Human Reproduction, Vol.33, No.8 pp.

1489–1498, 2018
Advanced Access publication on July 10, 2018 doi:10.1093/humrep/dey238

ORIGINAL ARTICLE Reproductive endocrinology

Diminished ovarian reserve and

poor response to stimulation in
patients <38 years old: a quantitative
but not qualitative reduction in

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performance
S.J. Morin1,3,*, G. Patounakis2, C.R. Juneau1, S.A. Neal1,3,
R.T. Scott Jr1,3, and E. Seli1,4
1
IVI RMA New Jersey, Basking Ridge, NJ 07920, USA 2IVI RMA Florida, Lake Mary, FL 32746, USA 3Department of Obstetrics and
Gynecology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA 4Department of Obstetrics,
Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06511, USA

*Correspondence address. Reproductive Medicine Associates of New Jersey, 140 Allen Rd. Basking Ridge, NJ 07920, USA.
E-mail: smorin@rmanj.com

Submitted on January 8, 2018; resubmitted on May 4, 2018; accepted on June 15, 2018

STUDY QUESTION: Do infertile women aged <38 years with quantitative evidence of diminished ovarian reserve and/or poor response
to stimulation also exhibit poor oocyte quality as measured by blastulation rates, aneuploidy rates, and live birth rates?
SUMMARY ANSWER: Young women with evidence of accelerated follicular depletion, either by precycle ovarian reserve testing or post-
cycle evidence of low oocyte yield, exhibit equivalent blastulation rates, aneuploidy rates and live birth rates per euploid embryo transfer as
age-matched controls with normal precycle and postcycle parameters.
WHAT IS KNOWN ALREADY: Previous studies are conflicted as to whether women with evidence of diminished ovarian reserve and/
or poor ovarian response are also at increased risk of exhibiting evidence of poor oocyte quality. Most prior studies have failed to adequately
control for the confounding effect of female age on typical markers of oocyte quality in poor responders. The rate of follicular depletion
occurs at around 38 years on average; thus, evidence of quantitative depletion before this would indicate a premature diminution of ovarian
reserve and allow evaluation of whether markers of oocyte quality are tied to quantitative markers.
STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study at a single center between 2012 and 2016. This time frame was
specifically chosen as all embryos were cultured to the blastocyst stage at this center during the study period (no cleavage stage transfers were per-
formed). Two comparisons were made: precycle assessment of ovarian reserve (based on anti-mullerian hormone (AMH) level) and postcycle
oocyte yield results. For each comparison, patients in <10th percentile were compared to patients in the interquartile range (IQR) with respect to
blastulation rate, aneuploidy rate and live birth rate. A mixed effects model was created to control for female age (in the <38 year old range) and cor-
relation among oocytes from a given cohort.
PARTICIPANTS/MATERIALS, SETTING, METHODS: For the precycle blastulation analysis, only patients with AMH data available
were included (345 patients with AMH in the <10th percentile versus 1758 patients with AMH in the 25th to 75th percentile (IQR)). To
compare aneuploidy rates, the subset of these patients who pursued preimplantation genetic testing for aneuploidy (PGT-A) was then ana-
lyzed (124 patients in the <10th percentile versus 782 patients in the IQR). For the postcycle blastulation analysis, all patients who proceeded
to retrieval (whether or not they also had AMH data available) were included (535 patients with oocyte yield in the <10th percentile versus
2675 patients in the IQR). To compare aneuploidy rates, the subset of these patients who pursued PGT-A was then analyzed (156 patients in
the <10th percentile versus 1100 patients in the IQR).
MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted odds of a given fertilized oocyte developing to a blastocyst, being aneu-
ploid or leading to a live birth after euploid transfer were no different if the oocyte was retrieved from a cycle with ovarian reserve parameters

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1490 Morin et al.

or oocyte yield in the <10th percentile compared to an oocyte retrieved in a cycle with those parameters in the 25–75th percentile.
An AMH level in the <10th percentile did more commonly result in cycle cancellation prior to retrieval and after retrieval prior to transfer
due to global arrest of embryos.
LIMITATIONS, REASONS FOR CAUTION: The timing of retrieval in patients with fewer oocytes may be more optimal given the great-
er ability to discern the overall maturity of the cohort, thus enhancing performance per retrieved oocyte. Analyses included only first cycles.
Subsequent adjustment of protocol due to prior performance may mean that some patients in the <10th percentile for oocyte yield are actu-
ally better prognosis patients than their first cycle indicates. Data on whether or not patients were on oral contraceptives at time that AMH
level drawn was not available. Other unknown biases are also likely to be present given retrospective nature of the study.
WIDER IMPLICATIONS OF THE FINDINGS: While young women with evidence of quantitative depletion of ovarian reserve have lower
live birth rates per stimulation cycle, this not attributable to poor oocyte quality because the blastulation rate per fertilized oocyte and live birth
rate per embryo transfer are equivalent to that in women with normal quantitative markers of ovarian reserve. Thus, the pathophysiology mediat-

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ing a premature quantitative decline in ovarian reserve appears different than that which mediates markers of oocyte quality, such as aneuploidy.
Young poor responders may use this information to help guide embryo accumulation strategies when considering their family building plans.
STUDY FUNDING/COMPETING INTEREST(S): None.
TRIAL REGISTRATION NUMBER: N/A.

