Obstetrical, neonatal, and long-term

outcomes of children conceived from

in vitro matured oocytes
Eun Jeong Yu, M.D.,a Tae Ki Yoon, M.D., Ph.D.,a Woo Sik Lee, M.D., Ph.D.,b Eun A. Park, M.S.,a
Jin Young Heo, M.D.,a Ye Kyu Ko, M.D.,a and Jayeon Kim, M.D., M.P.H.a
a
Department of Obstetrics and Gynecology, CHA Seoul Fertility Center; and b Department of Obstetrics and Gynecology,
Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea

Objective: To investigate the obstetrical, neonatal, and long-term outcomes of in vitro maturation (IVM) compared with conventional
in vitro fertilization (IVF) in women with polycystic ovarian syndrome (PCOS).
Design: Matched retrospective case-control study.
Setting: University fertility clinic.
Patient(s): One hundred eighty-four patients undergoing IVM were compared with 366 patients undergoing conventional IVF. All had
PCOS and were matched for patient age, gestational age at birth, and the number of fetuses.
Intervention(s): None.
Main Outcome Measure(s): Obstetrics, neonatal outcomes, and childhood medical problems and development.
Result(s): Women's mean age at oocytes retrieval was 32.6
2.9 years. Children's mean age was 7.5
2.3 years. There were no dif-
ferences in the frequency of obstetrical and neonatal outcomes between the two groups. No difference was found in birth weights be-
tween the two groups. The incidence of congenital anomalies was similar between the groups (4.3% in IVM group vs. 4.1% in IVF group).
No significant difference was observed between the two groups in the frequency and duration of hospitalization during childhood.
Growth developmental status of both groups was within normal range.
Conclusion(s): In a matched setting between IVM and IVF babies born from women with PCOS, no significant increased risk associated
with IVM was been identified after a mean follow-up of 7.5 years. (Fertil SterilÒ 2019;112:691–9. Ó2019 by American Society for
Reproductive Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Oocyte, in vitro maturation, in vitro fertilization, safety, long-term
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
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M
ore than 8 million babies problems in the offspring (2). Although (3, 4). IVF pregnancies have also
have been born with the use most children conceived by in vitro been associated with detrimental
of assisted reproductive tech- fertilization (IVF) are healthy, it has neonatal outcomes, such as congenital
nologies (ART) since the birth of Louise been reported that IVF is associated anomalies, imprinting disorders, and
Brown in 1978 (1). Despite the benefits with an increased risk of adverse obstet- neurodevelopmental disorders (5–7).
of ART, the safety of the procedures rical and neonatal outcomes, including However, these adverse obstetrical
has been questioned, particularly hypertensive disorders of pregnancy, risks and congenital malformations
regarding their potential to cause health preterm labor, and low birth weight observed in IVF births are more likely
to be attributed to the additional age
Received February 28, 2019; revised May 23, 2019; accepted May 28, 2019; published online July 29,
of patients undergoing IVF (8), parity-
2019. related risk (9), infertility or subfertility
E.J.Y. has nothing to disclose. T.K.Y. has nothing to disclose. W.S.L. has nothing to disclose. E.A.P. has itself (3), or higher-order pregnancies
nothing to disclose. J.Y.H. has nothing to disclose. Y.K.K. has nothing to disclose. Y.K. has nothing
to disclose. derived from the transfer of multiple
Supported in part by grant from the South Korea Health Industry Development Institute (HI18C1837 embryos (10).
for J.K.) funded by the Korean government.
Reprint requests: Jayeon Kim, M.D., M.P.H., Department of Obstetrics and Gynecology, CHA Seoul Immature oocyte retrieval and
Fertility Center, CHA University, 416, Hangang-daero, Jung-gu, Seoul, Republic of Korea subsequent in vitro maturation (IVM)
(E-mail: jayeon_kim@chamc.co.kr).
of the oocyte without ovarian stimula-
Fertility and Sterility® Vol. 112, No. 4, October 2019 0015-0282/$36.00 tion is a relatively new technology in
Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. the realm of ART. IVM has been
https://doi.org/10.1016/j.fertnstert.2019.05.034

