Common practices among consistently high-performing in vitro fertilization programs in the U.S.: 10-year update

Abstract

Objective:

To evaluate similarities and differences in clinical and laboratory practices among high-performing fertility clinics.

Design:

Cross-sectional questionnaire study of selected programs

Setting:

Academic and private fertility practices performing in vitro fertilization (IVF)

Participants:

Thirteen IVF programs performing at least 100 cycles a year and having high cumulative singleton delivery rates for two years.

Intervention:

A comprehensive survey

Main Outcome Measure:

Clinical and Laboratory IVF practices

Results:

Although many areas of clinical practice vary among top programs some commonalities were observed. All programs use a combination of FSH and LH for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, ultrasound guided embryo transfers, and a required semen analysis prior to IVF cycle start. Common laboratory practices include vitrification of embryos at the blastocyst stage, air quality control with positive air pressure and HEPA filtration, use of incubator gas filters, working on heated microscope stages, and incubating embryos in a low oxygen environment, most often in benchtop incubators.

Conclusion:

Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success. High performing clinics are focused on singleton deliveries. As the field of IVF is rapidly evolving, it is imperative that we share best practices in an effort to improve outcomes from all clinics for the good of our patients.

Introduction

Evidence-based clinical practice requires high quality prospective randomized trials to inform clinical decisions. However, there are many facets of clinical practice that do not lend themselves to trials due in part to the time and expense required for such studies. There are numerous examples in medicine and business where emulating a successful practice has led to globally improved outcomes. A best practice publication ten years ago queried 10 consistently high-performing in vitro fertilization (IVF) programs about practice patterns that may have contributed to their success.(1) In that study, common patient evaluation practices included assessing all patients for endometrial defects, hydrosalpinges, and ovarian reserve. Common treatment practices included use of mixed LH and FSH stimulation protocols and ultrasound-guided embryo transfers. Common laboratory practices included selective use of ICSI, group embryo culture, and blastocyst embryo transfer. In addition, experienced personnel, standardization of practice, attention to detail and good communication were cited as important factors leading to success.

The past 10 years has seen an explosion of new IVF technologies and innovative approaches that have changed IVF practice with a greater emphasis now placed on maximizing the singleton delivery rate. Several high impact studies and articles called for changes in practices but the actual implementation in practices is not known. In the past 10 years, there have been 79 updated or new practice guidelines and committee opinions from the American Society for Reproductive Medicine (ASRM) ranging from minimal standards for practices offering assisted reproductive technology (ART), updates on number of embryos to transfer and pre-implantation genetic testing(2–4);

Our purpose is to update common clinical practices among top performing IVF programs in the United States. Our hope is that transparent reporting of value-generating practices, as reported in this survey, could lead to greater standardization and improved outcomes from IVF treatments similar to what has been seen in other areas of healthcare. (5)

Materials and Methods

This study was reviewed by the Institutional Review Board at the University of Iowa and determined to be exempt. Also, this study was approved by the SART research committee. Clinics were selected from the SART database and therefore must have been members of SART. We limited clinics to those performing at least 100 autologous egg retrieval cycles per year. High-performing IVF programs were selected as those having the highest cumulative singleton live birth rates in women less than or equal to 37 years of age in 2016 and 2017. The age groups were chosen to not penalize clinics with a higher proportion of older patients and the cycle limit was chosen to avoid spurious results from small numbers of cycles. A de-identified list of the top 30 (10%) of SART-reporting programs for each year was provided to review the inclusion and exclusion criteria. Clinics were compared to national averages for each year and were excluded for low prospective reporting (less than 55%), a high rate of “converted” cycles from fertility preservation, or extremely low cycle cancellation (less than 2%) rates. A “converted” cycle is when a cycle was designated as fertility preservation and yet an embryo was transferred within one year of the cycle start. Fertility preservation cycles are not counted in the denominator of cycles performed and high rates of selectively reporting those that resulted in a delivery can artificially inflate a program’s pregnancy rates. All three of these criteria have been identified by the SART validation committee as “red flags” for inaccurate reporting of cycles. There were 13 programs that met criteria both years and these clinics were identified by the investigators but will remain anonymous in this report.

An electronic survey consisting of a clinical section and a laboratory section was created by two embryologists and four reproductive endocrinologists. The clinical survey queried practice demographics, clinic personnel, patient selection criteria, pre-IVF testing, medication and supplement use, ovarian stimulation protocols, and embryo testing and transfer practices. The laboratory survey contained questions pertaining to andrology and embryology lab personnel and environment as well as laboratory practice. In total the survey consisted of 61 questions plus branching stem questions. Study data were collected and managed using REDCap (Research Electronic Data Capture) hosted at UT Health San Antonio.(6,7)

The medical director at each SART member clinic was contacted by phone to confirm the correct email address to send the survey. If the medical director was unavailable by phone, then an email was sent to the medical director or if no answer, then to the laboratory director. The medical director completed surveys with input from the laboratory director. Results from all responding programs were extracted from REDCap, de-identified, analyzed and summarized using REDCap and Microsoft Excel. This study was deemed exempt from Institutional review board review secondary to the de-identified nature of the survey and no more than minimal risk to participants.

