Abstract
Purpose
To investigate the relationship between different duration of estrogen administration and live birth rate (LBR) after autologous single frozen blastocyst transfer with hormone replacement therapy.
Methods
A total of 2026 frozen blastocyst transfer cycles in the assisted reproductive center of northwest women and children’s hospital from January, 2017, to August, 2020, were retrospectively analyzed. All the cycles were allocated into 3 groups according to the duration of estrogen administration: group A, 11–14 days (n = 346); group B, 15–18 days (n = 1191), and group C, ≥ 19 days (n = 489). Baseline data, clinical, and perinatal outcomes of the three groups were compared. A multivariate regression model was constructed to analyze the association between duration of estradiol administration and clinical outcomes.
Results
We did not observe a significant association between duration of estrogen supplementation and LBR in group B (adjusted odds ratio [aOR] 1.14; 95% confidence interval [CI], 0.89–1.45) or group C (aOR 1.16; 95% CI, 0.86–1.56) patients with group A as the reference group, through logistic regression analysis. No statistical differences were observed in perinatal outcomes among the three groups.
Conclusion
The duration of estrogen administration was not associated with the likelihood of live birth in women undergoing frozen-thawed autologous single-blastocyst transfer.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10815-022-02481-5.
Keywords: Frozen embryo transfer, Hormone replacement therapy, Estrogen treatment duration, Live birth rate
Introduction
With the improvements in embryo cryopreservation techniques, frozen embryo transfer (FET) has become an important part in the field of assisted reproduction technology (ART). Coinciding with the growing of “freeze all embryos” strategy or single embryo transfer, the proportion of FET has increased dramatically in the past decades [1, 2]. At the same time, the understanding of the synchronicity of endometrium and embryo is gaining. Natural cycles and hormone replacement therapy (HRT) with or without a gonadotrophin releasing hormone agonist are three classic regimens to prepare the endometrium for embryo implantation. A number of retrospective studies and prospective randomized controlled studies have suggested that there was no statistical difference in live birth rate (LBR) among the three schemes [3, 4]. Therefore, endometrium preparation method could be selected according to other factors, such as the personal schedule, the habitual practice of different reproductive centers, or whether have ovulation disorder.
For HRT, estrogen is supplied either orally or transdermally from the beginning of the menstrual period. Then, the progesterone is sequentially administered to synchronize “endometrium” and “embryo” [5]. In recent years, the optimal duration of progesterone before transplantation and the mode of administration of progesterone have been studied a lot due to the narrow window of implantation [6]. S. Madero concluded that the dosage of estrogen and the route of estrogen administration have no correlation with the LBR in oocyte donation cycles with fresh embryo transfer [7], which is consistent with the conclusion of a meta-analysis by Glujovsky et al. [8]. However, the optimal exposure time of estrogen remains to be further clarified.
Previous studies have suggested a close relationship between exposure period of estrogen and pregnancy outcome. A minimum of 5 days of estrogen administration have been reported to be sufficient for endometrium proliferation and implantation of the embryo in the oocyte donation cycles [9]. Although some previous studies conducted in oocyte donation cycles have suggested the optimal duration of estrogen exposure prior to the transfer of embryo, the results have been conflicting. In addition, these studies had small sample sizes with limited potency [9–12]. In the most recent two studies about autologous frozen blastocyst transfer cycles with HRT, Bourdon et al. identified the decrease of LBR with prolonged duration of estrogen supplementation, but Sekhon et al. failed to observe such an effect [13, 14]. Therefore, the objective of this research was to retrospectively assess the effect of different duration of estrogen administration before transfer on LBR of patients undergoing frozen-thawed autologous single-blastocyst transfer based on our data.