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION
proposed as a useful alternative to conventional IVF for elim-
inating the risk of the ovarian hyperstimulation syndrome in
women with polycystic ovarian syndrome (PCOS) or PCOS-
like ovaries (11, 12). Moreover, the procedure is more cost-
effective than IVF because it does not involve expensive
gonadotropin injections (13, 14). Since Cha et al. reported
the first pregnancy resulting from IVM of unstimulated
ovaries (15), many pregnancies have been reported (16).
Despite these technologic advances, data on the safety of
IVM exist only for the short-term outcome of infants (17–
21), so there are still controversy surrounding the safety of
IVM. Previous small observational studies report that
obstetrical outcomes and health of IVM-conceived children
are similar to those for conventional IVF–conceived children
(22, 23). A recent study suggests that birth weight and height
of babies born after IVM are significantly higher than those
for babies born from conventional IVF (24). In addition, a
higher rate of chromosomal abnormalities was found in
embryos fertilized after IVM (25), with a higher rate of
abnormalities linked to a longer period of maturation
in vitro (26). Previous literature on bovine models report
that oocytes retrieved from less developed follicles have less
abundant levels of mitochondrial RNA transcripts compared
with oocytes from later phases of follicular development,
which correlates well with quality of embryonic
development (27, 28). Animal studies suggest that
deregulation of imprinted genes controlling fetal and
placental growth might be caused by inappropriate culture
conditions during oocyte maturation (29). A recent update
of a Cochrane review comparing IVM to conventional IVF
(30) reveals that the potential efficacy and safety of IVM
has not yet been confirmed. So far, there are no long-term
safety data available on the growth and development of
IVM-conceived children.
The present report is a long-term follow-up of our previ-
ous study regarding the safety of IVM (18, 19). The objective
of the present study was to investigate the obstetrical,
neonatal, and long-term outcome of IVM treatment. The out-
comes of IVM pregnancies were compared with those of
matched control IVF pregnancies to fulfill this objective.
MATERIALS AND METHODS
Study Population
This matched retrospective case-control study included 447
women. Only women who had been diagnosed with PCOS
and gave birth after fresh embryo transfer in a cycle of oocyte
retrieval from January 1999 to December 2015 were included.
The diagnosis of PCOS was made if two out of three of
following criteria were met, based on the Rotterdam criteria:
oligo- or anovulation, clinical or biochemical signs of hyper-
androgenism, and polycystic ovaries (31). After the diagnosis
of PCOS, all women were given thorough information about
the pros and cons of IVM and IVF. Patients who opted for
IVM selectively pursued IVM and others underwent IVF.
Pregnancies following IVM served as the study group (IVM
group) and those following IVF with intracytoplasmic sperm
injection (ICSI) served as a control group (IVF group). Control
subjects were matched to the study subjects age, gestational
692
age at birth, and number of fetuses. Pregnancies using preim-
plantation genetic tests, testicular sperm extraction, or donor
gametes were excluded. This study was approved by the Insti-
tutional Review Board of CHA Medical Center, CHA Univer-
sity, Seoul, Korea (GCI-18-19).
IVM Group
Patients underwent a baseline ultrasound scan on day 2 or 3
either of a natural menstrual cycle or after withdrawal
bleeding induced by progesterone treatment, to determine
the number and size of antral follicles and endometrial thick-
ness. The same evaluation was repeated on day 7 or 8. When
endometrial thickness was >7 mm, patients received 250 or
500 mg of recombinant hCG (Ovidrel; Serono). The cycle
was cancelled if the patient had a dominant follicle
(R14 mm in diameter) on the day of hCG administration.
Oocyte cumulus complexes were retrieved 34–36 hours after
hCG administration by means of transvaginal ultrasound-
guided aspiration.
The retrieved immature oocytes were washed in oocyte
washing medium (Sage; Cooper Surgical) and then transferred
into IVM medium (G2 Medium; Vitrolife) supplemented with
20% human follicular fluid, 75 mIU/mL recombinant FSH, 0.5
IU/mL hCG, 1 mg/mL E2, and 10 mg/mL melatonin for matu-
ration. All IVM procedures were performed at 37 C in a hu-
midified 5% CO2 atmosphere. After the oocytes were
cultured for 24–48 hours, they were denuded with hyaluron-
idase solution (ICSI Cumulase; Origio). The maturity of the oo-
cytes was microscopically determined by the presence of the
first polar body. Mature oocytes were inseminated by means
of ICSI to initiate fertilization and embryonic development.
At 66–70 hours after ICSI, two or three embryos were selected
and transferred into the patient's uterus.
For endometrial preparation, patients received 6 mg/
d oral E2 valerate (Progynova; Bayer-Schering Pharma) start-
ing on the day of oocyte retrieval. Luteal support was pro-
vided by 200 mg intravaginal P (Utrogestan; Piette) three
times daily or 50 mg P daily intramuscularly (Progesterone;
Watson Pharmaceuticals) starting on the day of ICSI and
continued, along with E2 valerate, until the 8th or 9th weeks
of gestation, if pregnant.
IVF Group
In general, ovarian stimulation was initiated on day 2 or 3
with an individualized dose of gonadotropin based on the
woman's age, result of ovarian reserve test, and previous
ovarian response to gonadotropins during stimulated cycles.
Following the conventional GnRH antagonist protocol,
0.25 mg cetrorelix acetate (Cetrotide; Serono, Baxter
Oncology) was first administered when the lead follicle
reached R14 mm in diameter and continued until the day
of hCG injection. When at least two or three follicles reached
18 mm in diameter, 250 or 500 mg recombinant hCG was
administered for ovulation triggering. Endometrial thickness
was also evaluated during ovarian stimulation. Oocyte
retrieval was performed by means of transvaginal
ultrasound-guided aspiration at 34–36 hours after
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 Fertility and Sterility®

