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European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Full length article

Perinatal and maternal outcomes after frozen versus fresh embryo

transfer cycles in women of advanced maternal age
Xinyi Zhanga,b , Lina Baic , Haiqin Renc , Xinyu Liud, Shuaishuai Guoe , Peng Xuc , Jia Zhengf ,
Liqiang Zhengg , Jichun Tana,b,*
a
Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110022, Liaoning,
China
b
Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang, 110022, Liaoning, China
c
Jinghua Hospital, Shenyang Eastern Medical Group, Shenyang, 110005, Liaoning, China
d
Shenyang 204 Hospital, Shenyang, 110043, Liaoning, China
e
Reproductive Medical Center, Shenyang Women’s and Children’s Hospital, Shenyang, 110011, Liaoning, China.
f
Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
g
Department of Clinical Epidemiology, Library, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China

A R T I C L E I N F O A B S T R A C T

Article history: Objective: The delay of childbearing in women has become a worldwide issue in recent decades. The
Received 20 November 2019 application of assisted reproductive technology in women of advanced maternal age (AMA) is increasing.
Received in revised form 22 September 2020 Evidence on the safety and outcomes of frozen embryo transfer (FET) compared with fresh embryo
Accepted 28 September 2020
transfer (ET) in AMA women is still lacking. Therefore, the objective of the present study was to compare
Available online xxx
perinatal and maternal outcomes after autologous FET and fresh ET cycles in women of AMA.
Study design: A retrospective study of 1663 FET and 3964 fresh ET cycles in reproductive medical centers
Keywords:
from 2009 to 2014. Women who aged 35 years and had clinical pregnancies after autologous frozen or
Advanced maternal age
Frozen embryo transfer
fresh ET were included. The main perinatal outcomes included birth weight, gestational age, rates of
Perinatal outcomes preterm birth, macrosomia, low birth weight (LBW), and very low birth weight. The main maternal
Maternal outcomes outcomes included rates of hypertensive disorders of pregnancy, gestational diabetes mellitus, and
preterm premature rupture of the membranes.
Results: Women who underwent FET had an increased risk of hypertensive disorders of pregnancy [1.1 %
vs. 0.4 %, adjusted OR (95 % CI): 2.76 (1.39 5.51); p = 0.004]. Singletons born after FET had significantly
higher mean birth weight (3388.78  538.47 vs. 3316.19  549.08; p = 0.001). Furthermore, increased risk
of macrosomia [13.5 % vs. 10.4 %, adjusted OR (95 % CI): 1.35 (1.07 1.71); p = 0.013] and decreased risk of
LBW [3.6 % vs. 5.3 %, adjusted OR (95 % CI): 0.67 (0.45 1.00); p = 0.048] were found in singletons born after
FET.
Conclusions: Perinatal risks of AMA patients are higher in FET than in fresh ET, including higher birth
weight, risks of macrosomia in singleton births, and hypertensive disorders of pregnancy.
© 2020 Elsevier B.V. All rights reserved.

Introduction
Worldwide, the delay in women having their first child has
increasingly become an issue in recent decades. From 1990–2014,
the birth rate among women aged 20–34 years was stable, and that
* Corresponding author at: Shengjing Hospital of China Medical University,
Shenyang, 110022, China.
E-mail addresses: 850894651@qq.com (X. Zhang), 709411631@qq.com (L. Bai),
2335254500@qq.com (H. Ren), 13889106885@163.com (X. Liu),
shuaishuai197411@sina.com (S. Guo), 2285852636@qq.com (P. Xu),
1637643374@qq.com (J. Zheng), zhenglq@sj-hospital.org (L. Zheng),
tjczjh@163.com (J. Tan).
among women aged 35–44 years was steadily rising [1]. Advanced
maternal age (AMA) is related to lower fecundity, higher risks of
infertility, and adverse outcomes [2,3]. From 2008–2010, the
proportion of women aged 40 years undergoing non-donor
assisted reproductive technology (ART) increased from 20.8%–
23.2% [4]. The application of ART has contributed to the increase in
birth rates among women of AMA, which has brought about a
challenge in choosing ART strategies to achieve better perinatal
and maternal outcomes.
There was a clear trend toward increased autologous frozen
embryo transfer (FET) usage from 2006 to 2012 [5]. Conflicting
results have been revealed in a number of studies comparing
outcomes of fresh embryo transfer (ET) and FET cycles. FET cycles

https://doi.org/10.1016/j.ejogrb.2020.09.047
0301-2115/© 2020 Elsevier B.V. All rights reserved.