Key words: ovarian reserve / oocyte quality / aneuploidy / ovarian stimulation / assisted reproduction

to meet developmental milestones and/or an increased likelihood of

Introduction
Diminished ovarian reserve (DOR) and poor response (PR) to stimu-
lation are frequently encountered during infertility treatment (Devine
et al., 2015). However, characterizing the physiology underlying DOR
has been challenging due to: (i) the lack of consensus regarding the
diagnostic criteria for DOR/PR, (ii) the difficulty untangling age-
dependent (physiologic) from premature (nonphysiologic) declines in
ovarian function (Sun et al., 2008) and (iii) disagreement regarding
whether DOR/PR represents solely a quantitative or also qualitative
decline in oocyte and embryo performance (Abdalla and Thum, 2004).
Historically, assessments of ovarian reserve have been divided into
two categories: pretreatment diagnostics and post-treatment review
of response to stimulation. Pretreatment evaluations have been exten-
sively studied and include basal FSH, inhibin B, ovarian volume, antral
follicle count (AFC) and anti-mullerian hormone (AMH) levels (ASRM
Practice Committee, 2012). While each of these tests provides useful
prognostic information, serum AMH has emerged as most widely used
pretreatment diagnostic test due to its consistency within and between
menstrual cycles and its high specificity for prognosticating a PR to
stimulation (Hehenkamp et al., 2006; Dewailly et al., 2014).
Completion of an ovarian stimulation cycle allows for post-
treatment review of ovarian responsiveness. This ‘stress test’ provides
valuable diagnostic information regarding the capacity of ovary to pro-
duce a sufficient number of oocytes and withstand the normal attrition
observed at each developmental level in clinical ART. Indeed, it is well
recognized that a PR to treatment portends a low likelihood of even-
tual success with autologous oocytes. This effect is exacerbated at
more advanced ages (Kyrou et al., 2009).
Despite the extensive literature examining clinical characteristics of
patients with DOR or PR, there is still no consensus regarding whether
their poor outcomes are solely the product of quantitative challenge
presented by starting with fewer oocytes or whether there is an add-
itional qualitative penalty. In other words, does an oocyte retrieved
from a patient with DOR or PR also demonstrate a reduced capacity
aneuploidy?
These questions have been partially addressed in a number of prior
studies. Some investigations have concluded that pretreatment mar-
kers of DOR or post-treatment evidence of PR are associated with
evidence of reduced oocyte quality. Indeed, evidence of DOR/PR has
been associated with a decrease in embryo morphology grades and an
increase in pregnancy loss, aneuploid miscarriages and viable aneuploid
pregnancies (trisomy 13, 18, and 21) in young patients (Nasseri et al.,
1999; van Montfrans et al., 1999; Silberstein et al., 2006; Haadsma
et al. 2010; van der Stroom et al., 2011; Tarasconi et al., 2017).
However, other studies have demonstrated no association between
DOR/PR and the same markers of oocyte quality (Thum et al., 2008;
Thum and Abdalla, 2009; Ebner et al., 2006; Smeenk et al., 2007; Riggs
et al., 2011).
A major limitation of the current literature characterizing the oocyte
quality in the context of DOR/PR is that both depletion of the follicu-
lar pool and a reduction in oocyte quality are physiologic events that
accompany reproductive aging. The available studies do not address
whether a premature depletion of the follicular pool (DOR/PR in
younger patients) is also associated with accelerated reduction in
oocyte quality. In other words, if patients exhibit a quantitative decline
in ovarian reserve earlier than expected, do they also exhibit evidence
of accelerated ovarian aging i.e. a qualitative decline as well (as evi-
denced by poor embryo development, aneuploidy risk and poor preg-
nancy outcomes).
To evaluate that question, we utilized a large retrospective database
of patients <38 years old with pretreatment AMH values and available
oocyte yields and compared markers of embryo quality between
patients with DOR/PR and patients with normal results.
Materials and Methods
All autologous IVF cycles at a single institution (RMANJ, Basking Ridge, NJ,
USA) between 2012 and 2016 were evaluated for inclusion in the analysis.
Young patients with DOR do not have higher aneuploidy rates
This time frame was chosen as all embryos were cultured to blastocyst at
this clinic during the study period. No cleavage stage transfers were per-
formed, regardless of the number of embryos present on Day 3. Thus,
performance through blastulation could be observed of all embryos in the
laboratory. Only the first cycle was included for each patient to eliminate
previous failure bias. Patients with a history of ovarian surgery, chemother-
apy or radiation exposure, fragile X premutation or abnormal karyotype
were excluded from the analysis as our intention was to characterize
patients with idiopathic reduction in ovarian reserve. Cases involving surgi-
cal sperm retrieval or chromosomal translocations were excluded given
their propensity for poor blastocyst formation (Balaban et al., 2001;
Munne et al., 1998). This study was performed under institutional review
board approval.
The stimulation approach was selected by each patient’s primary
physician and was based on ovarian reserve testing (AMH, AFC, day 3
FSH). All cycles included medications with FSH (recombinant or urin-
ary) and LH activity (human menopausal gonadotropin or low-dose
HCG). Starting doses for FSH varied from 150 to 450 IU per physician
discretion. Doses were adjusted according to response to stimulation
(as measured by ultrasounds and estradiol measurements). GnRH
antagonist, agonist long down regulation, and microflare protocols
were employed.
Only patients <38 years old at time oocyte retrieval were included in
the analysis for multiple reasons. First, multiple studies have demonstrated
that the rate of follicular depletion increases substantially when the number
of primordial follicles falls below a critical threshold of 25,000 (Gougeon
et al., 1994). This number is reached at an average age of 37.5 years across
multiple populations (Faddy et al., 1992). As a result, the number of folli-