administration of hCG. Fertilization was performed by means
of ICSI and verified by the presence of two pronuclei after 16–
18 hours. Starting on the day of oocyte retrieval, 600 mg/
d transvaginal progesterone (Utrogestan; Piette) or 50 mg/
d intramuscular progesterone (Progesterone; Watson Phar-
maceuticals) for luteal phase support was administered until
either a negative pregnancy test or approximately the 8th or
9th week of intrauterine gestation.
Survey Development and Distribution
Questions were compiled based on clinical experience of the
specialized reproductive endocrinologists and previous
studies reporting obstetrical and neonatal outcomes and
childhood development (32, 33). The questions were divided
into several categories, including maternal characteristics
(e.g., age, medical and social history before pregnancy),
pregnancy complications (e.g., gestational diabetes,
hypertension, placenta previa, placental abruption, vaginal
bleeding, poly- or oligohydramnios, infectious diseases,
short cervical length, premature rupture of membranes,
hospitalization), pregnancy outcomes (e.g., gestational
duration, birth weight, method of delivery), neonatal
problems, and childhood health/developmental status (e.g.,
congenital malformations, incidence of childhood diseases,
diagnosis of pulmonary, cardiac, liver and kidney
dysfunction, physical disabilities; Supplemental Table 1,
available online at www.fertstert.org). Two physicians
reviewed the questions for content and clarity. Three
physicians who specialized in reproductive endocrinology
administered telephone interviews with the use of the survey.
Data Collection
Patients' demographic and medical information, including
the IVM or IVF laboratory and clinical outcomes, was ex-
tracted from their medical charts.
Statistics
Data were analyzed with the use of SPSS 25.0 (IBM) and an
Excel spreadsheet (Microsoft). Statistical analysis was per-
formed with the use of the Student t test for continuous vari-
ables and the chi-square test or Fisher exact test for categoric
variables. A P value of < .05 was considered to be statistically
significant.
RESULTS
The study included a total of eligible 511 women. Among
those, 455 were successfully contacted and 447 women
completed the telephone survey (response rate 87.4%).
Finally, the analysis included a total of 550 children (345

TABLE 1

Characteristics of women who conceived after IVM or IVF treatments (n [ 550).