Results

Clinic stats/demographics:

All thirteen clinics identified completed the questionnaire. The average number of fresh retrieval cycles in 2017 per clinic was 687 (range 200s-3000s) and total cycles 1472 (range 400s-7000s). The median cumulative singleton birth per egg retrieval start in 2016 was 59% for the women <35 and 47% for the women 35–37 years old. In 2017, the median cumulative singleton birth per egg retrieval start was 61% for the women <35 and 50% for the women 35–37 years old (Table1). These clinics averaged 85% prospective reporting (65–96%), 6% cycle cancellation rates (2–11%) and 0.3% “converted” rates (0–1%). The majority of the clinics were academic (n=5) or single practice/small business (n=6) with the others being fertility center franchise or other. Of the 13 practices, six had been together 21+ years, two for 16–20 years and three for 11–15 years.

TABLE 1.

Clinical outcomes in 2016 and 2017

Singleton birth cumulative outcome per egg retrieval	2016		2017
	High performing clinics (N=13)	All programs	High performing clinics (N=13)	All programs
Women <35 yo	59% (53–65%)	45%	61% (52–66%)	48%
Women 35–37yo	47% (38–55%)	34%	50% (36–60%)	36%
% eSET rate in first transfer per clinic
Women <35 yo	78% (56–100%)	56%	85%(43–100%)	68%
Women 35–37yo	71% (61–100%)	46%	74% (37–100%)	59%
Singleton delivery per eSET-First transfer
Women <35 yo	62% (46–72%)	51%	61% (51–77%)	51%
Women 35–37yo	57% (47–68%)	48%	56% (51–70%)	49%

Personnel:

All clinics had the expected personnel including physicians, nurses and lab personnel. In addition nearly all used medical assistants, financial counselors and had clinical psychology support. Seven of 13 clinics had sonographers and 7 of 13 had advanced practice providers (APPs). The most common duties of APPs included new and return patient visits, performing ultrasounds, saline infusion sonohystograms, and IUIs. No programs reported APPs performing egg retrievals, embryos transfers or surgeries. Eleven of the 13 clinics had an onsite laboratory director with 2 having an offsite director. In describing why their clinic is outstanding, the majority of the clinics reported teamwork and weekly meetings for communication as critically important. They also described consistency in practice, and careful attention to details along with excellent laboratory staff.

Medical Practice

Restrictions for use of autologous eggs:

Ten of 13 programs had age restrictions for using autologous oocytes. The median age limit was 45 years old (yo) with a range of 44–50 yo. Twelve clinics had BMI restrictions for using autologous eggs with a median BMI limit of 40 with range of 40–50. Only three clinics reported ovarian reserve restrictions for IVF using autologous eggs with those having a restriction using a serum FSH cutoff ranging from 12–25 mIU/mL.

Pre-cycle assessments:

The majority of clinics (8/13) required a uterine cavity assessment within 12 months and performed the mock embryo transfer prior to cycle start. None of the programs did the mock embryo transfer at time of egg retrieval or during stimulation.

Supplements:

In women with diminished ovarian reserve (DOR), most clinics recommend CoQ10, allow acupuncture and discourage metformin, aspirin and testosterone use. In women with DOR, the clinics were nearly evenly split on DHEA and growth hormone use. For the average polycystic ovarian syndrome (PCOS) patient, most recommend weight loss, allow metformin and acupuncture and discourage DHEA. The recommendations varied on CoQ10 and inositol use.

Ovarian stimulation:

The majority (n=12) of clinics use birth control pills for some IVF starts with a median use in 65% of cycles and a range of 5–95% of cycles. For IVF stimulation medications, all clinics used a combination of FSH and LH although there was variation in how the medications were used with nearly equal numbers of clinics reporting their protocols to be step-up dosing, step-down dosing and continuing the same dose over the course of stimulation.

Progesterone:

The majority (n=10) of clinics measure serum progesterone levels during stimulation. The timing of when progesterone was measured varied with 40% (n=4) testing levels on all blood samples during stimulation, 30% (n=3) testing several blood samples later in stimulation and 30% (n=3) testing only on the day of trigger. For those clinics that perform fresh embryo transfers, the progesterone used to advise a “freeze all” cycle ranged from 1.5–2 ng/dL.