Materials and methods
Study population and ethical approval
This was a retrospective study from a single center. The study population was comprised of women who had undergone single autologous blastocyst with HRT from January 2017 to August 2020 at the ART center of Northwest Women’s and Children’s Hospital in the People’s Republic of China. Inclusion criteria were as follows: (1) meet the requirement of IVF or ICSI treatment; (2) age ≤ 38 years at the time of egg retrieval; (3) endometrial thickness ≥ 7 mm, serum progesterone < 1.5 ng/ml before the start of progesterone supplied; (4) endometrial thickness ≥ 7 mm on the HCG day of fresh cycle; (5) underwent HRT-FET of single autologous blastocyst; Exclusion criteria included the following: (1) FET after preimplantation genetic testing; (2) vitrified oocytes for fertilization; (3) transdermal or both oral and transdermal estradiol were used to prepare endometrium; (4) women with other factors affecting pregnancy such as intrauterine adhesion, endometrial polyps, uterine cavity effusion, and untreated hydrosalpinx.
The present study was approved by the ethics committee of the hospital and written informed consent was obtained from each woman before IVF or intracytoplasmic sperm injection (ICSI) treatment. Due to the retrospective nature, informed consent of the present study was waived.
Preparation of endometrium
To exclude pregnancy, women underwent urine HCG test on the 5th day of menstruation first. Then, they received a vaginal ultrasound to examine endometrial thickness and ovarian condition. The estrogen was administered as follows: oral estradiol valerate tablets (4 mg–6 mg/day, Bayer, Germany) were given according to the endometrium thickness of the previous fresh cycle. Five to 10 days later, vaginal ultrasound was performed to measure the endometrium thickness. Endometrium and serum progesterone values were evaluated before progesterone administration, and the transfer was canceled if the serum progesterone value was more than 1.5 ng/ml.
Intramuscular injection of progesterone (20 mg per day for one day, then 40 mg per day for 2 days, then 60 mg per day for 3 days) would be initiated if the conditions of transfer (endometrial thickness ≥ 7 mm and serum progesterone value < 1.5 ng/ml) were met. Due to the flexibility of HRT-FET, different doctors have different personal preference and some women require to adjust the transfer time. Hence, the days of estrogen exposure before blastocyst transfer range from 11 to 30 days.
Blastocyst transfer should be performed on the 7th day of progesterone exposure. The dose of luteal support after transfer was the same as described before [15]. Blood HCG was measured 12 days after transfer. The dose of estrogen was gradually decreased at the same speed after confirming of biochemical pregnancy. And luteal support lasts until 10 weeks of gestation at the same dose.
Baseline characteristics and outcome measure
The baseline characteristics of study population were collected, including women’s age at oocyte retrieval (years), BMI (weight (kg)/[height (m)]2), basline FSH (bFSH, FSH value on days 2–4 of menstrual period), number of antral follicle count (AFC), gravidity (0, 1, or ≥ 2), parity (0, 1, or ≥ 2), insemination (IVF, ICSI, or half IVF-half ICSI[IVF + ICSI]), number of FET cycles, endometrial thickness before progesterone administration (Em), triple-line endometrial pattern, day, and quality of embryo development at transfer.
The primary outcome of this study was live birth (LB): LB was delivered at more than 22 weeks of pregnancy; secondary outcome included HCG positive (HP): the value of HCG was more than 7mIu/ml after 12 days of transfer, clinical pregnancy (CP): intrauterine sac and embryo cardiac activity were found under ultrasound at 6–8 weeks of gestation, and early pregnancy loss: spontaneous abortion before 13 weeks of pregnancy or no gestational sac was confirmed after biochemical pregnancy. Maternal complications included pregnancy-induced hypertension disorders (PIH), gestational diabetes mellitus (GDM). Neonatal outcomes included term birth (gestational age at delivery ≥ 37 weeks) or preterm birth (gestational age at delivery < 37 weeks), low (< 2500 g), or normal (2500 g–4000 g) birthweight or macrosomia (> 4000 g). For perinatal outcomes, we restricted the analysis to singletons to rule out the influences of multiple pregnancies.