Singleton pregnancy (n [ 345) Multiple pregnancy (n [ 205)
IVM group IVF group IVM group IVF group
Characteristic (n [ 115) (n [ 230) (n [ 69; 34 sets) (n [ 136; 68 sets)
Age at IVM or IVF treatment (y) 32.6
3.0 33.0
2.9 31.1
2.7 31.8
2.2
AMH (ng/mL) 10.7
2.3 11.0
3.3 11.4
5.6 11.8
9.4
Antral follicle count 20.8
4.7 21.2
1.5 21.4
7.3 21.5
8.8
Maturation rate (%) 62.4
8.7 68.5
3.8 62.9
5.7 69.1
7.3
Fertilization rate (%) 85.5
2.5 91.2
2.8 86.3
4.1 92.3
3.9
No. of embryos transferred 2.2
0.6 2.5
0.3 2.4
0.9 2.9
0.5
No. of oocytes retrieved 17.2
10.0 19.5
9.2 17.9
7.9 20.6
8.9
Stage of embryo(s) at transfer
Cleavage 88 (76.5%) 176 (76.5%) 23 (67.6%) 46 (67.6%)
Blastocyst 27 (23.5%) 54 (23.5%) 11 (32.4%) 22 (32.4%)
Before pregnancy
Smoking 0 0 0 0
Alcohol 0 0 0 0
Preexisting hypertension 1 (0.9%) 0 0 0
Diabetes mellitus 2 (1.7%) 0 0 0
During pregnancy
Smoking 0 0 0 0
Alcohol 0 0 0 0
Gestational diabetes 3 (2.6%) 5 (2.1%) 0 1 (1.5%)
IUGR 0 0 0 0
Preeclampsia 3 (2.6%) 1 (0.4%) 2 (5.9%) 2 (2.9%)
Placental abruption 0 0 0 0
Polyhydramnios 1 (0.9%) 2 (0.9) 0 0
Oligohydramnios 1 (0.9%) 0 0 0
IIOC 3 (2.6%) 1 (0.4%) 4 (11.8%) 2 (2.9%)
2nd- or 3rd-trimester bleeding 0 1 (0.4) 0 0
PROM 3 (2.6%) 7 (3.0%) 3 (8.8%) 2 (2.9%)
Note: Values are presented as mean
standard deviation or n (%). AMH ¼ antim€
ullerian hormone; IIOC ¼ incompetent internal os of cervix; IUGR ¼ intrauterine growth restriction; IVF ¼ in vitro
fertilization; IVM ¼ in vitro maturation; PROM ¼ premature rupture of membranes.
Yu. Long-term outcomes of IVM children. Fertil Steril 2019.

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION
FIGURE 1
Age distribution of the singletone children born from in vitro maturation (IVM) versus conventional in vitro fertilization (IVF) procedures.
Yu. Long-term outcomes of IVM children. Fertil Steril 2019.
singletons, 101 sets of twins, and 1 set of triplets) born from
447 pregnancies. The IVM group included 184 children (115
singletons, 33 sets of twins, and 1 set of triplets) and the
IVF group included 366 children (230 singletons and 68 sets
of twins).
The characteristics of mothers at the time of IVF or IVM
procedures are summarized in Table 1. Mean maternal age
was 32.6
2.9 years. There were no significant differences
in antim€ ullerian hormone, antral follicle count, maturation
rate, and fertilization rate between IVM and IVF groups.
The mean number of oocytes retrieved and embryos trans-
ferred were similar between the two groups. In both groups,
most embryos were transferred at cleavage stage (71.5%). In
both singleton and multiple pregnancies, no differences
between IVF and IVM groups were noted in the incidence
of obstetrical complications, such as preeclampsia, gesta-
tional diabetes, placenta abruption, and preterm rupture of
membranes.
The children's age distribution is presented in Figure 1.
The characteristics of children are summarized in Table 2.
Children's mean current age was 7.5
2.3 years. The rate
of cesarean section was similar in both groups. Neonatal char-
acteristics, such as malpresentation or fetal death, did not
significantly differ between groups. In singleton and multiple
pregnancies, mean birth weights were 3,283.7
419.7 g and
2,392.3
451.6 g, respectively. Birth weights were not signif-
icantly different between IVF and IVM groups in both
singleton (P¼ .51) and multiple pregnancies (P¼ .74). Growth
parameters (current height and weight) of children were
694
similar between the two groups at the time of the survey
and were appropriate for their age according to the Korean
reference growth charts from the general population in
2017 (33). In singleton births, 5.2% (6/115) and 4.3% (10/
230) of children weighed above the 95th percentile for their
age (P¼ .73) and 0.8% (1/115) and 0.8% (2/230) below the
5th percentile (P¼ .92) in the IVM and IVF groups, respec-
tively. After excluding prematurely born children from the
analyses, the IVM children tended to be taller and heavier
than IVF children, but the differences failed to reach statistical
significance (117.5
14.5 cm and 23.2
8.1 kg vs. 116.3