Embryo transfers:

Top performing clinics had a higher rate of SET in the first transfer cycle than SART national averages (Table 1). Three of the thirteen clinics perform only frozen embryo transfers while 10 perform embryo transfers in the “fresh” cycle. For the fresh transfers, there is a split between the clinics on when they start progesterone in relationship to the retrieval with some starting the evening of retrieval and others the morning or evening after retrieval. When performing a programmed cycle for frozen embryo transfer, the minimal acceptable endometrial thickness varied among clinics with limits reported as 6mm (n=5), 7mm (n=4), and 8mm (n=2). Two clinics reported having no minimal endometrial thickness. All clinics use IM progesterone for frozen embryo transfers and the majority start it at 120–131 hours prior to transfer. Thirty percent or less of the clinics use antibiotics or corticosteroids before embryo transfers. Testing for receptivity of the endometrium was either not or rarely performed in 8/13 clinics. If an assay for endometrial receptivity was performed, the most common indication was for recurrent failed embryo transfer. All clinics use ultrasound guidance for all embryo transfers and most had the patients ambulate immediately after the transfer.

Laboratory Practices

PGT-A:

Two clinics recommend PGT-A to women under 35 years old, and 6 recommend it to women age 35–37 years. The majority of clinics (n=12) recommend PGT-A for women 38 years and older. The clinics reported their percent of autologous cycles using PGT-A as 0–25% (n=3) 26–50% (n=2), 51–75% (n=4), 76–90% (n=2), 91–100% (n=1). Ovarian reserve is not a factor considered in counseling about use of PGT-A in a majority of clinics. Eight laboratories perform only ICSI for PGT-A. When queried about the advantages of PGT-A, the top three reasons were a reduced miscarriage rate, an increased single embryo transfer rate and a decreased time to pregnancy. The most reported disadvantages of PGT-A were increased cost, clinical uncertainty about how to handle mosaic results and concerns that the trophoectoderm biopsy is not representative of the entire embryo.

Mosaic reports:

Nine of the clinics receive mosaic reports from PGT-A and will transfer mosaic embryos. The majority of clinics report mosaic embryos to their patients and transfer mosaic embryos depending on the chromosomes involved and the percent of mosaicism, with most transferring embryos with up to 50% mosaicism. Three of the clinics would transfer aneuploid embryos.

Routine Male test:

All laboratories require a routine semen analysis prior to IVF. None of the laboratories routinely perform DNA fragmentation, semen culture or test for anti-sperm antibodies.

Laboratory techniques:

Four of the 13 (31%) laboratories perform ICSI for all procedures and three laboratories (23%) reported male factor as the only indication for ICSI. The top three indications for ICSI other than male factor were cryopreserved semen, unexplained infertility and PGT-A. When asked about utilization of additional tools to position oocytes or select sperm for ICSI, none of the laboratories reported using a Polscope for oocyte positioning. Two laboratories employ methods to physiologically select sperm for ICSI (PICSI) and one laboratory reported use of ultra-high magnification for sperm selection (IMSI).

Various degrees of assisted hatching (AH) is performed by most laboratories. Four of the clinics only perform AH for embryo biopsy. The most common indications for AH other than embryo biopsy were thawed or warmed embryos (n=9) and embryos with thick zona pellucidae (n=5). When AH is performed, the majority of laboratories perform it at the cleavage stage (n=9), one at the morula stage and four perform AH at the blastocyst stage. All clinics vitrify embryos at the blastocyst stage, however there was no consensus regarding minimum criteria for degree of blastocoel expansion or embryo grade for vitrification. Most (n=10) laboratories collapse the blastocoel prior to vitrification. All laboratories indicated they prescribed a minimum recovery period between embryo warming and transfer. The shortest recovery time was 2 hours (n=7) and the longest recovery time was 5 hours (n=3).

Laboratory equipment and setting:

The tools used by laboratories to control air quality are shown in Figure 1. Equipment and practices to further optimize conditions in and out of the incubator are described in Figure 2. For embryo culture most laboratories reported using benchtop incubators alone (n=1) or in combination (n=11) with small/benchtop or big box incubators. All laboratories use a tri-gas mix of O₂, N₂ and CO₂ to control the embryo culture environment. Two laboratories reported using time-lapse imaging for embryo monitoring with only one of them routinely using the time-lapse algorithm for embryo selection. There was no consensus among laboratories regarding the type of embryo culture media and replenishing strategy as there was a 3-way split among the options of single step continuous (n=5), single step replenished (n=4), and sequential (n=4) culture media.

Figure 1:

Frequency of HVAC Features Employed by Laboratories. Frequencies reported as percentage of laboratories that reported use.