cles reaching the growth phase in each menstrual cycle decreases substan-
tially from around 45 in women <30 years old to approximately 6 in
women over the age of 38 (Faddy and Gosden, 1995). Thus, a quantitative
decline in ovarian reserve is considered physiologic in women greater than
38 years old, whereas DOR prior to this age reflects a premature
depletion.
Furthermore, large-scale studies of women pursuing preimplantation
genetic testing for aneuploidy (PGT-A) demonstrate that aneuploidy
sharply rises beginning at age 38 (Franasiak et al., 2014). In addition, older
patients have an increased risk of embryo arrest prior to the blastocyst
stage (Dessolle et al., 2009; Thomas et al., 2010). Thus, to attempt to
determine if a quantitative decline in ovarian function was linked to a quali-
tative decline, we sought only to evaluate women with evidence of a pre-
mature or nonphysiologic depletion of the follicular pool (occurring at <38
years) to see if they also exhibited evidence of qualitative decline in oocyte
function.
Precycle assessment ovarian reserve
In order to analyze the pretreatment evaluation of ovarian reserve, all
patients with AMH levels drawn in the 6 months prior to initiating a stimu-
lation cycle were included in the analysis. All AMH measurements were
performed by an outside reference laboratory using Gen II ELISA Kit
(A73818, Beckman Coulter, California, USA). The number of oocytes
retrieved and the number of clinically usable blastocysts (at least a 4CC by
modified Gardner grading) were recorded for each patient (Gardner et al.,
2000). All patients pursuing their first IVF cycle during the study period
were included in this assessment (those planned for PGT-A and those
planned for non-PGT-A cycles). All cycles that were canceled prior to
retrieval were also recorded and compared. Finally, implantation rates
(IRs, number of fetal heart beats per embryo transferred), live birth
rates (LBRs, live births per embryo transfer procedure) and pregnancy
loss rates (pregnancy loss after a positive beta-hCG) embryo transfers
were compared between the groups.
1491
In order to compare aneuploidy rates between the groups, a subgroup
analysis was performed among only patients who underwent PGT-A. In
order to be included in this group, at least one blastocyst must have been
available for biopsy. For aneuploidy screening, diagnostic categories during
the study period were only euploid or aneuploid (there were no segmental
imbalance or mosaic aneuploidy diagnoses made). Finally, IRs, LBRs and
pregnancy loss rates after euploid embryo transfers were compared
between the groups.
Post-cycle diagnosis of PR
In order to assess ovarian reserve based on post-treatment parameters,
the number of oocytes collected for each patient who proceeded to
retrieval was recorded. Again, the number of oocytes retrieved and the
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number of clinically usable blastocysts (at least a 4CC by modified Gardner
grading) were recorded for each patient. Pregnancy outcomes were also
compared. Notably, this group included some patients who were not
included in the precycle analysis as some patients did not have an AMH
drawn in the 6 months prior to stimulation. Again, this assessment included
all patients who completed retrieval (both patients planning PGT-A and
patients not planning PGT-A).
Similarly, in order to compare aneuploidy rates between the groups, a
subgroup analysis was performed among the patients who underwent
PGT-A. The percentage of aneuploid blastocysts for each patient was
recorded and compared. Pregnancy outcomes were also compared.
Definitions of study groups and control
groups
In the precycle analysis, patients with AMH values in bottom 10th percent-
ile were compared to patients in the interquartile range IQR; 25–75th per-
centile). The bottom 10th percentile was selected as the study group as
these patients were most likely to manifest a true quantitative depletion of
ovarian reserve. The IQR was selected as a control group as these patients
were thought to best represent the typical state of physiologic ovarian
reserve among infertility patients in this age-group. The highest quartile
was intentionally not included given evidence that patients with high AMH
levels are at increased risk of poor blastocyst development (likely due to
the enrichment of PCOS patients in this category; Tal et al., 2014; Arce
et al., 2014; Rubio et al., 2010).
Similarly, in the postcycle analysis, patients with total number of oocytes
retrieved in the bottom 10th percentile were compared to patients in the
IQR (25–75th percentile).
Statistical analysis
Patient and cycle characteristics were compared between the <10th per-
centile and IQR for both precycle (AMH) and postcycle (oocyte yield)
assessments. Continuous variables were compared using Student’s t-test
when data were normally distributed and by Mann–Whitney U when the
data were not normally distributed. Chi-squared tests were used to com-
pare proportions.
The primary outcomes were blastulation rate (defined as clinically
usable blastocyst per 2PN), aneuploidy rate (determined by trophecto-
derm biopsy and whole chromosome aneuploidy assessment using a 24-
chromosome qPCR-based platform) (Treff et al., 2012) and LBR per
euploid blastocyst transfer. All patients (including patients utilizing PGT-A
and patients not utilizing PGT-A) were included in the blastulation rate
assessment, while only patients pursing PGT-A were included in the aneu-
ploidy and live birth analyses. IRs and pregnancy loss rates were also
compared.
For both precycle and postcycle analyses, a mixed effects model was
employed to account for the effect of female age and to account for
1492
correlation between oocytes and embryos derived from the same patient.
Using this model, adjusted odds ratios for blastulation, aneuploidy and live
birth were calculated.
A subgroup analysis of patients who met the Bologna Criteria for PR to
ovarian stimulation was also performed. As per the Bologna criteria, at
least two of the following risk factors are required: (i) female age ≥40 years
(or other risk factor for PR, such as genetic causes known to reduce follicle
number), (ii) previous PR (≤3 oocytes) and (iii) abnormal ovarian reserve
testing (AMH < 0.5 or AFC < 5–7). Given that patients over 38 and
