To compare the clinical outcomes of fresh embryo transfers (ETs) and frozen-thawed embryo transfers (FETs) after a freeze-all cycle in women ≥40 years old with poor ovarian response (POR).
We performed a single-center, retrospective, case-control study of patients who underwent
The mean maternal ages and number of oocytes retrieved (43.2 years and 2.3 in both groups,
FET after the freeze-all strategy had no beneficial impact on the clinical outcomes of women ≥40 years with POR.
With the development of
In the last century, there have been extensive studies that have compared the IVF outcomes of fresh embryo transfer (ET) and FET [
Recently, a few observational studies compared the fresh ET and FET outcomes in poor ovarian responders and the results were equivocal. A retrospective cohort study that included 82,935 cycles showed that both the clinical pregnancy rate (CPR) and LBR were higher after fresh ET compared with FET in intermediate (6–14 oocytes retrieved; 49.6% vs. 44.2% and 41.2% vs. 35.3%, respectively) and low responders (1–5 oocytes retrieved; 33.2% vs. 15.9% and 25.9% vs. 11.5%). However, the results derived from both the cleavage-stage embryo and blastocyst transfer data exhibited high heterogeneity [
To the best of our knowledge, there are no studies that have previously evaluated the clinical outcomes of fresh ET and FET after use of the freeze-all strategy in advanced maternal age (AMA) patients with POR. This study aimed to investigate whether AMA patients with POR can benefit from the freeze-all strategy.
This was a retrospective case-control study that analyzed the data of AMA patients with POR who underwent fresh ET and FET after the “freeze-all” strategy from January 2014 to June 2019 at the Reproductive Centre of the 901th Hospital of the Joint Logistics Support Force of The People’s Liberation Army. All the patients provided written informed consent. The eligibility criteria were as follows: 1) aged 40 years or older; 2) 3 or less oocytes retrieved after controlled ovarian stimulation (COS) including the gonadotropin-releasing hormone (GnRH) antagonist, GnRH agonist short, mild stimulation, and medroxyprogesterone acetate (MPA) pituitary down-regulation protocols [
A total of 192 patients who met the criteria were included in this study. Of these patients, 101 and 91 received fresh ETs and FETs after undergoing the freeze-all strategy, respectively. We collected the patients’ demographic information from medical records, including their age; infertility duration and type; body mass index (BMI); basic follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin levels; and antral follicle count (AFC).
All of the patients received COS. The starting gonadotropin dose was 150–300 IU FSH based on the patient’s age, hormone profile, AFC, and BMI. The dose was adjusted according to the ovarian response through serial ultrasonography and serum FSH, LH, E2, and progesterone level monitoring. The doctors would add 75 IU human menopausal gonadotropin (Lizhu Pharmaceutical Trading Co., Ltd., Zhuhai, China) at their discretion. When one or 2 leading follicles reached 18 mm or more in diameter, 250 μg recombinant human chorionic gonadotropin (The Merck Group, Darmstadt, Germany) was administered to induce oocyte maturation. All the oocytes that were ≥12 mm in diameter were transvaginally retrieved 36 hours later.
All of the oocytes that were retrieved were fertilized with conventional IVF or intracytoplasmic sperm injection (ICSI) 2–4 hours after oocyte retrieval was performed, according to the sperm quality. The embryos were graded according to the system proposed by Cummins et al. [
For the patients who received fresh ETs, ≤3 available embryos were transferred into the uterine cavity under ultrasonographic guidance on day 3 after the oocyte retrieval. A daily intramuscular injection of 40 mg progesterone (Zhejiang Xianju Pharmaceutical Co Ltd., Taizhou, China) was used for luteal support from the day of oocyte retrieval until 10 weeks of gestation after clinical pregnancy was confirmed (defined as the presence of a gestational sac on ultrasound 30–35 days after ET).
