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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 169-176

Effects of endometrial stimulation timings and techniques on pregnancy outcomes in patients without prior embryo transfer: A systematic review and meta-analysis


1 Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
2 Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Date of Submission23-Dec-2019
Date of Decision21-Feb-2020
Date of Acceptance19-Jun-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Jun Zhai
Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.296549

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  Abstract 


Objective: To investigate the effects of endometrial stimulation timings and techniques on pregnancy outcomes in patients without prior embryo transfer (ET).
Methods: We included a total of 10 studies related to the impact of endometrial stimulation on the pregnancy outcome of infertile patients with the first ET from 2010 to 2019. These studies were found by searching databases including China Science and Technology Journal Database (VIP), Chinese Biological Med (CBM), Chinese Medical Current Content (CMCC), China National Knowledge Internet (CNKI), WanFang Med Online, Cochrane Library, Web of Science, PubMed, Medline, ScienceDirect, and EMBASE. A total of 1,983 cycles were included, of which 725 were cycles with endometrial stimulation. Clinical outcomes included clinical pregnancy, implantation, abortion, multiple pregnancy, and live birth rate.
Results: The implantation rate (IR) was higher in the fresh cycle endometrial stimulation group than in the control group (relative risk [RR] = 1.21, 95% confidence interval [CI] = 1.03–1.42; P = 0.02), but there were no significant between-group differences in the live birth rate (LBR) and abortion rate (AR). Subgroup analysis showed that whether follicular or luteal endometrial stimulation was performed before the ET cycle had no effect on the clinical pregnancy outcome, and endometrial stimulation on the day of oocyte retrieval reduced the clinical pregnancy rate (CPR) (RR = 0.37, 95% CI = 0.19–0.75; P = 0.005). Whether the technique involved the use of a curette or catheter, there was no significant between-group difference in CPR.
Conclusions: Fresh cycle endometrial stimulation can improve the embryo IR in patients without prior ET, but it cannot increase CPR, LBR, or AR. Subgroup analysis showed that different endometrial stimulation timings and techniques did not significantly improve CPR and that endometrial stimulation on the day of oocyte retrieval reduced CPR.

Keywords: Endometrial Injury; Endometrial Stimulation; In vitro Fertilization/Intracytoplasmic Sperm Injection; Pregnancy Outcomes


How to cite this article:
Cao YR, Shi H, Zhai J. Effects of endometrial stimulation timings and techniques on pregnancy outcomes in patients without prior embryo transfer: A systematic review and meta-analysis. Reprod Dev Med 2020;4:169-76

How to cite this URL:
Cao YR, Shi H, Zhai J. Effects of endometrial stimulation timings and techniques on pregnancy outcomes in patients without prior embryo transfer: A systematic review and meta-analysis. Reprod Dev Med [serial online] 2020 [cited 2020 Oct 29];4:169-76. Available from: https://www.repdevmed.org/text.asp?2020/4/3/169/296549




  Introduction Top


The mechanism of embryo implantation is complex; a high-quality embryo and good endometrial receptivity are the most important factors for successful embryo implantation. In 1907, Loeb et al.[1] first found that local scratching can promote the decidualization of endometrial cells in guinea pig animal models. Recently, a large number of clinical randomized controlled studies and meta-analyses have reported that in cases of artificial insemination, frozen-thawed embryo transfer (ET) cycles, or previous transplant failure, or in patients with recurrent miscarriage, endometrial stimulation is helpful for embryo implantation, and it significantly improves the pregnancy rate. The reason for this could be that endometrial stimulation may remove aging cells and cells with abrupt pathological changes in the lining; stimulate endometrial growth; accelerate endometrial decidualization; promote the production of implantation-related local factors, such as homeobox protein, transforming growth factor, and interleukins; and improve endometrial receptivity, thus improving the pregnancy outcomes. However, for patients without prior ET, it remains unclear whether it is beneficial to increase the pregnancy rate by performing endometrial stimulation before embryo transplantation. Studies investigating whether different endometrial stimulation timings and techniques influence the pregnancy outcomes have reported different results;[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] therefore, this remains unclear. The purpose of this study was to systematically evaluate through literature review the clinical application value of endometrial stimulation in infertile patients undergoing their first ET and to analyze whether different endometrial stimulation timings and techniques have an impact on pregnancy outcomes.


