of our single-centre data.
WIDER IMPLICATIONS OF THE FINDINGS These findings reassure providers and patients that gonadotropin dosage, duration of
ovarian stimulation, estradiol level, follicle size at ovulation trigger and number of oocytes retrieved, within certain ranges, do not appear to
significantly influence euploidy rates or LBRs, regardless of the woman’s age.
STUDY FUNDING/COMPETING INTEREST(S): No external funding was received and there are no competing interests to declare.
TRIAL REGISTRATION NUMBER: N/A
Key words: ovarian stimulation / oocyte yield / euploidy rate / live birth rate / preimplantation genetic testing for aneuploidy
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.
Introduction .
.
follicular size on the day of trigger affect embryo aneuploidy rates or
. live birth rates (LBRs) of euploid embryos transferred in subsequent
Women face a gradual decline in fertility after reaching age 35, which .
. single frozen-thawed embryo transfer cycles (FET).
is reflected by the lower fecundability and higher miscarriage rates .
.
seen in older women (Leridon 2004; Steiner and Jukic 2016). This .
.
trend has been attributed to the steep increase in aneuploidy rates in .
women older than 34 years old (y.o.) (Franasiak et al. 2014). Hence,
.
.
Materials and Methods
.
the principal goal of ovarian stimulation is to overcome these high .
.
. Cycle selection
aneuploidy rates and increase the likelihood of obtaining a euploid .
. The Weill Cornell Medicine Institutional Review Board approved this
embryo (Sunkara et al. 2011; Steward et al. 2014). However, high .
. retrospective cohort study. All IVF cycles in which embryos were
oocyte yield is associated with increased risks of complications, includ- .
. biopsied for preimplantation genetic testing for aneuploidy (PGT-A)
ing intra-abdominal bleeding, ovarian torsion and ovarian hyperstimu- .
. at the Ronald O. Perelman and Claudia Cohen Center for Repro-
lation syndrome (OHSS) (Bodri et al. 2008). OHSS, which is the most .
.
. ductive Medicine between January 2013 and December 2017 were
serious and potentially life-threatening complication, has been largely .
. included.
mitigated by the administration of GnRH agonist to trigger final oocyte .
.
maturation followed by the cryopreservation of all embryos in women .
. Clinical protocols
with high ovarian response (Engmann et al. 2008). .
.
Several studies have suggested that a high response to stimulation . Ovarian stimulation, trigger of final oocyte maturation, oocyte
.
might be embryotoxic and/or increase aneuploidy rates by enhancing . retrieval, fertilisation, embryo culture and transfer were carried out
.
abnormal segregation of chromosomes during meiosis (Vogel and . according to our standard protocols (Huang and Rosenwaks 2014).
.
.
Spielmann 1992; Valbuena et al. 2001; Van der Auwera and D’Hooghe . The stimulation protocol was selected based on patient age, weight,
.
2001; Lee et al. 2005; Roberts et al. 2005; Baart et al. 2007). Animal . evaluation of ovarian reserve and response to previous stimulation.
.
studies have indicated that superovulation delays embryonic and foetal . The patients received daily exogenous gonadotropins (Gonal-F, EMD-
.
development, and it may accelerate nuclear maturation and affect . Serono Inc.; Follistim, Merck, Kenilworth, NJ, USA; and Menopur,
.
chromosome congression during prometaphase and metaphase, thus . Ferring Pharmaceuticals Inc., Parsippany, NJ, USA). The response to
.
causing a higher risk of aneuploidies (Vogel and Spielmann 1992; Van . stimulation was assessed by measuring serum E2 levels and performing
.
.
der Auwera and D’Hooghe 2001; Lee et al. 2005; Roberts et al. . transvaginal ultrasounds. GnRH antagonist (Ganirelix acetate, Merck,
.
2005). Furthermore, a small study has suggested that stimulation with . Kenilworth, NJ, USA; or Cetrotide, EMD-Serono Inc., Rockland, MA,
.
high-dose exogenous gonadotropins might lead to higher aneuploidy . USA) or GnRH agonist (leuprolide acetate, Abbott Laboratories,
.
rates compared to mild stimulation (Baart et al. 2007). A recent small . Chicago, IL, USA) was used for pituitary suppression. Human chorionic
.
retrospective study also showed higher aneuploidy rates in women . gonadotropin (Novarel, Ferring Pharmaceuticals Inc., Parsippany, NJ,
.
.
undergoing stimulation with higher gonadotropin dosages (Sachdeva . USA) and/or GnRH agonist (leuprolide acetate, Abbott Laboratories,
.
et al. 2018). In addition, a high level of estradiol (E2) has been proposed . Chicago, IL, USA) were used to trigger the final oocyte maturation.
.
to be embryotoxic, with a progressive reduction in embryonic adhe- . Ultrasound-guided oocyte retrieval was performed 35–37 h after the
.
sion occurring after exposure to gradually higher E2 levels (Valbuena . trigger.
