Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization: A Randomized Clinical Trial

Yun Sun; Linlin Cui; Yao Lu; Jichun Tan; Xi Dong; Tianxiang Ni; Junhao Yan; Yichun Guan; Guimin Hao; Jia-Yin Liu; Bo Zhang; Daimin Wei; Yan Hong; Yaqiong He; Jia Qi; Bing Xu; Juanjuan Lu; Qian Zhang; Shanshan Zhao; Xiaowei Ji; Xiaofang Du; Jie Zhang; Jinyong Liu; Jing Wang; Yingqin Huang; Dongmei Huang; Yanzhi Du; Hugo Vankelecom; Heping Zhang; Zi-jiang Chen

doi:10.1001/jama.2023.5302

. 2023 May 2;329(17):1460–1468. doi: 10.1001/jama.2023.5302

Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization

A Randomized Clinical Trial

Yun Sun ^1,^2,^✉, Linlin Cui ^3,^4,^5,^6,^7,⁸, Yao Lu ^1,², Jichun Tan ^9,¹⁰, Xi Dong ¹¹, Tianxiang Ni ^3,^4,^5,^6,^7,⁸, Junhao Yan ^3,^4,^5,^6,^7,⁸, Yichun Guan ¹², Guimin Hao ¹³, Jia-Yin Liu ¹⁴, Bo Zhang ¹⁵, Daimin Wei ^3,^4,^5,^6,^7,⁸, Yan Hong ^1,², Yaqiong He ^1,², Jia Qi ^1,², Bing Xu ^1,², Juanjuan Lu ^3,^4,^5,^6,^7,⁸, Qian Zhang ^3,^4,^5,^6,^7,⁸, Shanshan Zhao ^9,¹⁰, Xiaowei Ji ¹¹, Xiaofang Du ¹², Jie Zhang ¹³, Jinyong Liu ¹⁴, Jing Wang ¹⁴, Yingqin Huang ¹⁵, Dongmei Huang ¹⁵, Yanzhi Du ^1,², Hugo Vankelecom ¹⁶, Heping Zhang ¹⁷, Zi-jiang Chen ^1,^2,^3,^4,^5,^6,^7,⁸

¹Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

²Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

³Center for Reproductive Medicine, Shandong University, Jinan, China

⁴Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China

⁵Shandong Key Laboratory of Reproductive Medicine, Jinan, China

⁶Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China

⁷Shandong Technology Innovation Center for Reproductive Health, Jinan, China

⁸National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China

⁹Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China

¹⁰Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang, China

¹¹Reproductive Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, China

¹²Reproductive Medicine Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

¹³Department of Reproductive Medicine, the Second Hospital of Hebei Medical University, Shijiazhuang, China

¹⁴Department of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, Nanjing, China

¹⁵Center for Reproductive Medicine, Maternal and Child Health Hospital/Obstetrics and Gynecology Hospital of Guangxi Zhuang Autonomous Region, Guangxi, China

¹⁶Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

¹⁷Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut

^✉

Corresponding Authors: Yun Sun, MD, PhD, Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 845 Lingshan Rd, Shanghai 200135, China (syun163@163.com); Zi-Jiang Chen, MD, PhD, Center for Reproductive Medicine, Shandong University, 157 Jingliu Rd, Jinan 250001, China (chenzijiang@hotmail.com).

Accepted for Publication: March 18, 2023.

Author Contributions: Drs Sun and Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Sun, Cui, Y. Lu, Tan, Dong, and Ni contributed equally to this article.

Concept and design: Sun, Cui, Y. Lu, Dong, Guan, J.-Y. Liu, J. Lu, Y. Du, H. Zhang, Chen.

Acquisition, analysis, or interpretation of data: Sun, Y. Lu, Tan, Dong, Ni, Yan, Hao, J.-Y. Liu, B. Zhang, Wei, Hong, He, Qi, Xu, Q. Zhang, Zhao, Ji, X. Du, J. Zhang, J. Liu, Wang, Y. Huang, D. Huang, Y. Du, Vankelecom, H. Zhang, Chen.

Drafting of the manuscript: Sun, Y. Lu, Tan, Dong, Wei, J. Lu, J. Zhang.

Critical revision of the manuscript for important intellectual content: Sun, Cui, Tan, Dong, Ni, Yan, Guan, Hao, J.-Y. Liu, B. Zhang, Wei, Hong, He, Qi, Xu, Q. Zhang, Zhao, Ji, X. Du, J. Liu, Wang, Y. Huang, D. Huang, Y. Du, Vankelecom, H. Zhang, Chen.

Statistical analysis: Y. Lu, Ni, Yan, Wei, He, J. Lu, Q. Zhang, H. Zhang, Chen.

Obtained funding: Sun, Chen.

