Performing the embryo transfer: a guideline (2017)
Download a PDF of this document
A systematic review of the literature was conducted which examined each of the major steps of embryo transfer. Recommendations made for improving pregnancy rates are based on interventions demonstrated to be either beneficial or not beneficial. (Fertil Steril 2017;107:882–96. 2017 by American Society for Reproductive Medicine.)
One of the most critical steps in the process of in vitro fertilization (IVF) is the embryo transfer. Studies have consistently demonstrated that embryo transfer pregnancy rates differ depending upon the clinician performing the procedure (1–3). In addition, data are accumulating that demonstrate a paucity of training in current fellowship programs or for practitioners who may have embryo transfer success rates consistently below the mean. A recent survey of Society for Assisted Reproductive Technology (SART) medical directors demonstrates that essentially all practitioners are allowed to perform embryo transfer if they desire, no matter what their skill (4). Half of the programs allow clinicians to perform embryo transfer using their personal ‘‘procedure’’ rather than having a standard protocol for all clinicians to follow. The results of that comprehensive survey demonstrate the breakdown of responses for 84 questions. From that survey, steps were identified for which the majority of practitioners demonstrated concordance, others were found to have nearly equal discordance, and, for most, a few outliers were identified. From those data a Common Practice Protocol was developed (4). The purpose of this guideline for performing embryo transfer is to examine the various steps of the Common Practice Protocol by a systematic review of the literature to determine which of the steps, if any, are supported by sufficient data.
This clinical practice guideline was based on a systematic review of the literature. A systematic literature search of relevant articles was performed in the electronic database MEDLINE through PubMed in December 2016, with a filter for human subject research. No limit or filter was used for time period or English language, but articles were subsequently culled for English language. A combination of the following medical subject headings or text words/keywords were used: acupuncture; acupuncture therapy; afterloading; ambulation; analgesia; analgesic; analgesics; anesthesia; anti anxiety; antibacterial hand soaps; antibiotic; antibiotics; antibiotic prophylaxis; bed rest; bedrest; birth; bleeding; blastocyst transfer; blood; catheter; catheter remains; catheter remnants; catheterization; catheterization/adverse effects; catheterization/methods; cervix; Chinese medicine; cleanse; cleanser; cleansing; deposition; disinfection; duration; ejection; embryo retention; embryo transfer; embryo transfer catheter; embryo transfer/instrumentation; embryo transfer/methods; embryo transfer protocol; embryo transfer techniques; endometrial; endometrial cavity; endometrium; expel; expulsion; flushing; gloves; hand disinfection; hand hygiene; hand washing; hand washing/behavior; hand washing/behaviors; hand disinfectant; hand disinfectants; hand washing/glove; implantation; injection; in vitro fertilization; IVF; load; loading; massage; medicine, Chinese traditional relaxant; mucus; mucous; physician; physician's role; placement; plunge; plunger; pregnancy; pressure; recumbency; recumbent; recumbent position; recumbent posture; release; replacement; rest; retained embryos; sedation; simulation; skin scrub; speed; stiletto; stylet; stylette; success; success rate; supine; surgical gloves; surgical scrub; time; time factors; time interval; transcutaneous electrical acupoint stimulation; transcutaneous electrical nerve stimulation; transfer techniques; ultrasound; ultrasound guidance; ultrasound guided embryo transfer; uteri; uterus; vaginal flush; vaginal preparation.
Initially, titles and abstracts of potentially relevant articles were screened and reviewed for inclusion/exclusion criteria. Protocols and results of the studies were examined according to specific inclusion criteria. Only studies that met the inclusion criteria were assessed in the final analysis. Studies were eligible if they met one of the following criteria: level I or II studies that assessed the effectiveness of a procedure correlated with an outcome measure (pregnancy, implantation, or live-birth rates); meta-analyses; and relevant articles from bibliographies of identified articles. This guideline focuses principally on pregnancy rate since most of the studies report pregnancy rates rather than live-birth rates.
Three members of an independent task force reviewed the full articles of all citations that possibly matched the predefined selection criteria. Final inclusion or exclusion decisions were made on examination of the articles in full. Disagreements about inclusion among reviewers were discussed and solved by consensus or arbitration after consultation with an independent reviewer/epidemiologist.
The quality of the evidence was evaluated using the following grading system and is assigned for each reference in the bibliography:
Level I: Evidence obtained from at least one properly designed randomized, controlled trial.
Level II-1: Evidence obtained from well-designed controlled trials without randomization.
Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
Level III: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
Systematic reviews/meta-analyses were individually considered and included if they followed a strict methodological process and assessed relevant evidence.
The strength of the evidence was evaluated as follows:
Grade A: There is good evidence to support the recommendation, either for or against.
Grade B: There is fair evidence to support the recommendation, either for or against.
Grade C: There is insufficient evidence to support the recommendation, either for or against.
Number of studies identified in electronic search and from examination of reference lists from primary and review articles: 2,086. Number of studies included: 143.
When current meta-analyses were not available to combine existing data, selected meta-analyses of studies were performed by the American Society for Reproductive Medicine (ASRM) Practice Committee to estimate the pooled relative risk (RR) ratios of outcomes of interest. Statistical analyses and construction of forest and funnel plots were performed with Stata version 12.1. RR ratios, and 95% confidence intervals (CIs) were calculated for each outcome. Random effects models were used for the meta-analyses. Heterogeneity was assessed with the use of the I2 test. Publication bias was assessed by constructing funnel plots. Tables listing inclusion/exclusion criteria are available online as Supplemental Material.
Acupuncture. Acupuncture has been the focus of significant interest and research, as it is an important tradition in Chinese medicine that dates back over 3,000 years. Acupuncture involves the insertion of fine needles through the skin intended to alter the flow of energy throughout the body. There are a variety of different acupuncture protocols based upon the underlying diagnosis. Protocols can include varying acupuncture points and treatment intervals during ovarian stimulation, retrieval, and before and after transfer.
A review of the medical literature is challenging as there is no consensus regarding a particular acupuncture protocol, and studies vary in regard to their inclusion and exclusion criteria, investigator blinding, and treatment of the control groups, including sham acupuncture.
A number of randomized controlled trials (RCTs) on acupuncture have been published with contradictory results. There are five RCTs showing some benefit of acupuncture (5–9). Anxiety levels were lower (P<.05) and clinical pregnancy, implantation, and live-birth rates were higher (P<.017) in the auricular acupuncture groups vs the sham auricular acupuncture and control groups in the largest of the trials, which included 305 IVF patients (7). In another trial of 273 women treated with IVF-intracytoplasmic sperm injection (ICSI), the treatment group received acupuncture on the day of embryo transfer and had a clinical pregnancy rate of 39% compared with a control group that had no acupuncture 24% (P=.038) (9). A meta-analysis of seven trials and 1,366 patients also showed an improved clinical pregnancy rate (odds ratio [OR] 1.65, 95% CI 1.27–2.14; seven trials) and live-birth rate (OR 1.91, CI 1.39–2.64; four trials) when acupuncture was given with embryo transfer (10).
A systematic review did not show significant improvement in clinical pregnancy rate with acupuncture on the day of embryo transfer, 25 minutes before and after the transfer. It found a pooled benefit when performed 30 minutes after transfer and at implantation (RR 1.76, 95% CI 1.22–2.55; four trials) and also in the follicular phase and 25 minutes before and after transfer (RR 1.56, 95%CI 1.04–2.33; four trials) (11). In addition, there was a 3-fold increased rate of pregnancy (95% CI 0.8, 8.0) and lower stress (not significant [NS]) associated with acupuncture in an observational cohort study of 57 women (12).
While there were five RCTs that showed some benefit, seven RCTs showed no benefit to acupuncture (13–19). In a trial of 416 women less than 36 years of age undergoing IVF with ICSI, the treatment group received acupuncture 25 minutes before and after embryo transfer with a pregnancy rate of 40.4% compared with the control group without acupuncture of 32.3% (P=.652) (15). Four meta-analyses similarly found no difference between acupuncture and control patients (11, 20–22). In addition, a systematic review of eight studies (N=2,505) in which acupuncture was performed on or around the day of embryo transfer showed no evidence that acupuncture improved live-birth rate in ART (OR=1.22, 95% CI 0.87–1.70) (Fig. 1) (23).
Failure to demonstrate a difference in pregnancy rates with acupuncture could be a failure of the actual protocol tested rather than acupuncture itself. There may be some circumstances where pregnancy rates are improved with acupuncture, but there is no consistent evidence that livebirth rates are improved with acupuncture. Overall, the trials vary in design and have different findings, which make firm conclusions challenging.
Summary statement:
METHODS
This clinical practice guideline was based on a systematic review of the literature. A systematic literature search of relevant articles was performed in the electronic database MEDLINE through PubMed in December 2016, with a filter for human subject research. No limit or filter was used for time period or English language, but articles were subsequently culled for English language. A combination of the following medical subject headings or text words/keywords were used: acupuncture; acupuncture therapy; afterloading; ambulation; analgesia; analgesic; analgesics; anesthesia; anti anxiety; antibacterial hand soaps; antibiotic; antibiotics; antibiotic prophylaxis; bed rest; bedrest; birth; bleeding; blastocyst transfer; blood; catheter; catheter remains; catheter remnants; catheterization; catheterization/adverse effects; catheterization/methods; cervix; Chinese medicine; cleanse; cleanser; cleansing; deposition; disinfection; duration; ejection; embryo retention; embryo transfer; embryo transfer catheter; embryo transfer/instrumentation; embryo transfer/methods; embryo transfer protocol; embryo transfer techniques; endometrial; endometrial cavity; endometrium; expel; expulsion; flushing; gloves; hand disinfection; hand hygiene; hand washing; hand washing/behavior; hand washing/behaviors; hand disinfectant; hand disinfectants; hand washing/glove; implantation; injection; in vitro fertilization; IVF; load; loading; massage; medicine, Chinese traditional relaxant; mucus; mucous; physician; physician's role; placement; plunge; plunger; pregnancy; pressure; recumbency; recumbent; recumbent position; recumbent posture; release; replacement; rest; retained embryos; sedation; simulation; skin scrub; speed; stiletto; stylet; stylette; success; success rate; supine; surgical gloves; surgical scrub; time; time factors; time interval; transcutaneous electrical acupoint stimulation; transcutaneous electrical nerve stimulation; transfer techniques; ultrasound; ultrasound guidance; ultrasound guided embryo transfer; uteri; uterus; vaginal flush; vaginal preparation.Initially, titles and abstracts of potentially relevant articles were screened and reviewed for inclusion/exclusion criteria. Protocols and results of the studies were examined according to specific inclusion criteria. Only studies that met the inclusion criteria were assessed in the final analysis. Studies were eligible if they met one of the following criteria: level I or II studies that assessed the effectiveness of a procedure correlated with an outcome measure (pregnancy, implantation, or live-birth rates); meta-analyses; and relevant articles from bibliographies of identified articles. This guideline focuses principally on pregnancy rate since most of the studies report pregnancy rates rather than live-birth rates.
Three members of an independent task force reviewed the full articles of all citations that possibly matched the predefined selection criteria. Final inclusion or exclusion decisions were made on examination of the articles in full. Disagreements about inclusion among reviewers were discussed and solved by consensus or arbitration after consultation with an independent reviewer/epidemiologist.
The quality of the evidence was evaluated using the following grading system and is assigned for each reference in the bibliography:
Level I: Evidence obtained from at least one properly designed randomized, controlled trial.
Level II-1: Evidence obtained from well-designed controlled trials without randomization.
Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
Level III: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
Systematic reviews/meta-analyses were individually considered and included if they followed a strict methodological process and assessed relevant evidence.
