Preimplantation genetic testing for

aneuploidy in patients with partial X

monosomy using their own oocytes:
is this a suitable indication?
Juan Giles, M.D.,a Marcos Meseguer, Ph.D.,a Amparo Mercader, Ph.D.,a Carmen Rubio, Ph.D.,b
Lucia Alegre, Ph.D.,a Carmen Vidal, M.D.,a Martina Trabalon, M.D.,c and Ernesto Bosch, M.D.a
a
IVI-RMA Global Valencia, INCLIVA-Universidad de Valencia, Valencia, Spain; b Igenomix, Valencia, Spain; and c IVI-RMA
Global Murcia, Murcia, Spain

Objective: To describe the outcome of preimplantation genetic testing (PGT-A) using their own oocytes in patients with mosaic Turner
Syndrome (MTS). The impact of the assisted reproduction technique (ART) performed (PGT-A or oocyte donation) and the type of
absence of the X chromosome (total or partial) were considered.
Design: Retrospective observational multicenter study.
Setting: University-affiliated private in vitro fertilization center.
Patient(s): Fifty-six patients with MTS with whom 65 ovarian stimulation cycles for PGT-A (fluorescence in situ hybridization/arrays-
next generation sequencing) were performed. The study included 90 women with MTS and 20 women with pure Turner Syndrome (PTS)
who underwent 140 and 25 oocyte donation (OD) cycles, respectively.
Intervention(s): In vitro fertilization for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) or OD.
Main Outcome Measure (s): Reproductive outcome and feto-maternal outcomes.
Results: The live birth rate (LBR) per embryo transfer in patients with MTS tended to be higher in OD 37.7% (95% confidence interval
[CI]: 29.3–46.1) than that observed for PGT-A 22.5% (95% CI 7.8–38.2), and the cumulative LBR (CLBR), with 77.6% vs. 43.3%,
respectively. Likewise, the LBR per patient was significant when comparing PGT-A vs. OD, with 12.5% (95 CI 3.9–21.1) vs. 51.1%
(40.7–61.4), respectively. While focusing on the X chromosome, partial MTS (PTS), we found significant differences in the CLBR per
embryo transfer, with 77.6% vs. 29.2%, and also in the LBR per patient: 51.1% (40.7–61.4) in MTS vs. 15% (95 CI 0.0–30.1) in PTS.
Conclusion(s): Oocyte donation is the best reproductive option in females with Turner Syndrome with or without mosaicisms. Never-
theless, PGT-A is a valid therapeutic option in patients with MTS using their own oocytes, and OD should not necessarily be directly
recommended. (Fertil SterilÒ 2020;114:346-53. Ó2020 by American Society for Reproductive Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Turner Syndrome, mosaic Turner, preimplantational genetic diagnosis, oocyte donation
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/64307-29449

T
urner Syndrome (TS), character- icism with an abnormal X chromosome synaptic formation failures during
ized by the total or partial absence or a structural abnormality in one of the zygote and oocyte loss. Hence, the se-
of one X chromosome, affects one X chromosomes. vere mismatching of the homologous
in every 2,500–5,000 female births. The degree of gonadal dysgenesis chromosome leads to primary amenor-
Approximately 60% of cases completely depends on the size of the unpaired re- rhoea, unlike the somewhat lacking
lack one of the X chromosomes, whereas gion of the homologous chromosome in synchronization that allows a consider-
the remaining cases have either a mosa- the meiotic prophase, which leads to able number of oocytes to survive,
which facilitates fertility (1).
Received December 5, 2019; revised and accepted April 1, 2020. In line with this, about 30% of
J.G. has nothing to disclose. M.M. has nothing to disclose. A.M. has nothing to disclose. C.R. has
nothing to disclose. L.A. has nothing to dislose. C.V. has nothing to disclose. M.T. has nothing
diagnosed women, most with mosaic
to disclose. E.B. has nothing to disclose. karyotypes, at least present some pu-
Reprint requests: Marcos Meseguer, Ph.D., IVI-RMA Global Valencia, Plaza de la Policía Local, 3, Valen- bertal development, and 2%–5% are
cia 46015, Spain (E-mail: marcos.meseguer@ivirma.com).
estimated to be fertile (2, 3), although
Fertility and Sterility® Vol. 114, No. 2, August 2020 0015-0282/$36.00 they are associated with a high inci-
Copyright ©2020 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2020.04.003
dence of abortions and malformations