  Methods Top


Search strategy

We searched multiple electronic databases, including China Science and Technology Journal Database (VIP), Chinese Biological Med (CBM), Chinese Medical Current Content (CMCC), China National Knowledge Internet (CNKI), WanFang Med Online, Cochrane Library, Web of Science, PubMed, Medline, ScienceDirect, and EMBASE, from their inception until January 2019. The key search words were as follows:in vitro fertilization OR embryo transfer OR IVF-ET OR ICSI OR randomized controlled trial (S) endometrium OR endometrial injury OR endometrial scratch OR endometrial trauma OR endometrial damage.

Inclusion and exclusion criteria

Inclusion criteria

  1. Studies that were controlled clinical trials, whether prospective or retrospective, and that were in Chinese or English
  2. Studies including infertile patients without prior ET
  3. Studies with intervention methods: The intervention group received endometrial stimulation including endometrial biopsy under hysteroscopy (Pipelle catheter, scoop); operation time and manner were not limited. The control group received ineffective intervention or no intervention at the same time
  4. Studies with a clearly defined sample size
  5. Studies with the following main outcome measures: Clinical pregnancy rate (CPR), implantation rate (IR), abortion rate (AR), and live birth rate (LBR).


Exclusion criteria

  1. Studies including patients with diseases that affect pregnancy rate: Hydrosalpinx, tubal tuberculosis, mediastinal uterus, unicorn uterus, saddle uterus, endometrial polyps, endometrial tuberculosis, and other endocrine diseases
  2. An unclear or undefined sample size, or literature lacking original data for a comparative analysis.


Search outcome

Based on the aforementioned inclusion and exclusion criteria, 20 articles were included. Further, nine articles were excluded because of unclear intervention methods and incomplete results, and one article was excluded because of low evaluation quality. Finally, 10 studies were included in the meta-analysis, including nine randomized controlled studies and one retrospective study from 2010 to 2019. The retrieval process is shown in [Figure 1].
Figure 1: Flow diagram of literature retrieval.

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Study selection and data extraction

At least two researchers independently screened the titles and abstracts, evaluated the study content, and checked the references of the retrieved studies. After that, the selected studies were checked again. Any disagreement between the two researchers was resolved by discussion or through judgment by a third party. Finally, a researcher extracted study characteristics, population (number and inclusion criteria), interventions (tools and timing), collaborative interventions (hysteroscopy, antibiotics), ET cycles (ovarian stimulation, ET), and study results. Another researcher examined the entire data and process.

Technology quality assessment

The nine included randomized controlled studies were evaluated and graded based on the improved Jadad scale from the Cochrane collaboration RCT evaluation manual, which included following standards: random sequence generation, allocation concealment, blinding method, consistent baselines, incomplete outcome data (percentage of lost visits and exits was controlled within 20%), and intention-to-treat. Compliance with the specification is 1 point, otherwise 0 points. Aggregate score is 5, and 3–5 are high-quality literature divided into A Grade. 0–2 are classified as low-quality literature divided into B or C Grade. The included retrospective cohort study was evaluated against the Newcastle–Ottawa Scale (NOS) including three parts: study population selection (case-cohort representative; selection of nonexposed control group; ascertainment of exposure; outcome negative at start), intergroup comparability (comparability by design and analysis), and outcome measurement (outcome assessment; completion of follow-up; duration of follow-up). Each entry in the study population selection and outcome measurement sections can get at most one “*”, which means 1 point, and the intergroup comparability section get a maximum of 2 points. Aggregate score: 9 points. The higher the score, the higher the quality of the literature. We define a score of 0 in any part of the NOS as a high risk of bias in the literature, a score of 1 in any part is defined as a moderate bias risk of the literature, and score of ≥2 in each part is defined as a low risk of bias in the literature.

Outcome measures

The primary outcome was CPR. Secondary outcomes included IR, LBR, and AR. Clinical pregnancy was defined as the presence of an intrauterine gestational sac on ultrasound at 5–6 weeks with heart beat or other definitive clinical signs. The IR was the number of sacs detected on ultrasound divided by the number of embryos transferred. The LBR was defined as the ratio of the number of births divided by the total number of cycles undergoing embryos transfer. AR was the number of patients who had a spontaneous abortion before 24 weeks of pregnancy divided by the total number of clinical pregnancies.