.
et al. 2001). Moreover, a recent study demonstrated a remarkable . Blastocysts were cryopreserved after biopsy, and the euploid
.
difference in euploidy rates, ranging from 39.5 to 82.5%, among young . embryos were transferred in FET cycles. In general, women with regu-
.
.
oocyte donors in 42 fertility centres, potentially suggesting an iatrogenic . lar menstrual cycles underwent natural FET cycles in which they were
.
etiology resulting from different stimulation methods (Munne et al. . monitored during the last few days of the follicular phase to detect the
.
2017). . LH surge and ensure adequate endometrial development. The transfer
.
Determining the effect of exogenous gonadotropins on embryo . was performed 5 days after the LH surge. Vaginal progesterone supple-
.
ploidy in women undergoing ovarian stimulation is critical for the . mentation (Endometrin, Ferring Pharmaceuticals Inc., Parsippany, NJ,
.
selection of the best stimulation protocols. Therefore, this large study . USA) was administered after embryo transfer to some women based
.
.
was conducted to identify whether the duration of stimulation, total . on physician discretion. Alternatively, patients underwent programmed
.
gonadotropin dosage, number of oocytes retrieved, peak E2 level or . FET cycles in which E2 patches were applied for ∼2 weeks before1084 Irani et al.
Table I Demographic and embryo ploidy data for women who underwent IVF/PGT-A cycles.
Age (years)
...........................................................................................................................................................................................
Parameters 42 (n = 300) P value
...........................................................................................................................................................................................
Age (years) 31.6 ± 2.2 36.0 ± 0.8 39.1 ± 0.8 41.4 ± 0.5 43.7 ± 0.9Ovarian stimulation and blastocyst viability 1085
Table II Clinical outcomes of IVF/PGT-A cycles.
Euploidy rates (%) in women of different age groups (years)
Age (# embryos) 42 (n = 1157)
...........................................................................................................................................................................................
Duration of stimulation (days)
12 (n = 256 cycles) 60.9 44.2 35.5 16.6 8.5
P value NS NS NS NS NS
Gonadotropin dosages (IU)
6000 (n = 170 cycles) 62.3 38.4 32.4 22.6 5.1
P value NS NS NS NS NS
# oocytes retrieved1086 Irani et al.
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Figure 2 Live birth rates according to ovarian stimulation methods and outcomes in different age groups of women. There was
no significant difference in LBRs after single frozen-thawed euploid embryo transfer cycles in which patients had different (A) gonadotropin dosages,
(B) durations of stimulation, (C) numbers of oocytes retrieved, (D) peak estradiol levels or (E) sizes of the largest follicle on the day of the ovulation
trigger during their ovarian stimulation cycles.
.
When cycles were stratified according to the largest follicle size .
.
Discussion
on the day of trigger, cycles in which follicles were ≥20 mm were .
.
associated with comparable euploidy rates with cycles in which follicles . This study evaluated the effects of ovarian stimulation on embryo
.
wereOvarian stimulation and blastocyst viability 1087
implantation potential present conflicting data (Golbus 1981; Vogel . Given that stimulation does not seem to affect ploidy rates, the
.
.
and Spielmann 1992; Jackson et al. 1998; Katz-Jaffe et al. 2005; Baart . reported differences in euploidy rates among young oocyte donors
.
et al. 2007; Gianaroli et al. 2010; Labarta et al. 2012; Tur-Kaspa . from 42 centres could be related to other factors such as culture
.
2012; Hong et al. 2019). Jackson et al. reviewed 483 IVF cycles . conditions (e.g. variations in PH or temperature) (Pickering et al.
.
and suggested that higher E2 levels and a higher number of oocytes . 1990; Almeida and Bolton 1995; Munne et al. 1997; Munne et al.
.
.
retrieved are associated with increased embryo multinucleation and . 2017). It is important to note that the majority of patients included
.
lower clinical pregnancy rates (Jackson et al. 1998). A small study by . in our study in the high E2 group (>3000 pg/mL) had E2 levels
.
Baart et al. including women younger than 38 y.o. used fluorescence . that ranged between 3000 and 5000 pg/mL, with a mean level of
.
in situ hybridisation (FISH) to compare the ploidy rates of cleavage- . 3703 ± 658 pg/mL. Furthermore, most women in the high oocyte
.
stage embryos generated after a mild stimulation regimen with those . yield group (≥20 oocytes) had 20–35 retrieved oocytes (mean 25 ± 6
.
.
obtained after a conventional high-dose exogenous gonadotropin . oocytes). Therefore, the conclusions of this single-centre study must
.
regimen (Baart et al. 2007). The latter was associated with a greater . be interpreted with caution, as we rarely encounter women whose
.
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number of oocytes and embryos but also a higher aneuploidy rate . E2 is >5000 pg/mL or who have >35 oocytes (Valbuena et al. 2001).