346 VOL. 114 NO. 2 / AUGUST 2020


(2, 4, 5). For this reason, women with TS may consider prena-
tal testing, or even in vitro fertilization (IVF) with preimplan-
tation genetic testing (PGT-A) (6).
Oocyte donation (OD) has been used as a therapeutic
alternative to this situation after the first case was described
by Lutjen et al. in 1984 (7). Since then, several articles on
this subject have appeared (4, 8–12) and now it is
considered the first-line treatment for these patients. Preg-
nancy rates after embryo transfer (ET) with donated oocytes
are similar to those observed in other groups of oocyte recip-
ients, whereas other authors have observed lower pregnancy
and implantation rates, probably related to a uterine factor
(13, 14). However, the rates of clinical miscarriages and
biochemical pregnancies are higher in most publications
due to the uterine factor. These pregnancies also carry partic-
ular risks because as many as 5%–50% of women with TS can
have cardiovascular malformation or hypertensive disorders
(15–17). Hence multidisciplinary antenatal screening is
mandatory and is followed closely during pregnancy (18–20).
When there is a high risk of TS mosaics transmitting chro-
mosomal abnormalities to offspring, the PGT-A technique is
another alternative because it allows chromosomally normal
embryos to be selected prior to transfer in IVF and, thus, offers
a better reproductive prognosis (21–23).
However, only one publication can be found about a case
using fluorescence in situ hybridization (FISH) for five chro-
mosomes with the limitation of being unable to study aneu-
ploidies for total chromosomes (24).
The objective of the present study was to analyze differ-
ences in the reproductive outcomes of PGT-A in patients
with mosaic TS (MTS) using their own oocytes and in ovum
donation cycles in patients with mosaic TS (MTS) and patients
with pure TS (PTS). To assess whether PGT-A really is a valid
therapeutic option in MTS or OD, it should be recommended
directly as the treatment of choice. We hope that this informa-
tion will be useful for medical providers to become aware of
the possibilities of therapeutic approaches for women diag-
nosed with the total or partial absence of one X chromosome
to provide patients with proper counselling.
MATERIAL AND METHODS
Study Design
This is a retrospective cohort study conducted from January
2001 to December 2018 that scrutinized more than 120,000
IVF cycles from 14 infertility clinics in Spain to search for
PTS or MTS, confirmed based on karyotype. The Institutional
Review Board and the institution’s Ethics Committee
approved this study.
Before treatment, patients were referred for cardiological
study to minimize the risk of complications during pregnancy.
The current recommendation is to perform cardiac and aortic
imaging, transthoracic echography with color Doppler, and car-
diac magnetic resonance within 2 years before pregnancy, as
well as measuring blood pressure. The exclusion criteria were
systemic or cardiological (18, 19, 25) pathologies, body mass in-
dex (BMI) >30 kg/m2, sperm concentrations <5 x 106/mL, and
uterine alterations diagnosed using ultrasound or hysteroscopy
(polyps, fibroids involving endometrial cavity, or both).
VOL. 114 NO. 2 / AUGUST 2020
Fertility and Sterility®
Ovarian Stimulation, Embryo Culture, and Biopsy
The antagonist and agonist protocols used for ovarian stimu-
lation (OS) have been described elsewhere (26). Ovarian stim-
ulation was carried out with either a GnRH antagonist
protocol using 150–300 IU of recombinant follicle-
stimulating hormone (rFSH) (Gonal-F, Merck-Serono) or
rFSH plus human menopausal gonadotropin (Menopur, Fer-
ring Pharmaceutical) daily according to female age, BMI,
and ovarian reserve assessment (antral follicular count
[AFC] and day 3 FSH and estradiol, and more recently anti-
m€ ullerian hormone and AFC). After a normal basal ultra-
sound, gonadotropins were administered from day 2–3 after
menstruation. Serial transvaginal ultrasound examinations
and serum E2 determination were initiated on day 5 of
controlled ovarian stimulation and repeated every 48 hours
to monitor ovarian response. When a leading follicle reached
R14 mm, a GnRH antagonist (Cetrotide, Merck- Serono; Or-
galutran, MSD) was administered at 0.25 mg/d. Usually, final
oocyte maturation was triggered with a single dose of a GnRH
agonist (0.1 mg of Decapeptyl, Ipsen Pharma) when the mean
diameter of two follicles was R18 mm. In the early years,
triggering was performed with 250 mg of recombinant HCG
(rHCG; Ovitrelle, Merck-Serono, Madrid, Spain). Oocyte
retrieval was scheduled 36 hours later.
The GnRH agonist (0.1 mg/d) was initiated on day 21 of
the previous cycle (long protocol). On day 3 of the menstrual
cycle, rFSH and human menopausal gonadotropin were
administered as explained. After meeting triggering criteria,
ovulation was induced by administering rHCG (250 mg).
Intracytoplasmic sperm injection was performed in all
cases, and fertilization was assessed 17–20 hours after micro-
injection. Embryo cleavage was recorded every 24 hours. Em-
bryos were cultured by two different approaches depending
on the laboratory. In some laboratories, IVF/CCM medium
(1/1) (Vitrolife) was used until day 3, and then embryos
were cultured subsequently in CCM medium until day 5. In
the other laboratories, a global sequential culture system
(LifeGlobal) was used with tri-gas incubators (7% O2 and
5% CO2) (27).
Embryo biopsy was performed on day 3 as follows: em-
bryos were placed in a droplet containing Ca2 ‡/Mg2ç ‡-free
medium (G-PGD, Vitrolife or LifeGlobal), the zona pellucid
was perforated using laser technology (OCTAX), and a single
blastomere was withdrawn from each embryo. Only the em-
bryos with six nucleated blastomeres or more and <25% frag-
mentation were biopsied. For blastomere washing and
handling, 1% polyvinylpyrrolidone was used. Individual blas-
tomeres were placed in 0.2 mL polymerase chain reaction
(PCR) tubes containing 2 mL of phosphate-buffered saline.
After blastomere loading, PCR tubes were frozen immediately
at -20
C and kept in the freezer until they were transported to
the genetic analysis laboratory. The properly developed
euploid embryos were transferred on day 5, and the surplus
euploid blastocysts were vitrified on day 5 or 6 (28).
The study was performed over a long period of time, dur-
ing which procedures and outcomes significantly changed.