Administrative, technical, or material support: Sun, Cui, Tan, Dong, Ni, Yan, Guan, Hao, J.-Y. Liu, B. Zhang, Wei, Hong, He, Qi, Xu, Q. Zhang, X. Du, J. Zhang, J. Liu, Wang, Y. Huang, D. Huang, Y. Du, Vankelecom, Chen.

Supervision: Sun, Cui, Dong, Hong, Ji, Chen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This trial was funded by grants 82130046 from the National Natural Science Foundation of China, SHDC2020CR1046B from the Clinical Research Plan of SHDC, and SHSMU-ZLCX20210200, SHSMU-ZLCX20210201 from the Innovative research team of high-level local universities in Shanghai.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank all the women who participated in this study and all the research staff in study sites. We thank the following persons, who participated in data collection and site monitoring: Minzhi Gao, MD, PhD, Gang Sun, PhD, Xueping Huang, BS, and Peiying Li, MD, PhD, at the Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; and for database management Zhangsheng Yu, PhD, at Shanghai Jiao Tong University and Baisong Wang, PhD, at the School of Medicine, Shanghai Jiao Tong University; and for manuscript review Richard S. Legro, MD, at Pennsylvania State College of Medicine, Hershey, and Jiaan Huang, MS, at the Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; and the members of the data and safety monitoring committee: Joe Leigh Simpson, MD (chair), Tin Chiu Li, MD, PhD, Yi Lin, MD, PhD, Jun Zhang, PhD, and Cong Zhang, PhD. No one mentioned herein received compensation for their contributions.

^✉

Corresponding author.

PMCID: PMC10155063 PMID: 37129654

Key Points

Question

Does the use of 10 mg of prednisone, compared with placebo, improve the chances of achieving live birth among women with recurrent implantation failure?

Findings

In this randomized clinical trial that included 715 women who had experienced 2 or more unsuccessful embryo transfer cycles, the live birth rate was 37.8% among women who received 10 mg of prednisone vs 38.8% among women who received placebo, a nonsignificant difference.

Meaning

The findings do not support the routine use of 10 mg of prednisone in women with recurrent implantation failure.

Abstract

Importance

Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate.

Objective

To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure.

Design, Setting, and Participants

A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021).

Interventions

Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy.

Main Outcomes and Measures

The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks’ gestation with signs of life.

Results

Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, −1.0% [95% CI, −8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights.

Conclusions and Relevance

Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure.

Trial Registration

Chinese Clinical Trial Registry Identifier: ChiCTR1800018783

This randomized clinical trial evaluates whether the administration of prednisone would increase the rate of live birth in women with recurrent implantation failure.

Introduction

In vitro fertilization (IVF) is widely used for infertile couples. More than 2 million cycles were performed in Europe, the US,¹ and China² in 2016, with IVF use increasing steadily. Despite substantial advances in assisted reproductive technologies, between 50% and 60% of IVF cycles do not result in a successful implantation.^3,4,5 Recurrent implantation failure (RIF), defined as failure to achieve a clinical pregnancy after repeated embryo transfer attempts, is a commonly encountered condition among patients undergoing IVF, which causes great distress and frustration to both patients and clinicians.⁶ As a result, clinicians may be tempted or feel pressure to “do something different” after 2 or more unsuccessful embryo transfer cycles.⁷ Although various therapeutic interventions have been proposed and used, very few are evidence based.⁸

The establishment of implantation and early pregnancy requires a complex and delicate immunological equilibrium.⁹ Previous research suggested that failure of apparently viable embryos to implant can be caused by irregularities in the cellular adhesion molecules, the imbalance in the network of cytokines, or the overactivity of uterine natural killer cells.¹⁰ According to a 2020 international survey, 69% of clinicians reported that they consider that immunological factors contribute to an RIF diagnosis, and 46% said they would offer immune-regulation therapy in such cases.¹¹

Prednisone is a potent immune-regulatory agent that has been used worldwide to improve embryo implantation and to protect against pregnancy loss for many years.^12,13 Studies have shown its capacity to promote trophoblast proliferation and invasion, to normalize cytokine expression and uterine natural killer cell activity, and to stimulate the secretion of human chorionic gonadotropin (hCG).^14,15 That prednisone is inexpensive, convenient, and generally considered safe at low doses also contributes to its widespread use in clinical practice.¹⁶

Retrospective and prospective studies have indicated that prednisone could positively effect implantation and clinical pregnancy rates.^{9,17,18,19,20,21} However, these studies were also limited by methodological weaknesses including combined regimens of either aspirin or low-molecular-weight heparin (LMWH), small sample size, or nonrandomized or quasi-randomized design. A Cochrane review of 16 randomized trials showed no beneficial evidence of peri-implantation corticosteroids for clinical outcomes among the general IVF population but noted that this conclusion cannot be extrapolated to women with RIF.²²

Despite widespread use of prednisone, no randomized clinical trial has been conducted to evaluate the effect of prednisone on live birth among women with RIF. The 2018 guideline on immunotherapy in IVF by the American Society for Reproductive Medicine appealed for trials to focus on women with implantation failure because it is the subpopulation for which potential benefits may exist.¹⁴ This multicenter, randomized, double-blind, placebo-controlled trial evaluated whether the administration of prednisone would increase the rate of live births in women with RIF.