Data analysis and statistics
All data were exported from the electronic medical record system; analyses were performed using IBM®SPSS® software (version: 22.0, SPSS Inc. Headquarters, USA) and empower stats software (version: 2.0, X&Y-SOLUTIONS, USA). Data were displayed as the mean ± SEM. The differences were considered as statistically significant at a P value < 0.05. Pearson χ2 test or Fisher’s exact test was used for qualitative data like as follows: insemination, number of FET cycles, triple-line endometrial pattern, day, and quality of embryo development at transfer. Kruskal–Wallis test were used for quantitative data, such as age, BMI, infertility period, bFSH, AFC, and Em. Logistic regression analysis was used to identify the possible confounders and independent factors that may modify the odds of LB.
Results
This study recruited 2026 single frozen-blastocyst transfer cycles. During the study period, 68 women received more than one FET cycle. The mean period of estrogen exposure was 16.88 ± 3.13 days (range from 11 to 30 days). The distribution of patients according to the duration of estradiol supplementation is shown in Supplemental Figure 1.
Supplemental Figure 2A shows the raw relationship between live birth rate and estrogen duration through a smooth curve-fitting model. After adjusting for women age, endometrium thickness, dosage of E2, and embryo quality, a fitting curve is shown in Supplemental Fig. 2B, suggesting that the LBR was stabilized during the period of days 11–30.
In order to further evaluate the relationship between the duration of estrogen and clinical outcome, we divided the patients into three groups according to the estrogen duration: group A, 11–14 days (n = 346); group B, 15–18 days (n = 1191); and group C, ≥ 19 days (n = 489) (Fig. 1).
Fig. 1.
Flow chart
Characteristics of the patients
As shown in Table 1, there were no statistical differences among the three groups in mean female’s age at retrieval, mean male age, BMI, infertility years, bFSH, protocol in fresh cycle, insemination method, triple-line endometrial pattern, serum progesterone values before progesterone administration, and number of transfer cycles. AFC in the group B was slightly higher when compared with group A and C (14.86 ± 5.66 versus 13.36 ± 5.34 and 13.63 ± 5.41, P = 0.041). The endometrial thickness was the thinnest in the group C when compared with group A and B (10.82 ± 1.47 versus 10.34 ± 1.38 and 9.39 ± 1.38, P < 0.001). Group A had the lowest proportion of nulligravid and nullipara patients when compared with group B and C (73.99 versus 79.68% and 81.8%, 79.77 versus 87.66% and 89.98%, P < 0.05). The dosage of estrogen used was significantly different in the three groups (71.53 ± 17.01 versus 88.95 ± 18.23 versus 117.50 ± 20.94 g, A versus B versus C, respectively). The proportion of blastocysts transferred at day 5 was higher in the group B and C when compared with group A (90.26 and 89.98 versus 84.68%, P = 0.011). Patients in group B and C had a significantly higher proportion of transfers involving good-quality blastocysts when compared with women in group A (51.64 and 51.33 versus 42.40%, P = 0.007).
Table 1.