Among the main changes were those related to chromosome
screening. Until 2011, FISH tests were performed. From 2012
347
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
onward, only comprehensive genome hybridization-arrays or
next generation sequencing (NGS) have been performed.
Trophectoderm biopsy was performed on day 5 or 6. After
this biopsy, samples were washed in 5 mL of phosphate-
buffered saline 1% polyvinylpyrrolidone buffer (Cell
Signaling Technology) and transferred to a 0.2 mL PCR tube
under sterile conditions. Tubes were stored at -20
C until
further analyses. For arrays comprehensive genome hybridi-
zation, the DNA from a single blastomere (or 4–6 trophecto-
derm cells) was amplified via whole genome amplification.
The amplified DNA was then labelled with different fluores-
cent probes, and combined and hybridized onto a slide
containing specific bacterial artificial chromosome probes
that spanned the length of chromosomes with 1 megabase
coverage (24sure kit, Illumina, Cambridge, UK). Chromosome
loss or gain was revealed by the color of each spot after hy-
bridization. Fluorescence intensity was detected using a laser
scanner and data were processed using the Bluefuse software
(Illumina), which can analyze whole chromosome aneuploidy
and subchromosomal structural imbalances. In NGS, whole
genome amplification with DNA barcoding was performed
with the Ion Reproseq PGS Kit (Thermo Fisher Scientific).
Automated template preparation and chip loading were auto-
mated with Ion Chef. Chips were placed in an S5TM XL
sequencer (Thermo Fisher Scientific). The sequencing data
were processed and sent to the Ion Reporter Software version
5.4 (Thermo Fisher Scientific) for data analysis.
We performed 42 FISH cycles and 23 arrays/NGS. To
discard the genetic test as a potential source of bias and in
an attempt to avoid a stratified test that could fragment
numbers in excess (by drawing uncertain conclusions), we
analysed the relationship between the test and the outcome/
distribution in the patients with TS. The endometrial prepara-
tion protocol for frozen ET has been described elsewhere (29).
Briefly, the subjects received oral estradiol valerate (EV) (Pro-
gynova, 6 mg/d; Schering) starting on day 2/3 of their period.
Approximately 10 days after initiating EV, the serum E2
levels and endometrial thickness were measured. Micronized
vaginal progesterone (P; 800 mg/d, vaginally; Progeffik, Effik
Laboratories) was administered 5 days prior to ET. If preg-
nancy was achieved, administration of EV and P was main-
tained until gestation week 12.
Oocyte Donation
The OS protocol in donors has been described previously (30).
Anonymous donors were matched with their recipients ac-
cording to phenotype and blood groups.
The endometrial preparation protocol for recipients has
been described in this article. For those recipients with pre-
served ovarian function, GnRH antagonist was administered
daily from cycle day 1–3 for 7 days after confirming ovarian
quiescence using ultrasound, or recipients were down-
regulated in the mid-luteal phase with a single dose of
long-acting GnRH agonist (Decapeptyl, 3.75 mg; Ipsen
Pharm, Ferring) (31).
A beta-HCG test was used to test for biochemical preg-
nancies. A vaginal ultrasound was performed to test for clin-
ical pregnancy, and was considered positive when the
348
embryonic sac (or sacs) was visualized using vaginal ultra-
sound. Those pregnancies surpassing gestation week 12
were considered ongoing pregnancies. Miscarriage was
defined as loss of clinical pregnancy before gestation week 13.
Statistical Analysis
The main outcome measurements were the live birth rate
(LBR) and the cumulative live birth rate (CLBR) per cycle.
The secondary outcomes were the clinical and ongoing preg-
nancy rates and obstetrical and neonatal outcomes (birth
weight, gestational age at delivery, etc.). Both the primary
and secondary outcomes were compared according to TS
type (MTS or PTS) and performed treatment (PGT-A or OD).
For comparison purposes, the Chi-square test or the Fisher
exact test was used when proportions were compared, with
the T-test used for quantitative variables. Averages and pro-
portions were calculated also, including 95% confidence in-
tervals (95% CI) using SPSS (v22). The whole existing
database of cases up to 2018 was analyzed. Our intention
was purely descriptive, and we did not perform any sample
size calculation prior to the study.
RESULTS
In all, 56 patients with MTS were recruited, on whom 65
controlled ovarian hyperstimulation cycles for PGT-A
(FISH/CGH-NGS) were performed. This study also included
90 women with MTS and 20 women with PTS who underwent
140 cycles (of them, 16 cases underwent a previous intracyto-
plasmic sperm injection PGT-A cycle) and 25 OD cycles,
respectively (Table 1).
Their mean ages were 38.1 years (range, 37.3–39) in MTS
PGT-A, 38.46 years (range, 37.6–39.3) in OD-MTS, and 34.68
years (range, 32.2–37.1) in PTS-OD (P< .05). No significant
differences appeared in BMI, number of oocytes (retrieved
or donated), or number of transferred embryos (Table 1).
The number of cycles without ET in MTS-PTS was
remarkable (52.3%) (Table 1). The reasons for cancelling ET
were no response or a very low response to OS (13/34;
38.2%) and absence of either chromosomally normal embryos
(18/34; 52.9%) or viable embryos (3/34, 8.8%), which were
comparable between the OD groups (7.8% MTS vs. 4% PTS).
The most frequent cause in these patients was vaginal
bleeding before donation or inadequate endometrial line,
with self-cancelation or poor embryo development in the re-
maining cycles.
In the MTS-PGT-A group, 256 embryos were analyzed, of
which 74 (28.9%) were euploid, 24 (9.4%) were mosaic, and
157 (61.3%) were aneuploid (one embryo with amplification
failure). Three of the 25 (12%) euploid embryos analysed us-
ing FISH were unsuitable for transfer on day 5.
Implantation rate per ET, pregnancy rate per cycle, clin-
ical pregnancy rate, and multiple and miscarriage rates re-
mained statistically comparable (Table 2). The first three
parameters tended to be higher in OD-MTS, whereas the
miscarriage rate presented a noticeably higher rate when us-
ing donated oocytes in PTS. In contrast, pregnancy rate (PR)
per ET, ongoing pregnancy rate (OPR), LBR, and CLBR were
statistically different (P< .05) (Table 2).
VOL. 114 NO. 2 / AUGUST 2020
 Fertility and Sterility®