The strength of the evidence was evaluated as follows:
Grade A: There is good evidence to support the recommendation, either for or against.
Grade B: There is fair evidence to support the recommendation, either for or against.
Grade C: There is insufficient evidence to support the recommendation, either for or against.
Number of studies identified in electronic search and from examination of reference lists from primary and review articles: 2,086. Number of studies included: 143.
Summary of Inclusion/Exclusion Criteria
When current meta-analyses were not available to combine existing data, selected meta-analyses of studies were performed by the American Society for Reproductive Medicine (ASRM) Practice Committee to estimate the pooled relative risk (RR) ratios of outcomes of interest. Statistical analyses and construction of forest and funnel plots were performed with Stata version 12.1. RR ratios, and 95% confidence intervals (CIs) were calculated for each outcome. Random effects models were used for the meta-analyses. Heterogeneity was assessed with the use of the I2 test. Publication bias was assessed by constructing funnel plots. Tables listing inclusion/exclusion criteria are available online as Supplemental Material.
CLINICAL PRACTICE
Is Patient Preparation, including Acupuncture, Relaxant, Sedation, or Antibiotics, before Embryo Transfer Necessary and Does It Affect Pregnancy and Live-birth Rates?
Over the past two decades there has been significant interest in maximizing assisted reproductive technology (ART) pregnancy rates through enhancing patient preparation prior to embryo transfer. These attempts have included acupuncture, analgesics, anesthesia, massage, transcutaneous electrical acupoint stimulation (TEAS), whole-systems traditional Chinese medicine (WS-TCM), and prophylactic antibiotics. These interventions provide theoretical benefits, which include modulating hormones, altering energy flow throughout the body, enhancing blood flow to the uterus, reducing stress, and reducing microbial colonization of the genital tract.Acupuncture. Acupuncture has been the focus of significant interest and research, as it is an important tradition in Chinese medicine that dates back over 3,000 years. Acupuncture involves the insertion of fine needles through the skin intended to alter the flow of energy throughout the body. There are a variety of different acupuncture protocols based upon the underlying diagnosis. Protocols can include varying acupuncture points and treatment intervals during ovarian stimulation, retrieval, and before and after transfer.
A review of the medical literature is challenging as there is no consensus regarding a particular acupuncture protocol, and studies vary in regard to their inclusion and exclusion criteria, investigator blinding, and treatment of the control groups, including sham acupuncture.
A number of randomized controlled trials (RCTs) on acupuncture have been published with contradictory results. There are five RCTs showing some benefit of acupuncture (5–9). Anxiety levels were lower (P<.05) and clinical pregnancy, implantation, and live-birth rates were higher (P<.017) in the auricular acupuncture groups vs the sham auricular acupuncture and control groups in the largest of the trials, which included 305 IVF patients (7). In another trial of 273 women treated with IVF-intracytoplasmic sperm injection (ICSI), the treatment group received acupuncture on the day of embryo transfer and had a clinical pregnancy rate of 39% compared with a control group that had no acupuncture 24% (P=.038) (9). A meta-analysis of seven trials and 1,366 patients also showed an improved clinical pregnancy rate (odds ratio [OR] 1.65, 95% CI 1.27–2.14; seven trials) and live-birth rate (OR 1.91, CI 1.39–2.64; four trials) when acupuncture was given with embryo transfer (10).
A systematic review did not show significant improvement in clinical pregnancy rate with acupuncture on the day of embryo transfer, 25 minutes before and after the transfer. It found a pooled benefit when performed 30 minutes after transfer and at implantation (RR 1.76, 95% CI 1.22–2.55; four trials) and also in the follicular phase and 25 minutes before and after transfer (RR 1.56, 95%CI 1.04–2.33; four trials) (11). In addition, there was a 3-fold increased rate of pregnancy (95% CI 0.8, 8.0) and lower stress (not significant [NS]) associated with acupuncture in an observational cohort study of 57 women (12).
While there were five RCTs that showed some benefit, seven RCTs showed no benefit to acupuncture (13–19). In a trial of 416 women less than 36 years of age undergoing IVF with ICSI, the treatment group received acupuncture 25 minutes before and after embryo transfer with a pregnancy rate of 40.4% compared with the control group without acupuncture of 32.3% (P=.652) (15). Four meta-analyses similarly found no difference between acupuncture and control patients (11, 20–22). In addition, a systematic review of eight studies (N=2,505) in which acupuncture was performed on or around the day of embryo transfer showed no evidence that acupuncture improved live-birth rate in ART (OR=1.22, 95% CI 0.87–1.70) (Fig. 1) (23).
Failure to demonstrate a difference in pregnancy rates with acupuncture could be a failure of the actual protocol tested rather than acupuncture itself. There may be some circumstances where pregnancy rates are improved with acupuncture, but there is no consistent evidence that livebirth rates are improved with acupuncture. Overall, the trials vary in design and have different findings, which make firm conclusions challenging.
Summary statement:
- There is fair evidence that acupuncture performed around the time of embryo transfer does not improve live-birth rates in IVF. (Grade B)
Figure 1
Analgesics. Analgesics are occasionally recommended to help improve ART outcomes; however, there were no relevant studies identified through the literature search showing that the use of analgesics are associated with embryo transfer outcomes.
Summary statement:
Anesthesia. In an uncontrolled preliminary study, IVF outcomes were compared for patients who did or did not receive general anesthesia for embryo transfer. In this preliminary analysis, anesthesia showed benefit on the pregnancy rate in patients who received sodium thiopentone and alfentanyl (36%; n=86) vs matched controls who did not receive anesthesia (21%; n=131). However, when these investigators subsequently analyzed their data for two larger cohorts: one (n=603 embryo transfers) without anesthesia before the analysis, and a second group (n=795 embryo transfers) that received general anesthesia after the study, the pregnancy rate was 18% in the embryo transfers without anesthesia, and 19% in the embryo transfers with anesthesia. In this larger comparison, general anesthesia did not have a beneficial impact on pregnancy rate (24).
Summary statement:
Massage. Massage therapy is proposed as a way to relieve physical and psychological discomfort and has been suggested as a therapeutic modality without significant risk or side effects in an IVF cycle prior to embryo transfer. Only one study—a retrospective, observational analysis—assessed massage therapy before blastocyst transfer in cryopreservation cycles and demonstrated evidence of improved pregnancy and live-birth rates (25).
Summary statement:
Transcutaneous electrical acupoint stimulation. One prospective, randomized trial on the effect of transcutaneous electrical acupoint stimulation (TEAS) on embryo transfer in 309 patients showed that electrodes placed on acupoints instead of needles improved the clinical pregnancy and live-birth rates relative to controls (26). No statistically significant demographic differences were noted among the three groups (group I, mock TEAS; group II, single TEAS; group III, double TEAS; all treatments 30 minutes after embryo transfer). Also, the authors state that the number of transfers were not different among the three groups, but did not include these data in the manuscript. Clinical pregnancy and live-birth rates increased significantly in patients who received TEAS on the day of embryo transfer; the clinical pregnancy rate was 29.3% with mock TEAS vs 42.7% with single TEAS treatment (P=.044), and the live-birth rate was 21.2% with mock TEAS vs 37.3% with single TEAS treatment (P=.011). In patients who received TEAS also on the day before embryo transfer, the clinical pregnancy rate further increased to 50% (P=.003) and live-birth rate increased to 42% (P=.002) (26). No additional studies of TEAS are available.
Summary statement:
Whole-systems traditional Chinese medicine. Whole-systems traditional Chinese medicine (WS-TCM) as an approach to improve pregnancy rates in IVF can include acupuncture, Chinese herbal medications, diet, and lifestyle recommendations. Only one observational study of 119 non-donor and 21 donor patients was identified assessing WS-TCM and IVF-embryo transfer outcomes. This retrospective cohort study showed an improved live-birth rate of 61.3% with WS-TCM relative to 50.8% in the acupuncture group and 48.2% among controls in non-donor cycles (P=.03) (27). However, a number of limitations existed, including the retrospective nature of the study with lack of randomization, the fact that patients chose their treatment, and the lack of control of differing embryo quality between the groups.
Summary statement:
Prophylactic antibiotics. Another intervention that has been considered to improve embryo transfer success rates is the use of prophylactic antibiotics. Only one RCT has addressed this issue (28). In that trial, 350 patients were randomized to receive either prophylactic antibiotics or no antibiotics. Those randomized to the treatment group received amoxicillin and clavulanic acid on the day before and the day of transfer. The catheter tips were cultured after the transfer. While the antibiotics significantly reduced catheter contamination rates, the clinical pregnancy rates between the two groups were not different. Live-birth rates were not an outcome of that trial. A systematic review of the literature in 2012 did not find any additional studies to help determine whether prophylactic antibiotics for embryo transfer were helpful, particularly for improving live-birth rates (29). Their conclusion was that the finding of this single study did not support the use of amoxicillin and clavulanic acid to improve IVF success rates and that the effect of other regimens on IVF outcomes is unknown.
Summary statement:
Given that optimal handling of the embryo is imperative during embryo transfer, it is natural to consider the effect of the type of glove worn by the clinician performing the embryo transfer on outcome. There is no question that both powdered and unpowdered gloves are toxic when in direct contact with embryos. However, with the potential transmission of the powder from the gloves to the embryo transfer catheter through the air, particular concern has been raised regarding the use of powdered gloves during embryo transfer. Only one randomized controlled study addresses the impact of the type of glove utilized for embryo transfer on pregnancy rate. This study of 712 women evaluated the effect of powdered gloves on clinical pregnancy rate in IVF (37.6%) in comparison with unpowdered gloves (37.4%) and did not find a difference in pregnancy rate with the use of powdered gloves (P=1.0) (30). These investigators concluded that as long as direct contact is avoided, powdered gloves can safely be used in embryo transfer. There are no studies assessing glove use and live-birth rates. Therefore, although some physicians may opt to avoid non-sterile, latex, or powdered gloves in hopes of minimizing embryo toxicity, no data support the usage of a particular type of glove to optimize pregnancy rate.
Summary statement:
There are 35 RCTs and cohort studies among other published data that examine the use of abdominal ultrasound guidance during embryo transfer. Ultrasound was introduced with the hope that it would diminish the likelihood that the embryo transfer catheter would traumatize the endometrium as compared with a blind approach or touch technique.
With regard to the transfer of fresh embryos in eight RCTs and four cohort studies, transabdominal (TA) ultrasound—guided embryo transfer was found to improve the implantation rate and/or pregnancy rate (31–40), clinical or ongoing clinical pregnancy rates, and/or live-birth rate (33, 36, 41–43). These findings were supported by five meta-analyses or systematic reviews (44–48). A recent review found that ultrasound-guided embryo transfer was associated with improved clinical pregnancy rate (OR 1.31, 1.17–1.45; 20 trials; N=6,711 women) and live-birth rate/ ongoing pregnancy rate (OR 1.47, 1.30–1.65; 13 trials; N=5,859 women), compared with clinical touch (Fig. 2) (48). Studies have also shown improved outcomes using ultrasound guidance with frozen embryo transfer and programmed recipient cycles using donor eggs (32, 49).
In contrast to the preponderance of studies that have shown improved IVF outcome with the use of TA ultrasound guidance, a few studies have not been able to replicate these findings. One RCT of 374 patients found a similar pregnancy rate between ultrasound-guided and blind transfers (50). Likewise, an RCT of day-3 embryo transfers that included 50 fresh cycles found no statistically significant difference between ultrasound-guided and clinical touch transfers (51). In addition, a cohort study showed that the pregnancy rate was equivalent in 241 embryo transfers performed with and without ultrasound (52). Two underpowered RCTs showed a trend toward a benefit of TA ultrasound guidance that did not reach statistical significance (53, 54). Two RCTs showed no benefit of TA ultrasound guidance (55, 56).