Characteristics of the patients (mean ± SEM or n%)
| Variables | Estrogen administration days before blastocyst transfer | |||
|---|---|---|---|---|
| A (11–14 days) | B (15–18 days) | C (≥ 19 days) | P-value | |
| n | 346 | 1191 | 489 | |
| Women age at retrieval | 30.76 ± 3.45 | 30.29 ± 3.56 | 30.43 ± 3.61 | 0.094 KW |
| < 25 | 8 (2.31) | 64 (5.37) | 20 (4.09) | 0.112 K |
| 25–34 | 280 (80.93) | 963 (80.86) | 398 (81.39) | |
| ≥ 35 | 58 (16.76) | 164 (13.77) | 71 (14.52) | |
| Male age | 32.36 ± 4.31 | 32.03 ± 4.40 | 31.92 ± 4.24 | 0.324 K |
| BMI | 22.44 ± 3.46 | 23.08 ± 3.35 | 22.87 ± 3.60 | 0.318 KW |
| Infertile years | 3.86 ± 3.00 | 3.72 ± 2.81 | 3.68 ± 2.87 | 0.727 KW |
| Ovarian reserve function | ||||
| bFSH | 7.64 ± 3.77 | 7.19 ± 2.78 | 6.91 ± 2.64 | 0.250 K |
| AFC | 13.36 ± 5.34 | 14.86 ± 5.66 | 13.63 ± 5.41 | 0.041 K |
| Gravidity | 0.014 K | |||
| 0 | 256 (73.99) | 949 (79.68) | 400 (81.80) | |
| 1 | 46 (13.30) | 141 (11.84) | 40 (8.18) | |
| ≥ 2 | 44 (12.72) | 101 (8.48) | 49 (10.02) | |
| Parity | < 0.001 K | |||
| 0 | 276 (79.77) | 1044 (87.66) | 440 (89.98) | |
| 1 | 64 (18.50) | 138 (11.59) | 41 (8.38) | |
| ≥ 2 | 6 (1.73) | 9 (0.76) | 8 (1.64) | |
| Protocol in fresh cycle | 0.892 K | |||
| Agonist | 268 (77.46) | 936 (78.66) | 383 (78.32) | |
| Antagonist | 78 (22.54) | 254 (21.35) | 106 (21.68) | |
| Insemination | 0.213 K | |||
| IVF | 262 (75.72) | 895 (75.15) | 379 (77.51) | |
| ICSI | 78 (22.54) | 254 (21.33) | 101 (20.65) | |
| IVF + ICSI | 6 (1.73) | 42 (3.53) | 9 (1.84) | |
| Transfer rank | 0.918 K | |||
| 1 | 265 (76.59) | 905 (75.99) | 381 (77.91) | |
| 2 | 63 (18.21) | 220 (18.47) | 81 (16.56) | |
| ≥ 3 | 18 (5.20) | 66 (5.54) | 27 (5.52) | |
| Dosage of E2 (mg) | 71.53 ± 17.01 | 88.95 ± 18.23 | 117.50 ± 20.94 | < 0.001 KW |
| Em (mm) | 10.818 ± 1.470 | 10.344 ± 1.376 | 9.391 ± 1.383 | < 0.001 KW |
| Triple-line endometrial pattern | 0.651 K | |||
| A | 65 (18.79) | 196 (16.46) | 86 (17.59) | |
| B | 253 (73.12) | 917 (76.99) | 371 (75.87) | |
| C | 28 (8.09) | 78 (6.55) | 32 (6.54) | |
| P (ng/ml) | 0.69 ± 0.46 | 0.68 ± 0.40 | 0.64 ± 0.38 | 0.672 K |
| Day of embryo development at transfer | 0.011 K | |||
| 5 | 293 (84.68) | 1075 (90.26) | 440 (89.98) | |
| 6 | 53 (15.32) | 116 (9.74) | 49 (10.02) | |
| Embryo quality | 0.007 K | |||
| Lower-quality embryo | 200 (57.80) | 576 (48.36) | 238 (48.67) | |
| Good-quality embryo | 146 (42.20) | 615 (51.64) | 251 (51.33) | |
Significant difference values are in bold
Note: BMI body mass index; AFC antral follicle count; FSH follicle-stimulating hormone; Em endometrial thickness before progesterone administration; P serum progesterone values before progesterone administration; A good-quality embryo was defined as a B4, B5, or B6 embryo ≥ BB (AA, AB, BA, BB) according to the grading scale proposed by Gardner; KW Kruskal–Wallis test; K Pearson’s chi-square test
Logistic regression to assess risk of duration of estrogen administered
No differences were found between the three groups in terms of HP rate (64.45 versus 68.26 versus 68.92%, P > 0.05), CP rate (57.23 versus 62.05 versus 61.15%, P > 0.05), LB rate (46.82 versus 50.29 versus 48.26%, P > 0.05), and early pregnancy loss rate (11.66 versus 13.28 versus 16.02%, P > 0.05) (group A versus group B versus group C, respectively). Women’s age at retrieval, Em, day of embryo development, and quality of embryo at transfer and transfer rank (2nd versus 1st) were associated with LB in the univariate analysis (Supplemental Table 1). After controlling for these variables, the adjusted RR (aRR) for LB, HP, CP, and early pregnancy loss were similar in group B (LB aOR 1.14, 95% CI 0.89–1.45, HP aOR 1.18, 95% CI 0.91–1.52, CP aOR 1.23, 95% CI 0.96–1.58, EPL aOR 1.23, 95% CI 0.77–1.95) and group C (LB aOR 1.16, 95% CI 0.86–1.56, HP aOR 1.35, 95% CI 0.99–1.84, CP aOR 1.32, 95% CI 0.98–1.78, EPL aOR 1.50, 95% CI 0.88–2.56) when compared with group A.