TABLE 1

Baseline characteristics and in vitro fertilization data.

Characteristic MTS–PGT-A MTS OD TS OD P value
Patients, n 56 90 20
Cycles, n 65 140 25
Age (y) 38.16 (37.3–39.03) 38.46 (37.6– 39.3) 34.68 (32.2–37.1) < .05
BMI (kg/m2) 24.62 (23.43–25.81) 23.65 (22.93–24.36) 23.35 (21.84–24.87) NS
Oocytes MII retrieved, n 9.12 (7.79–10.45) 9.1 (8.2–10.1) 9.28 (8.06–10.50) NS
Cancelation rate (34/65) 11/140 1/25 < .01
95% CI (40.2–64.4) 95% CI (3.4.6–12.2) 95% CI (0.0–11.7)
52.3% 7.8% 4.0%
ET (%) (31/65) 129/140 24/25 < .01
47.7% 92.2% 96%
95% CI (35.6–59.8) 95% CI (87.8–96.7) 95% CI (35.6–59.8)
Blastocyst transfer - 52/129 8/24 NS
40.3% 33.3%
95% CI (31.8–48.7) 95% CI (14.4–52.1)
Embryos transferred, n 1.5 (1.3–1.7) 1.81 (1.7–1.9) 1.68 (1.4–2.0) NS
Embryos frozen, n 14 321 39 -
Note: BMI ¼ body mass index; CI ¼ confidence interval; ET ¼ embryo transfer; IVF ¼ in vitro fertilization; MII ¼ metaphase II; MTS ¼ mosaic Turner Syndrome; NS ¼ not significant; OD ¼ oocyte
donation; PGT-A ¼ preimplantation genetic testing; TS ¼ Turner Syndrome.
Giles. Outcomes of PGT-A in mosaic Turner Syndrome. Fertil Steril 2020.

The LBR per patient in the women with MTS when
comparing PGT-A to OD was significant with 12.5% (95%
CI 3.9–21.1) vs. 51.1% (95% CI 40.7–61.4), respectively. It
was significant also in those who underwent OD cycles
because the LBR per patient was 51.1% (95% CI 40.7–61.4)
in MTS vs. 15% (95% CI 0.0–30.1) in PTS.
Additional tables show the overall OD results, without
comparing between MTS and PTS (Supplemental Tables 1
and 2, available online).
We performed 42 FISH cycles and 23 arrays/NGS. To
discard the genetic test as a potential source of bias, we pro-
vided clinical outcomes separately (Supplemental Table 3,
available online).
When we analyzed the data according to the Assisted
Reproduction Technique (ART) performed, PGT-A or OD, in
the MTS patients, no differences were found, except in the
PR per cycle, with PGT-A 20% (95% CI 10.3–29.7) vs. OD
52.2% and CLPR 43.3% and 77.6%, respectively (Table 3).
The implantation rates per ET were 22.58% (95% CI 8.5–
36.65) in PGT-A and 36.67% (95% CI 31.25–46.09) in OD,
which were not statistically significant, but showed differ-
ences. Pregnancy rates tended to be higher in OD 56.6%
(95% CI 73–129) vs. PGT-A 41.9% (95% CI 24.8–59.0).
Miscarriage rates remained statistically comparable, albeit
higher, when using own oocytes, with OD 21.9 (95% CI
12.4–31.3) vs. PGT-A 30.9% (95% CI 24.8–59). This resulted

TABLE 2

Clinical outcome.
Variable MTS–PGT-A MTS OD TS OD P value
Implantation rate/ET 22.58 % (8.5–36.65) 36.67% (31.25–46.09) 16.67% (3.22–30.12) NS
Pregnancy rate/ET, n 41.9% (13/31) 56.6% (73/129) 29.2% (7/24) < .05
95% CI (24.8–59.0) 95% CI (48.8–65.2) 95% CI (11.4–47.2)
Pregnancy rate/cycle, n 20.0% (13/65) 52.2% (73/140) 28.0% (7/25) NS
95% CI (10.3–29.7) 95% CI (43.9–60.5) 95% CI (10.4–45.6)
Clinical pregnancy rate 29.0% (9/31) 45.7% (64/140) 24.0% (6/25) NS
95% CI (13.0–45.0) 95% CI (37.4–54.0) 95% CI (7.3–40.7)
Ongoing pregnancy rate 29.0% (9/31) 40.7% (57/140) 16% (4/25) < .05
95% CI (13.0–45.0) 95% CI (32.5–48.8) 95% CI (1.7–30.4)
Cumulative pregnancy rate 43.3% 77.6 29.2% < .05
Multiple pregnancy rate (1/13) 14.28% (24/73) 32.8% (2/7) 28.57% NS
95% CI (0.0–33.3) 95% CI (22.0–43.6) 95% CI (0.0–62.0)
Ectopics 0 0 0
Miscarriage rate, 30.9% (4/13) 21.9 (16/73) 42.8% (3/7) NS
95% CI (24.8–59.0) 95% CI (12.4–31.4) 95% CI (6.1–79.5)
Terminations of pregnancy, n (%) 0 0 0 -
Note: CI ¼ confidence interval; ET ¼ embryo transfer; MTS ¼ mosaic Turner Syndrome; NS ¼ not significant; OD ¼ oocyte donation; PGT-A ¼ preimplantation genetic testing; TS ¼ Turner
Syndrome.
Giles. Outcomes of PGT-A in mosaic Turner Syndrome. Fertil Steril 2020.