The level of difficulty of embryo transfer has also been the subject of investigation. One RCT showed that ultrasound guidance offered no improvement if a mock transfer was performed and found to be easy (57), while another showed no improvement if the uterine cavity length had previously been recorded prior to embryo transfer (58). One cohort study suggested that ultrasound prior to embryo transfer helped identify potentially difficult transfers (59), while another suggested that tactile technique was not as reliable as ultrasound for confirmation of catheter placement (60). In cases of difficult embryo transfer, two studies found benefit with ultrasound guidance (43, 61).
Limited centers have utilized transvaginal (TV) ultrasound for embryo transfer (62–65). A few studies have compared TA and TV ultrasound guidance for embryo transfer. One study found that TV guidance improved patient comfort relative to TA ultrasound due to the lack of bladder filling but increased the duration of the procedure (64). Similarly, an RCT comparing TA-guided transfer to TV uterine length measurement, immediately followed by an unguided, cleaved embryo placement based on the calculated distance, showed no difference in pregnancy rates. However, in this study the TV approach had less moderate to severe discomfort largely attributable to lack of bladder filling (65).
Summary statements:
Summary statement:
- There is insufficient evidence to recommend for or against analgesics to improve IVF-embryo transfer outcomes. (Grade C)
Anesthesia. In an uncontrolled preliminary study, IVF outcomes were compared for patients who did or did not receive general anesthesia for embryo transfer. In this preliminary analysis, anesthesia showed benefit on the pregnancy rate in patients who received sodium thiopentone and alfentanyl (36%; n=86) vs matched controls who did not receive anesthesia (21%; n=131). However, when these investigators subsequently analyzed their data for two larger cohorts: one (n=603 embryo transfers) without anesthesia before the analysis, and a second group (n=795 embryo transfers) that received general anesthesia after the study, the pregnancy rate was 18% in the embryo transfers without anesthesia, and 19% in the embryo transfers with anesthesia. In this larger comparison, general anesthesia did not have a beneficial impact on pregnancy rate (24).
Summary statement:
- There is insufficient evidence that anesthesia during embryo transfer improves pregnancy rates. Given that there is no clear benefit and that there are inherent risks associated with anesthesia, routine anesthesia is not recommended to improve IVF-embryo transfer outcomes. (Grade C)
Massage. Massage therapy is proposed as a way to relieve physical and psychological discomfort and has been suggested as a therapeutic modality without significant risk or side effects in an IVF cycle prior to embryo transfer. Only one study—a retrospective, observational analysis—assessed massage therapy before blastocyst transfer in cryopreservation cycles and demonstrated evidence of improved pregnancy and live-birth rates (25).
Summary statement:
- There is insufficient evidence to recommend for or against massage therapy to improve IVF-embryo transfer outcomes. (Grade C)
Transcutaneous electrical acupoint stimulation. One prospective, randomized trial on the effect of transcutaneous electrical acupoint stimulation (TEAS) on embryo transfer in 309 patients showed that electrodes placed on acupoints instead of needles improved the clinical pregnancy and live-birth rates relative to controls (26). No statistically significant demographic differences were noted among the three groups (group I, mock TEAS; group II, single TEAS; group III, double TEAS; all treatments 30 minutes after embryo transfer). Also, the authors state that the number of transfers were not different among the three groups, but did not include these data in the manuscript. Clinical pregnancy and live-birth rates increased significantly in patients who received TEAS on the day of embryo transfer; the clinical pregnancy rate was 29.3% with mock TEAS vs 42.7% with single TEAS treatment (P=.044), and the live-birth rate was 21.2% with mock TEAS vs 37.3% with single TEAS treatment (P=.011). In patients who received TEAS also on the day before embryo transfer, the clinical pregnancy rate further increased to 50% (P=.003) and live-birth rate increased to 42% (P=.002) (26). No additional studies of TEAS are available.
Summary statement:
- There is fair evidence based on only one RCT that TEAS improves IVF-embryo transfer outcomes. (Grade B). However, given the lack of any other studies, a recommendation for or against TEAS to improve IVF-ET outcomes cannot be made.
Whole-systems traditional Chinese medicine. Whole-systems traditional Chinese medicine (WS-TCM) as an approach to improve pregnancy rates in IVF can include acupuncture, Chinese herbal medications, diet, and lifestyle recommendations. Only one observational study of 119 non-donor and 21 donor patients was identified assessing WS-TCM and IVF-embryo transfer outcomes. This retrospective cohort study showed an improved live-birth rate of 61.3% with WS-TCM relative to 50.8% in the acupuncture group and 48.2% among controls in non-donor cycles (P=.03) (27). However, a number of limitations existed, including the retrospective nature of the study with lack of randomization, the fact that patients chose their treatment, and the lack of control of differing embryo quality between the groups.
Summary statement:
- There is insufficient evidence to recommend for or against WS-TCM to improve IVF-embryo transfer outcomes. (Grade C)
Prophylactic antibiotics. Another intervention that has been considered to improve embryo transfer success rates is the use of prophylactic antibiotics. Only one RCT has addressed this issue (28). In that trial, 350 patients were randomized to receive either prophylactic antibiotics or no antibiotics. Those randomized to the treatment group received amoxicillin and clavulanic acid on the day before and the day of transfer. The catheter tips were cultured after the transfer. While the antibiotics significantly reduced catheter contamination rates, the clinical pregnancy rates between the two groups were not different. Live-birth rates were not an outcome of that trial. A systematic review of the literature in 2012 did not find any additional studies to help determine whether prophylactic antibiotics for embryo transfer were helpful, particularly for improving live-birth rates (29). Their conclusion was that the finding of this single study did not support the use of amoxicillin and clavulanic acid to improve IVF success rates and that the effect of other regimens on IVF outcomes is unknown.
Summary statement:
- There is fair evidence based on a single RCT that an antibiotic regimen that includes amoxicillin and clavulanic acid given on the day before and the day of embryo transfer does not improve pregnancy rates. (Grade B). Given these results and the lack of other evidence in the literature to support prophylactic antibiotics at embryo transfer, a recommendation for routine prophylactic antibiotics cannot be made.
Does Physician Preparation, including the Use of Sterile Latex-free Gloves, before an Embryo Transfer Procedure Affect Pregnancy and Livebirth Rates?
Given that optimal handling of the embryo is imperative during embryo transfer, it is natural to consider the effect of the type of glove worn by the clinician performing the embryo transfer on outcome. There is no question that both powdered and unpowdered gloves are toxic when in direct contact with embryos. However, with the potential transmission of the powder from the gloves to the embryo transfer catheter through the air, particular concern has been raised regarding the use of powdered gloves during embryo transfer. Only one randomized controlled study addresses the impact of the type of glove utilized for embryo transfer on pregnancy rate. This study of 712 women evaluated the effect of powdered gloves on clinical pregnancy rate in IVF (37.6%) in comparison with unpowdered gloves (37.4%) and did not find a difference in pregnancy rate with the use of powdered gloves (P=1.0) (30). These investigators concluded that as long as direct contact is avoided, powdered gloves can safely be used in embryo transfer. There are no studies assessing glove use and live-birth rates. Therefore, although some physicians may opt to avoid non-sterile, latex, or powdered gloves in hopes of minimizing embryo toxicity, no data support the usage of a particular type of glove to optimize pregnancy rate.Summary statement:
- There is fair evidence based on one, single-center RCT that powdered gloves worn during embryo transfer do not have an adverse effect on pregnancy rates. (Grade B). No specific type of glove is recommended for embryo transfer.
Does Routine Use of Abdominal Ultrasound for Guidance during Embryo Transfer Improve Pregnancy and Live-birth Rates?
There are 35 RCTs and cohort studies among other published data that examine the use of abdominal ultrasound guidance during embryo transfer. Ultrasound was introduced with the hope that it would diminish the likelihood that the embryo transfer catheter would traumatize the endometrium as compared with a blind approach or touch technique.With regard to the transfer of fresh embryos in eight RCTs and four cohort studies, transabdominal (TA) ultrasound—guided embryo transfer was found to improve the implantation rate and/or pregnancy rate (31–40), clinical or ongoing clinical pregnancy rates, and/or live-birth rate (33, 36, 41–43). These findings were supported by five meta-analyses or systematic reviews (44–48). A recent review found that ultrasound-guided embryo transfer was associated with improved clinical pregnancy rate (OR 1.31, 1.17–1.45; 20 trials; N=6,711 women) and live-birth rate/ ongoing pregnancy rate (OR 1.47, 1.30–1.65; 13 trials; N=5,859 women), compared with clinical touch (Fig. 2) (48). Studies have also shown improved outcomes using ultrasound guidance with frozen embryo transfer and programmed recipient cycles using donor eggs (32, 49).
In contrast to the preponderance of studies that have shown improved IVF outcome with the use of TA ultrasound guidance, a few studies have not been able to replicate these findings. One RCT of 374 patients found a similar pregnancy rate between ultrasound-guided and blind transfers (50). Likewise, an RCT of day-3 embryo transfers that included 50 fresh cycles found no statistically significant difference between ultrasound-guided and clinical touch transfers (51). In addition, a cohort study showed that the pregnancy rate was equivalent in 241 embryo transfers performed with and without ultrasound (52). Two underpowered RCTs showed a trend toward a benefit of TA ultrasound guidance that did not reach statistical significance (53, 54). Two RCTs showed no benefit of TA ultrasound guidance (55, 56).
The level of difficulty of embryo transfer has also been the subject of investigation. One RCT showed that ultrasound guidance offered no improvement if a mock transfer was performed and found to be easy (57), while another showed no improvement if the uterine cavity length had previously been recorded prior to embryo transfer (58). One cohort study suggested that ultrasound prior to embryo transfer helped identify potentially difficult transfers (59), while another suggested that tactile technique was not as reliable as ultrasound for confirmation of catheter placement (60). In cases of difficult embryo transfer, two studies found benefit with ultrasound guidance (43, 61).
Limited centers have utilized transvaginal (TV) ultrasound for embryo transfer (62–65). A few studies have compared TA and TV ultrasound guidance for embryo transfer. One study found that TV guidance improved patient comfort relative to TA ultrasound due to the lack of bladder filling but increased the duration of the procedure (64). Similarly, an RCT comparing TA-guided transfer to TV uterine length measurement, immediately followed by an unguided, cleaved embryo placement based on the calculated distance, showed no difference in pregnancy rates. However, in this study the TV approach had less moderate to severe discomfort largely attributable to lack of bladder filling (65).
Summary statements:
- There is good evidence based on 10 RCTs to recommend TA ultrasound guidance during embryo transfer to improve clinical pregnancy rate and live-birth rate. (Grade A)
- While selected ultrasound guidance for an anticipated difficult embryo transfer may be an alternative to routine ultrasound guidance, there is insufficient evidence to recommend for or against this practice. (Grade C)
Figure 2
Does Removing Mucus from the Endocervical Canal Improve Pregnancy and Live-birth Rates?
Some studies have indicated that cervical mucus interferes with embryo transfer by blocking the passage of embryos through the tip of the catheter, pulling embryos back from the site of expulsion, or contaminating the intrauterine environment with cervical flora. However, it has been suggested that removing cervical mucus might stimulate uterine contractility or cervical bleeding, with a possible negative impact on pregnancy outcomes.One RCT (66) and a prospective cohort study (67) demonstrated that removing mucus from the endocervical canal with sterile cotton swabs or aspiration with a catheter, respectively, improves clinical outcomes. An additional published RCT was not comparable since the mucus was removed with a cervical brush (68). A systematic review was unable to make a definitive conclusion on this topic, which was limited by the inclusion of an abstract that was never subsequently published and a study using the cytobrush (69). Therefore, data from the only well-designed RCT (N=530) and a prospective, controlled cohort study (N=286) were used for the recommendation (66, 67). The RCT showed improved clinical pregnancy rate (39.2% study vs 22.6% controls, P<.001) and live-birth rate (33.6% study vs 17.4% controls, P<.001) with the removal of cervical mucus (66). The clinical pregnancy rate was significantly higher in the group that had mucus aspiration compared with the group with no aspiration (P=.003; OR = 2.18, 95% CI = 1.32–3.58) in the cohort study (67).