Obstetric and perinatal complications
Of the 997 women who achieved newborns, 980 women had singletons, and 17 women had twins. Neonatal and delivery outcomes in terms of sex ratio, mean birth weight, mean length, gestational age at delivery, proportion of GDM, and caesarian section were comparable among the three groups. The proportion of PIH was higher in the group C than group A and B, and the difference was not significant. There was one neonatal death in the group A and one in the group B.
Discussion
Over recent years, the number of FET has increased dramatically. However, few studies were published focusing on the effect of duration of estrogen supplementation in autologous blastocyst HRT-FET cycles, and the conclusions were controversial. To our knowledge, the present research is the largest study (n = 2026) of its kind to retrospectively analyze the effect of exposure time of estrogen on ART outcomes in autologous single blastocyst HRT-FET cycles. Univariate and multivariate analyses showed that in HRT-FET cycles, the duration of oral estrogen was not correlated with LBR which is in line with the result of a retrospective study by Sekhon et al. [13].
The receptivity of the endometrium is one of the main factors for the success of embryo transfer [16]. Higher pregnancy rate was achieved in the donor oocyte cycle, suggesting that estrogen and progesterone are critical determinants in establishment of endometrial receptivity [17]. Estrogen is intended to thicken the endometrium, and progesterone is sequentially supplied for conversion of endometrium to receptive state. Previous animal studies suggested that the window of endometrial receptivity would be disrupted if high estrogen was administered, and the expression of some implantation genes were also altered [18–20]. In our center, patients apply the transdermal estradiol gel by a dosimeter themselves, which may cause the difference of dose applied. Hence, we excluded women who applied transdermal estradiol gel or a combination of transdermal and oral estradiol, which could increase the bias of estrogen dosage. Ultimately, in our present study, the dosage of estrogen did not affect the odds of LB through the univariate analysis (Supplemental Table 1), which was consistent with previous studies [7, 21]. A study published by Andrew J Levi etc. [22] compared clinical outcome of patients who undergone IVF-ET after controlled ovarian hyperstimulation (COH) with recipients of donor oocytes. The patients who received IVF-ET after COH had significantly higher AUC (area under the curve) for estrogen exposure compared with donor oocyte recipient (3059 ± 137 versus 2445 ± 123 pg/ml, P < 0.001). Clinical outcomes were nearly identical for both groups (Tables 2 and 3). These results indicated that supraphysiologic estrogen did not alter endometrial receptivity. On the other hand, the range of estrogen may be less restrictive in humans than in animals like mice. Several studies also showed that the dosage and the route of estrogen administration did not have adverse influence on LBR in oocyte donation cycles or autologous oocyte cycles [7, 23].
Table 2.