patients with genetic risk factors for DOR were excluded, the oocyte yield
in the studied cycle could only be used to qualify patients for the Bologna
criteria (as opposed to a prior history of PR to stimulation). As a result,
patients in this analysis had ≤3 oocytes retrieved and had an AMH of <0.5.
Blastulation rates, aneuploidy rates for PGT-A patients and LBRs per
euploid blastoyst transfer were calculated. The rates of cancellation after
retrieval and prior to transfer were also calculated
Results
Precycle comparison
Of the 3457 patients who met inclusion criteria and had AMH drawn
within 6 months of their first IVF cycle start during the study period,
the threshold for the <10th percentile was ≤0.5 ng/ml. A total of 345
patients had values in this range. The IQR for AMH was 1.1–4.5 ng/ml.
A total of 1758 patients had AMH values in this range. Patients in the
<10th percentile were slightly older and had higher basal FSH levels and
lower AMH levels than patients in the IQR. They also had lower estra-
diol levels on the day of the LH surge and their cycles produced fewer
oocytes and embryos. Patients in the <10th percentile had a lower LBR
per stimulation start, likely due to greater likelihood of cycle cancellation
both prior to oocyte retrieval due to PR and after oocyte retrieval due
to the global arrest of embryos. However, the blastulation rate was no
different between the groups. Furthermore, once a blastocyst was avail-
able for transfer, the LBR was no different between the groups (Table I).
Among the subset of patients utilizing PGT-A, there were similar dif-
ferences in patient characteristics and laboratory cycle outcomes.
However, the aneuploidy rate was not different between the groups.
The LBR, IR and pregnancy loss rate were also not different between
the groups (Table I).
A mixed effects model was performed to control for female age and
to control for correlation between oocytes and embryos from the
same patient cohort. After adjustment, a precycle AMH level in the
<10th percentile did not decrease the odds of an embryo blastulating
when compared to a precycle AMH level in the IQR. Among PGT-A
patients, precycle AMH in the <10th percentile did not increase the
odds of an embryo being aneuploid. Finally, a low AMH also did not
decrease the odds of live birth after euploid embryo transfer. These
data are depicted in Figure 1.
A subset analysis was performed of patients with the highest AMH
levels (75–100th percentile). The blastulation rate, aneuploidy rate
and LBR for these patients were also no different to either the <10th
percentile group or the IQR. Data for these patients are included in
Supplementary Table S1.
Postcycle comparison
Of the 5372 patients who met inclusion criteria and had their first
oocyte retrieval during the study period, the threshold for the <10th
Morin et al.
percentile was ≤5 oocytes retrieved. A total of 535 patients had
oocyte yields in this range. The IQR for yield was 10 to 21 oocytes. A
total of 2675 patients had oocyte yields in this range. Patients with
oocyte yield in the <10th percentile were slightly older and had higher
basal FSH levels and lower AMH levels than patients in the IQR. They
also had lower estradiol levels on the day of LH surge and their cycles
produced fewer oocytes and embryos. The cycles were more likely to
be canceled prior to embryo transfer due to global arrest of embryos.
As a result, the overall LBR per retrieval was lower for patients in the
<10th percentile. However, the overall blastulation rate was equiva-
lent between the two groups. Furthermore, the LBR once a blastocyst
was available for transfer was no different (Table II).
Among the subset of patients utilizing PGT-A, there were similar dif-
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ferences in patient characteristics and laboratory cycle outcomes.
However, the aneuploidy rate was not different between the groups.
The LBR, IR and pregnancy loss rate were also not different between
the groups (Table II).
A mixed effects model was performed to control for female age and
to control for correlation between embryos from the same patient
cohort. The adjusted odds of an embryo blastulating were actually
increased if it is originated from a cycle with oocyte yield in the <10th
percentile compared to the IQR. Among PGT-A patients, embryos
derived from oocytes in the <10th percentile of oocyte yield were at
no increased risk of aneuploidy compared to those in the IQR. Finally,
the odds of live birth was not decreased when the transferred embryo
was originated from a retrieval with <10th percentile for oocyte yield.
These data are depicted in Figure 2.
A subset analysis was performed of patients with the highest oocyte
yields (75th to 100th percentile). The blastulation rate, aneuploidy
rate and LBR for these patients were also no different to either the
<10th percentile group or the IQR. Data for these patients are
included in Supplementary Table SII.
Bologna criteria subanalysis
A total of 45 patients met the Bologna criteria for PR to stimulation.
The blastulation rate for this group was 51.3% (41/80). Of these, a
total of 15 patients utilized PGT-A. The aneuploidy rate per embryo
was 40% (8/20). While underpowered to make a comparison to the
entire group, the blastulation and aneuploidy rates were consistent
with the overall cohort (blastulation rate: 52.0% (17 238/33150);
aneuploidy rate: 31.1% (2333/7511)). The cancellation rate due to
global arrest of embryos was 31.1% (14/45) for patients meeting the
Bologna criteria. This was predictably higher than that for the overall
cohort rate (12.4% (394/3180)).
Discussion
PR to stimulation has long been known to significantly limit the success
of assisted reproduction (Alviggi et al., 2016). Given the attrition seen
at each stage of the IVF process, the quantitative challenge presented
by retrieving fewer oocytes is an obvious factor in the poor pregnancy
rates in patients with DOR/PR. However, a number of studies have
also suggested that patients with evidence of follicular depletion also
exhibit reduced oocyte quality. This conclusion is logically given the
fact that most patients with PR to stimulation are at an age where mar-
kers of oocyte quality are also compromised. However, most studies
Young patients with DOR do not have higher aneuploidy rates 1493