Methods

Study Design and Setting

This was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted at 8 academic fertility centers in China. The trial was approved by the ethics committees of all centers, and all participants gave written informed consent. A data and safety monitoring board was established to monitor the study. The study protocol, available in Supplement 1, has been published.²³

Study Participants

This trial included women who have undergone 2 or more embryo transfer cycles with good-quality embryos (see eTable 1 in Supplement 2 for the criteria) but did not achieve a clinical pregnancy. Eligible women were younger than 38 years when oocytes were retrieved, were planning to undergo another frozen-thawed embryo transfer cycle, and had at least 1 good-quality blastocyst or 2 good-quality cleavage embryos following IVF or intracytoplasmic sperm injection (ICSI) or preimplantation genetic testing for aneuploidy (Figure). Women with 2 previous failed embryo transfer cycles were eligible only if at least 3 good-quality embryos had been transferred cumulatively.

Figure. — ^aCould have 1 or more reasons for ineligibility or nonenrollment.

^bTransfers canceled because of thin endometrium, elevated progesterone level, personal issues, or other adverse effects.

^cDid not fulfill the criteria for recurrent implantation failure or did not have a history of recurrent pregnancy loss.

^dMedication adherence was considered to be poor if the reported intake of tablets was less than 85% of the total number that participants were expected to have taken.

^eProtocol adherence was defined as any of the following: taking at least 85% of medication; not taking prohibited concomitant medications; following the trial protocol for endometrial preparation or embryo transfer; not missing any more than 2 study visits; fulfilling the eligible criteria; or remaining in the study through completion.

Women were excluded if they had known autoimmune diseases; were currently taking corticosteroids or confounding immunosuppression medications; had diagnosed diseases affecting the cavity; or had a history of recurrent pregnancy loss (defined as ≥2 failed clinical pregnancies), a thin endometrium (<6 mm), or abnormal results on parental karyotyping. Additional exclusion criteria were contraindications to corticosteroid and contraindications to assisted reproductive technologies and/or pregnancy.

Randomization and Blinding

Participants were randomly assigned in a 1:1 ratio to receive either 10 mg of prednisone or placebo (Figure). The randomization sequence was computer generated in the data coordinating center in Shanghai Jiao Tong University School of Medicine. Blocked randomization (sized 4) was used and was stratified by the stage of embryo (blastocyst or cleavage) and center.

Prednisone and placebo were manufactured and donated by Xianju Pharmaceutical Co Ltd. The appearance, size, and odor of placebo tablets were indistinguishable from the prednisone tablets. All tablets were packed for oral administration in identical bottles, each containing 100 tablets. Group allocation was incorporated into the tablet packaging by the data coordinating center via sequential numbering. At subsequent visits, the same number was used to allocate further packs containing the same allocation without revealing group allocation if more packs were required. Participants were asked to bring their remaining tablets to assess medication adherence at each visit. All remaining tablets were collected when the medication was discontinued. The total number of tablets taken was calculated by subtracting the number of tablets remained from the number of tablets dispensed. Medication adherence was considered to be good if the reported intake of tablets was at least 85% of the total number that participants were expected to have taken. Throughout the trial, neither the study personnel nor the participants were aware of the group allocation.

Procedures

After randomization, women were instructed to take 2 prednisone or placebo tablets each day with the onset of endometrial preparation for frozen-thawed embryo transfer and to continue taking them after the transfer. If pregnancy was confirmed, administration of the study medication was continued until week 12 of gestation.

All participants underwent frozen-thawed embryo transfer, for whom a programmed regimen was used for endometrial preparation. In brief, estradiol valerate (Progynova, Delpharm Lille SAS) and/or estradiol tablets (Femoston, Abbott) at a dose of 2 to 8 mg daily began on days 2 through 5 of the menstrual cycle or 28 through 35 days after long-acting gonadotropin-releasing hormone agonist suppression. When the thickness of the endometrium was sufficient, luteal phase support was added with vaginal progesterone gel (Crinone, Merck Serono) 90 mg daily and oral dydrogesterone (Duphaston, Abbott) 10 mg twice daily. One good-quality blastocyst or 2 good-quality cleavage embryos were transferred for each participant, after 5 or 3 days of progesterone administration, respectively. If pregnancy was achieved, oral estradiol was gradually reduced and luteal phase support was continued until 8 to 12 weeks of gestation. We followed up all conceptions until the end of pregnancy and obtained pregnancy and neonatal outcomes through obstetrical and neonatal medical records.