Clinical outcomes after a frozen-thawed blastocyst transfer
| Estrogen administration days before blastocyst transfer | |||
|---|---|---|---|
| A (11–14 days) | B (15–18 days) | C (≥ 19 days) | |
| n | 346 | 1191 | 489 |
| Primary outcome | |||
| Live birth | |||
| n (%) | 162/346 (46.82) | 599/1191 (50.29) | 236/489 (48.26) |
| Crude model OR (95%CI) | Reference | 1.15 (0.90, 1.46) | 1.06 (0.80, 1.40) |
| Adjusted model OR (95%CI) | Reference | 1.14 (0.89, 1.45) | 1.16 (0.86, 1.56) |
| Secondary outcome | |||
| HCG positive | |||
| n (%) | 223/346 (64.45) | 813/1191 (68.26) | 337/489 (68.92) |
| Crude model OR (95%CI) | Reference | 1.19 (0.92, 1.53) | 1.22 (0.91, 1.64) |
| Adjusted model OR (95%CI) | Reference | 1.18 (0.91, 1.52) | 1.35 (0.99, 1.84) |
| Clinical pregnancy | |||
| n (%) | 198/346 (57.23) | 739/1191 (62.05) | 299/489 (61.15) |
| Crude model OR (95%CI) | Reference | 1.22 (0.96, 1.56) | 1.18 (0.89, 1.56) |
| Adjusted model OR (95%CI) | Reference | 1.23 (0.96, 1.58) | 1.32 (0.98, 1.78) |
| Early pregnancy loss | |||
| n (%) | 26/223 (11.66) | 108/813 (13.28) | 54/337 (16.02) |
| Crude model OR (95%CI) | Reference | 1.16 (0.74, 1.83) | 1.45 (0.88, 2.39) |
| Adjusted model OR (95%CI) | Reference | 1.23 (0.77, 1.95) | 1.50 (0.88, 2.56) |
Note: OR, odds ratio; CI, confidence interval; Crude model, we did not adjust for any covariates; Adjusted model, we adjusted for age at retrieval, Em, triple-line endometrial pattern, transfer rank, day 5/6 blastocyst, quality of blastocyst (good and lower quality blastocyst)
Table 3.
Obstetrical, delivery, and neonatal outcomes
| Variables | Estrogen administration days before embryo or blastocyst transfer | |||
|---|---|---|---|---|
| A (11–14 days) | B (15–18 days) | C (≥ 19 days) | P-value | |
| Live birth (n) | 162 | 599 | 236 | |
| Singleton | 159 (98.15) | 590 (98.50) | 231 (97.88) | 0.815 K |
| Twin | 3 (1.85) | 9 (1.50) | 5 (2.12) | |
| Sex ratio | 0.338 K | |||
| Male (%) | 80 (50.31) | 335 (56.78) | 126 (54.55) | |
| Female (%) | 79 (49.69) | 255 (43.22) | 105 (45.45) | |
| Gestational age at delivery(days) | 272.49 ± 10.41 | 272.05 ± 12.46 | 270.06 ± 13.41 | 0.465 KW |
| Term delivery (%) | 147 (92.45) | 544 (92.20) | 201 (87.01) | 0.051 K |
| Preterm (%) | 12 (7.55) | 46 (7.80) | 30 (12.99) | |
| Mean birth weight(g) | 3369.12 ± 485.93 | 3346.53 ± 527.19 | 3274.98 ± 544.68 | 0.236 KW |
| < 2500 g (%) | 6 (3.77) | 28 (4.75) | 15 (6.49) | 0.361 K |
| 2500–4000 g (%) | 134 (84.28) | 510 (86.44) | 200 (86.58) | |
| > 4000 g (%) | 19 (11.95) | 52 (8.81) | 16 (6.93) | |
| Mean length (cm) | 50.05 ± 1.32 | 49.96 ± 1.84 | 49.78 ± 1.84 | 0.268 KW |
| Gestational diabetes (%) | 9 (5.66) | 32 (5.42) | 10 (4.33) | 0.785 K |
| Pre-eclampsia (%) | 5 (3.14) | 28 (4.75) | 18 (7.79) | 0.093 K |
| Caesarian section (%) | 125 (78.62) | 448 (75.93) | 186 (80.52) | 0.342 K |
| Neonatal mortality (%) | 1 (0.62) | 1 (0.17) | 0 (0) | |
Note: KW Kruskal–Wallis test; K Pearson’s chi-square test
To the best of our knowledge, several studies in oocyte donation programs have shown that duration of estrogen administration influence the clinical outcome, but the “duration” remains controversial. Younis et al. demonstrated that the “duration” should be limited from 12 to 19 days [10]. Michalas et al. put forward that the best “period” was 6–11 days, since the clinical outcome declined with the prolongation of estrogen exposure [9]. Soares et al. showed that the estrogen treatment time could be extended to 7 weeks, without significantly decrease of pregnancy rate [11]. However, Borini A et al. concluded that the “duration” could be extended to 2 months, but the optimal range was 11 to 40 days [12]. Due to the high heterogeneity and small sample sizes of the population, it is very complicated to explain the discrepancy.