Please cite this article as: X. Zhang, L. Bai, H. Ren et al., Perinatal and maternal outcomes after frozen versus fresh embryo transfer cycles in
women of advanced maternal age, Eur J Obstet Gynecol, https://doi.org/10.1016/j.ejogrb.2020.09.047
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EURO-11636; No. of Pages 5
X. Zhang, L. Bai, H. Ren et al.
have been reported to improve pregnancy and live birth rates,
decrease risks of preterm birth (PTB) and low birth weight (LBW),
and prevent ovarian hyperstimulation syndrome (OHSS) [6–8].
However, higher risks of large for gestational age, macrosomia, and
several maternal complications were found after FET [9–11].
Furthermore, data comparing outcomes after FET and fresh ET
cycles in women of AMA are still lacking.
The objective of the present study was to compare the perinatal
and maternal outcomes after autologous FET and fresh ET cycles in
women of AMA (35 years of age). In addition, pregnancy
outcomes and maternal complications were also evaluated. We
aim to provide clinical evidence in choosing better ET methods for
women of AMA.
Methods
Study design and ART treatments
We compared the perinatal and maternal outcomes after FET
and fresh ET in this retrospective study. ET cycles included were
performed during January 2009 to December 2014 in Shenyang,
China. Only women who aged 35 years and had clinical
pregnancies with the presence of gestational sac with fetal heart
observed on ultrasonography 4–5 weeks after ET were included. A
patient was included once into either the FET or fresh ET group. All
embryos transferred were autologous for couples. Cycles involving
donor oocytes, preimplantation genetic diagnosis (PGD) or
preimplantation genetic screening (PGS), vanishing twins, and
incomplete records were excluded. Cycles that met the inclusion
criteria were extracted from the ART database. A flow chart of the
included and excluded cycles is displayed in Fig. 1.
Participants in this study received the ovarian stimulation
regimen, including either the long-term, short-term, mini-stimu-
lus, or antagonist protocol. A transvaginal ultrasound-guided
oocyte aspiration was performed 34 36 hours after inducing
oocyte maturation. The oocytes were retrieved and then fertilized
by in vitro fertilization (IVF) or intracytoplasmic sperm injection
Fig. 1. Flow chart of the included and excluded cycles.
ET, embryo transfer; AMA, advanced maternal age; PGD, preimplantation genetic
diagnosis; PGS, preimplantation genetic screening.
European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (xxxx) xxx–xxx
(ICSI) procedures based on the semen characteristics. ETs were
carried out on day 3 of culture in the cleavage stage in the fresh ET
group. Patients in fresh ET group initiated daily progesterone
administration after oocyte retrieval. Endometrial preparation of
FET cycles was conducted on either a hormone replacement
therapy cycle or a natural cycle. Among patients who underwent
FET cycles, day-3 frozen embryos were thawed and transferred. All
subjects received luteal phase support, which continued until
approximately 10 weeks of gestation.
Measurement outcomes
Pregnancy and birth information were either reported by the
participants or obtained from obstetric records. Pregnancy out-
comes included live birth, miscarriage, ectopic pregnancy, and
perinatal mortality. Live birth referred to the delivery of live infants
who survived for at least 7 days. The live delivery of a singleton or a
twin pregnancy was considered as one live birth per clinical
pregnancy. Miscarriage referred to spontaneous pregnancy loss.
Ectopic pregnancy referred to an extrauterine gestational sac
determined through ultrasound or laparoscopy. Perinatal mortality
was defined as intrauterine fetal death after 28 weeks of gestation,
stillbirth, or neonatal death within 7 days after birth. Hypertensive
disorders of pregnancy (HDP), gestational diabetes mellitus
(GDM), preterm premature rupture of the membranes (PPROM),
placenta previa, and placenta abruption were included as maternal
complications during pregnancy. Outcomes of singletons born
were compared by gestational age at delivery (weeks), birth weight
(g), PTB (<37 weeks), LBW (birth weight 1500 g and <2500 g),
very low birth weight (VLBW, birth weight <1500 g), macrosomia
(birth weight 4000 g), and sex ratios between the FET and fresh
ET group.
Statistical analyses
All statistical analyses in this study were performed using SPSS
software, version 22.0. The Chi-square or Fisher’s exact test for
categorical variables and the independent samples t-test for
continuous variables were used. The results were described in
percentages and mean  standard deviation [SD], respectively. We
performed a univariate analysis to compare baseline character-
istics, perinatal, and maternal outcomes between the two groups.
Logistic regression analysis was performed to control potentially
confounding factors, such as maternal age, gravidity, duration of
infertility, causes of infertility, and mode of fertilization. A value of
p < 0.05 was considered statistically significant.
Results
Baseline characteristics of the study groups
A total of 5627 cycles, consisting of 1663 FET and 3964 fresh ET
cycles, were identified for analysis in our study. Baseline
characteristics of the two groups are described in Table 1. Both
groups had comparable maternal age and gravidity history, while
causes of infertility were different. In addition, the FET group had a
shorter duration of infertility (6.94  4.99 vs. 7.29  4.86, p = 0.017).
Pregnancy outcomes and maternal complications
As shown in Table 2, the live birth rate per clinical pregnancy
was 66.6 % (1108/1663) in the FET group and 68 % (2695/3964) in
the fresh ET group, without statistically significant difference. Both
groups had comparable rates for miscarriage, ectopic pregnancy,
and perinatal mortality per clinical pregnancy. Significantly higher
incidence of maternal complications [2.5 % vs. 1.6 %, adjusted OR
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Table 1 Discussion
Baseline characteristics of the FET group and fresh ET group.