Statistical analysis

Meta-analysis was performed using RevMan 5.3 software (The Cochrane Collaboration https://training.cochrane.org). Relative risk (RR) and 95% confidence interval [CI] were used to count data, and the test level was P < 0.05, indicating that the difference was statistically significant. Measurement data were expressed by weighted mean (MD) and 95% CI. When P > 0.1 and I2< 50%, the fixed effects model is selected. When P < 0.1 and I2 > 50%, heterogeneity exists among studies; the sources of heterogeneity were analyzed, and subgroup analysis was performed. If heterogeneity persisted, the random effects model was selected. Sensitivity analysis and publication bias were assessed using Stata 12.0 software (Statacorp LLC., Texas, USA), and the existence of publication bias was observed according to Begg's and Egger's tests of a biased P value and funnel plot symmetry.


  Results Top


Study selection and study characteristics

Ten articles were included in the meta-analysis, including nine randomized controlled studies and one retrospective study. There was a total of 1,983 participants, including 725 in the intervention group and 1,258 in the control group. The basic characteristics and technology quality assessment of the included studies are presented in [Supplementary Table 1], [Supplementary Table 1], [Supplementary Table 1].



Meta-analysis results

Clinical pregnancy rate

Ten studies reported CPR (n = 1,983). After examination, a high degree of heterogeneity was found among the studies (P < 0.00001, I2 = 78%), which required subgroup analysis. The random effects model was selected for meta-analysis, and the results showed that there was no significant difference in CPR between the two groups (RR = 1.11, 95% CI = 0.84–1.47; P = 0.46) [Figure 2]a.
Figure 2: (a) Effect of endometrial stimulation on CPR; (b) Effect of endometrial stimulation on IR; (c) Effect of endometrial stimulation on LBR; (d) Effect of endometrial stimulation on AR. CRP: Clinical pregnancy rate; IR: Implantation rate; AR: Abortion rate; LBR: Live birth rate.

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Implantation rate

Six studies reported IR, and four of them were statistically analyzed (n = 1,602). After examination, no heterogeneity was found among the studies (P = 0.14, I2 = 45%). The fixed effects model was selected for meta-analysis. The intervention experiment group had higher IR than the control group (RR = 1.21, 95% CI = 1.03–1.42; P = 0.02) [Figure 2]b.

Live birth rate

Three studies reported LBR (n = 704). After examination, a high degree of heterogeneity was found among the studies (P < 0.0001, I2 = 91%). Because of few articles included, no subgroup analysis was performed. A random effects model was selected for meta-analysis, and the results showed that there was no significant difference in LBR between the two groups (RR = 1.36, 95% CI = 0.71–2.60; P = 0.35) [Figure 2]c.

Abortion rate

Five studies reported AR (n = 684). After examination, no heterogeneity was found among the studies (P = 0.17, I2 = 37%). The fixed effects model was selected for meta-analysis. No benefit of endometrial stimulation was observed (RR = 0.84, 95% CI = 0.56–1.26; P = 0.40) [Figure 2]d.

Subgroup analysis

A high degree of heterogeneity was found among the studies for the analysis of CPR (P < 0.00001, I2 = 78%); therefore, the random effects model was used for subgroup analysis. The results showed that endometrial stimulation on the day of oocyte retrieval had a negative influence on CPR (RR = 0.37, 95% CI = 0.19–0.75; P = 0.005). There was no significant difference in CPR between the follicular endometrial stimulation group and the control group (RR = 0.95, 95% CI = 0.56–1.6; P = 0.84). A high degree of heterogeneity (P = 0.001, I2 = 68%) persisted among the included studies in the luteal endometrial stimulation subgroup; therefore, sensitivity analysis was further performed. In addition, subgroup and sensitivity analyses were performed to determine whether the types of ET cycles and endometrial stimulation techniques affected CPR. The results showed that whether it was a fresh ET cycle or a frozen-thawed cycle (RR = 1.12, 95% CI = 0.82–1.52; P = 0.49) and whether a catheter or a curette was used (RR = 1.12, 95% CI = 0.84–1.49; P = 0.44) did not affect CPR. However, due to the high heterogeneity of the fresh cycle subgroup (P < 0.00001, I2 = 82%) and the catheter subgroup (P = 0.002, I2 = 69%) included in each study, sensitivity analysis was adopted to explore the sources of heterogeneity [Figure 3]].
Figure 3: Subgroup analysis (a) Effect of endometrial stimulation timing on CPR; (b) Effect of ET cycle on CPR; (c) Effect of endometrial stimulation technique on CPR. CRP: Clinical pregnancy rate; ET: Embryo transfer.