Table I Baseline characteristics and IVF cycle outcomes for patients with AMH levels <10th percentile compared to
patients with AMH values in the 25–75th percentile.

Characteristic <10th percentile 25–75th percentile P-value

(AMH ≤ 0.5 ng/ml) (AMH 1.1–4.5 ng/ml)
.............................................................................................................................................................................................
All patients (including PGT-A and non-PGT-A patients)
n 345 1758
Age (y) 34.3 ± 3.0 33.0 ± 3.3 <0.001a
Duration of infertility (months) 10 ± 3.3 11 ± 3.3 0.67a
Primary diagnosis DOR: 75.1% (259/345) DOR: 26.0% (457/1758) <0.001c
Male factor: 17.3% (60/345) Male factor: 45.0% (791/1758)

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Tubal factor: 4.1% (14/345) Tubal factor: 9.6% (169/1758)
Unexplained: 3.5% (12/345) Unexplained: 19.4% (341/1758)
AFC 6 (4–9) 18 (12–24) <0.001b
Day 3 FSH 10.1 ± 3.5 7.4 ± 2.2 <0.001a
AMH 0.28 (0.016–0.4) 2.3 (1.4–4.7) <0.001b
Stimulation protocol GnRH antagonist: 81.6% (280/345) GnRH antagonist: 85% (1494/1758) 0.14c
Long agonist: 2% (7/345) Long agonist: 5% (88/1758)
Agonist microflare: 16.8% (58/345) Agonist microflare: 10% (176/1758)
Total FSH dose (IU) 3620 (1950–4000) 2180 (1700–2550) <0.001a
Cancellation rate prior to oocyte retrieval 11.3% (39/345) 1.7% (30/1758) <0.001c
(cancellations per stimulation start)
E2 on day of surge 1108 (485–1875) 2086 (1250–2703) <0.001b
No. oocytes retrieved 6 (2–10) 14 (8–19) <0.001b
No. of 2PNs 3 (1–4) 9 (7–11) <0.001b
No. of usable blastocysts 2 (0–3) 4 (1–8) <0.001b
Percentage of cycles with no usable 17% (52/306) 5.3% (92/1728) <0.001c
blastocyst after oocyte retrieval
Blastulation rate (usable blastocyst/2PN) 51.8% (667/1297) 51.2% (9289/18 153) 0.88c
LBR per cycle start 41.2% (142/345) 53.1% (933/1758) <0.001c
LBR per embryo transfer 55.9% (142/254) 57% (933/1636) 0.79c
PGT-A patients only
n 124 782
Age (y) 34.7 ± 2.5 33.4 ± 3.2 <0.001a
Duration of infertility (months) 10 ± 4.2 10 ± 4.1 0.21c
Primary diagnosis DOR: 66.9% (83/124) DOR: 21.0% (164/782) <0.001c
Male factor: 14.5% (18/124) Male factor: 42.1% (329/782)
Tubal factor: 4.0% (5/124) Tubal factor: 7.8% (61/782)
Unexplained: 14.5% (18/124) Unexplained: 29.2% (228/782)
AFC 7 (5–10) 18 (12–25) <0.001b
Day 3 FSH 9.5 ± 3.7 7.3 ±2.2 <0.001a
AMH 0.29 ± 0.12 2.4 (1.3–5.0) <0.001b
Stimulation protocol GnRH Antagonist: 79% (98/124) GnRH Antagonist: 80.6% (100/124) 0.31c
Long agonist: 1.6% (2/124) Long agonist: 4.8% (6/124)
Agonist microflare: 19.4% (24/124) Agonist microflare: 14.6% (18/124)
Total gonadotropin dose (IU) 3520 (2175–4175) 1925 (1200–2650) <0.001a
E2 on day of surge 1250 (439–1933) 2155 (1101–2940) <0.001b
No. oocytes retrieved 6 (2–10) 15 (9–20) <0.001b
No. of 2PNs 4 (1–4) 11 (8–13) <0.001b
No. of usable blastocysts 2 (0–3) 5 (2–8) <0.001b

Continued
1494 Morin et al.