13.7 cm and 22.2
7.3 kg, respectively, in singleton pregnan-
cies [P¼ .46]; 117.4
15.6 cm and 24.3
8.3 kg vs. 114.9

13.5 cm and 22.1
7.1 kg, respectively, in multiple pregnan-
cies [P¼ .31]). We found no significant difference in the sex
distribution of the babies between the two groups (P¼ .54).
The incidence of congenital malformations was similar
between the IVM and IVF groups (4.3% vs. 4.1% in IVM
and IVF groups, respectively; P¼ .65). In the IVM group, eight
children (4.3%) had congenital anomalies (hypospadias,
congenital hearing loss, patent ductus arteriosus [PDA], ven-
tricular septal defect [VSD], congenital megacolon, imperfo-
rate anus). Similarly, 15 children (4.1%) in the IVF group
had congenital anomalies (PDA, VSD, congenital giant pig-
mented nevus, strabismus, atrial septum defect). No chromo-
somal defects were found in either group. Neonatal mortality
was also similar in both groups (P¼ .14).
The characteristics of hospitalization after birth in both
groups are presented in Table 3. The most frequent neonatal
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TABLE 2

Characteristics of children born from IVM or IVF procedures.

Singleton pregnancy (n [ 345) Multiple pregnancy (n [ 205)
IVM group IVF group IVM group IVF group
Characteristic (n [ 115) (n [ 230) P value (n [ 69; 34 sets) (n [ 136; 68 sets) P value
Delivery
Postpartum bleedinga 7 (6.1%) 5 (2.2%) .11 1 (2.9%) 3 (4.4%) .72
Delivery mode
Vaginal delivery 69 (60%) 147 (63.9%) .48 3 (8.8%) 7 (10.3%) .56
Cesarean section 46 (40%) 83 (36.1%) 31 (91.2%) 61 (89.7%)
Malpresentation 11 (9.6%) 12 (5.2%) .17 5 (14.7%) 3 (4.4%) .11
Fetal death 0 0 0 0
Gestational age (wk) 38.7
1.8 38.8
1.3 .68 35.3
2.5 35.9
1.8 .28
Preterm laborb 7 (6%) 9 (3.9%) .34 16 (47.0%) 34 (50%) .24
Birth weight (g) 3,306.2
473.9 3,272.4
390.4 .51 2,416.7
580.8 2,380.1
375.3 .74
Sex .15
Male 60 (52.2%) 128 (55.7%) .54 34 (49.2%) 63 (46.3%)
Female 55 (47.8%) 102 (44.3%) 35 (50.7%) 73 (53.6%)
Fetal malformation 3 (2.6%)c 7 (3.0%)d .64 5 (7.2%)e 8 (5.9%)f .22
NICU care
Intracranial hemorrhage 0 1 (0.4%) .48 1 (1.4%) 0 .33
Seizures 0 0 0 0
Sepsis 0 0 2 (2.9%) 0 .11
Respiratory distress 2 (1.7%) 2 (0.9%) .60 4 (5.9%) 2 (1.9%) .09
Mechanical ventilation 2 (1.7%) 1 (0.4%) .26 4 (5.9%) 2 (1.9%) .09
Fetal death 0 0 0 0
NICU care at birth 5 (4.3%) 8 (3.5%) .76 11 (15.9%) 12 (8.8%) .14
Note: Values are presented as mean
standard deviation or n (%). NICU ¼ neonatal intensive care unit; other abbreviations as in Table 1.
a
Defined as the loss of >500 mL blood within 24 hours of delivery or the need of blood transfusion for excessive bleeding at the time of delivery.
b
Defined as delivery before 37 completed weeks.
c
Including hypospadias, congenital hearing loss, patent ductus arteriosus (PDA).
d
Including PDA, ventricular septal defect (VSD; 2 children), congenital giant pigmented nevus, strabismus (3 children).
e
Including PDA (2 children), congenital megacolon, imperforate anus, VSD.
f
Including VSD (4 children), atrial septal defect (2 children), PDA (2 children).
Yu. Long-term outcomes of IVM children. Fertil Steril 2019.