VOL. 114 NO. 2 / AUGUST 2020 349

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

TABLE 3

Obstetric outcome.
Variable MTS PGT-A MTS OD TS OD P value
Delivery rate 22.5% (7/31) 37.7% (46/129) 12.5% (3/24) < .05
95% CI (7.8–38.2) 95% CI (29.3–46.1) 95% CI (0.0–25.7)
Multiple births, n (1/7) 14.6% (13/46) 28.3% 0 NS
Gestational age 38.8 38.9 39.0 NS
95% CI (37.7–39.7) 95% CI (35.1–42.8) 95% CI (36.6–41.3)
Birth weight, g 3,166 2,946 3,285 NS
95% CI (2,649–3,683) 95% CI (2,548–3,343) 95% CI (2,624–3,945)
Small for gestational age, % (n) 0 8.7% (4/46) 0 < .05
95% CI (0.5–.16.8)
Vaginal delivery, % (n) 57.1% (4/7) 45.7% (21/46) 66.3% (2/3) NS
95% CI (20.4–93.8) 95% CI (31.3–60.1) 95% CI (12.8–100)
Caesarean, % (n) 42.9% (3/7) 54.3% (25/46) 33.3% (1/3) NS
95% CI (6.2–79.6) 95% CI (39.9–68.7) 95% CI (0–86.6)
Cardiovascular complications, % (n) 0 0 0 NS
Note: CI ¼ confidence interval; ET ¼ embryo transfer; MTS ¼ mosaic Turner Syndrome; NS ¼ not significant; OD ¼ oocyte donation; PGT-A ¼ preimplantation genetic testing; TS ¼ Turner Syndrome
Giles. Outcomes of PGT-A in mosaic Turner Syndrome. Fertil Steril 2020.

in LBRs of OD of 37.7% (95% CI 29.3–46.1), which were DISCUSSION

higher than those observed for PGT-A 22.5% (95% CI 7.8–
38.2) (Table 3).
When focusing on the type of X chromosome absence, for
example, partial (MTS) or total (PTS) in the patients who un-
derwent OD, we found significant differences in the implan-
tation rate per ET, PR per ET, OPR, LBR, and CLBR. These
numbers were similar to those shown in previous compari-
sons. The implantation rate per ET of 36.67% (95% CI
31.25–46.09) vs. 16.67 (95% CI 3.22–30.12) and the preg-
nancy rate of 56.6% (95% CI 48.8–65.2) vs. 29.2% (95% CI
11.4–47.2) were significantly higher in OD-MTS than in
PTS-OD. Miscarriage rates remained statistically comparable,
albeit at a noticeably higher rate in PTS, with OD-MTS of
21.9% (95% CI 12.4–31.3) and OD-PTS of 42.8% (95% CI
6.1–79.5). This led to LBRs of OD-MTS of 37.7% (95% CI
29.3–46.1), which were three-fold higher than those observed
for OD-PTS of 12.5% (95% CI 0.0–25.7).
The obstetric and perinatal outcomes are detailed in
Table 3. Only the delivery rates, OD-MTS of 37.7% (95% CI
29.3–46.1), which almost doubled those observed for PGT
A-MTS with 22.5% (95% CI 7.8–38.2) and were three-fold
higher than those for OD-PTS, with 12.5% (95% CI 0.0-
25.7), and small for gestational age, were statistically
different.
The mean gestational age at delivery was 38 weeks, with
(95% CI 38.9–42.8) in OD-MTS, 38 (95% CI 37.7–39.7) in
PGT-A MTS, and 39% (95% CI 36.6–41.3) in OD-PTS.
Caesarean section was performed in 54.3% (95% CI 39.9–
68.7) of OD-MTS deliveries, in 42.9% (95% CI 6.2–79.6) of
PGT-A MTS, and in 33.3% (95% CI 0–86.6) of OD-MTS
women. The mean birth weight was 2,946 g (95% CI 2,548–
3,343) in OD-MTS, 3,166 g (95% CI 2,649–3,683) in PGT-A
MTS, and 3,285 g (95% CI 2,624–3,945) in OD-MT. Neither
malformations during pregnancy or after birth in any new-
borns nor cardiac complications in any pregnant women dur-
ing pregnancy or postpartum were detected.
To the best of our knowledge, this study comprises the
first and largest series published to date on the use of
PGT-A in patients with MTS. It includes the results ob-
tained with 56 women with MTS who underwent PGT-A
with a mean age of 38.16 years. This study lacks a control
group, which would include patients not affected by TS.
As a reference, we considered a group of PGT-A of
advanced maternal age (AMA) women whose results
have been published previously (24).
The degree of oocyte loss was variable and ovarian func-
tion is thought to rely on the percentage of 46 XX (6). The
number of retrieved oocytes metaphase II was similar to
those observed in women with AMA (24) and other TS groups
(32–34), whereas other authors refer to reduced ovarian
reserve (35) in patients lacking the X chromosome.
However, no correlation was found between levels of
markers of ovarian response (antim€ ullerian hormone or
AFC) and the number of retrieved oocytes (33, 34).
The rate of chromosomal defects in spontaneous Turner
pregnancies is higher, but the involved mechanisms are not
elucidated fully, which compromises their reproductive ca-
pacity (36–38). PGT-A improved the likelihood of successful
pregnancy and live births compared with conventional
morphological embryo selection in patients at increased risk
of embryo aneuploidy. However, current knowledge about
the usefulness of PGT-A as a tool to increase the chances of
motherhood in women diagnosed with TS is scarce. In line
with this, 61.3% of the analysed embryos in the patients
with MTS in our study were aneuploid and 9.4% were mosaic.
The number of cycles with transfer (47.7% vs. 68%) and
the implantation (22.5% vs. 52.8%), clinical pregnancy/ET
(29% vs. 54.4%), and delivery (22.5% vs. 52.9%) rates were
lower, whereas the miscarriage rate was higher (30.9% vs.
2.7%) for the MTS group vs. the women with AMA (24). The
previously described compromise in oocyte quality and