Summary statement:
- There is fair evidence based on one RCT and one prospective cohort study that there is a benefit to removing cervical mucus at the time of embryo transfer to improve clinical pregnancy and live-birth rates. (Grade B)
Does the Type of Catheter Used for Embryo Transfer Affect Pregnancy and Live-birth Rates?
While the literature is fraught with ambiguity, there exist a number of controlled trials that provide insight into the role that the transfer catheter plays in IVF outcomes. The data assessing the influence of embryo transfer catheter type and IVF outcomes span almost three decades. Varying definitions of soft and firm (also called hard) catheters complicate the analysis. For this analysis, any embryo transfer catheter with a soft inner catheter was classified as soft; the remainder were classified as hard catheters. In some cases, the catheters were reclassified.Two RCTs were designed to determine if different firm catheters affected IVF outcomes (70, 71). In both trials, the Tight Difficult Transfer (TDT) catheter (Prodimed) appeared inferior. Of firm catheters studied, Tomcat (Meditech; Sherwood Medical) and Frydman (Eurosurgical; Prodimed) catheters seemed to confer a higher pregnancy rate than the Tefcat (Cook) or TDT (Meditech; Prodimed) (52, 70–73). However, data on firm catheters are mostly from the year 2000 or earlier and therefore are mainly of historical significance. Firm catheters are no longer used as a first choice for today's embryo transfer. The use of firm catheters has been supplanted by soft transfer catheters.
Two RCTs and two cohort studies favor soft over firm catheters as a means of improving IVF pregnancy rates (40, 74–76). In order to obtain pooled estimates from the two well-designed RCTs comparing soft vs firm catheters as currently defined, a meta-analysis was performed by the ASRM Practice Committee using a random-effects model. This analysis showed that pregnancy rates were higher using soft catheters for embryo transfer compared with firm catheters (RR 1.36, 95% CI 1.16–1.59) (74, 75) (Fig. 3). No controlled trial favors firm over soft catheters (77).
A cohort study assessing the influence of catheter type on difficult embryo transfers failed to find benefit in using a soft catheter (78). In total, the data do not support benefit of using a firm catheter for routine use. In a trial in which patients were alternately assigned to either the Edwards-Wallace catheter (H.G. Wallace Ltd.) or the rigid metal Erlangen catheter (not a true randomization), the rigid system showed higher pregnancy rates (19% Wallace vs 30% Erlangen, [recalculated] P=.0381) (77). In this study, the transfer technique was also different depending on the catheter system used. The combination of a non-randomization system, the variable use of a cervical tenaculum, and the lack of ultrasound guidance may account for the lack of benefit seen with the Edwards-Wallace catheter. Three meta-analyses (44, 79, 80) comparing soft vs ‘‘hard’’ or ‘‘firm’’ catheters were excluded from this analysis, because the authors of these studies categorized the Rocket Embryon®, TDT, and Labotect catheters, with soft inner and firm outer components, as firm catheters.
The majority of the literature, including 10 RCTs and 1 cohort study, shows no difference in IVF outcomes (clinical pregnancy rate, pregnancy rate, implantation rate) when comparing different types of soft catheters (81–91). A single RCT and one cohort study favored the Edwards-Wallace catheter compared with rigid catheters when looking at pregnancy rate (92, 93). None of the trials included demonstrated a difference in birth rates when comparing soft catheters to one another. The totality of the data strongly supports similar pregnancy rates and, in some studies, implantation rates when comparing transfers using a variety of soft catheters.
It appears that no soft embryo transfer catheter is clearly superior and that commercially available soft catheters perform similarly. Personal choice and cost can guide differential use of one soft catheter over the other.
Summary statement:
- There is good evidence to recommend the use of a soft embryo transfer catheter to improve IVF-embryo transfer pregnancy rates. (Grade A). Data on live-birth rates and specific types of soft catheters are limited.
Figure 3
Does Positioning the Catheter at the Time of Embryo Transfer Affect IVF-Embryo Transfer Implantation, Pregnancy, and Live-birth Rates?
In terms of embryo transfer technique, it is widely accepted that avoiding touching the uterine fundus is one of the most important factors leading to a successful transfer. However, what is unclear is the ideal location for embryo placement within the uterine cavity. Four RCTs were designed to answer this question (94–97). One RCT examined three different placement locations (1.0, 1.5, and 2.0 cm) from the uterine fundus (94). It found statistically significantly (P<.05) higher implantation rates for placement between 1.5 cm and 2.0 cm compared with 1.0 cm, and statistically significantly higher (P<.05) pregnancy rates when the selected location was approximately 2 cm from the uterine fundus compared with 1 cm from the fundus (94). When placement was compared between <1 cm and 1–1.5 cm, one randomized controlled study demonstrated improved pregnancy rates and implantation rates at the location farther from the fundus (97). Two additional randomized controlled studies found no difference in implantation rate and pregnancy rate, with one study dividing placement into the upper vs lower half of the endometrial cavity (95) and the other comparing 2 cm from the fundus vs the uterine cavity midpoint (96). Five cohort studies (98–102) assessing the influence of embryo placement produced mixed results. Only one of those studies found no impact on pregnancy outcome based on embryo placement position (98). However, it was the oldest of the studies, reported in 1996.The majority of the studies found that embryo placement impacted pregnancy rates, with pregnancy rates highest when the embryo was placed in the upper or middle area of the uterine cavity, at least 1 cm away from the fundus (94, 96, 97, 99–102). A 2015 RCT that demonstrated no difference when the catheter tip was 2 cm from the fundus or in the middle third of the uterine cavity further supports placement in the upper or middle uterine cavity for embryo expulsion (96). One difficulty when comparing studies examining optimal embryo placement is the lack of consistency in comparative placements, with some studies assessing exact distances from the fundus, and others dividing the uterine cavity into areas.
Finally, the placement of the outer catheter may also affect pregnancy rates. In a cohort study of 408 patients who underwent embryo transfer, overall pregnancy rates were significantly better in those patients (n=218) for whom the outer sheath did not go beyond the internal os compared with patients (n=190) for whom the catheter was placed through the internal os, 57.3% vs 43.1%, P=.0054 (103).
Summary statements:
- There is fair evidence based on six studies (two RCTs and four cohort studies) that embryo transfer catheter placement affects implantation and pregnancy rates. (Grade B)
- There is fair evidence based on seven studies (three RCTs and four cohort studies) that placement of the catheter tip in the upper or middle (central) area of the uterine cavity, greater than 1 cm from the fundus for embryo expulsion, optimizes pregnancy rates. (Grade B)
- There is insufficient evidence for more specific recommendations regarding the positioning of the catheter at the time of embryo transfer. (Grade C)
Does the Time Interval before Withdrawing the Catheter Affect IVF-Embryo Transfer Pregnancy and Live-Birth Rates?
Once the embryo(s) is discharged from the embryo catheter the physician has the option of immediately withdrawing the transfer catheter or pausing before withdrawal of the catheter. A randomized, controlled study of 100 patients (104) compared immediate withdrawal to a 30-second delay and found no difference in pregnancy rates. A follow-up cohort study of 218 patients (105) examined immediate withdrawal compared with a 60-second delay before withdrawal, and similarly found no difference in pregnancy rates based on timing of catheter withdrawal. It can therefore be concluded that a delay in catheter withdrawal after embryo placement does not lead to improved pregnancy rates.Summary statement:
- There is fair evidence based on one RCT and one cohort study to recommend immediate withdrawal of the embryo transfer catheter after embryo expulsion. (Grade B)
Is the Presence of Mucus on the Catheter (after It Is Removed) Associated with Pregnancy and Livebirth Rates?
The goal of embryo transfer is to attain a smooth, atraumatic passage of the catheter through the endocervical canal and lower uterine segment. Clinicians have debated whether the presence of mucus on the catheter after the embryo transfer adversely affects IVF success rates. Seven cohort studies (106–112) showed that the presence of mucus in or on the catheter (once it is withdrawn) does not adversely affect clinical pregnancy rate or live-birth rate. In a cohort study that compared direct embryo transfer with the afterload technique, a higher pregnancy rate, not statistically significant, was found with the afterload technique vs the direct technique. For the latter, more catheters were contaminated with mucus, which was statistically significant (113). This was the only study that implicated a negative outcome with the presence of mucus contamination after withdrawing the catheter.Summary statement:
- There is fair evidence based on seven cohort studies that the presence of mucus on the embryo transfer catheter, once it is withdrawn, is not associated with a lower clinical pregnancy rate or live-birth rate. (Grade B)
Does the Presence of Blood on the Catheter (once It Is Withdrawn) Make a Difference in Pregnancy or Live-birth Rate?
The presence of blood on the catheter once removed at the time of embryo transfer and its possible implications have been studied often, suggesting an increased interest and concern about blood and embryo transfer techniques. A total of 17 studies (1 RCT, 1 systematic review/meta-analysis, and 15 cohort studies) were evaluated. Many of the cohort studies were performed 10 to 15 years ago. A small RCT (70) compared pregnancy outcomes in patients randomized to embryo transfer with the Tomcat catheter (n=32) vs the TDT catheter (n=34). They reported the presence of blood and/or mucus on the catheter as a secondary outcome measurement and found no impact of blood on clinical pregnancy rate and implantation rate. A large cohort study from an Australian database (109) also demonstrated no significant difference on clinical pregnancy rate based on catheter tip contamination (30.2% no contamination, 24% mucus only, 30% blood only, 39.1% mucus and blood, 26.4% much mucus and blood, P=NS). One systematic review/meta-analysis (114) and six other cohort studies (78, 108, 110, 111, 115, 116) were in agreement.In contrast to the RCT (70), meta-analysis (114), the recent large Australian cohort study (109), and five other cohort studies showing no adverse association between pregnancy rates and blood on the withdrawn embryo transfer catheter, eight other cohort studies (44, 106, 112, 117–121) demonstrated an opposite finding. A 2002 cohort study of 640 IVF-ICSI cycles showed that clinical pregnancy rate was significantly (P<.01) higher when there was no blood during transfer vs with blood. The OR was 0.54 (0.35–0.84) for diminished pregnancy rate in cycles with blood during embryo transfer vs bloodless (120). In another cohort study (584 consecutive cycles), blood on the catheter was the most important transfer characteristic in predicting implantation rate (P=.042) and clinical pregnancy rate (P=.018) (106). The presence of blood on the catheter was associated with decreased clinical pregnancy rate (31.7% blood vs 51.7% no blood, P=.004; strength of association: P=.01) or implantation rate (19.5% blood vs 31.3% no blood, P=.015; strength of association: P=.04), when only high-grade embryos or blastocysts were transferred (106). There is a suggestion that embryos are more likely to be retained in a catheter when it is contaminated with mucus or blood, but retention of embryos has not been associated conclusively with poorer outcomes.
Summary statement:
- Given the mixed results of studies, there is insufficient evidence to state conclusively that the presence of blood on the catheter, once it is withdrawn, is associated with implantation or pregnancy rates. (Grade C)
Does the Rate of Injection of the Catheter Load Affect Pregnancy and Live-birth Rates?