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Sensitivity analysis

Sensitivity analysis was performed after the studies included in each index were serially removed; the results obtained were compared with those obtained before the exclusion to observe the influence of the combined effect and the stability of the results. The results obtained for the LBR, AR, and CPR of fresh ET cycle endometrial stimulation subgroup showed no significant changes, indicating that the sensitivity was low and that the results were stable and reliable. When analyzing the influence of luteal endometrial stimulation on CPR, after excluding the studies of Mahran et al.[4] or Frantz et al.,[7] the results were found to have changed: there was a significant difference in CPR between the intervention group and the control group (RR = 1.18, 95% CI = 1.02–1.37; P = 0.03. RR = 1.34, 95% CI = 1.07–1.69; P = 0.01). In the catheter subgroup, excluding the study of Mahran et al.,[4] CPR in the intervention group was significantly higher than that in the control group (RR = 1.20, 95% CI = 1.02–1.42; P = 0.03). The results showed high sensitivity and low robustness, which may be due to the different inclusion and exclusion criteria of the subjects. After excluding the studies of Maged et al.[5] or Yeung et al.,[3] the results obtained for IR changed. There was no significant difference between the intervention group and the control group (RR = 1.11, 95% CI = 0.90–1.36; P = 0.32. RR = 1.15, 95% CI = 0.95–1.38; P = 0.15). The results showed high sensitivity and low robustness, which may be due to the small number of included studies [Figure 4].
Figure 4: Sensitivity analysis (a) Effect of luteal endometrial stimulation on CPR; (b) Effect of using catheter on CPR; (c) Effect of fresh ET cycle on CPR; (d) Effect of endometrial stimulation on IR. CRP: Clinical pregnancy rate; IR: Implantation rate.

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Publication bias

Publication bias was also assessed. The funnel plot of CPR (a) or LBR (c) is asymmetric and skewed, and the results of Begg's and Egger's tests of CPR (a) and LBR (c) were inconsistent (CPR: Begg's test Pr > |z| = 0.21 > 0.05; Egger's test P > |t| = 0.023 < 0.05 and LBR: Begg's test Pr > |z| = 0.296 > 0.05; Egger's test P > |t| = 0.009 < 0.05). This may show the existence of publication bias. For IR (b) and AR (d), all Begg's and Egger's tests showed P > 0.05, and the funnel plot was basically symmetrical. The distribution of the effect values of included literature is more scattered, and most of them are arranged symmetrically around the center line, showing that publication bias was less likely [Figure 5].
Figure 5: Funnel plot of publication bias (a) CPR; (b) IR; (c) LBR; (d) AR. CRP: Clinical pregnancy rate; IR: Implantation rate; LBR: Live birth rate; AR: Abortion rate.

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  Discussion Top


The question of how to improve endometrial receptivity of infertile patients to improve CPR has long been a hot topic in reproductive medicine. The current methods thought to improve endometrial receptivity include hormone regulation, anticoagulant application, endometrial mechanical stimulation, intrauterine perfusion, and hydrosalpinx amputation.

Research on endometrial mechanical stimulation to promote embryo implantation mainly focuses on the inflammatory mechanism and gene regulation. Endometrial local injury induces inflammation, thereby increasing tumor necrosis factor alpha levels, which is necessary to initiate the inflammatory reaction, and induces macrophage inflammatory protein-1b (MIP-1b) expression. The levels of growth-regulating oncogene-α (GRO-α) and interleukin 15 also increase. MIP-1b, GRO-α, and osteopontin increase the number of macrophages and dendritic cells by recruiting or stimulating monocytes to differentiate into macrophages and dendritic cells, respectively.[12],[13] Subsequently, macrophages and dendritic cells secrete a series of cytokines, chemokines, and enzymes that participate in tissue mediation and angiogenesis.[14] In a study performing gene regulation, microarray was sequenced to analyze all the expressed genes between the two groups; in the endometrial stimulation group, urinary protein plaques 1b, mucin transmembrane protein 1, and phospholipase A2, all of which may participate in the process of endometrial implantation, increased.[15] Studies have also reported that mechanical stimulation by scraping an irregular endometrium facilitates epithelial and stromal cell proliferation and differentiation, causes endometrium spiral artery generation and endometrial angiogenesis, adjusts the capillary blood flow and diastolic activity, increases endometrial blood flow, and leads to a normal endometrial morphology.[16]