Characteristic FET (n = 1663) Fresh ET (n = 3964) P value To the best of our knowledge, this study is currently the largest
Age, years 37.20  2.40 37.30  2.22 0.14 retrospective study comparing perinatal and maternal outcomes
Duration of infertility, years 6.94  4.99 7.29  4.86 0.017 after autologous FET and fresh ET cycles in women of AMA. Our
Gravidity, n (%) 0.09 results indicated that the rates of live birth, miscarriage, ectopic
0 677 (40.7 %) 1710 (43.1 %)
pregnancy, and perinatal mortality per clinical pregnancy were
1 986 (59.3 %) 2254 (56.9 %)
Causes of infertility, n (%) < 0.001
comparable between the two groups. Higher birth weight, lower
Maternal factors 1116 (67.1 %) 2472 (62.4 %) risk of LBW, and higher risk of macrosomia were found in the
Male factors 217 (13.0 %) 697 (17.6 %) singletons born after FET. In addition, higher incidence of HDP was
Mixed factors 265 (15.9 %) 624 (15.7 %) identified in women receiving FET.
Unexplained factors 65 (3.9 %) 171 (4.3 %)
There is still debate on whether FET is better for perinatal
outcomes. Our results demonstrated that perinatal mortality rate
was not higher in the FET group. However, a few studies reported
(95 % CI): 1.54 (1.04 2.28); p = 0.033] and of HDP [1.1 % vs. 0.4 %, that FET could increase perinatal mortality rate in singletons [9,12].
adjusted OR (95 % CI): 2.76 (1.39 5.51) ; p = 0.004] were found in In earlier studies, FET has been reported to be associated with
the FET group after adjusting for confounding factors. higher implantation rates, clinical pregnancy rates, and live birth
rates [8,13]. However, FET did not significantly improve live birth
Neonatal outcomes of singletons born after FET and fresh ET rates based on the results of two recent randomized, controlled
trials [14,15]. In women of AMA, we found no statistical difference
The neonatal outcomes of 924 singletons born after FET and in the live birth rates between the FET group and fresh ET group.
2125 singletons born after fresh ET are listed in Table 3. The mean Considering no adjustment of the number and quality of embryos,
gestational age, incidence of PTB, and sex ratio were comparable further prospective and randomized studies are needed to validate
between the two groups. Significantly higher mean birth weight of and supplement our findings.
singletons was found after FET (3388.78  538.47 vs. 3316.19  Increased risk of HDP after FET among women of AMA was
549.08; p = 0.001). The incidence of macrosomia in the FET group found in this study. In accordance with our results, a study on
was significantly higher than that in the fresh ET group after frozen-thawed single blastocyst transfer with an average maternal
adjusting for confounding factors [13.5 % vs. 10.4 %, adjusted OR age >35 years suggested that FET increased the incidence of
(95 % CI): 1.35 (1.07 1.71); p = 0.013]. Furthermore, the frequency pregnancy-induced hypertension [10]. Moreover, a randomized,
of LBW in the FET group was significantly lower than in the fresh ET controlled trial among polycystic ovary syndrome women
group [3.6 % vs. 5.3 %, adjusted OR (95 % CI): 0.67 (0.45 1.00); indicated that FET increased the incidence of pre-eclampsia
p = 0.048]. [16]. The reasons may be related to embryo cryopreservation

Table 2
Pregnancy outcomes and maternal complications after FET cycles and fresh ET cycles.