Outcomes

The primary outcome was live birth after embryo transfer, defined as the delivery of any number of newborns at 28 weeks or more of gestation with signs of life. Secondary outcomes included biochemical pregnancy, clinical pregnancy, implantation, pregnancy loss, pregnancy and perinatal complications, birthweight, congenital anomalies, and other adverse events. The definitions of secondary outcomes are provided in eTable 2 in Supplement 2.

Sample Size Calculation

Based on previous meta-analysis or national-based data, the live birth rate among women with 2 or more failed embryo transfer cycles was estimated to be around 20%.^24,25,26 This study was designed to have 80% power to detect an absolute difference of 10% between the prednisone and placebo groups in live birth rate (30% vs 20%) at a 2-sided significance level of .05, requiring a minimum sample of 294 patients for each treatment group. We increased the group sample size to 346 to allow for a dropout rate of 15%.

Statistical Analysis

The primary analysis was done according to the intention-to-treat principle. For categorical variables, between-group differences were assessed by the Pearson χ² test, with the Fisher exact test for expected frequencies of less than 5. The relative ratio (RR) and 95% CI were calculated. For continuous variables, the t test was used if data were normally distributed and the Wilcoxon rank-sum test for nonnormally distributed data. A secondary per-protocol analysis was performed among the participants who adhered to the trial protocol. Protocol nonadherence was defined as any of the following: poor medication adherence (see above), taking prohibited concomitant medications, not following the trial protocol for endometrial preparation or embryo transfer, not attending 2 or more study visits, not fulfilling the eligible criteria, or dropping out before study completion. A logistic regression model was fitted to compare the treatment groups with respect to live birth adjusting for age, body mass index (BMI), number of failed embryo transfer cycles, stage of embryo transferred, and study site. Results were presented with odds ratios (ORs) and 95% CIs. We also performed post hoc analyses stratified by stage of embryos transferred, number of previous failed embryo transfer cycles, and subgroup analyses by age at oocyte retrieval, BMI, previous oocyte retrieval cycles, and autoantibody positivity. A 2-sided P value < .05 was considered to indicate statistical significance. No adjustment was performed for multiplicity of secondary outcomes. All analyses were performed using SPSS version 21.0 (IBM SPSS Inc).

Results

Study Participants

We screened 1027 women, and recruited 715 women (69.6%) who were randomly assigned to receive either prednisone (357 women) or placebo (358 women; Figure). The baseline characteristics of the participants were similar between the 2 study groups (Table 1), as were the characteristics of embryo transfer procedures (Table 2). Forty-seven women (6.6%) did not receive embryo transfer or dropped out of the study (27 or 7.6% in the prednisone group and 20 or 5.6% in the placebo group). The main reasons for not undergoing embryo transfer are presented in Table 2. Additionally, 28 women (7.8%) in the prednisone group and 25 (7.0%) in the placebo group deviated from the study protocol (Figure). The overall proportion of withdrawals and deviations was similar between groups (P = .27). Follow-up was completed in August 2021, which determined the live birth outcome among 714 of 715 participants (99.9%) and the 1 lost to follow-up was treated as a no live birth delivery.

Table 1. Characteristics of the Participants at Baseline.

Characteristics	Prednisone group (n = 357)	Placebo group (n = 358)
Age, y
At consent
Mean (SD)	31.9 (3.5)	32.3 (3.5)
Median (IQR)	32 (30-35)	32 (30-35)
At oocyte retrieval
Mean (SD)	31.1 (3.6)	31.5 (3.5)
Median (IQR)	31 (29-34)	31 (29-34)
BMI, mean (SD)	22.7 (3.1)	22.7 (3.1)
Fertility history, No. (%)
Previous miscarriage	119 (33.3)	114 (31.8)
Previous live birth	56 (15.7)	52 (14.5)
Indications for IVF
Tubal factor	156 (43.7)	141 (39.4)
Male factor	39 (10.9)	57 (15.9)
Ovulatory dysfunction	29 (8.1)	25 (7.0)
Endometriosis	6 (1.7)	9 (2.5)
Combined factors	112 (31.4)	111 (31.0)
Unexplained^a	15 (4.2)	15 (4.2)
Basal follicle-stimulating hormone
No.	356	355
Mean (SD), IU/L	6.7 (2.4)	6.7 (2.0)
Previous oocyte retrievals
Mean (SD)	2.0 (1.3)	2.1 (1.3)
Median (IQR)	2 (1-2)	2 (1-3)
Previous failed embryo transfer cycles
Mean (SD)	2.9 (1.1)	3.0 (1.2)
Median (IQR)	3 (2-3)	3 (2-3)
Failed transfer type, No. (%)
Fresh embryo	250 (24.5)	262 (24.6)
Frozen embryo	771 (75.5)	803 (75.4)
Previous embryos transferred, mean (SD)	4.5 (2.0)	4.7 (2.3)
Previous good-quality embryos transferred, mean (SD)	4.1 (1.7)	4.3 (2.0)
Good-quality cleavage embryos transferred	2.7 (1.9)	2.7 (2.1)
Good-quality blastocysts transferred	1.4 (1.5)	1.6 (1.7)
Previous hysteroscopy, No. (%)	255 (71.4)	256 (71.5)

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Abbreviations: BMI, body mass index, calculated as weight in kilograms divided by the square of the height in meters; IVF, in vitro fertilization.