Barash et al.[17] first emphasized the role of endometrial mechanical stimulation in promoting embryo implantation inin vitro fertilization (IVF). Endometrial stimulation has been widely used in improving ART pregnancy outcomes in recent years; a meta-analysis of 1,349 patients, including six randomized controlled studies, showed that patients receiving endometrial stimulation before artificial insemination were more likely to achieve clinical pregnancy than those without any treatment.[18],[19] Another meta-analysis, including 10 randomized controlled studies involving a total of 1,478 patients, emphasized that for patients who had two or more failed transplants, endometrial stimulation before fresh cycle ET significantly increased LBR (RR = 1.38, 95% CI = 1.05–1.80; P = 0.02) and CPR (RR = 1.34, 95% CI = 1.07–1.67; P = 0.01). In addition, the study found that LBR (RR = 1.54, 95% CI = 1.10–2.16; P = 0.01) and CPR (RR 1.30, 95% CI = 1.03–1.65; P = 0.03) were the highest in the group that received two luteal endometrial stimulations (Pipelle catheter) before the ET cycle. However, a single luteal endometrial stimulation conferred no benefits for pregnancy outcomes.[20] The present study has preliminarily explored endometrial stimulation timings and techniques, but excluded the patient without prior ET. For these patients, it remains unclear whether endometrial stimulation before transplant can improve IR and CPR and whether different endometrial stimulation timings and techniques can impact pregnancy outcomes.

The participants of this study were patients without prior ET, and the results showed that endometrial stimulation before embryo transplantation can improve embryo implantation success rate, but cannot improve CPR; furthermore, LBR and AR remained unaffected. We hypothesize that brief and soft stimulation of the functional layer, without injury to the underlying endometrium, is beneficial to embryo implantation, but due to the complex processes involved in achieving pregnancy, the improvement in the endometrium alone cannot completely address other infertility-related factors; therefore, endometrial stimulation cannot improve CPR and LBR.

The study subgroup analyzed the effects of endometrial stimulation during luteal phase and follicular period and on the day of oocyte retrieval on CPR of the patients without prior ET and depth discussed the influence of endometrial stimulation timing on pregnancy outcomes of these patients. Karimzade et al.[2] performed endometrial biopsy via curettage on the day of oocyte retrieval during an IVF cycle and transferred embryos during the same cycle. The results showed that endometrial stimulation on the day of oocyte retrieval during a fresh IVF cycle reduced CPR. The reason for this may be that endometrial repair time is short and endometrial thinning caused by biopsy actually reduces endometrial receptivity, which is not conducive to embryo implantation. Liu et al.[6] studied the effects of single follicular endometrial stimulation before an IVF cycle on the outcome of clinical pregnancy using a Pipelle catheter. The results showed no improvement in pregnancy outcomes. Luteal endometrial stimulation during the IVF cycle had no effect on CPR. However, the sensitivity analysis suggested that the results were not robust and reliable, which may be related to the lack of literature and inconsistent research methods regarding inclusion and exclusion criteria in the articles. Therefore, the benefits cannot be completely denied. In addition to this, the results of a prospective randomized controlled study included in the present study showed that luteal endometrial stimulation before a frozen-thawed ET cycle caused no significant improvement in the CPR of patients with first ET.[9]

In addition, this study explored the impact of endometrial stimulation techniques on pregnancy outcomes in patients without prior ET. Among the included studies, a Pipelle catheter was used in eight studies and the curette in the remaining two. Subgroup analysis showed that there was no significant between-group difference in CPR, suggesting that different operating tools did not affect the pregnancy outcome of patients with the first ET. It is worth mentioning that in a prospective randomized controlled study, Shohayeb and El-Khayat[21] found that a single endometrial stimulation using curette in the follicular phase before an IVF–ET cycle has a positive effect on the pregnancy outcomes of patients with repeated transplant failure.

In conclusion, the present study systematically evaluated the effects of fresh cycle endometrial stimulation on pregnancy outcomes in infertile patients without prior ET. The results showed that endometrial stimulation before the ET cycle could indeed improve the embryo IR, but it could not improve CPR or LBR and not increase AR. Neither endometrial stimulation timing and technique nor the ET cycle type significantly improved CPR; moreover, endometrial stimulation on the day of oocyte retrieval even had a negative influence on embryo implantation and pregnancy. Because of the limited literature and existing research, the frequency of endometrial stimulation as well as the influence of different ovulation induction schemes on pregnancy outcomes of infertile patients could not be explored further. Large-scale, high-quality, prospective randomized controlled double-blind trials need to be designed to provide clinical evidence so as to better guide clinical treatment.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Acknowledgments

We thank the Reproduction Medicine Department of theFirst Affiliated Hospital of Zhengzhou University for providing us with a rich research platform.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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