The ideal speed at which the embryo should be injected at the time of embryo transfer is unknown, as this may be one of the most difficult aspects to quantify and thus compare. The earliest attempt at assessing the ideal velocity of injection was in 2003 when a computational model suggested that high injection speeds may lead to ectopic pregnancies (122). This hypothesis was corroborated by several studies using both mathematical and simulated in vitro models. These studies all suggested that the injection velocity of the embryo could impact the trajectory of the placement, and therefore potentially impact implantation rate and the risk of ectopic pregnancy if a fast speed was used too near the fundus (123–126). A 2012 simulation study assessed standardization of injection speed by evaluating a pump-regulated embryo transfer (PRET) device compared with manual injection. The PRET device generated reliable and reproducible injection speeds, whereas manual injection showed large variation in speed even with a standardized protocol (127). A nonblinded randomized trial also utilizing the same PRET device resulted in less variance in embryo positioning as assessed by ultrasound measurement compared with manual injection (128).Summary statement:
- Given the paucity of data, there is insufficient evidence to recommend any specific injection speed of the catheter at the time of embryo transfer. (Grade C)
Do Retained Embryos in the Transfer Catheter and Immediate Re-transfer of Them Affect Implantation, Clinical Pregnancy, or Spontaneous Abortion Rates?
Retained embryo(s) after the initial transfer attempt is an uncommon, but clinically worrisome event, creating anxiety for patients and practitioners. The majority of studies addressing this question report an incidence of retained embryo(s) of <3%; however, three studies reported rates of 5%, 7.5%, and 10%, respectively (106, 121, 129).The nature of this problem precludes an RCT. All published studies report an immediate re-transfer and retrospective analyses of this variable. The evaluated data include 12 studies (secondary outcome of 1 RCT, 10 cohort studies, 1 series) (85, 106, 107, 111, 121, 129–135). In all but one report, the clinical outcomes of implantation, clinical pregnancy, and spontaneous abortion rates were statistically unchanged for patients undergoing re-transfer after embryo retention. That study reported a statistically significant decline in implantation rate from 17% to 13% (P=.03) after 29/584 re-transfers of embryos at either the cleavage or blastocyst stage. There was no statistical difference in clinical pregnancy rate (106).
Summary statement:
- There is fair evidence based on the secondary outcome of one RCT, nine cohort studies, and one series that retained embryos in the transfer catheter and immediate re-transfer do not affect implantation, clinical pregnancy, or spontaneous abortion rates. (Grade B)
Does Bed Rest or Ambulation Affect IVF-Embryo Transfer Pregnancy and Live-birth Rates?
Among the many empiric practices of embryo transfer that have been scrutinized by studies designed to improve IVF success rates, bed rest has emerged as a prime candidate to study. In particular, a number of studies were designed to focus on the duration of time patients remained at bed rest following the transfer of embryos into the endometrial cavity. During the early years of IVF compared to recent times, the longest variations of time that patients were kept supine existed in hopes of avoiding uterine contractions and ‘‘premature expulsion’’ of embryos from the uterus. Anecdotal reports have included durations of bed rest for many that extended up to 24 hours and for some as long as 2 weeks.Of 14 studies included from this systematic literature review, none of them demonstrated a benefit of bed rest of any duration. Three RCTs between 1997 and 2004 included 712 patients randomized to different periods of bed rest and showed no benefit of any of the following durations: 1 hour vs 24 hours (N=378), 20 minutes vs 24 hours (N=182), and immediate ambulation vs 30 minutes (N=152) (136–138). One additional RCT randomized 120 patients to either bed rest for 15 minutes or immediate ambulation and followed outcome of the air bubbles in the endometrial cavity by ultrasound, demonstrating no difference between the two groups (139). Three systematic reviews (N= 724; N=542; N=757, respectively) (140–142) corroborated the findings of these RCTs. Furthermore, three cohort studies (143–145) (N=677) and two patient series (146, 147) (N=112) demonstrated that bed rest of different durations did not benefit pregnancy outcomes. One additional series followed the endometrial air bubbles with ultrasound in patients who stood up immediately after transfer and found a similar position of the air bubbles before and after standing, concluding that for these 101 IVF cycles ‘‘standing shortly after embryo transfer does not play a significant role in the final position of embryo-associated air.’’ (148).
In contrast to the studies that have shown no benefit, one well-designed recent RCT demonstrated possible harm (149). Two hundred-forty patients undergoing their first IVF cycle were randomized to either 10 minutes of bed rest or immediate ambulation. This study demonstrated that the live-birth rates were significantly (P=.02) higher in the no bed rest group (56.7%) when compared to 10 minutes of rest (41.6%). Given that this study was performed in recent years benefiting from more current success rates, used a more homogeneous patient population of first-time IVF cycles with similar demographic and cycle data between the two groups, and demonstrated a statistically significant lower success rate for the relatively short duration of bed rest of 10 minutes, the suggestion of harm for bed rest is noteworthy.
Summary statement:
- There is good evidence not to recommend bed rest after embryo transfer. (Grade A)
SUMMARY
Good Evidence (Grade A)
- There is good evidence based on 10 RCTs to recommend TA ultrasound guidance during embryo transfer to improve clinical pregnancy rate and live-birth rate. (Grade A)
- There is good evidence to recommend the use of a soft embryo transfer catheter to improve IVF-embryo transfer pregnancy rates. (Grade A). Data on live-birth rates and specific types of soft catheters are limited.
- There is good evidence not to recommend bed rest after embryo transfer. (Grade A)
Fair Evidence (Grade B)
- There is fair evidence that acupuncture performed around the time of the embryo transfer does not improve livebirth rates in IVF. (Grade B)
- There is fair evidence based on only one RCT that transcutaneous electrical acupoint stimulation (TEAS) improves IVF-embryo transfer outcomes. (Grade B). Given the lack of any other studies, a recommendation for or against TEAS to improve IVF-embryo transfer outcomes cannot be made.
- There is fair evidence based on a single RCT that an antibiotic regimen that includes amoxicillin and clavulanic acid given on the day before and the day of embryo transfer does not improve pregnancy rates. (Grade B) Given these results and the lack of other evidence in the literature to support prophylactic antibiotics at embryo transfer, a recommendation for routine prophylactic antibiotics cannot be made.
- There is fair evidence based on one, single-center RCT that powdered gloves worn during embryo transfer do not have an adverse effect on pregnancy rates. (Grade B) No specific type of glove is recommended for embryo transfer.
- There is fair evidence based on one RCT and one prospective cohort study that there is a benefit to removing cervical mucus at the time of embryo transfer to improve clinical pregnancy and live-birth rates. (Grade B)
- There is fair evidence based on six studies (two RCTs and four cohort studies) that embryo transfer catheter placement affects implantation and pregnancy rates. (Grade B)
- There is fair evidence based on seven studies (three RCTs and four cohort studies) that placement of the catheter tip in the upper or middle (central) area of the uterine cavity, greater than 1 cm from the fundus for embryo expulsion, optimizes pregnancy rates. (Grade B)
- There is fair evidence based on one RCT and one cohort study to recommend immediate withdrawal of the embryo transfer catheter after embryo expulsion. (Grade B)
- There is fair evidence based on seven cohort studies that the presence of mucus on the embryo transfer catheter, once it is withdrawn, is not associated with a lower clinical pregnancy rate or live-birth rate. (Grade B)
- There is fair evidence based on the secondary outcome of one RCT, nine cohort studies, and one series that retained embryos in the transfer catheter and immediate retransfer do not affect implantation, clinical pregnancy, or spontaneous abortion rates. (Grade B)
Insufficient Evidence (Grade C)
- There is insufficient evidence to recommend for or against analgesics to improve IVF-embryo transfer outcomes. (Grade C)
- There is insufficient evidence that anesthesia during embryo transfer improves pregnancy rates. Given that there is no clear benefit and that there are inherent risks associated with anesthesia, routine anesthesia is not recommended to improve IVF-embryo transfer outcomes. (Grade C).
- There is insufficient evidence to recommend for or against massage therapy to improve IVF-embryo transfer outcomes. (Grade C)
- There is insufficient evidence to recommend for or against whole systems–traditional Chinese medicine to improve IVF-embryo transfer outcomes. (Grade C)
- While selected ultrasound guidance for an anticipated difficult embryo transfer may be an alternative to routine ultrasound guidance, there is insufficient evidence to recommend for or against this practice. (Grade C)
- There is insufficient evidence for more specific recommendations regarding the positioning of the catheter at the time of embryo transfer. (Grade C)
- Given the mixed results of studies, there is insufficient evidence to conclusively state that the presence of blood on the catheter, once it is withdrawn, is associated with lower implantation or pregnancy rates. (Grade C)
- Given the paucity of data, there is insufficient evidence to recommend any specific injection speed of the catheter at the time of embryo transfer. (Grade C)
RECOMMENDATIONS
Embryo transfer is considered a critical step in the IVF process. Extensive literature exists regarding all aspects of embryo transfer, which supports its importance to overall IVF success. While there are insufficient data to provide guidance on a number of techniques used during embryo transfer, the literature does provide guidance for many aspects of this critical component of IVF.The following interventions are supported by the literature for improving pregnancy rates:
- Abdominal ultrasound guidance for embryo transfer
- Removal of cervical mucus
- Use of soft embryo transfer catheters
- Placement of embryo transfer tip in the upper or middle (central) area of the uterine cavity, greater than 1 cm from the fundus, for embryo expulsion
- Immediate ambulation once the embryo transfer procedure is completed
- Acupuncture
- Analgesics, massage, general anesthesia, whole systems–traditional Chinese medicine
- Prophylactic antibiotics to improve embryo transfer outcomes
- Waiting after expulsion of embryos for any specific period of time before withdrawing the embryo transfer catheter
CONCLUSIONS
A systematic review of the literature allowed the development of this guideline for standardization of the embryo transfer process. Many, but not all, of the current techniques employed are supported by the literature as evidenced by the recommendations made above. For other techniques used to enhance pregnancy rates during the embryo transfer, such as TEAS, more studies are needed. In designing the ASRM embryo transfer protocol, data from the survey of medical directors helped determine the most commonly used technique when the literature did not inform an outcome-based recommendation.
Acknowledgments:
This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report.This document was reviewed by ASRM members and their input was considered in the preparation of the final document. The Practice Committee acknowledges the special contribution of Kristen Bendikson, M.D.; David Frankfurter, M.D.; Alan Penzias, M.D.; Richard Reindollar, M.D.; John Schnorr, M.D.; Thomas Toth, M.D.; Eric Widra, M.D.; Carla Stec, M.A in the preparation of this document. The following members of the ASRM Practice Committee participated in the development of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document.
Alan Penzias, M.D.; Kristin Bendikson, M.D.; Samantha Butts, M.D., M.S.C.E.; Christos Coutifaris, M.D.; Tommaso Falcone, M.D.; Gregory Fossum, M.D.; Susan Gitlin, Ph.D.; Clarisa Gracia, M.D., MSCE; Karl Hansen, M.D., Ph.D.; Andrew La Barbera, Ph.D.; Jennifer Mersereau, M.D.; Randall Odem, M.D.; Richard Paulson, M.D.; Samantha Pfeifer, M.D.; Margareta Pisarska, M.D.; Robert Rebar, M.D.; Richard Reindollar, M.D.; Mitchell Rosen, M.D.; Jay Sandlow, M.D.; Michael Vernon, Ph.D.