^{^a}

Unexplained infertility is defined as the absence of identifiable causes for the infertility.

Table 2. Outcomes of Endometrial Preparation and Embryo Transfer.

Characteristics	Prednisone group (n = 357)	Placebo group (n = 358)
Endometrial thickness
No.	342	354
Mean (SD), mm	9.1 (1.7)	8.9 (1.6)
No. of embryos transferred
Mean (SD)	1.3 (0.4)	1.3 (0.4)
Single embryo transfer, No. (%)	241 (73.0)	250 (74.0)
Double embryo transfer, No. (%)	89 (27.0)	88 (26.0)
Embryo(s) transferred, No. (%)^a
Day 3	79 (23.9)	80 (23.7)
Day 5	168 (50.9)	183 (54.1)
Day 6	83 (25.2)	75 (22.2)
Euploid blastocyst transfer, No. (%)	26 (7.9)	20 (5.9)
Did not undergo embryo transfer, No. (%)
No. of cycles	27 (7.6)	20 (5.6)
Reasons
Personal issue	12 (3.4)	10 (2.8)
Thin endometrium	4 (1.1)	5 (1.4)
Elevated progesterone level	4 (1.1)	1 (0.3)
Adverse effects	7 (2.0)	4 (1.1)
Vaginitis	3 (0.8)	1 (0.3)
Vaginal bleeding	1 (0.3)	1 (0.3)
Hyperthyroidism	1 (0.3)	1 (0.3)
Allergy	1 (0.3)	0
Upper respiratory tract infection	1 (0.3)	0
Abdominal pain	0	1 (0.3)

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^{^a}

Day of embryo transferred represented days of embryos cultured in vitro.

Primary Outcome

In the intention-to-treat analysis, the live birth rate was 37.8% (135 of 357) in the prednisone group, and 38.8% (139 of 358) in the placebo group (absolute difference, −1.0% [95% CI, −8.1% to 6.1%]; RR, 0.97 [95% CI, 0.81 to 1.17; P = .78; Table 3). The frequency of singleton live births was similar between groups. The frequency of the twin live birth rate was 4.2% in the prednisone group and 1.7% in the placebo group (absolute difference, 2.5% [95% CI, 0.1% to 5.0%]; RR, 2.51 [95% CI, 0.98 to 6.39]; P = .05).

Table 3. Live Birth, Pregnancy, and Pregnancy Loss.

Outcome	Prednisone group (n = 357)	Placebo group (n = 358)	Absolute difference (95% CI), %^a	Relative ratio (95%CI)	P value^b
Primary outcome
Live birth, No. (%)^c	135 (37.8)	139 (38.8)	−1.0 (−8.1 to 6.1)	0.97 (0.81 to 1.17)	.78
Singleton	120 (33.6)	133 (37.2)	−3.5 (−10.5 to 3.5)	0.90 (0.74 to 1.10)	.32
Twin	15 (4.2)	6 (1.7)	2.5 (0.1 to 5.0)	2.51 (0.98 to 6.39)	.05
Secondary outcomes
Birthweight, mean (SD), g
Singleton	3361 (597)	3377 (543)	−16 (−158 to 125)	NA	.82
Twin	2488 (484)	2473 (487)	15 (−320 to 350)	NA	.93
Biochemical pregnancy, No. (%)^d	196 (54.9)	182 (50.8)	4.1 (−3.3 to 11.4)	1.08 (0.94 to 1.24)	.28
Implantation, No. (%)^e	178/419 (42.5)	172/426 (40.4)	2.1 (−4.5 to 8.8)	1.05 (0.90 to 1.24)	.53
Clinical pregnancy, No. (%)^f	161 (45.1)	163 (45.5)	−0.4 (−7.7 to 6.9)	0.99 (0.84 to 1.16)	.91
Pregnancy loss, No. (%)	61/196 (31.1)	42/182 (23.1)	8.0 (−0.9 to 17.0)	1.35 (0.96 to 1.89)	.08
Biochemical pregnancy loss	34 /196 (17.3)	18/182 (9.9)	7.5 (0.6 to 14.3)	1.75 (1.03 to 2.99)	.04
Clinical pregnancy loss	26/161 (16.2)	23/163 (14.1)	2.0 (−5.8 to 9.8)	1.14 (0.68 to 1.92)	.61
First trimester	22/161 (13.7)	21/163 (12.9)	0.8 (−6.6 to 8.2)	1.06 (0.61 to 1.85)	.84
Second trimester	4/161 (2.5)	2/163 (1.2)	1.3 (−1.7 to 4.2)	2.02 (0.38 to 10.90)	.45

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Abbreviation: NA, not applicable.