To date, there have been several studies about the influence of estrogen administration period before autologous FET on LBR. Bourdon et al. [14] have analyzed the LBR of 1377 single autologous blastocyst HRT-FET cycles. They concluded that the prolonged estrogen exposure decreased the LBR, and the best range of estrogen administration was less than 28 days. Their research population included women whose endometrial thickness was more than 6 mm, but ours was more than 7 mm. They did not mention whether they ruled out women with disorders affecting pregnancy such as intrauterine adhesion, uterine cavity effusion, and untreated hydrosalpinx. And they did not take the dose of estrogen into account. Since there is no limitation number of frozen embryo transfer each day, our clinicians plan transfer day based on personal habits and women’s schedule, and the range of E2 administered in our population is 11–30 days. Hence, it cannot be discriminated whether the difference between Bourdon’s study and our results is attributed to different confounders or to the difference of populations. As talked before, Sekhon et al. [13] concluded that the duration of estrogen treatment before FET did not influence clinical outcome, which was in line with our study. It is worth noting that our results apply to women undergoing routine IVF, and moreover, the range of estrogen duration before blastocyst transfer was different from theirs.
As is known, damaged endometrium tends to respond poorly to estrogen. Hence, for damaged endometrium, estrogen will be supplied more and longer inevitably. The cut-off thickness of endometrium is frequently reported as 7 mm which is related to pregnancy rate [24]. One of the strengths of our study is that we excluded women with endometrium thickness of fresh cycle < 7 mm to avoid the influence of damaged endometrium to some extent. Another strength is that we took into account the effects of several factors like age, embryo quality, ovarian reserve function, transfer rank, and also the dosage of estrogen administration. Multivariate analysis was also conducted to assess the relationship between the duration of estrogen supplementation and clinical outcomes. In addition, our study is the largest (n = 2026) one to study the duration and dose of estrogen before autologous frozen blastocyst transfer as far as we know.
We also recognize some weaknesses of our study. Due to the nature of retrospective study, we could not adjust for all potential confounders, such as smoking status, adjustment of clinicians’ habits and opinions during the study period, and coagulation disorders. Although a study suggested that longer duration and higher dosage of estradiol usage did not affect the clinical outcome in inadequate endometrium (< 8 mm) patients [23], the readers should be cautious to extrapolating to patients older than 38 years of age and endometrium thickness of fresh cycle < 7 mm. In addition, the readers should also be cautious to extrapolating the conclusion to patients who were administered estrogen for more than 30 days. Lastly, the study only included single-center population in northwest China.
In conclusion, the current study concluded that the duration of estrogen administration (range 11–30 days) did not modify the odds of LB, obstetric, and perinatal complications in population of Northwest China. Clinicians could plan the transfer day according to patient and/or clinic preference when the thickness of endometrium is more than 7 mm, and could counsel patients about their clinical outcomes. Further well-designed prospective studies are needed to optimize this finding.
Supplementary Information
Below is the link to the electronic supplementary material.
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Acknowledgements
The authors wish to thank all the staff from Northwest Women’s and Children’s Hospital for their assistance with the data collection, and we thank all the patients in this study.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
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Contributor Information
Na Li, Email: linasmiling@126.com.
Haiyan Bai, Email: bhy1212@126.com.
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