350 VOL. 114 NO. 2 / AUGUST 2020


endometrial receptivity (8, 13, 39) could play a role in the
poorer outcomes observed in MTS.
PGT-A could be considered an alternative in those infer-
tile patients with MTS or to reduce the risk of miscarriage or
transmission of total/partial X chromosome absence to
offspring because no significant differences appeared in rela-
tion to OD in terms of PR, CLBR, miscarriage rate, or delivery
rate. Thus, OD seems to be the best reproductive option when
taking into account the CLBR, which was significantly higher,
and the LBR per patient. The OD model highlights the effect of
the uterine factor by observing similar implantation rates, but
also higher miscarriage rates and lower LBR rates compared
with studies about OD in patients without TS (31, 40), and
in other studies that have included patients with and without
TS (8, 10, 13). However, the differences that appeared in most
of them were not significant because of the insufficient power
of their sample size.
Regarding the type of X chromosome absence in the pa-
tients who underwent OD (the data for which are not reflected
in most studies), those lacking an entire X chromosome
showed the worst reproductive and obstetric outcomes (lower
IR/ET, PR/ET, OPR, LBR, CLBR, and LBR per patient) in accor-
dance with Yaron et al. (13). The miscarriage rates, which var-
ied in other series from 17%–60% (10, 11, 13, 41), were 21.9%
in mosaic Turner Syndrome and 42.8% in PTS.
The actual trend for such patients is single ET to avoid
obstetrical complications (2, 11, 35). In this study, we trans-
ferred a mean of 1.5 and 1.7 embryos in the PGT-A MTS pa-
tients and in OD, respectively. The number of transferred
embryos progressively decreased in the last few years of this
study. The increased prevalence of underlying cardiac defects
in patients with TS places their pregnancies at risk, with an
incidence of cardiovascular complications described as being
0–40% of cases (10, 11, 42–44). Thus, in an attempt to lower
the incidence of these complications, careful pregnancy
screening is advisable. Nevertheless, no cardiologic
complications were detected during either pregnancy or the
postpartum for our gestations, and only one patient in the
MTS OD group had undergone previous aortic coarctation
surgery. The mean gestational age at delivery was 38 weeks
in MTS and 39 weeks in PTS because our study failed to
support previous findings that the TS patients were at high
risk of prematurity (10, 41, 45). In relation to this factor, the
mean birth weight was 3,166 g in MTS PGT-A, 2,946 g in
MTS-OD, and 3,285 g in PTS-OD. In this series, 8.7% of new-
borns were small for gestational age, but otherwise healthy,
which is a lower percentage than previously observed by
others (11, 41). Although caesarean section was the most
frequent form of delivery, our series obtained a notably low
rate (10, 11, 41, 45) owing to maternal short stature, which
predisposes them to fetopelvic disproportion. Another factor
to consider that favors caesarean section is the aortopathy
predisposition of some of these patients, which may increase
during pregnancy or labor.
The retrospective nature of this study may be one reason
for caution. Despite being the largest sample size ever re-
ported with PGT-A in MTS, to our knowledge our sample
size is still small. Another aspect to bear in mind is that
most gestational controls and deliveries were not carried
VOL. 114 NO. 2 / AUGUST 2020
Fertility and Sterility®
out in our centers. Subsequently, the reached conclusions
should be taken carefully until a larger body of evidence be-
comes available. To conclude, OD seems to be the best repro-
ductive option in those females lacking one of the X
chromosomes, either with or without mosaicisms. Neverthe-
less, PGT-A is a valid therapeutic option in patients with
MTS using their own oocytes, and OD should not necessarily
be recommended directly as the treatment of choice.
REFERENCES
1. Ogata T, Matsuo N. Turner syndrome and female sex chromosome aberra-
tions: deduction of the principal factors involved in the development of clin-
ical features. Hum Genet 1995;95:607–29.
2. Hovatta O. Pregnancies in women with Turner's syndrome. Ann Med 1999;
31:106–10.
3. Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pu-
bertal development in Turner's syndrome. Italian Study Group for Turner's
Syndrome. J Clin Endocrinol Metab 1997;82:1810–3.
4. Abir R, Fisch B, Nahum R, Orvieto R, Nitke S, Ben Rafael Z. Turner's syndrome
and fertility: current status and possible putative prospects. Hum Reprod Up-
date 2001;7:603–10.
5. Landin-Wilhelmsen K, Bryman I, Hanson C, Hanson L. Spontaneous preg-
nancies in a Turner syndrome woman with Y-chromosome mosaicism. J As-
sisted Reprod Genet 2004;21:229–30.
6. Grynberg M, Bidet M, Benard J, Poulain M, Sonigo C, Cedrin-Durnerin I,
et al. Fertility preservation in Turner syndrome. Fertil Steril 2016;105:13–9.
7. Lutjen P, Trounson A, Leeton J, Findlay J, Wood C, Renou P. The establish-
ment and maintenance of pregnancy using in vitro fertilization and embryo
donation in a patient with primary ovarian failure. Nature 1984;307:174–5.
8. Press F, Shapiro HM, Cowell CA, Oliver GD. Outcome of ovum donation in
Turner's syndrome patients. Fertil Steril 1995;64:995–8.
9. Khastgir G, Abdalla H, Thomas A, Korea L, Latarche L, Studd J. Oocyte dona-
tion in Turner's syndrome: an analysis of the factors affecting the outcome.
Hum Reprod 1997;12:279–85.
10. Foudila T, Soderstrom-Anttila V, Hovatta O. Turner's syndrome and preg-
nancies after oocyte donation. Hum Reprod 1999;14:532–5.
11. Alvaro Mercadal B, Imbert R, Demeestere I, Englert Y, Delbaere A. Pregnancy
outcome after oocyte donation in patients with Turner's syndrome and par-
tial X monosomy. Hum Reprod 2011;26:2061–8.
12. Deligeoroglou E, Stergioti E, Dimopoulos KD, Karountzos V, Prapas Y. Preg-
nancy outcome after oocyte donation in patients with Turner's syndrome:
clinical experience and management. J Obstet Gynaecol 2016;36:504–7.
13. Yaron Y, Ochshorn Y, Amit A, Yovel I, Kogosowki A, Lessing JB. Patients with
Turner's syndrome may have an inherent endometrial abnormality affecting
receptivity in oocyte donation. Fertil Steril 1996;65:1249–52.
14. Rogers PA, Murphy CR, Leeton J, Hoise MJ, Beaton L. Turner's syndrome pa-
tients lack tight junctions between uterine epithelial cells. Hum Reprod
1992;7:883–5.