Supplemental material: Embryo Transfer Protocol Inclusion/Exclusion Criteria
Is patient preparation, including acupuncture, relaxant, sedation, or antibiotics, before embryo transfer necessary and does it affect pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does physician preparation, including the use of sterile latex-free gloves, before an embryo transfer procedure affect pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does routine use of abdominal ultrasound for guidance during embryo transfer improve pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does removing mucus from the endocervical canal improve pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does the type of catheter used for embryo transfer affect pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does positioning the catheter at the time of embryo transfer affect IVF-embryo transfer implantation, pregnancy, and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does the time interval before withdrawing the catheter affect IVF-embryo transfer pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Is the presence of mucus on the catheter (after it is removed) associated with pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does the presence of blood on the catheter (once it is withdrawn) make a difference in pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Does the rate of injection of the catheter load affect pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
Do retained embryos in the transfer catheter and immediate retransfer of them affect implantation, clinical pregnancy, or spontaneous abortion rates?
INCLUDE: | EXCLUDE: |
|
|
Does bed rest or ambulation affect IVF-embryo transfer pregnancy and live-birth rates?
INCLUDE: | EXCLUDE: |
|
|
REFERENCES
- Karande VC, Morris R, Chapman C, Rinehart J, Gleicher N. Impact of the ‘physician factor’ on pregnancy rates in a large assisted reproductive technology program: Do too many cooks spoil the broth? Fertil Steril 1999;71:1001–9, Level II-2.
- Hearns-Stokes RM, Miller BT, Scott L, Creuss D, Chakraborty PK, Segars JH. Pregnancy rates after embryo transfer depend on the provider at embryo transfer. Fertil Steril 2000;74:80–6, Level II-2.
- Angelini A, Brusco GF, Barnocchi N, El-Danasouri I, Pacchiarotti A, Selman HA. Impact of physician performing embryo transfer on pregnancy rates in an assisted reproductive program. J Assist Reprod Genet 2006;23:329–32, Level II-2.
- Toth TL, Lee MS, Bendikson KA, Reindollar RH. Embryo Transfer Techniques: An ASRM Survey of Current SART Practices. Fertil Steril 2017;107:1003–11, Level II-2.
- Domar AD, Meshay I, Kelliher J, Alper M, Powers RD. The impact of acupuncture on in vitro fertilization outcome. Fertil Steril 2009;91:723–6, Level I.
- Paulus WE, Zhang M, Strehler E, El-Danasouri I, Sterzik K. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril 2002;77:721–4, Level I.
- Qu F, Zhang D, Chen LT, Wang FF, Pan JX, Zhu YM, et al. Auricular acupressure reduces anxiety levels and improves outcomes of in vitro fertilization: a prospective, randomized and controlled study. Sci Rep 2014;4:5028, Level I.
- Rashidi BH, Tehrani ES, Hamedani NA, Pirzadeh L. Effects of acupuncture on the outcome of in vitro fertilisation and intracytoplasmic sperm injection in women with polycystic ovarian syndrome. Acupunct Med 2013;31:151–6, Level I.
- Westergaard LG, Mao Q, Krogslund M, Sandrini S, Lenz S, Grinsted J. Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial. Fertil Steril 2006;85:1341–6, Level I.
- Manheimer E, Zhang G, Udoff L, Haramati A, Langenberg P, Berman BM, et al. Effects of acupuncture on rates of pregnancy and live birth among women undergoing in vitro fertilisation: systematic review and meta-analysis. BMJ 2008;336:545–9, Level III.
- Shen C, Wu M, Shu D, Zhao X, Gao Y. The role of acupuncture in in vitro fertilization: a systematic review and meta-analysis. Gynecol Obstet Invest 2015;79:1–12, Level III.
- Balk J, Catov J, Horn B, Gecsi K, Wakim A. The relationship between perceived stress, acupuncture, and pregnancy rates among IVF patients: a pilot study. Complement Ther Clin Pract 2010;16:154–7, Level II-2.
- Andersen D, Lossl K, Nyboe Andersen A, Furbringer J, Bach H, Simonsen J, et al. Acupuncture on the day of embryo transfer: a randomized controlled trial of 635 patients. Reprod Biomed Online 2010;21:366–72, Level I.
- Craig LB, Rubin LE, Peck JD, Anderson M, Marshall LA, Soules MR. Acupuncture performed before and after embryo transfer: a randomized controlled trial. J Reprod Med 2014;59:313–20, Level I.
- Madaschi C, Braga DP, Figueira Rde C, Iaconelli A Jr, Borges E Jr. Effect of acupuncture on assisted reproduction treatment outcomes. Acupunct Med 2010;28:180–4, Level I.
- Moy I, Milad MP, Barnes R, Confino E, Kazer RR, Zhang X. Randomized controlled trial: effects of acupuncture on pregnancy rates in women undergoing in vitro fertilization. Fertil Steril 2011;95:583–7, Level I.
- Smith C, Coyle M, Norman RJ. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril 2006;85:1352–8, Level I.
- So EW, Ng EH, Wong YY, Lau EY, Yeung WS, Ho PC. A randomized double blind comparison of real and placebo acupuncture in IVF treatment. Hum Reprod 2009;24:341–8, Level I.
- So EW, Ng EH, Wong YY, Yeung WS, Ho PC. Acupuncture for frozen-thawed embryo transfer cycles: a double-blind randomized controlled trial. Reprod Biomed Online 2010;20:814–21, Level I.
- El-Toukhy T, Sunkara SK, Khairy M, Dyer R, Khalaf Y, Coomarasamy A. A systematic review and meta-analysis of acupuncture in in vitro fertilization. BJOG 2008;115:1203–13, Level III.
- El-Toukhy T, Khalaf Y. The impact of acupuncture on assisted reproductive technology outcome. Curr Opin Obstet Gynecol 2009;21:240–6, Level III.
- Manheimer E, van der Windt D, Cheng K, Stafford K, Liu J, Tierney J, et al. The effects of acupuncture on rates of clinical pregnancy among women undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2013;19:696–713, Level III.
- Cheong YC, Dix S, Hung Yu Ng E, Ledger WL, Farquhar C. Acupuncture and assisted reproductive technology. Cochrane Database Syst Rev 2013:Cd006920, Level III.
- van der Ven H, Diedrich K, Al-Hasani S, Pless V, Krebs D. The effect of general anaesthesia on the success of embryo transfer following human in-vitro fertilization. Hum Reprod 1988;3(Suppl 2):81–3, Level II-2.
- Okhowat J, Murtinger M, Schuff M, Wogatzky J, Spitzer D, Vanderzwalmen P, et al. Massage therapy improves in vitro fertilization outcome in patients undergoing blastocyst transfer in a cryo-cycle. Altern Ther Health Med 2015;21:16–22, Level II-2.
- Zhang R, Feng XJ, Guan Q, Cui W, Zheng Y, Sun W, et al. Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo-controlled study. Fertil Steril 2011;96:912–6, Level I.
- Hullender Rubin LE, Opsahl MS, Wiemer KE, Mist SD, Caughey AB. Impact of whole systems traditional Chinese medicine on in-vitro fertilization outcomes. Reprod Biomed Online 2015;30:602–12, Level II-2.
- Brook N, Khalaf Y, Coomarasamy A, Edgeworth J, Braude P. A randomized controlled trial of prophylactic antibiotics (co-amoxiclav) prior to embryo transfer. Hum Reprod 2006;21:2911–5, Level I.
- Kroon B, Hart RJ, Wong BM, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database Syst Rev 2012:Cd008995, Level III.
- Hannoun A, Zreik TG, Ghaziri G, Abu Musa A, Awwad J. Effect of powdered gloves, worn at the time of embryo transfer, on the pregnancy outcome of IVF cycles. J Assist Reprod Genet 2009;26:25–7, Level I.
- Coroleu B, Carreras O, Veiga A, Martell A, Martinez F, Belil I, et al. Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization. Hum Reprod 2000;15:616–20, Level I.
- Coroleu B, Barri PN, Carreras O, Martinez F, Veiga A, Balasch J. The usefulness of ultrasound guidance in frozen-thawed embryo transfer: a prospective randomized clinical trial. Hum Reprod 2002;17:2885–90, Level I.
- Li R, Lu L, Hao G, Zhong K, Cai Z, Wang W. Abdominal ultrasound-guided embryo transfer improves clinical pregnancy rates after in vitro fertilization: experiences from 330 clinical investigations. J Assist Reprod Genet 2005;22:3–8, Level I.
- Matorras R, Urquijo E, Mendoza R, Corcostegui B, Exposito A, Rodriguez-Escudero FJ. Ultrasound-guided embryo transfer improves pregnancy rates and increases the frequency of easy transfers. Hum Reprod 2002;17:1762–6, Level I.
- Tang OS, Ng EH, So WW, Ho PC. Ultrasound-guided embryo transfer: a prospective randomized controlled trial. Hum Reprod 2001;16:2310–5, Level I.
- Ali CR, Khashan AS, Horne G, Fitzgerald CT, Nardo LG. Implantation, clinical pregnancy and miscarriage rates after introduction of ultrasound-guided embryo transfer. Reprod Biomed Online 2008;17:88–93, Level II-2.
- Mirkin S, Jones EL, Mayer JF, Stadtmauer L, Gibbons WE, Oehninger S. Impact of transabdominal ultrasound guidance on performance and outcome of transcervical uterine embryo transfer. J Assist Reprod Genet 2003;20:318–22, Level II-2.
- Prapas Y, Prapas N, Hatziparasidou A, Prapa S, Nijs M, Vanderzwalmen P, et al. The echoguide embryo transfer maximizes the IVF results. Acta Eur Fertil 1995;26:113–5, Level II-1.
- Prapas Y, Prapas N, Hatziparasidou A, Vanderzwalmen P, Nijs M, Prapa S, et al. Ultrasound-guided embryo transfer maximizes the IVF results on day 3 and day 4 embryo transfer but has no impact on day 5. Hum Reprod 2001;16:1904–8, Level II-2.
- Wood EG, Batzer FR, Go KJ, Gutmann JN, Corson SL. Ultrasound-guided soft catheter embryo transfers will improve pregnancy rates in in-vitro fertilization. Hum Reprod 2000;15:107–12, Level II-2.
- Eskandar M, Abou-Setta AM, Almushait MA, El-Amin M, Mohmad SE. Ultrasound guidance during embryo transfer: a prospective, single-operator, randomized, controlled trial. Fertil Steril 2008;90:1187–90, Level I.
- Hurley VA, Osborn JC, Leoni MA, Leeton J. Ultrasound-guided embryo transfer: a controlled trial. Fertil Steril 1991;55:559–62, Level I.
- Kan AK, Abdalla HI,Gafar AH, Nappi L, Ogunyemi BO, Thomas A, et al. Embryo transfer: ultrasound-guided versus clinical touch. Hum Reprod 1999;14:1259–61, Level I.
- Sallam HN, Sadek SS. Ultrasound-guided embryo transfer: a meta-analysis of randomized controlled trials. Fertil Steril 2003;80:1042–6, Level III.
- Abou-Setta AM, Mansour RT, Al-Inany HG, Aboulghar MM, Aboulghar MA, Serour GI. Among women undergoing embryo transfer, is the probability of pregnancy and live birth improved with ultrasound guidance over clinical touch alone? A systemic review and meta-analysis of prospective randomized trials. Fertil Steril 2007;88:333–41, Level III.
- Buckett WM. A meta-analysis of ultrasound-guided versus clinical touch embryo transfer. Fertil Steril 2003;80:1037–41, Level III.
- Teixeira DM, Dassuncao LA, Vieira CV, Barbosa MA, Coelho Neto MA, Nastri CO, et al. Ultrasound guidance during embryo transfer: a systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol 2015;45:139–48, Level III.
- Brown J, Buckingham K, Buckett W, Abou-Setta AM. Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women. Cochrane Database Syst Rev 2016:CD006107, Level III.
- Lindheim SR, Cohen MA, Sauer MV. Ultrasound guided embryo transfer significantly improves pregnancy rates in women undergoing oocyte donation. Int J Gynaecol Obstet 1999;66:281–4, Level II-2.