For the patients who underwent FET, hormone replacement treatment was carried out for endometrial preparation. Briefly, 4–8 mg oral E2 valerate tablets (Progynova; Bayer Schering Pharma, Beijing, China) were administered from day 3 of the second menstrual cycle after oocyte retrieval or later. An intramuscular progesterone injection at a dose of 40 mg per day was added for 3 days when the endometrial thickness reached 8 mm or more. For patients that had an endometrial thickness that was less than 8 mm after prolonged oral E2 valerate tablet usage (18 days) and that did not have any disorders identified by hysteroscopy, endometrial transformation with 40 mg progesterone were also performed. The frozen embryos were thawed with a commercial warming kit (Kitazato Biopharma Co., Yanagishima, Japan), and ≤3 surviving embryos (defined by at least 50% retention of intact cells) were transferred into the uterine cavity under ultrasonographic guidance. Luteal support with the original E2 valerate dose and intramuscular progesterone injections were continued until 10 weeks of gestation once clinical pregnancy was confirmed.
The primary outcome in this study was the LBR. Live birth was defined as the birth of at least one newborn that exhibited any signs of life. The secondary outcomes were the biochemical pregnancy, clinical pregnancy, and miscarriage rates. Biochemical pregnancy was defined as an human chorionic gonadotropin level more than 20 IU/L 14 days after ET. Miscarriage was defined as the loss of a clinical pregnancy at <24 weeks’ gestation.
The mean birth weights, premature infant rates, number of multiple pregnancies, and numbers of neonates with low birth weights and fetal macrosomia were recorded. A premature infant was defined as preterm birth at <37 weeks’ gestation. Multiple pregnancy was defined as at least 2 detectable gestational sacs or heartbeats on ultrasound. Low birth weight and macrosomia were defined as birth weights <2,500 g and ≥4,000 g, respectively.
Continuous variables are expressed as the mean with the standard deviation or the median with the interquartile range, categorical variables are expressed as numbers (percentages). Comparisons between the patients who underwent fresh ET and FET were performed using the
To identify the differences in the reproductive and neonatal characteristics between the fresh ET and FET groups, multivariate logistic regression analysis was used to derive the odds ratios (ORs) and 95% confidence intervals (CIs). The potential confounders were variables that resulted in more than 10% variation in the coefficient of the principal study factor when added into the model. Results were presented after adjusting for maternal age, BMI (model 1), LH, and the number of good quality embryos transferred (model 2).
A 2-tailed
The patient characteristics are shown in
The outcomes are shown in
Six neonates were born after fresh ET and FET each. The mean birth weights were 3,583.3 g and 3,116.7 g in the fresh ET and FET groups, respectively (
With the rapid increase in the success rate with vitrified-thawed embryos, the number of autologous FETs increased over 2.5-fold from 2004 to 2013; however, the number of fresh ETs was approximately the same [
Although many studies have illustrated that IVF outcomes (LBR, implantation rate, and ongoing pregnancy) can be improved through the use of the freeze-all strategy, most of these studies were limited by the number of patients who were hyper- or normal ovarian responders [
POR, first described by Garcia et al. [
As an independent factor for ART outcomes, age predicts over 80% of IVF success [
There are several limitations to this study. First, the retrospective design had inherent problems relating to selection bias; thus, the characteristics and prognoses of the patients assigned to the study may have differed between the 2 groups. However, as shown in
In conclusion, compared with fresh ET, FET followed by a freeze-all cycle is not beneficial for women ≥40 years old with POR. RCTs with a large sample size should be carried out to confirm this conclusion.
The authors would like to thank the Reproductive Centre of the 901th Hospital of the Joint Logistic Support Force of People’s Liberation Army, as well as all its members of staff, and the patients who allowed for their data to be reported.
No potential conflict of interest relevant to this article was reported.
All the patients provided written informed consent.
All the patients provided written informed consent.
None.
Reason for frozen embryo transfer (n=91)
Reasons | Value |
---|---|
MPA pituitary down-regulation protocol | 50 (54.9) |
Endometrial thickness less than 8 mm | 12 (13.2) |
AMA per se | 11 (12.1) |
Level of progesterone over 1.5 ng/mL | 9 (9.9) |
Personal choice | 5 (5.5) |
Others | 4 (4.4) |
Values are presented as number (%).
MPA, medroxyprogesterone acetate; AMA, advanced maternal age.