15. Hagman A, Loft A, Wennerholm UB, Pinborg A, Bergh C, Aittomaki K, et al.
Obstetric and neonatal outcome after oocyte donation in 106 women with
Turner syndrome: a Nordic cohort study. Hum Reprod 2013;28:1598–609.
16. Chalas Boissonnas C, Davy C, Marszalek A, Duranteau L, de Ziegler D,
Wolf JP, et al. Cardiovascular findings in women suffering from Turner syn-
drome requesting oocyte donation. Hum Reprod 2011;26:2754–62.
17. Georgopoulos NA, Adonakis G, Papadopoulos V, Vagenakis GA, Tsoukas A,
Decavalas G. Feto-maternal risks associated with pregnancy achieved
through oocyte donation in a woman with Turner syndrome. Gynecol Endo-
crinol 2009;25:383–6.
18. Donadille B, Bernard V, Christin-Maitre S. How can we make pregnancy safe
for women with Turner syndrome? Am J Med Genet 2019;181:100–7.
19. Cabanes L, Chalas C, Christin-Maitre S, Donadille B, Felten ML, Gaxotte V,
et al. Turner syndrome and pregnancy: clinical practice. Recommendations
for the management of patients with Turner syndrome before and during
pregnancy. Eur J Obstet Gynecol Reprod Biol 2010;152:18–24.
351
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
20. Practice Committee of American Society for Reproductive Medicine.
Increased maternal cardiovascular mortality associated with pregnancy in
women with Turner syndrome. Fertil Steril 2012;97:282–4.
21. Gianaroli L, Magli MC, Ferraretti AP, Munne S. Preimplantation diagnosis for
aneuploidies in patients undergoing in vitro fertilization with a poor prog-
nosis: identification of the categories for which it should be proposed. Fertil
Steril 1999;72:837–44.
22. Kahraman S, Bahce M, Samli H, Imirzalioglu N, Yakisn K, Cengiz G, et al.
Healthy births and ongoing pregnancies obtained by preimplantation ge-
netic diagnosis in patients with advanced maternal age and recurrent im-
plantation failure. Hum Reprod 2000;15:2003–7.
23. De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing
repeated pregnancy losses. Hum Reprod 1990;5:519–28.
24. Onalan G, Yilmaz Z, Durak T, Sahin FI, Zeyneloglu HB. Successful pregnancy
with preimplantation genetic diagnosis in a woman with mosaic Turner syn-
drome. Fertil Steril 2011;95:1788.e1–3.
25. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME,
Klein KO, et al. Clinical practice guidelines for the care of girls and women
with Turner syndrome: proceedings from the 2016 Cincinnati International
Turner Syndrome Meeting. Eur J Endocrinol 2017;177:G1–70.
26. Rubio C, Bellver J, Rodrigo L, Castillon G, Guillen A, Vidal C, et al. In vitro
fertilization with preimplantation genetic diagnosis for aneuploidies in
advanced maternal age: a randomized, controlled study. Fertil Steril 2017;
107:1122–9.
27. Mercader A, Valbuena D, Simon C. Human embryo culture. Methods Enzy-
mol 2006;420:3–18.
28. Mir P, Rodrigo L, Mercader A, Buendia P, Mateu E, Milan-Sanchez M, et al.
False positive rate of an arrayCGH platform for single-cell preimplantation
genetic screening and subsequent clinical application on day-3. J Assisted
Reprod Genet 2013;30:143–9.
29. Soares SR, Troncoso C, Bosch E, Serra V, Simon C, Remohi J, et al. Age and
uterine receptiveness: predicting the outcome of oocyte donation cycles. J
Clin Endocrinol Metab 2005;90:4399–404.
30. Cobo A, Meseguer M, Remohi J, Pellicer A. Use of cryo-banked oocytes in an
ovum donation programme: a prospective, randomized, controlled, clinical
trial. Hum Reprod 2010;25:2239–46.
31. Vidal C, Giles J, Garrido N, Remohi J, Simon C, Bellver J, et al. GnRH antag-
onist for endometrial priming in an oocyte donation programme: a prospec-
tive, randomized controlled trial. Reprod Biomed Online 2018;37:415–24.
32. Mamsen LS, Charkiewicz K, Anderson RA, Telfer EE, McLaughlin M,
Kelsey TW, et al. Characterization of follicles in girls and young women
352
with Turner syndrome who underwent ovarian tissue cryopreservation. Fertil
Steril 2019;111:1217–25.e3.
33. Talaulikar VS, Conway GS, Pimblett A, Davies MC. Outcome of ovarian stim-
ulation for oocyte cryopreservation in women with Turner syndrome. Fertil
Steril 2019;111:505–9.
34. Oktay K, Bedoschi G. Oocyte cryopreservation for fertility preservation in
postpubertal female children at risk for premature ovarian failure due to
accelerated follicle loss in Turner syndrome or cancer treatments. J Pediatr
Adolescent Gynecol 2014;27:342–6.
35. Karnis MF. Fertility, pregnancy, and medical management of Turner syn-
drome in the reproductive years. Fertil Steril 2012;98:787–91.
36. Hadnott TN, Gould HN, Gharib AM, Bondy CA. Outcomes of spontaneous
and assisted pregnancies in Turner syndrome: the U.S. National Institutes
of Health experience. Fertil Steril 2011;95:2251–6.
37. Bernard V, Donadille B, Zenaty D, Courtillot C, Salenave S, Brac de la
Perriere A, et al. Spontaneous fertility and pregnancy outcomes amongst
480 women with Turner syndrome. Hum Reprod 2016;31:782–8.
38. Tarani L, Lampariello S, Raguso G, Colloridi F, Pucarelli I, Pasquino AM, et al.
Pregnancy in patients with Turner's syndrome: six new cases and review of
literature. Gynecol Endocrinol 1998;12:83–7.
39. Holl RW, Kunze D, Etzrodt H, Teller W, Heinze E. Turner syndrome: final
height, glucose tolerance, bone density and psychosocial status in 25 adult
patients. Eur Jo Pediatr 1994;153:11–6.
40. Budak E, Garrido N, Soares SR, Melo MA, Meseguer M, Pellicer A, et al. Im-
provements achieved in an oocyte donation program over a 10-year period:
sequential increase in implantation and pregnancy rates and decrease in
high-order multiple pregnancies. Fertil Steril 2007;88:342–9.
41. Bodri D, Vernaeve V, Figueras F, Vidal R, Guillen JJ, Coll O. Oocyte donation
in patients with Turner's syndrome: a successful technique but with an
accompanying high risk of hypertensive disorders during pregnancy. Hum
Reprod 2006;21:829–32.
42. Lippe B. Turner syndrome. Endocrinol Metab Clin North Am 1991;20:121–
52.
43. Nagel TC, Tesch LG. ART and high risk patients! Fertil Steril 1997;68:748–9.
44. Birdsall M, Kennedy S. The risk of aortic dissection in women with Turner
syndrome. Hum Reprod 1996;11:1587.
45. Chevalier N, Letur H, Lelannou D, Ohl J, Cornet D, Chalas-Boissonnas C,
et al. Materno-fetal cardiovascular complications in Turner syndrome after
oocyte donation: insufficient prepregnancy screening and pregnancy
follow-up are associated with poor outcome. J Clin Endocrinol Metab
2011;96:E260–7.
VOL. 114 NO. 2 / AUGUST 2020
 Fertility and Sterility®