- Garcia-Velasco JA, Isaza V, Martinez-Salazar J, Landazabal A, Requena A, Remohi J, et al. Transabdominal ultrasound-guided embryo transfer does not increase pregnancy rates in oocyte recipients. Fertil Steril 2002;78:534–9, Level I.
- Chen SC, Lai TH, Lee FK. The influence of abdominal ultrasound-guided embryo transfer on pregnancy rate: a preliminary report. Fertil Steril 2007;87:1235–7, Level I.
- al-Shawaf T, Dave R, Harper J, Linehan D, Riley P, Craft I. Transfer of embryos into the uterus: how much do technical factors affect pregnancy rates? J Assist Reprod Genet 1993;10:31–6, Level II-2.
- Ammar AR, Mousa KS, Rabei NH, Galal A. Effect of ultrasound guided embryo transfer on pregnancy rates. New York Sci J 2013;6:79–83, Level I.
- Davar R, Ghandi S, Tayebi N. Does transabdominal ultrasound-guided embryo transfer improve pregnancy rates in ART cycles. Iran J Reprod Med 2007;5:95–8, Level I.
- Drakeley AJ, Jorgensen A, Sklavounos J, Aust T, Gazvani R, Williamson P, et al. A randomized controlled clinical trial of 2295 ultrasound-guided embryo transfers. Hum Reprod 2008;23:1101–6, Level I.
- Kosmas IP, Janssens R, De Munck L, Al Turki H, Van der Elst J, Tournaye H, et al. Ultrasound-guided embryo transfer does not offer any benefit in clinical outcome: a randomized controlled trial. Hum Reprod 2007;22:1327–34, Level I.
- de Camargo Martins AM, Baruffi RL, Mauri AL, Petersen C, Oliveira JB, Contart P, et al. Ultrasound guidance is not necessary during easy embryo transfers. J Assist Reprod Genet 2004;21:421–5, Level I.
- LambersMJ, Dogan E, Kostelijk H, Lens JW, Schats R, Hompes PG. Ultrasonographic-guided embryo transfer does not enhance pregnancy rates compared with embryo transfer based on previous uterine length measurement. Fertil Steril 2006;86:867–72, Level II-2.
- Shamonki MI, Schattman GL, Spandorfer SD, Chung PH, Rosenwaks Z. Ultrasound-guided trial transfer may be beneficial in preparation for an IVF cycle. Hum Reprod 2005;20:2844–9, Level II-2.
- Woolcott R, Stanger J. Potentially important variables identified by transvaginal ultrasound-guided embryo transfer. Hum Reprod 1997;12:963–6, Level II-3.
- Flisser E, Grifo JA, Krey LC, Noyes N. Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome. Fertil Steril 2006;85:353–7, Level II-2.
- Anderson RE, Nugent NL, Gregg AT, Nunn SL, Behr BR. Transvaginal ultrasound-guided embryo transfer improves outcome in patients with previous failed in vitro fertilization cycles. Fertil Steril 2002;77:769–75, Level II-2.
- Kojima K, Nomiyama M, Kumamoto T, Matsumoto Y, Iwasaka T. Transvaginal ultrasound-guided embryo transfer improves pregnancy and implantation rates after IVF. Hum Reprod 2001;16:2578–82, Level II-2.
- Bodri D, Colodron M, Garcia D, Obradors A, Vernaeve V, Coll O. Transvaginal versus transabdominal ultrasound guidance for embryo transfer in donor oocyte recipients: a randomized clinical trial. Fertil Steril 2011;95:2263–8.e1, Level I.
- Revelli A, Rovei V, Dalmasso P, Gennarelli G, Racca C, Evangelista F, et al. Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer. Ultrasound Obstet Gynecol 2016;48:289–95, Level I.
- Moini A, Kiani K, Bahmanabadi A, Akhoond M, Akhlaghi A. Improvement in pregnancy rate by removal of cervical discharge prior to embryo transfer in ICSI cycles: a randomised clinical trial. Aust N Z J Obstet Gynaecol 2011;51:315–20, Level I.
- Eskandar MA, Abou-Setta AM, El-Amin M, Almushait MA, Sobande AA. Removal of cervical mucus prior to embryo transfer improves pregnancy rates in women undergoing assisted reproduction. Reprod Biomed Online 2007;14:308–13, Level II-1.
- Visschers BA, Bots RS, Peeters MF, Mol BW, van Dessel HJ. Removal of cervical mucus: effect on pregnancy rates in IVF/ICSI. Reprod Biomed Online 2007;15:310–5, Level I.
- Derks RS, Farquhar C, Mol BW, Buckingham K, Heineman MJ. Techniques for preparation prior to embryo transfer. Cochrane Database Syst Rev 2009:Cd007682, Level III.
- Meriano J, Weissman A, Greenblatt EM, Ward S, Casper RF. The choice of embryo transfer catheter affects embryo implantation after IVF. Fertil Steril 2000;74:678–82, Level I.
- Wisanto A, Janssens R, Deschacht J, Camus M, Devroey P, Van Steirteghem AC. Performance of different embryo transfer catheters in a human in vitro fertilization program. Fertil Steril 1989;52:79–84, Level I.
- Abou-Setta AM. Firm embryo transfer catheters for assisted reproduction: a systematic review and meta-analysis using direct and adjusted indirect comparisons. Reprod Biomed Online 2006;12:191–8, Level III.
- Gonen Y, Dirnfeld M, Goldman S, Koifman M, Abramovici H. Does the choice of catheter for embryo transfer influence the success rate of in-vitro fertilization? Hum Reprod 1991;6:1092–4, Level II-2.
- McDonald JA, Norman RJ. A randomized controlled trial of a soft double lumen embryo transfer catheter versus a firm single lumen catheter: significant improvements in pregnancy rates. Hum Reprod 2002;17:1502–6, Level I.
- van Weering HG, Schats R, McDonnell J, Vink JM, Vermeiden JP, Hompes PG. The impact of the embryo transfer catheter on the pregnancy rate in IVF. Hum Reprod 2002;17:666–70, Level I.
- Choe JK, Nazari A, Check JH, Summers-Chase D, Swenson K. Marked improvement in clinical pregnancy rates following in vitro fertilization-embryo transfer seen when transfer technique and catheter were changed. Clin Exp Obstet Gynecol 2001;28:223–4, Level II-2.
- Ghazzawi IM, Al-Hasani S, Karaki R, Souso S. Transfer technique and catheter choice influence the incidence of transcervical embryo expulsion and the outcome of IVF. Hum Reprod 1999;14:677–82, Level I.
- De Placido G, Wilding M, Stina I, Mollo A, Alviggi E, Tolino A, et al. The effect of ease of transfer and type of catheter used on pregnancy and implantation rates in an IVF program. J Assist Reprod Genet 2002;19:14–8, Level II-2.
- Abou-Setta AM, Al-Inany HG, Mansour RT, Serour GI, Aboulghar MA. Soft versus firm embryo transfer catheters for assisted reproduction: a systematic review and meta-analysis. Hum Reprod 2005;20:3114–21, Level III.
- Buckett WM. A review and meta-analysis of prospective trials comparing different catheters used for embryo transfer. Fertil Steril 2006;85:728–34, Level III.
- Allahbadia GN, Kadam K, Gandhi G, Arora S, Valliappan JB, Joshi A, et al. Embryo transfer using the SureView catheter-beacon in the womb. Fertil Steril 2010;93:344–50, Level I.
- Ata B, Isiklar A, Balaban B, Urman B. Prospective randomized comparison of Wallace and Labotect embryo transfer catheters. Reprod Biomed Online 2007;14:471–6, Level I.
- Boone WR, Johnson JE, Blackhurst DM, Crane MM. Cook versus Edwards-Wallace: are there differences in flexible catheters? J Assist Reprod Genet 2001;18:15–7, Level I.
- Coroleu B, Barri PN, Carreras O, Belil I, Buxaderas R, Veiga A, et al. Effect of using an echogenic catheter for ultrasound-guided embryo transfer in an IVF programme: a prospective, randomized, controlled study. Hum Reprod 2006;21:1809–15, Level I.
- El-Shawarby SA, Ravhon A, Skull J, Ellenbogen A, Trew G, Lavery S. A prospective randomized controlled trial of Wallace and Rocket embryo transfer catheters. Reprod Biomed Online 2008;17:549–52, Level I.
- Karande V, Hazlett D, Vietzke M, Gleicher N. A prospective randomized comparison of the Wallace catheter and the Cook Echo-Tip catheter for ultrasound-guided embryo transfer. Fertil Steril 2002;77:826–30, Level I.
- McIlveen M, Lok FD, Pritchard J, Lashen H. Modern embryo transfer catheters and pregnancy outcome: a prospective randomized trial. Fertil Steril 2005;84:996–1000, Level I.
- Rhodes TL, Higdon HL 3rd, Boone WR. Comparison of pregnancy rates for two embryo-transfer catheters. Fertil Steril 2007;87:411–6, Level I.
- Saldeen P, Abou-Setta AM, Bergh T, Sundstrom P, Holte J. A prospective randomized controlled trial comparing two embryo transfer catheters in an ART program. Fertil Steril 2008;90:599–603, Level I.
- Yao Z, Vansteelandt S, Van der Elst J, Coetsier T, Dhont M, De Sutter P. The efficacy of the embryo transfer catheter in IVF and ICSI is operator-dependent: a randomized clinical trial. Hum Reprod 2009;24:880–7, Level I.
- Urman B, Aksoy S, Alatas C, Mercan R, Nuhoglu A, Isiklar A, et al. Comparing two embryo transfer catheters. Use of a trial transfer to determine the catheter applied. J Reprod Med 2000;45:135–8, Level II-2.
- Foutouh IA, Youssef M, Tolba M, Rushdi M, Nakieb A, Meguid WA. Does embryo transfer catheter type affect pregnancy rate? Middle East Fertil Soc J 2003;8:154–8, Level I.
- Aboulfotouh I, Abou-Setta AM, Khattab S, Mohsen IA, Askalani A, el-Din RE. Firm versus soft embryo transfer catheters under ultrasound guidance: does catheter choice really influence the pregnancy rates? Fertil Steril 2008;89:1261–2, Level II-2.
- Coroleu B, Barri PN, Carreras O, Martinez F, ParriegoM, Hereter L, et al. The influence of the depth of embryo replacement into the uterine cavity on implantation rates after IVF: a controlled, ultrasound-guided study. Hum Reprod 2002;17:341–6, Level I.
- Franco JG Jr. Martins AM, Baruffi RL,Mauri AL, Petersen CG, Felipe V, et al. Best site for embryo transfer: the upper or lower half of endometrial cavity? Hum Reprod 2004;19:1785–90, Level I.
- Kwon H, Choi DH, Kim EK. Absolute position versus relative position in embryo transfer: a randomized controlled trial. Reprod Biol Endocrinol 2015;13:78, Level I.
- Pacchiarotti A, Mohamed MA, Micara G, Tranquilli D, Linari A, Espinola SM, et al. The impact of the depth of embryo replacement on IVF outcome. J Assist Reprod Genet 2007;24:189–93, Level I.
- Rosenlund B, Sjoblom P, Hillensjo T. Pregnancy outcome related to the site of embryo deposition in the uterus. J Assist Reprod Genet 1996;13:511–3, Level II-2.
- Oliveira JB, Martins AM, Baruffi RL, Mauri AL, Petersen CG, Felipe V, et al. Increased implantation and pregnancy rates obtained by placing the tip of the transfer catheter in the central area of the endometrial cavity. Reprod Biomed Online 2004;9:435–41, Level II-2.