admission diagnosis was low weight (12 in IVM group [6.5%],
15 in IVF group [4.1%]; P¼ .97), followed by jaundice (4 in
IVM group [2.1%], 13 in IVF group [3.5%]; P¼ .61) and heart
problems (2 in IVM group [1.0%], 3 in IVF group [0.8%];
P¼ .39). The duration of childhood hospital admission tended
to be longer in IVM singletons (1.9
1.1 days) compared with
IVF singletons (1.5
0.7 days), but this tendency did not
reach statistical significance (P¼ .08). Most admissions in
the IVM group occurred during the first year of life (42.8%
in singletons and 38.8% in twins).

TABLE 3

Characteristics of hospitalization of IVM and IVF children until the age of 19 years.
Singleton pregnancy (n [ 345) Multiple pregnancy (n [ 205)
IVM group IVF group IVM group IVF group
Characteristic (n [ 115) (n [ 230) P value (n [ 69; 34 sets) (n [ 136; 68 sets) P value
Newborn hospitalization 10 (8.6%) 13 (5.7%) .36 13 (18.8%) 21 (15.4%) .51
Cause .89 .24
Low birth weighta 3 (30%) 3 (23.1%) 9 (69.2%) 12 (57.3%)
Heart problemsb 2 (20%) 2 (15.4%) 0 1 (4.7%)
Jaundice 3 (30%) 6 (46.1%) 1 (7.7%) 7 (33.3%)
Otherc 2 (20%) 2 (15.4%) 3 (23.1%) 1 (4.7%)
Childhood hospitalization 28 (24.3%) 48 (20.9%) .49 18 (26.1%) 24 (17.6%) .09
No. of hospital admission 1.9
1.1 1.5
0.7 .08 1.5
0.7 1.3
0.7 .47
(n)
Developmental problems 2 (1.7%)d 1 (0.4%)e .29 1 (1.4%)f 1 (0.7%)g .65
Note: Values are presented as mean
standard deviation or n (%). Abbreviations as in Table 1.
a
Defined as a birth weight <2,500 g.
b
Including operation or treatment for congenital heart disease and observation for tricuspid regurgitation; pulmonary stenosis needed no treatment.
c
Including prematurity, respiratory distress due to aspiration of amniotic fluid or meconium, fever after immunization, and sepsis.
d
Including delayed speech development, fine-motor developmental delay.
e
Including delayed speech development (one of the twins).
f
Including multiple developmental delay.
g
Including attention deficit–hyperactivity disorder (one of the twins).
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Three children (1.6%) in the IVM group showed minor
developmental delay (speech, fine-motor developmental
delay from singleton birth, developmental delay from twin
birth) at the age of 4 years, whereas two children (0.5%) in
the IVF group appeared to have developmental problems
(P¼ .37). Two of the children from the IVM group caught up
to the normal developmental profile by the age of 6 years.
DISCUSSION
The IVM technique was first developed and introduced in the
late 1980s, but it has not been used as widely as conventional
IVF treatment despite its benefits of less hormonal stimula-
tion and lower incidence of ovarian hyperstimulation syn-
drome. The main reason for the lower utilization rate of
IVM compared with IVF may be the lack of the safety data
regarding IVM. Only a few small studies have investigated
the safety for IVM babies (17, 34, 35). In our previous
report, we showed that the obstetrical outcomes of 24 IVM
babies are similar to those of conventional IVF babies (19).
Although it is quite encouraging that all previous studies
report similar safety outcomes of IVM and conventional
IVF, they included very small numbers of IVM babies (up to
55) and had short follow-up periods (%2 years). To our
knowledge, the present study includes the largest patient pop-
ulation for evaluating the safety of IVM procedure and is the
first to explore the longer-term effects of IVM treatment on
children's health, growth, and developmental status.
Several aspects that are specific for IVM have been inves-
tigated regarding its safety. First, it has been suggested that
oocytes that mature in vitro are characterized by multiple
cellular and molecular deficiencies compared with oocytes
matured in vivo, thereby culminating an inferior develop-
mental potential of IVM oocytes (36). IVM involves several
additional steps compared with conventional IVF, including
isolation, handling, and culture of oocytes, which may exert
more environmental stress on oocytes compared with oocytes
matured in vivo (37). Furthermore, spindle alterations linked
to a longer period of maturation in vitro may predispose the
oocyte to aneuploidy or maturation arrest (38, 39).
Accordingly, the incidence of chromosomal abnormalities,