Diagnostico genetico preimplantacional de aneuploidías en pacientes con monosomía parcial en el cromosoma X a partir de sus propios
ovocitos: ¿Es esta una indicacion adecuada?
Objetivo: Describir el resultado de las pruebas geneticas previas a la implantaci
on (PGT-A) utilizando ovocitos propios en pacientes con
el síndrome de Turner en mosaico (MTS). Se consideraron el impacto de la tecnica de reproducci on asistida (ART) realizada (PGT-A o
donacion de ovocitos) y el tipo de ausencia del cromosoma X (total o parcial).
~o: Estudio observacional retrospectivo multicentrico.
Disen
on in vitro privado afiliado a la universidad.
Lugar: Centro de fertilizaci
Paciente (s): Cincuenta y seis pacientes con MTS se realizaron 65 ciclos de estimulaci
on ovarica para PGT-A (FISH / arrays-NGS). El
estudio incluyo a 90 mujeres con MTS y 20 mujeres con síndrome de Turner puro (PTS) que se sometieron a 140 y 25 ciclos de donaci
on
de ovocitos (OD), respectivamente.
Intervencion (es): Fecundaci
on in vitro para PGT-A (FISH / arrays-NGS) o OD.
Principales medidas de resultado: Resultados reproductivos y feto-maternos.
Resultados: La tasa de nacidos vivos (LBR) por transferencia embrionaria en pacientes con MTS tendio a ser mayor en OD 37.7% (in-
tervalo de confianza del 95% [IC]: 29.3–46.1) que la observada para PGT-A 22.5% (IC 95% 7.8-38.2), y la LBR acumulativa (CLBR), con
77.6% vs. 43.3%, respectivamente. Del mismo modo, la LBR por paciente fue significativa al comparar PGT-A versus OD, con 12.5% (95
IC 3.9-21-1) vs. 51.1% (40.7–61.4), respectivamente. Al centrarnos en el cromosoma X, MTS parcial (PTS), encontramos diferencias
significativas en la CLBR por transferencia embrionaria, con 77.6% vs. 29.2%, y tambien en la LBR por paciente: 51.1% (40.7–61.4)
en MTS vs. 15% (95 IC 0.0–30.1) en PTS.
Conclusion (es): La donacion de ovocitos es la mejor opci on reproductiva en mujeres con síndrome de Turner con o sin mosaicismos.
Sin embargo, la PGT-A es una opci on terapeutica valida en pacientes con MTS que usan sus propios ovocitos, y la OD no debe ser nec-
esariamente recomendada directamente.

VOL. 114 NO. 2 / AUGUST 2020 353