Table I Continued

Characteristic <10th percentile 25–75th percentile P-value

(AMH ≤ 0.5 ng/ml) (AMH 1.1–4.5 ng/ml)
.............................................................................................................................................................................................
Aneuploidy ratef 30% (108/360) 29% (1173/4051) 0.72c
LBR (per euploid embryo transfer) 62.4% (63/101) 66.6% (445/668) 0.47c
g
IR (per euploid embryo transfer) 56.2% (68/121) 62.3% (516/827) 0.22c
i d e
Pregnancy loss rate 21.8% (10 biochemical losses, 12 clinical losses) 16.8% (64 biochemical losses, 48 clinical losses) 0.27c
a
Student’s t-test.
b
Mann–Whitney U test.
c
Chi-squared test.

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d
One pregnancy termination not included.
e
One ectopic pregnancy, three pregnancy terminations not included.
f
Aneuploid diagnosis per analyzed embryo.
g
Number of fetal heart beats per embryo transferred.
h
Pregnancy loss per positive beta-hCG.

Figure 1 Patients with precycle AMH levels <10th percentile have lower oocyte yields than those in the 25–75th percentile. However, on mixed
effects model, a successfully fertilized oocyte derived from a patient with AMH in the <10th percentile has the same odds of forming a quality blasto-
cyst, being euploid and producing a live birth after transfer of an euploid blastocyst.

addressing this issue have failed to account for the confounding impact
of age on factors such as blastulation, aneuploidy and clinical
outcomes.
We sought to separate age-related diminution in oocyte quality by
studying only patients <38 years old. This age was carefully selected
given evidence from multiple studies that (i) average rate of follicular
depletion, (ii) aneuploidy rate and (iii) and embryo arrest rate all
increase significantly after age 38 (Faddy et al., 1992; Franasiak et al.,
2014; Thomas et al., 2010). Thus, if an accelerated deterioration in
aneuploidy, blastulation and pregnancy outcomes occurred in parallel
with DOR/PR in young patients, a unifying mechanism responsible for
both qualitative and quantitative decline would be the likely culprit.
However, if the blastulation, aneuploidy and pregnancy outcomes
remained consistent with age-related controls with normal response,
then the mechanisms governing follicular depletion and quality para-
meters would appear to be divergent.
The data presented here suggest that in patients <38 years old with
either precycle evidence of DOR or PR to stimulation, there is no
associated qualitative decline in oocyte performance. Thus, compared
to normal responders, a fertlised oocyte retrieved from a young
patient with DOR or PR is no less likely to form a quality blastocyst, be
euploid or produce a live birth.
These data contrast with prior observations that concluded that
aneuploid ongoing gestations and aneuploid miscarriages were more
common in poor responders (Haadsma et al., 2010). Furthermore, the
only study to utilize trophectoderm biopsy and 24-chromosome
screening platforms to address this issue at the embryonic level sug-
gested that aneuploidy was increased in blastocysts of patients with
DOR (Katz-Jaffe et al., 2013). However, patients in the DOR arm in
this study were older than patients with normal ovarian reserve para-
meters, thus confounding the aneuploidy results. We also specifically
included blastulation rates in the analysis, given evidence that
Young patients with DOR do not have higher aneuploidy rates 1495

Table II Baseline characteristics and IVF cycle outcomes for patients with oocyte yields in <10th percentile compared to
patients with oocyte yields in the 25–75th percentile

Characteristic <10th percentile (≤5 oocytes retrieved) 25–75th percentile (10–21 oocytes retrieved) P-value
.............................................................................................................................................................................................
All patients (including PGT-A and non-PGT-A patients)
n 535 2675
Age (y) 34.4 ± 2.9 32.9 ± 3.1 <0.001a
Duration of infertility (months) 10 ± 3.1 10 ± 3.0 0.45
Primary diagnosis DOR: 73.9% (395/535) DOR: 22.4% (599/2675) <0.001c
Male factor: 13.3% (71/535) Male factor: 48.0% (1284/2675)
Tubal factor: 3.8% (20/535) Tubal factor: 8.9% (238/2675)
Unexplained: 9.2% (49/535) Unexplained: 20.7% (554/2675)

Downloaded from https://academic.oup.com/humrep/article/33/8/1489/5052154 by guest on 23 August 2023