^{^a}

Absolute differences between percentages are given in percentage points; absolute differences between other values are given in the unit indicated for that value.

^{^b}

P value is generated with Pearson χ² test or Fisher exact test as appropriate.

^{^c}

Live birth was defined as the delivery of a live-born infant after 28 weeks or more of gestation. However, 1 delivery at 26 weeks, 1 day was counted as a live birth. One patient in the placebo group was lost to follow-up after the 37th week of gestation.

^{^d}

Biochemical pregnancy was defined as a serum level of human chorionic gonadotropin of more than 10 mIU/mL.

^{^e}

Implantation rate was calculated as number of intrauterine gestational sacs divided by number of embryos that were transferred.

^{^f}

Clinical pregnancy was defined as the observation of an intrauterine gestational sac on ultrasonographic scan.

Results of the per-protocol analysis were similar with the intention-to-treat analysis (eTable 3 in Supplement 2). One hundred twenty-three women of 302 women (40.7%) in the prednisone group and 126 of 312 women (40.4%) in the placebo group achieved a live birth (absolute difference, 0.3% [95% CI, −7.4% to 8.1%]; RR, 1.01 [95% CI, 0.83 to 1.22]; P = .93). Results of logistic regression did not reveal significant association between prednisone use and live birth (adjusted OR, 0.95 [95% CI, 0.69 to 1.31]; P = .75).

Secondary Outcomes

The rate of biochemical pregnancy loss was higher in the prednisone group than the placebo group (17.3% vs 9.9%; absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04) (Table 3). The rate of preterm delivery was 11.8% in the prednisone group and 5.5% in the placebo group (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). The rate of hyperemesis gravidarum was 0.6% in the prednisone group and 4.9% in the placebo group (absolute difference, −4.3% [95% CI, −7.8% to - 0.8%]; RR, 0.13 [95% CI, 0.02 to 1.00]; P = .04). No significant differences were observed for the other secondary outcomes (Table 4; eTable 4 in Supplement 2).

Table 4. Maternal, Fetal, and Neonatal Adverse Events.

Outcome	No./total (%)		Absolute difference (95% CI)
Outcome	Prednisone group (n = 357)	Placebo group (n = 358)	Absolute difference (95% CI)
Maternal
First trimester
Vaginal bleeding^a	21/196 (10.7)	16/182 (8.8)	1.9 (−4.1 to 7.9)
Hyperemesis gravidarum^b	1/161 (0.6)	8/163 (4.9)	−4.3 (−7.8 to −0.8)
Ectopic pregnancy^a	1/196 (0.5)	2/182 (1.1)	−0.6 (−2.4 to 1.2)
Infection^b	0/161	2/163 (1.2)	−1.2 (−2.9 to 0.5)
Upper respiratory tract infection	0/161	1/163 (0.6)	−0.6 (−1.8 to 0.6)
Tuberculosis	0/161	1/163 (0.6)	−0.6 (−1.8 to 0.6)
Second and third trimester
Gestational diabetes^b	23/161 (14.3)	20/163 (12.3)	2.0 (−5.4 to 9.4)
Preterm delivery^b	19/161 (11.8)	9/163 (5.5)	6.3 (0.2 to 12.4)
Singleton	11/144 (7.6)	6/152 (3.9)	3.7 (−1.6 to 9.0)
Twin	8/17 (47.1)	3/11 (27.3)	19.8 (−15.6 to 55.2)
Premature rupture of membrane^b	12/161 (7.5)	9/163 (5.5)	1.9 (−3.4 to 7.3)
Gestational hypertension^b	6/161 (3.7)	5/163 (3.1)	0.7 (−3.3 to 4.6)
Preeclampsia^b	4/161 (2.5)	4/163 (2.5)	0.0 (−3.4 to 3.4)
Anemia^b	3/161 (1.9)	7/163 (4.3)	−2.4 (−6.2 to 1.3)
Placenta previa^b	2/161 (1.2)	2/163 (1.2)	0.0 (−2.4 to 2.4)
Placental abruption^b	0/161	2/163 (1.2)	−1.2 (−2.9 to 0.5)
Threatened preterm delivery^b	2/161 (1.2)	1/163 (0.6)	0.6 (−1.5 to 2.7)
Cervical incompetence^b	1/161 (0.6)	5/163 (3.1)	−2.4 (−5.4 to 0.5)
After delivery
Postpartum hemorrhage^c	2/135 (1.5)	3/139 (2.2)	−0.7 (−3.8 to 2.5)
Postpartum anemia^c	2/135 (1.5)	2/139 (1.4)	0.0 (−2.8 to 2.9)
Puerperal infection^c	1/135 (0.7)	0/139	0.7 (−0.7 to 2.2)
Fetal, after 12 wk through neonatal period
Neonatal jaundice^d	37/150 (24.7)	48/145 (33.1)	−8.4 (−18.7 to 1.9)
Neonatal hospitalization >3 d^d	20/150 (13.3)	24/145 (16.6)	−3.2 (−11.4 to 4.9)
Congenital anomalies^d	8/150 (5.3)	6/145 (4.1)	1.2 (−3.6 to 6.0)
Neonatal infection^d	7/150 (4.7)	3/145 (2.1)	2.6 (−1.5 to 6.7)
Neonatal respiratory distress syndrome^d	3/150 (2.0)	3/145 (2.1)	−0.1 (−3.3 to 3.2)
Neonatal death^d	1/150 (0.7)	0/145	0.7 (−0.6 to 2.0)
Low birth weight^d^,^e	18/150 (12.0)	11/145 (7.6)	4.4 (−2.3 to 11.2)
Very low birth weight^d^,^f	4/150 (2.7)	2/145 (1.4)	1.3 (−1.9 to 4.5)
Macrosomia^d^,^g	11/150 (7.3)	13/145 (9.0)	−1.6 (−7.9 to 4.6)
Birth-weight percentile among singletons^d
<10th	16/150 (10.7)	11/145 (7.6)	3.1 (−3.5 to 9.6)
>90th	24/150 (16.0)	25/145 (17.2)	−1.2 (−9.7 to 7.3)