Outcome, n (%) FET (n = 1663) Fresh ET (n = 3964) Unadjusted Adjusted

COR (95 % CI) P value AOR (95 % CI) P value

Outcome of pregnancy cycles
Live birth 1108 (66.6) 2695 (68.0) 0.94 (0.83 1.06) 0.32 0.93 (0.83 1.06) 0.28
Miscarriage 499 (30.0) 1124 (28.4) 1.08 (0.96 1.23) 0.21 1.10 (0.96 1.25) 0.16
Ectopic pregnancy 50 (3.0) 124 (3.1) 0.96 (0.69 1.34) 0.81 0.93 (0.67 1.30) 0.66
Perinatal mortality 6 (0.4) 21 (0.5) 0.68 (0.27 1.69) 0.40 0.67 (0.27 1.67) 0.39

Maternal complications during pregnancy

Total 42 (2.5) 65 (1.6) 1.55 (1.05 2.30) 0.026 1.54 (1.04 2.28) 0.033
PPROM 7 (0.4) 18 (0.5) 0.93 (0.39 2.22) 0.86 0.94 (0.39 2.27) 0.90
HDP 18 (1.1) 15 (0.4) 2.88 (1.45 5.73) 0.002 2.76 (1.39 5.51) 0.004
GDM 16 (1.0) 27 (0.7) 1.42 (0.76 2.64) 0.27 1.38 (0.74 2.58) 0.31

COR, crude odds ratio; CI, confidence interval; AOR, adjusted odds ratio; PPROM, preterm premature rupture of the membranes; HDP, hypertensive disorders of pregnancy;
GDM, gestational diabetes mellitus.

Table 3
Neonatal outcomes of singletons born after FET cycles and fresh ET cycles.

Outcome FET Fresh ET Unadjusted Adjusted

(n = 924) (n = 2125) COR (95 %CI) P value AOR (95 %CI) P value
Gestational age, weeks 38.19  1.59 38.29  1.67 N/A 0.13
PTB, n (%) 105 (11.4 %) 236 (11.1 %) 1.03 (0.80 1.31) 0.84 1.02 (0.80 1.30) 0.88
Birth weight (g) 3388.78  538.47 3316.19  549.08 N/A 0.001
Macrosomia, n (%) 125 (13.5 %) 221 (10.4 %) 1.35 (1.07 1.70) 0.012 1.35 (1.07 1.71) 0.013
LBW, n (%) 33 (3.6 %) 112 (5.3 %) 0.67 (0.45 0.99) 0.043 0.67 (0.45 1.00) 0.048
VLBW, n (%) 5 (0.5 %) 10 (0.5 %) 1.15 (0.39 3.38) 0.80 1.18 (0.40 3.48) 0.77
Boy, n (%) 487 (52.7 %) 1087 (51.2 %)
Girl, n (%) 437 (47.3 %) 1038 (48.8 %)
Sex ratio 1.11:1 1.05:1 1.06 (0.91 1.24) 0.43 1.05 (0.90 1.23) 0.55

COR, crude odds ratio; CI, confidence interval; AOR, adjusted odds ratio; N/A, not applicable for continuous variables; PTB, preterm birth; LBW, low birth weight; VLBW, very low
birth weight.