- Cavagna M, Contart P, Petersen CG, Mauri AL, Martins AM, Baruffi RL, et al. Implantation sites after embryo transfer into the central area of the uterine cavity. Reprod Biomed Online 2006;13:541–6, Level II-2.
- Tiras B, Polat M, Korucuoglu U, Zeyneloglu HB, Yarali H. Impact of embryo replacement depth on in vitro fertilization and embryo transfer outcomes. Fertil Steril 2010;94:1341–5, Level II-2.
- Cenksoy PO, Ficicioglu C, Yesiladali M, Akcin OA, Kaspar C. The importance of the length of uterine cavity, the position of the tip of the inner catheter and the distance between the fundal endometrial surface and the air bubbles as determinants of the pregnancy rate in IVF cycles. Eur J Obstet Gynecol Reprod Biol 2014;172:46–50, Level II-2.
- Abdelmassih VG, Neme RM, Dozortsev D, Abdelmassih S, Diamond MP, Abdelmassih R. Location of the embryo-transfer catheter guide before the internal uterine os improves the outcome of in vitro fertilization. Fertil Steril 2007;88:499–503, Level II-2.
- Martinez F, Coroleu B, Parriego M, Carreras O, Belil I, Parera N, et al. Ultrasound-guided embryo transfer: immediate withdrawal of the catheter versus a 30 second wait. Hum Reprod 2001;16:871–4, Level I.
- Sroga JM, Montville CP, Aubuchon M, Williams DB, Thomas MA. Effect of delayed versus immediate embryo transfer catheter removal on pregnancy outcomes during fresh cycles. Fertil Steril 2010;93:2088–90, Level II-2.
- Alvero R, Hearns-Stokes RM, Catherino WH, Leondires MP, Segars JH. The presence of blood in the transfer catheter negatively influences outcome at embryo transfer. Hum Reprod 2003;18:1848–52, Level II-2.
- Awonuga A, Nabi A, Govindbhai J, Birch H, Stewart B. Contamination of embryo transfer catheter and treatment outcome in in vitro fertilization. J Assist Reprod Genet 1998;15:198–201, Level II-2.
- Ebner T, Yaman C, Moser M, Sommergruber M, PolzW, Tews G. The ineffective loading process of the embryo transfer catheter alters implantation and pregnancy rates. Fertil Steril 2001;76:630–2, Level II-2.
- Listijono DR, Boylan T, Cooke S, Kilani S, Chapman MG. An analysis of the impact of embryo transfer difficulty on live birth rates, using a standardised grading system. Hum Fertil 2013;16:211–4, Level II-2.
- Moragianni VA, Cohen JD, Smith SE, Schinfeld JS, Somkuti SG, Lee A, et al. Effect of macroscopic or microscopic blood and mucus on the success rates of embryo transfers. Fertil Steril 2010;93:570–3, Level II-2.
- Nabi A, Awonuga A, Birch H, Barlow S, Stewart B. Multiple attempts at embryo transfer: does this affect in-vitro fertilization treatment outcome? Hum Reprod 1997;12:1188–90, Level II-2.
- Tiras B, Korucuoglu U, Polat M, Saltik A, Zeyneloglu HB, Yarali H. Effect of blood and mucus on the success rates of embryo transfers. Eur J Obstet Gynecol Reprod Biol 2012;165:239–42, Level II-2.
- Neithardt AB, Segars JH, Hennessy S, James AN, McKeeby JL. Embryo afterloading: a refinement in embryo transfer technique that may increase clinical pregnancy. Fertil Steril 2005;83:710–4, Level II-2.
- Phillips JA, Martins WP, Nastri CO, Raine-Fenning NJ. Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2013;168:121–8, Level III.
- Plowden TC, Hill MJ, Miles SM, Hoyt B, Yauger B, Segars JH, et al. Does the presence of blood in the catheter or the degree of difficulty of embryo transfer affect live birth? Reprod Sci 2016 [Epub ahead of print], Level II-2.
- Silberstein T, Weitzen S, Frankfurter D, Trimarchi JR, Keefe DL, Plosker SM. Cannulation of a resistant internal os with the malleable outer sheath of a coaxial soft embryo transfer catheter does not affect in vitro fertilization-embryo transfer outcome. Fertil Steril 2004;82:1402–6, Level II-2.
- Goudas VT, Hammitt DG, Damario MA, Session DR, Singh AP, Dumesic DA. Blood on the embryo transfer catheter is associated with decreased rates of embryo implantation and clinical pregnancy with the use of in vitro fertilization-embryo transfer. Fertil Steril 1998;70:878–82, Level II-2.
- Munoz M, Meseguer M, Lizan C, Ayllon Y, Perez-Cano I, Garrido N. Bleeding during transfer is the only parameter of patient anatomy and embryo quality that affects reproductive outcome: a prospective study. Fertil Steril 2009;92:953–5, Level II-2.
- Rhodes TL, McCoy TP, Higdon HL 3rd, Boone WR. Factors affecting assisted reproductive technology (ART) pregnancy rates: a multivariate analysis. J Assist Reprod Genet 2005;22:335–46, Level II-2.
- Sallam HN, Agameya AF, Rahman AF, Ezzeldin F, Sallam AN. Ultrasound measurement of the uterocervical angle before embryo transfer: a prospective controlled study. Hum Reprod 2002;17:1767–72, Level II-1.
- Visser DS, Fourie FL, Kruger HF. Multiple attempts at embryo transfer: effect on pregnancy outcome in an in vitro fertilization and embryo transfer program. J Assist Reprod Genet 1993;10:37–43, Level II-2.
- Yaniv S, Elad D, Jaffa AJ, Eytan O. Biofluid aspects of embryo transfer. Ann Biomed Eng 2003;31:1255–62.
- Eytan O, Elad D, Jaffa AJ. Evaluation of the embryo transfer protocol by a laboratory model of the uterus. Fertil Steril 2007;88:485–93.
- Eytan O, Elad D, Jaffa AJ. Bioengineering studies of the embryo transfer procedure. Ann N Y Acad Sci 2007;1101:21–37.
- Yaniv S, Jaffa AJ, Elad D. Modeling embryo transfer into a closed uterine cavity. J Biomech Eng 2012;134:111003.
- Eytan O, Zaretsky U, Jaffa AJ, Elad D. In vitro simulations of embryo transfer in a laboratory model of the uterus. J Biomech 2007;40:1073–80.
- Groeneveld E, de Leeuw B, Vergouw CG, Visser OW, Lambers MJ, Heymans MW, et al. Standardization of catheter load speed during embryo transfer: comparison of manual and pump-regulated embryo transfer. Reprod Biomed Online 2012;24:163–9.
- Caanen MR, van der Houwen LE, Schats R, Vergouw CG, de Leeuw B, Lambers MJ, et al. Embryo transfer with controlled injection speed to increase pregnancy rates: A randomized controlled trial. Gynecol Obstet Invest 2016;81:394–404, Level I.
- Oraif A, Hollet-Caines J, Feyles V, Rebel M, Abduljabar H. Do multiple attempts at embryo transfer affect clinical pregnancy rates? J Obstet Gynaecol Can 2014;36:406–7, Level II-3.
- Lee HC, Seifer DB, Shelden RM. Impact of retained embryos on the outcome of assisted reproductive technologies. Fertil Steril 2004;82:334–7, Level II-2.
- Poindexter AN 3rd, Thompson DJ, Gibbons WE, Findley WE, Dodson MG, Young RL. Residual embryos in failed embryo transfer. Fertil Steril 1986;46:262–7, Level II-2.
- Tur-Kaspa I, Yuval Y, Bider D, Levron J, Shulman A, Dor J. Difficult or repeated sequential embryo transfers do not adversely affect in-vitro fertilization pregnancy rates or outcome. Hum Reprod 1998;13:2452–5, Level II-2.
- Vicdan K, Isik AZ, Akarsu C, Sozen E, Caglar G, Dingiloglu B, et al. The effect of retained embryos on pregnancy outcome in an in vitro fertilization and embryo transfer program. Eur J Obstet Gynecol Reprod Biol 2007;134:79–82, Level II-2.
- Yi HJ, Koo HS, Cha SH, Kim HO, Park CW, Song IO. Reproductive outcomes of retransferring retained embryos in blastocyst transfer cycles. Clin Exp Reprod Med 2016;43:133–8, Level II-2.
- Silberstein T, Trimarchi JR, Shackelton R, Weitzen S, Frankfurter D, Plosker S. Ultrasound-guided miduterine cavity embryo transfer is associated with a decreased incidence of retained embryos in the transfer catheter. Fertil Steril 2005;84:1510–2, Level II-2.
- Botta G, Grudzinskas G. Is a prolonged bed rest following embryo transfer useful? Hum Reprod 1997;12:2489–92, Level I.
- Amarin ZO, Obeidat BR. Bed rest versus free mobilisation following embryo transfer: a prospective randomised study. BJOG 2004;111:1273–6, Level I.
- Purcell KJ, Schembri M, Telles TL, Fujimoto VY, Cedars MI. Bed rest after embryo transfer: a randomized controlled trial. Fertil Steril 2007;87: 1322–6, Level I.
- Lambers MJ, Lambalk CB, Schats R, Hompes PG. Ultrasonographic evidence that bedrest after embryo transfer is useless. Gynecol Obstet Invest 2009;68:122–6, Level I.
- Li B, Zhou H, Li W. Bed rest after embryo transfer. Eur J Obstet Gynecol Reprod Biol 2011;155:125–8, Level III.
- Abou-Setta AM, Peters LR, D'Angelo A, Sallam HN, Hart RJ, Al-Inany HG. Post-embryo transfer interventions for assisted reproduction technology cycles. Cochrane Database Syst Rev 2014:Cd006567, Level III.
- Craciunas L, Tsampras N. Bed rest following embryo transfer might negatively affect the outcome of IVF/ICSI: a systematic review and meta-analysis. Hum Fertil (Camb) 2016;19:16–22, Level III.
- Ben-Rafael Z, Ashkenazi J, Shelef M, Farhi J, Voliovitch I, Feldberg D, et al. The use of fibrin sealant in in vitro fertilization and embryo transfer. Int J Fertil Menopausal Stud 1995;40:303–6, Level II-2.
- Su TJ, Chen YC, Hung YT, Yang YS. Comparative study of daily activities of pregnant and non-pregnant women after in vitro fertilization and embryo transfer. J Formos Med Assoc 2001;100:262–8, Level II-2.
- Bar-Hava I, Kerner R, Yoeli R, Ashkenazi J, Shalev Y, Orvieto R. Immediate ambulation after embryo transfer: a prospective study. Fertil Steril 2005;83:594–7, Level II-2.
- Sharif K, Afnan M, Lenton W, Khalaf Y, Ebbiary N, Bilalis D, et al. Do patients need to remain in bed following embryo transfer? The Birmingham experience of 103 in-vitro fertilization cycles with no bed rest following embryo transfer. Hum Reprod 1995;10:1427–9, Level II-3.
- Woolcott R, Stanger J. Ultrasound tracking of the movement of embryo-associated air bubbles on standing after transfer. HumReprod (Oxford, England) 1998;13:2107–9, Level II-3.
- Sharif K, Afnan M, Lashen H, Elgendy M, Morgan C, Sinclair L. Is bed rest following embryo transfer necessary? Fertil Steril 1998;69:478–81, Level II-3.
- Gaikwad S, Garrido N, Cobo A, Pellicer A, Remohi J. Bed rest after embryo transfer negatively affects in vitro fertilization: a randomized controlled clinical trial. Fertil Steril 2013;100:729–35, Level I.
Topic Resources
View more on the topic of embryo transfer
Topic Resources
View more on the topic of in vitro fertilization (IVF)