AFC 7 (4–9) 17 (12–23) <0.001b
Day 3 FSH 9.5 ± 4.5 7.2 ± 2.2 <0.001a
AMH 0.57 (0.016–1.0) 2.43 (1.13–4.6) <0.001b
Stimulation protocol GnRH Antagonist: 80.4% (430/535) GnRH Antagonist: 83% (2220/2675) 0.08c
Long agonist: 2.1% (11/535) Long agonist: 3.4% (90/2675)
Agonist microflare: 17% (91/535) Agonist microflare: 13.6% (365/2675)
Total FSH dose (IU) 3800 (2050–4700) 2450 (1700–3000) <0.001b
E2 on day of surge 970 (470–1470) 2140 (1380–2911) <0.001b
No. oocytes retrieved 4 (2–5) 15 (11–20) <0.001b
No. of 2PNs 2 (1–3) 9 (6–12) <0.001b
No. of usable blastocysts 1 (0–2) 5 (2–7) <0.001b
% of cycles with no usable blast after oocyte 28.7% (154/535) 4.2% (114/2675) <0.001c
retrieval
Blastulation rate (usable blastocyst/2PN) 55.8% (718/1286) 52.4% (13 413/25 592) <0.05c
LBR per cycle start 41.1% (220/535) 53% (1419/2675) <0.001c
LBR per embryo transfer 57.7% (220/381) 55.4% (1419/2561) 0.42c
PGT-A patients only
n 156 1100
Age (y) 34.5 ± 2.7 33.5 ± 2.3 <0.001a
Duration of infertility (months) 10 ± 3.3 11 ± 2.8 0.42
Primary diagnosis DOR: 65.4% (102/156) DOR: 21.4% (235/1100) <0.001c
Male factor: 18.6% (29/156) Male factor: 40.1% (441/1100)
Tubal factor: 2.6% (4/156) Tubal factor: 9.3% (102/1100)
Unexplained: 13.5% (21/156) Unexplained: 29.3% (322/1100)
AFC 7 (4–10) 17 (13–24) <0.001b
Day 3 FSH 9.2 ± 4.2 7.1 ± 2.4 <0.001a
AMH 0.55 (0.016–1.1) 2.4 (1.01–4.7) <0.001b
Stimulation protocol GnRH antagonist: 80.1% (125/156) GnRH antagonist: 82% (902/1100) 0.41c
Long agonist: 3.2% (5/156) Long agonist: 4% (44/1100)
Agonist microflare:16.7% (26/156) Agonist microflare: 14% (154/1100)
Total gonadotropin dose (IU) 3650 (2025–4975) 2275 (1850–3050) <0.001b
E2 on day of surge 947 (251–1369) 2131 (1288–2819) <0.001b
No. oocytes retrieved 4 (2–5) 15 (11–20) <0.001b
No. of 2PNs 3 (1–4) 9 (6–12) <0.001b
No. of usable blastocysts 2 (0–2) 5 (2–7) <0.001b
e
Aneuploidy rate 32.2% (127/394) 28.7% (1739/6053) 0.15c
LBR (per euploid embryo transfer) 75.9% (80/108) 64.3% (627/974) 0.057c
f
IR (per euploid embryo transfer) 70.1% (85/124) 60.0% (714/1199) 0.064c
g d
Pregnancy loss rate 13% (8 biochemical losses, 6 clinical losses) 18% (81 biochemical losses, 94 clinical losses) 0.24c
a
Student’s t-test.
b
Mann–Whitney U test.
c
Chi-squared test.
d
Three ectopic pregnancies, two pregnancy terminations not included.
e
Aneuploid diagnosis per analyzed embryo.
f
Number of fetal heart beats per embryo transferred.
g
Pregnancy loss per positive beta-hCG.
1496
Figure 2 Despite being derived from a cycle with significantly poorer response, an oocyte retrieved from a cycle with an oocyte yield in the <10th
percentile has the same odds of being euploid and producing a live birth after transfer of an euploid embryo, on mixed effects model. The adjusted
odds of forming a high quality blastocyst were higher for a successfully fertilized oocyte retrieved in a PR cycle.
aneuploid embryos are more likely to arrest in extended culture (Vega
et al., 2014). Thus, while ploidy was not measured in the arrested
embryos, equivalent blastulation in both groups is indicative of similar
aneuploidy rates in arrested embryos as well. Including blastulation in
the analysis also addressed nongenetic causes of embryo developmen-
tal competence that may be impacted by mechanisms of ovarian aging.
However, no association was observed as blastulation rate was not
different between the groups.
The equivalent aneuploidy rate in DOR/PR patients to age-related
controls also provides some insight into the biological processes medi-
ating the age-related increase in meiotic errors in the oocyte. Indeed,
there is still disagreement regarding whether segregation errors in
oocytes are a reflection of the size of the remaining follicular pool or a
function of cumulative, temporal exposure to oxidative damage and
other stressors that predispose to aneuploidy (Nagaoka et al., 2012).
Our data do not support the ‘first in, last out’ hypothesis, whereby the
last oocytes ovulated (irrespective of age) have the fewest recombin-
ation events and are thus at higher risk for segregation errors
(Henderson and Edwards, 1968). Instead, the normal age-related
aneuploidy rate and clinical performance of oocytes in these DOR/PR
patients suggest that errors are more a function of time-related dam-
age or deterioration in mechanisms responsible for maintaining cohe-
sion between sister chromatids (such as cohesins) (Liu and Keefe,
2008; Chiang et al., 2011; Jeffreys et al., 2003).
The ultimate test of oocyte and embryo quality is establishment of a
healthy pregnancy that progresses to delivery. While prior studies
have reported an age-independent association between DOR/PR and
decreased IRs (El Toukhy et al., 2002) and increased miscarriage rates
(Levi et al., 2001), we found no such effect. Our observation that an
oocyte retrieved from a DOR patient performs similarly to that from
age-matched controls has important implications for cycle planning.
Many patients bank embryos according to clinic-based projections
regarding how many embryos are needed for a patient’s ideal family
Morin et al.
Downloaded from https://academic.oup.com/humrep/article/33/8/1489/5052154 by guest on 23 August 2023
size. While prior literature has implied that more embryos were
required for each live birth in these patients, our data suggest that
ovarian reserve and response do not impact the anticipated compe-
tence of a given embryo. This is a valuable information for pretreat-