such as genetically mosaic unbalanced translocation or
chaotic embryos (defined as an embryo with >75% cells
carrying three or more whole-chromosome abnormalities),
has been reported to be higher in the IVM group than in the
IVF group (40). Finally, IVM was reported to induce perma-
nent changes in the expression of imprinted genes (41, 42).
DNA methylation has an important role in regulating
embryonic growth and establishing genomic imprints (43).
Incomplete methylation of maternal loci during in vitro
culture may cause serious consequences during
development, such as Beckwith-Wiedemann syndrome, An-
gelman syndrome, and Silver-Russell syndrome (43). Several
previous studies show a higher possibility of epigenetic ab-
normalities with the use of the IVM process (41–43). In our
study, no child had chromosomal abnormalities or
imprinting disorders. Our data support the report of Fadini
et al. which showed no chromosomal abnormalities in 196
infants who had been conceived through IVM treatments
696
(23). However, considering the low incidence of imprinting
disorders, our results are still underpowered to render any
definite conclusion. We found no evidence of an increased
risk of major birth defects after IVM compared with
conventional IVF. To validate the chromosomal stability of
IVM, it would be more reliable to investigate the first-
trimester miscarriage rate. In this study, we did not look up
the miscarriage rate, because the purpose of the study was
to evaluate the long-term safety of IVM babies. However, a
previous study which evaluated the miscarriage rate in IVM
and IVF groups reported no significant difference between
them (44).
Growth parameters in our study, such as height and
weight, were appropriate for age in both IVM and IVF groups.
These results agree with previous studies reporting no differ-
ence in growth between IVM and IVF children after 2 years of
follow-up (21, 24, 35). However, some studies showed that
IVM of human oocytes results in a higher incidence of
overweight babies compared with spontaneously conceived
and IVF infants (23, 45). The association between IVM
oocytes and large birth weight is known as large offspring
syndrome, which has been studied in cattle and sheep (46).
Some authors suggest that this difference in birth weight is
related to the embryo culture medium composition. They
have shown that the addition of serum to the culture
medium exaggerates large offspring syndrome, whereas
replacement of serum with bovine serum albumin
significantly reduces its occurrence. These data indicate that
premature blastulation, which is a characteristic of ovine
embryos incubated in serum medium, may impart a
property to the embryo that results in increased birth weight
through a shift in the ratio between the inner cell mass and
the trophectoderm (47). In a human epidemiologic study, a
trend of slightly greater birth weight in the IVM group
compared with the IVF group has also been reported (24).
However, those authors found a higher frequency of
gestational diabetes with fetal hyperinsulinemia in the IVM
group, which could be a critical confounding factor in
interpreting the results. It is well known that women with
PCOS often have insulin resistance and are at an increased
risk of having overweight offspring (48). In our study, all
subjects in both groups had PCOS and there was no
difference in birth weight between the two groups. These
results may indicate that the large offspring syndrome
observed in IVM babies is associated with a higher
incidence of PCOS in the patients who pursue IVM, not with
the embryo culture medium specifically used in IVM.
In this study, there were increased incidences of pre-
eclampsia in singleton pregnancies and of neonatal respira-
tory distress syndrome in multiple pregnancies. However,
we failed to demonstrate any statistically significant results
from our data. Although our work may include the largest
cohort compared with previously published research, still
larger studies are warranted to clarify the association between
IVM and several pregnancy-related disorders that have low
incidence.
After the first clinical application of IVM in 1999, contin-
uous efforts have been made to improve the pregnancy out-
comes of IVM, especially on the composition of IVM media
VOL. 112 NO. 4 / OCTOBER 2019