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^{^a}

Among biochemical pregnancies.

^{^b}

Among clinical pregnancies.

^{^c}

Among all deliveries.

^{^d}

Among live newborns.

^{^e}

Birth weight lower than 2500 g.

^{^f}

Birth weight lower than 1500 g.

^{^g}

Macrosomia was defined as birth weight larger than 4000 g.

Results of the per-protocol analysis were generally consistent with those of the primary analysis, except the between-group differences in the rates of biochemical pregnancy loss (16.4% vs 10.9%; absolute difference, 5.5% [95% CI, −1.8% to 12.7%]; RR, 1.50 [95% CI, 0.87 to 2.60]; P = .14) and preterm delivery (11.6% vs 5.5%; absolute difference, 6.1% [95% CI, −0.3% to 12.4%]; RR, 2.11 [95% CI, 0.94 to 4.74], P = .06) were no longer significant (eTables 3 and 5 in Supplement 2).

Post Hoc Analyses

No between-treatment-group differences in live birth rates were observed among women with cleavage or blastocyst transfers (eTables 6 and 7 in Supplement 2) or among women with 2, 3, 4, and 5 or more previous failed embryo transfer cycles (eTables 8-12 in Supplement 2). Exploratory subgroup analyses did not reveal significant between-treatment-group differences (eTable 13 in Supplement 2).

Discussion

This large multicenter, randomized, double-blind, placebo-controlled trial suggested that daily administration of 10 mg of prednisone during the peri-implantation and early pregnancy period did not improve the live birth rate among women with RIF. There were also no statistically significant differences between the groups in the rates of clinical pregnancy and implantation.

Previous studies have hypothesized that prednisone could provide a more receptive uterine environment for embryo implantation mediated by its anti-inflammatory and immune-regulatory properties.^10,14,15 The current study’s findings are inconsistent with 2 previous prospective trials involving women with implant failures that reported significant benefits.^20,21 Specifically, Fawzy et al²⁰ included 295 women with 1 or 2 unsuccessful ICSI attempts in a quasi-randomized trial; results showed that the combination of prednisolone and LMWH significantly increased the rates of successful implantation (23.9% vs 14.7%, P < .001) and clinical pregnancy (40.7% vs 27.5%, P = .02). Fan et al²¹ recruited 133 women with 1 failed IVF cycle, who had tested positive for antinuclear antibody, and also demonstrated that combined treatment of prednisone and aspirin could improve implantation rates (27.4% vs 13.6%, P = .002) and clinical pregnancy rates (53.3% vs 30.1%, P = .007). Both studies were open-label and investigated the effect of prednisone in combination with another agent (LMWH or aspirin); whereas the current trial evaluated the effect of prednisone in a double-blind, placebo-controlled setting without coadministrated medications. These findings are consistent with a Cochrane meta-analysis that found no beneficial effect of peri-implantation corticosteroids in a nonselected IVF population, with regard to live birth, clinical pregnancy, and miscarriage rates.²²

Although the rates of overall pregnancy loss were similar between the 2 groups in this current trial, the risk of biochemical pregnancy loss appeared to be increased in the prednisone group. This is probably because prednisone could stimulate the secretion of hCG,¹⁵ even though it did not increase the chance of implantation, leading to higher risk of pregnancy loss before clinical pregnancy.