ment counseling.
While these data provide the largest experience comparing
extended culture, aneuploidy screening and pregnancy outcomes
between DOR/PR patients and normal responders, there are limita-
tions given the retrospective nature of the analysis. Some patients in
the PR group may have done better in subsequent stimulations with
different protocols and thus may have no longer met criteria for PR.
Indeed, some of these patients may have been included in the ‘poor
responder’ group but in fact behaved more similarly to their age-
matched controls in subsequent cycles. Furthermore, given the limited
number of growing follicles in DOR/PR patients, retrieval timing in
patients with fewer follicles may have produced better average oocyte
developmental competence per follicle.
It is also important to note that the average duration of infertility in
the patients in this study was less than 12 months (the duration
required to meet the ICMART/WHO definition of infertility) (Zegers-
Hochschild et al., 2009). Thus, it is possible that the favorable blastula-
tion rate, euploidy rate and LBRs described in these patients may be at
least partially reflect the fact that some better prognosis patients were
included in the DOR/PR groups. This is especially important in the
precycle assessment, given evidence that AMH alone is poorly predict-
ive of fecundity (Steiner et al., 2017). However, a subset analysis of
patients with more than 12 months of infertility demonstrated similar
outcomes to the entire population analyzed here, so any confounding
influence of including women with less than 12 months of infertility
appears relatively limited.
Another limitation of this study is the inability to decipher whether
or not patients were on oral contraceptive pills (OCPs) at the time
their AMH level was drawn. We included all patients who had an
Young patients with DOR do not have higher aneuploidy rates
AMH drawn within 6 months of their cycle starts, but we did not have
any information regarding whether or not they were on OCPs at that
time. It is possible that the AMH of some patients in the <10th per-
centile group may have been influenced by suppressive effect of
OCPs. This may also partially explain why some patients in the low
AMH group had more oocytes retrieved than expected. However,
this may also simply reflect the limitations of AMH to prognosticate
stimulation outcomes in all patients. These are only some examples of
potential confounders that may influence our retrospective data.
There are almost certainly others that are present but difficult to con-
trol for in this retrospective study. Prospective studies will be required
to better elucidate the issues addressed here.
Another caveat to mention is the fact that results from the blastula-
tion rate analysis included both PGT-A and non-PGT-A patients. In
contrast, the aneuploidy rate calculation was only able to be per-
formed for patients who pursued PGT-A. As a result, the population
of patients was slightly different for the blastulation and aneuploidy
evaluations. This was carefully considered by the authors, and we
thought that including as many patients as possible in the blastulation
rate analysis was preferable in order to improve external validity to
our data. Had we limited this analysis to only PGT-A patients, it would
have been less clear if these findings were applicable to patients not
pursuing aneuploidy screening. As a result, we thought on balance it
was more valuable to providers to include all relevant patients in the
blastulation analysis than including only one study population and limit
the applicability to other practice preferences.
Finally, age-specific percentiles for AMH or oocyte yield were not
calculated for each age category in the <38-year old range. It is almost
certain that the bottom 10th percentile is different for a patient in her
mid-20s than a patient in her mid-30s. However, maintaining power to
perform comparisons becomes challenging when creating further sub-
categories of patients who already have a relatively rare outcome
(severe DOR in a young patient). Furthermore, the AMH threshold
used for the entire population of patients (0.5 ng/ml) represented the
12th percentile for the oldest category of patients in the group (age
35–37.9 years). Thus, even at this threshold, older patients in the
study group still represented patients with significantly DOR testing
than the vast majority of their age-matched controls. The differences
in percentiles according to age were also accounted for in the mixed
effects model.
Despite these potential limitations, these data provide evidence
from a large cohort that the lower LBR observed in young poor
responders is due to the quantitative challenge of starting with fewer
oocytes and not due to an additional qualitative penalty of poor oocyte
development in the laboratory or after transfer.
Supplementary data
Supplementary data are available at Human Reproduction online.
Authors’ roles
S.J.M., G.P. and E.S. conceived of the study and participated in its
design. C.R.J. and S.A.N. assisted in data collection. S.J.M. and G.P.
performed the statistical analysis. S.J.M. wrote the manuscript. G.P.,
R.T.S and E.S. critically revised the manuscript.
1497
Funding
No specific research funding was used for this study.
Conflict of interest
None.
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