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procedures. Outcomes of sibling pregnancies found that FET
increased the risk of HDP than fresh ET [17]. Increased spindle
abnormalities were also found in vitrified blastocysts than in fresh
blastocysts [18]. Furthermore, differences in gene expression of
embryos have been identified in FET compared to fresh ET [19].
Higher neonatal birth weight, lower risk of LBW, and higher
incidence of macrosomia were found in singletons born after FET,
which are in line with several studies [9,20–22]. A meta-analysis
study revealed that FET was related to lower incidence of LBW and
higher incidence of large for gestational age [23]. There is still
controversy regarding the risk of PTB after FET. A multicenter,
randomized trial of singletons born after FET and fresh ET found no
significant difference in PTB rates, and neither did another
retrospective cohort study [16,24]. However, lower incidence of
PTB in singletons born after FET has been reported [25]. Therefore,
more evidence is required for a convincible conclusion.
A meta-analysis based on the general population reported that
the singletons born after FET were at lower risks of LBW,
increased risks of maternal HDP, large for gestational age, and
high birth weight than fresh ET [26]. Our main findings in AMA
patients are partly in consistent with the results regarding
outcomes of singletons after FET. There is still a lack of evidence
on how maternal age affects perinatal outcomes in ART. A recent
study suggested that pregnancy outcomes significantly declined
with the increasing maternal age after freeze-all strategy,
whereas no significant link was found between maternal age
and adverse neonatal outcomes [27]. In another study including
only fresh ET cycles, the risk of HDP was higher in women aged
>35 years. However, the risks of PTB, macrosomia, and LBW in
singletons did not change with maternal age [28]. Another
prospective study in the context of infants born after fresh ET
demonstrated a different result that advancing maternal age was
associated with macrosomia [29]. AMA has been reported to
increase the risks of maternal and perinatal morbidities,
including macrosomia [30–32]. We speculate that these risks
in women of AMA may be higher than those in young women and
further investigation is needed to clarify the impact of AMA on
different ART procedures.
The mechanisms underlying these findings have not been
entirely elucidated. A number of studies hypothesize that the
differences were mainly due to the consequences of controlled
ovarian stimulation (COS) on uterine environment [33,34]. COS
is related to supraphysiologic levels of estradiol, progesterone,
and other hormones, leading to the alteration of endometrial
receptivity [35,36]. A more natural uterine environment in FET
cycles is considered better for early placentation and embryo-
genesis [37]. Higher implantation potential, leading to better
placentation and overgrowth of the foetus could be a possible
explanation for macrosomia [23]. Moreover, neonatal birth
weight was also affected by the duration of embryonic culture,
the culture and freeze-thawing medium as well as the
manipulation of freezing and thawing [22,38]. Procedures of
FET affect the expression of imprinted genes and DNA
methylation in foetus and placenta [39]. Epigenetic alterations
related to the FET procedures have been reported to influence
developmental processes and intrauterine growth potential
[40].
IVF has advanced greatly over the last decade and whether to
perform a freeze-all cycle followed by FET in all the patients is still
in dispute [41]. Subgroup analysis conducting in normal respond-
ers indicated that favorable outcomes of the freeze-all strategy
decrease with worsening ovarian response [42]. In intermediate
and low responders, higher clinical pregnancy and live birth rates
were found after fresh ET in compare with freeze-all cycles, based
on the number of oocytes retrieved [43]. Increasing age has been
reported to be associated with lowered ovarian reserve and oocyte
European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (xxxx) xxx–xxx
competence [44,45]. These findings indicated that the freeze-all
strategy may not be beneficial for women of AMA.
Our study has several limitations. First of all, it is limited by the
nature of retrospective study. Although vitrification protocols have
been widely adopted during the study period, we were unable to
determine whether any slow-freezing embryos were included in
this study. Moreover, data were not available for other factors such
as smoking habit, body mass index, sperm source, the number and
quality of transferred embryos, and total dose of gonadotropins,
which might potentially influence the pregnancy and neonatal
outcomes.
Conclusions
A higher risk of HDP after FET was found in women of AMA in
this retrospective study. Furthermore, lower incidence of LBW,
higher neonatal birth weight, and higher incidence of macrosomia
were found in singletons born after FET. The main goal of ART is to
achieve good perinatal and maternal outcomes during the
tendency of childbearing delay. Our findings suggest that the
freeze-all strategy may not be beneficial for all the patients and
individualized ET strategies should be applied.
Funding
This work was granted from Key Laboratory of Reproductive
Dysfunction Diseases and Fertility Remodeling of Liaoning
Province (2018225107), the National Key Research and Develop-
ment Program (2018YFC1002105), and the Key Research and
Development Program of Liaoning Province (2018225093).
Declaration of Competing Interest
The authors report no declarations of interest.
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