There appears to be an increased risk of preterm delivery in women being treated with prednisone than with placebo, which may be partly due to a higher twin live birth rate in the prednisone group. It is also noteworthy that the increased risk of prematurity introduced by corticosteroids has been constantly reported since the 1990s.^27,28 Similar associations were observed in women with recurrent pregnancy loss, asthma, and rheumatoid arthritis when the dose of oral corticosteroid exposure was 10 mg or more of prednisone equivalent daily during early pregnancy.^27,29,30

The incidence of hyperemesis gravidarum trended less in the prednisone group in this trial. This is not entirely unexpected because corticosteroids have been postulated to modify the chemoreceptor trigger zone, for which it has been used as a third-line treatment for severe hyperemesis gravidarum.^31,32

To our knowledge, this is the first multicenter, double-blind, placebo-controlled trial evaluating the effect of 10 mg of prednisone on women with RIF. The primary outcome, live birth rate, was the most recommended and patient-centered outcome for infertility trials. The setting of frozen-thawed embryo transfer cycles allowed us to eliminate the detrimental effect that ovarian stimulation might have on endometrial receptivity.^3,33 Moreover, as the past 10 years have demonstrated that a rapid rise in the use of embryo cryostorage and frozen-thawed embryo transfer, which accounts for approximately 60% of all assisted reproductive technologies cycles,^1,2,34 results were expected to be generalizable to the current practice setting.

These findings have practice-changing implications for millions of patients with RIF worldwide. The Canadian Fertility and Andrology Society and the British Fertility Society consecutively published guidelines regarding the management of RIF in 2020 and 2021, both concluded that immunotherapies, including corticosteroids, remained largely empirical for RIF and additional data were required to make a firm recommendation.^7,8 The results herein suggested that treatment with 10 mg of prednisone was ineffective and unnecessary among our study population. Along with the possibly increased risk of preterm delivery and biochemical pregnancy loss, these findings may add evidence to recommend against the routine use of 10 mg of prednisone for women with RIF in clinical practice. Moreover, besides corticosteroids, other adjuvant immunotherapies such as intravenous immunoglobulin and intralipids have also been provided to patients while clinical evidence remains insufficient.¹⁴ The current trial may serve as an alarm that costly add-ons with uncertain benefits and potential risks should not be recommended routinely until efficacy and risk assessment are clearly demonstrated in adequately powered and well-designed randomized trials.

Limitations

Several limitations should be considered in this study. First, for safety reasons, the effect of oral prednisone at a dose of 10 mg daily to avoid serious infections during pregnancy was studied,³⁵ so these results may not be applicable to patients receiving other doses or regimens. Second, although there seemed to be no increase in the risk of neonatal complications or congenital anomalies among offspring of women treated with prednisone during early pregnancy, this study was neither designed nor powered to show differences for these outcomes. Additionally, the observed live birth rate was higher than expected in both groups. This may be partly due to the utilization of frozen-thawed embryo transfer. Another possible reason was that only women with the availability of good-quality embryos were recruited, while those with no embryos or poor-quality embryos were excluded before randomization. Thus participants in this trial had relatively good prognosis. We should be cautious to extrapolate these results to women with less favorable prognosis.

Conclusions

Among women with recurrent implantation failure, the administration of 10 mg of prednisone, compared with placebo, did not significantly improve the rate of live birth. Given the possible additional risk of preterm delivery and biochemical pregnancy loss along with its administration, these data results do not support the routine use of 10 mg of prednisone for the treatment of recurrent implantation failure.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(309.3KB, pdf)}

Supplement 2.

eTable 1. Criteria of good-quality embryo

eTable 2. Definition of secondary outcomes

eTable 3. Live birth, Pregnancy, and Pregnancy loss among patients who complied with the protocol

eTable 4. Details of congenital anomalies based on the intention to treat analysis

eTable 5. Maternal, Fetal and Neonatal Adverse Events among patients who complied with the protocol

eTable 6. Live birth, Pregnancy, and Pregnancy loss among patients with cleavage embryo transfer cycles

eTable 7. Live birth, Pregnancy, and Pregnancy loss among patients with blastocyst transfer cycles

eTable 8. Live birth rate among patients with 2, 3, 4, and 5 or more failed embryo transfer cycles

eTable 9. Live birth, Pregnancy, and Pregnancy loss among patients with 2 failed embryo transfer cycles

eTable 10. Live birth, Pregnancy, and Pregnancy loss among patients with 3 failed embryo transfer cycles

eTable 11. Live birth, Pregnancy, and Pregnancy loss among patients with 4 failed embryo transfer cycles

eTable 12. Live birth, Pregnancy, and Pregnancy loss among patients with 5 or more failed embryo transfer cycles

eTable 13. Live birth between prednisone and placebo in subgroup analysis

Click here for additional data file.^{(324.6KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(12.6KB, pdf)}

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