in our center. Although mainly commercial IVM media was
used throughout the study period, melatonin was added to
the commercial media in 2009. Although the in vitro oocyte
maturation rate was significantly improved by adding mela-
tonin (49), no improvement in clinical outcomes, such as
pregnancy rate and live birth rate, has been reported so far.
When we compared the health status of IVM children who
were conceived before and after 2009, there was no signifi-
cant difference.
The present study has several strengths and limitations.
This is a well designed matched case-control study evaluating
long-term safety of IVM treatment. Importantly, it is the
largest study evaluating the safety of IVM compared with pre-
vious reports that included small numbers of subjects. In addi-
tion, to ensure acquisition of well qualified information, the
entire telephone interview was performed by physicians
who specialize in reproductive endocrinology. The retrospec-
tive nature of this study does not allow randomization of pa-
tients between the IVM and IVF groups, and patient allocation
was based on preference which might cause hidden bias.
However, to mitigate this limitation caused by the retrospec-
tive study design, we matched important factors between the
IVM and IVF groups. There was no significant difference in
the basic characteristics of the women between the two
groups. Finally, because the data were collected via question-
naire completed by the mothers, there is a possibility of self-
reporting bias.
This is the first study evaluating the long-term
consequences for children conceived using the IVM tech-
nique. Despite the biologic and genetic evidence of the
possible risks associated with the IVM procedure, our results
provide epidemiologic data showing that children born after
IVM grow and develop normally up to the mean follow-up
of 7.5 years. Studies with longer follow-up duration and
larger subject numbers are warranted to render a definite
conclusion.
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 Fertility and Sterility®

Medidas obstetricas, neonatales y a largo plazo de ni~nos concebidos a partir de ovocitos madurados in vitro
Objetivo: Investigar las medidas obstetricas, neonatales y a largo plazo de la maduraci
on in vitro (IVM) comparada con la fecundaci
on
in vitro convencional (IVF) en mujeres con síndrome de ovario poliquístico (PCOS).
~o: Estudio retrospectivo caso-control emparejado.
Disen
Ubicacion: Clínica de fertilidad universitaria.
Paciente(s): Ciento ochenta y cuatro pacientes que realizaron IVM fueron comparadas con 366 que realizaron IVF convencional. Todas
tenían PCOS y fueron emparejadas seg un edad de la paciente, edad gestacional al nacimiento y n
umero de fetos.
Intervencion(es): Ninguna.
Principal(es) medida(s) de resultado(s): Medidas obstetricas, neonatales y problemas medicos y de desarrollo en la infancia.
Resultados(s): La edad media de las mujeres en el momento de la obtenci on de ovocitos fue 32.6
2.9 a~
nos. La edad media de los ni~nos
fue 7.5
2.3 a~nos. No hubo diferencias en la frecuencia de las medidas obstetricas y neonatales entre ambos grupos. No se encontr o
ninguna diferencia en los pesos al nacer entre los dos grupos. La incidencia de anomalías congenitas fue similar entre los grupos (4.3%
en el grupo de IVM vs. 4.1% en el grupo de IVF). No se observ
o diferencia significativa entre los dos grupos en la frecuencia y duraci
on de
hospitalizaci
on durante la infancia. El estatus del crecimiento evolutivo de ambos grupos estuvo dentro de límites normales.
Conclusion(es): En un contexto similar entre bebes IVM e IVF nacidos de mujeres con PCOS, no se identific
o un aumento significativo
del riesgo asociado con la IVM despues de un seguimiento medio de 7,5 a~ nos.

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