.
compared to the former, leading to a comparable number of euploid . Similarly, we cannot attest to the safety of administering hCG at follicles
.
.
embryos (Baart et al. 2007). Katz-Jaffe et al. also suggested that a . >22 mm because the overwhelming majority of our patients included
.
higher daily gonadotropin dose during IVF is associated with a greater . in this study were triggered when the average size of the largest follicle
.
number of meiotic errors compared to a lower daily gonadotropin .
. was ≤22 mm.
dose (Katz-Jaffe et al. 2005). Vogel et al. analysed the chromosomes . The reassuring findings of this study should not be misinterpreted as a
.
of pronuclei from mouse zygotes and reported an increased rate . promotion to aggressively stimulate patients, especially since extreme
.
.
of aberrations in the oocyte-derived nuclei following superovulation . ovarian responses are linked to higher risks of complications such as
.
compared to spontaneous ovulation (Vogel and Spielmann 1992). . intra-abdominal bleeding, ovarian torsion and OHSS (Bodri et al. 2008;
.
Conversely, Golbus et al. reported comparable mouse oocyte . Steward et al. 2014). It must also be emphasised that using GnRH
.
aneuploidy rates between oocytes obtained after superovulation and . agonist triggers followed by a freeze-all policy minimises, but does
.
.
those from spontaneous ovulation (Golbus 1981). Hong et al. also . not eliminate, the risk of OHSS (Fatemi et al. 2014; Ling et al. 2014).
.
reported comparable aneuploidy rates between 369 natural cycles . Another reason to avoid aggressive stimulation is the finding that some
.
and 2846 gonadotropin-stimulated IVF cycles (Hong et al. 2019). In . women undergoing GnRH antagonist IVF stimulation protocols may fail
.
addition, Labarta et al. conducted a prospective study to compare . to respond to the GnRH agonist trigger, and thus may require hCG to
.
the aneuploidy rates in oocyte donors (mean age = 25.4 ± 4.0 years) . trigger final oocyte maturation (Meyer et al. 2015).
.
.
between unstimulated and stimulated IVF cycles (Labarta et al. 2012). . In conclusion, this study reassures clinicians and patients that the
.
Of the 51 women who underwent unstimulated cycles, 46 also . total gonadotropin dosage, duration of ovarian stimulation, size of the
.
completed stimulated cycles. Embryo biopsy was performed at the . largest follicle on the day of trigger, peak estradiol level and oocyte
.
cleavage stage, and FISH was used for chromosomal analysis. There . yield, within certain ranges, do not appear to influence aneuploidy rates
.
.
was no significant difference in the aneuploidy rates between the . or the viability of the euploid embryos, in any age category.
.
unstimulated cycles (34.8%) and stimulated cycles (40.6%) (P = 0.45) .
.
(Labarta et al. 2012). The authors could not extrapolate these .
.
interesting results to older or infertile women because they only .
.
.
Acknowledgements
included young oocyte donors. Our findings are consistent with their .
. The study was presented in oral format at the 34th Annual Meeting
reassuring data and, most importantly, include infertile women in all age .
. of the European Society of Human Reproduction and Embryology,
categories who were high or poor responders and received different .
. Barcelona, Spain, 1–4 July 2018.
gonadotropin dosages. .
.
The impact of ovarian stimulation and oocyte yield on the cumulative .
.
LBR can be interpreted as an indirect indicator of their impact on .
.
embryo development and implantation potential. For instance, a large
.
.
Authors’ roles
.
multicenter retrospective study followed 14 469 patients for at least . M.I., C.C., A.R., B.M., V.G., X.Q., C.Z., K.X., Z.R.: conception and
.
2 years after their retrieval cycles to assess the outcomes of fresh and . design of study, acquisition of data, analysis of data and approval of
.
frozen cycles (Polyzos et al. 2018). They reported a steady increase in . the final version. M.I.: drafting the manuscript. C.C., A.R., B.M., V.G.,
.
. X.Q., C.Z., K.X., Z.R.: revising the manuscript critically for intellectual
the cumulative LBR, which did not reach a plateau, with the increase .
.
in the number of oocytes retrieved (Polyzos et al. 2018). The positive . content.
.
correlation between oocyte yield and cumulative LBR has also been .
.
confirmed by other studies (Ji et al. 2013; Drakopoulos et al. 2016). A .
.
.
high number of retrieved mature oocytes (>20 mature oocytes) was .
.
Funding
also correlated with comparable implantation and ongoing pregnancy .
. The authors received no specific funding for this work.
rates of euploid embryos to those with a lower number of mature .
.
oocytes (6–10 and 10–20 mature oocytes) (Unal et al. 2009). These .
.
results suggest that high oocyte yield is not embryotoxic, which is .
.
consistent with our data that showed comparable aneuploidy rates and
.
.
Conflict of interest
.
LBRs between groups with different oocyte yields. . The authors have nothing to disclose.1088 Irani et al.
.
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