Characteristics of patients
Characteristics | Fresh ET group (n=101) | Frozen ET group (n=91) | |
---|---|---|---|
Age (yr) | 43.2±2.6 | 43.2±2.2 | 0.902 |
Infertility duration (yr) | 4.9±4.7 | 5.7±4.9 | 0.276 |
Infertility type | |||
Primary infertility | 13 (12.9) | 12 (14.5) | 0.755 |
Secondary infertility | 88 (87.1) | 71 (85.5) | |
BMI (kg/m2) | 25.0±4.1 | 23.9±3.1 | 0.044 |
Basal FSH (IU/L) | 13.1±7.3 | 13.7±9.2 | 0.668 |
Basal LH (IU/L) | 5.2±3.2 | 6.5±6.3 | 0.087 |
Basal oestrogen (pg/mL, median [IQR]) | 47.5 (53) | 55.5 (63.5) | 0.513 |
Basal prolactin (ng/mL, median [IQR]) | 11.2 (7.1) | 12.0 (9.0) | 0.598 |
AFC | 4.9±3.1 | 4.7±3.7 | 0.673 |
Values are presented as mean±standard deviation or number (%) unless otherwise indicated.
ET, embryo transfer; BMI, body mass index; FSH, follicle stimulating hormone; LH, luteinizing hormone; IQR, interquartile range; AFC, antral follicle count.
The outcomes of controlled ovarian stimulation
Characteristics | Fresh ET group | Frozen ET group | |
---|---|---|---|
Days of ovarian stimulation (day) | 7.7±3.2 | 7.6±3.3 | 0.804 |
Total gonadotropin dose (IU) | 1,933.8±877.2 | 1,911.9±1,054.2 | 0.877 |
Endometrial thickness (mm) | 9.6±2.6 | 7.9±2.7 | <0.001 |
Oocytes retrieved | 2.3±0.7 | 2.3±0.7 | 0.927 |
Available embryos | 1.8±0.7 | 1.9±0.6 | 0.616 |
Good quality embryos | 1.5±0.8 | 1.6±0.7 | 0.396 |
Embryos transferred | 1.8±0.7 | 1.9±0.5 | 0.687 |
Good quality embryo transferred | 0.9±0.8 | 1.6±0.6 | <0.001 |
Values are presented as mean±standard deviation.
ET, embryo transfer.
The outcomes of
Characteristics | Fresh ET group | Frozen ET group | Unadjusted OR (95% CI) in frozen ET group | Model 1 OR (95% CI) in frozen ET group | Model 2 OR (95% CI) in frozen ET group | |||
---|---|---|---|---|---|---|---|---|
Biochemical pregnancy | 16/101 (15.8) | 14/91 (15.4) | 0.97 (0.44–2.11) | 0.931 | 1.07 |
0.878 | 1.28 |
0.641 |
Clinical pregnancy | 11/101 (10.9) | 11/91 (12.1) | 1.13 (0.46–2.73) | 0.795 | 1.17 |
0.745 | 1.16 |
0.802 |
Miscarriage rate | 5/11 (45.5) | 5/11 (45.5) | 1.00 (0.19–5.36) | 1.000 | 1.58 |
0.665 | 1.01 |
0.995 |
Live birth rate | 6/101 (5.9) | 6/91 (6.6) | 1.12 (0.35–3.60) | 0.852 | 1.24 |
0.719 | 1.28 |
0.750 |
No. of neonate | 6 | 6 | - | - | - | - | - | - |
Birth weight (g) | 3,583.3±467.6 | 3,116.7±468.7 | - | - | - | - | - | - |
Premature infant rate | 1/6 (16.7) | 2/6 (33.3) | 2.50 (0.16–38.60) | 0.512 | 1.81 |
0.349 | - | - |
Values are presented as number (%) or mean±standard deviation.
ET, embryo transfer; OR, odds ratio; CI, confidence interval.
Adjusted for maternal age, body mass index;
Adjusted for maternal age, body mass index, luteinizing hormone and the number of good quality embryo transferred;
Adjusted for maternal age.