Figure 2:

Frequency of Other Environmental Controls used by Laboratories. Frequencies reported as percentage of laboratories that reported use.

Performance indicators;

The performance indictors most frequently employed by laboratories for quality assurance for oocyte retrieval cycles includes fertilization rate - conventional insemination (9/9 centers that perform conventional insemination), ICSI fertilization rate (n=12), oocyte degeneration after ICSI (n=8), day 5 embryo quality (n=12) and day 6 embryo quality (n=10). Most clinics did not use cleavage stage embryo assessments as performance measures. Laboratories also reported monitoring the no result rate for PGT by the embryologist performing the biopsy and loading the sample (n=9), and the warmed embryo survival rate per embryologist (n=9). As all programs reported a high rate of eSETs, close attention is paid to the eSET clinical pregnancy rate by transfer physician (n=10) and transfer embryologist (n=9).

Discussion

Many industries have transformed themselves through standardization of value-generating practices, outcome measurement and transparent reporting of quality measures. In contrast, medical practice has been described as a “cottage industry” with small independent and often competitive practices with little ability to share or coordinate best practice concepts.(5) Some physicians are skeptical about standardization, preferring individualized care plans tailored to the patient’s circumstances. As a result, care is often fragmented and inconsistent, sometimes leading to suboptimal outcomes.

With the presence of a large database reporting outcomes of IVF, we can select clinics that have consistently outstanding results and study them for common practices. We have hypothesized practices common to these centers may be important in obtaining optimal outcomes whereas practices that are not as consistently utilized are likely to be of less importance or at least are not critical to achieving excellent outcomes.

Overall, most high performing programs practice similarly. There were a few practice patterns that all programs performed including the combination of FSH and LH for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, used ultrasound guided transfer, and required a semen analysis prior to IVF cycle start. In regards to laboratory practices, all clinics vitrify embryos at the blastocyst stage and laboratories are control air quality with positive air pressure and HEPA filtration and ensure the embryo environment is optimized by using incubator gas supply filters, working on heated microscope stages and incubating embryos in a low oxygen environment, most often in benchtop incubators.

Although it has been 10 years since the publication of the prior survey of high performing IVF programs; much of what high performing clinics report as important to their success remains the same on this present survey. When comparing the two surveys, common patient evaluation practices included assessing all patients for endometrial defects, and ovarian reserve. Common treatment practices included use of mixed LH and FSH stimulation protocols for ovulation induction and ultrasound-guided embryo transfers in both the prior and current survey. (6) Common laboratory practices included selective use of ICSI, and blastocyst embryo transfer in both surveys. In addition, experienced personnel, standardization of practice, attention to detail and good communication were cited as important factors leading to success in both surveys.

However, much has changed with greater use of new technology like PGT-A on the current survey and a greater shift to emphasizing the importance of single embryo transfers to decrease the risk of multiple gestation and improve the safety of IVF for the mother and child. Although not directly comparable, the singleton live birth rate among study participants in 2016–17 compared to 2006–2007 reveals an approximately 25% increase in the singleton live birth rate (60% vs. 35%) for women <35 and a 18% increase (49% vs. 31%) in those 35–37, respectively. It is clear that these high performing clinics achieve very high live birth rates despite the move to the greater implementation of elective single embryo transfer and without routine use of PGT-A. Similar to the widespread introduction of ICSI into IVF practice more than 25 years ago, the introduction of PGT-A was done without analysis of its effects via large scale randomized controlled trials. (8) Consistent with the controversy surrounding the use of this technology, high performing clinics varied on their recommendation of PGT-A. The majority of high performing clinics recommended its use routinely in women 38 or older or for specific indications. This is consistent with the majority not using PGT-A routinely for those less than 35yo and still maintaining a high live birth rate. There was a wide range in percent of cycles that are PGT-A with not all clinics transferring mosaic embryos which is consistent with a previous survey.(2) A study in 2019 of 405 clinics reported that only 36% receive mosaicism data on their aneuploidy report. (9)

The majority of programs have similar evaluations prior to starting IVF that are evidence based. (10) Most of the programs measure progesterone during the stimulation, which has been controversial in the literature but supported by some studies. (11,12) As for supplementation, CoQ10 for DOR and weight loss for PCOS were the most recommended. Overall, there was a lack of consensus regarding recommendations for the “add-on” IVF supplements that lack clear clinical benefits defined in the literature.(13) None of the practices performed mock transfers at the time of retrieval, which is information that is not included in the ASRM embryo transfer committee opinion, but consistent with a previous survey in 2010 showing deviation to guidelines based on certain situations.(14,15) Fresh and frozen embryo transfers occur at most clinics, which is consistent with the literature. (16)

Similarities and Variations in Practices- laboratory:

The results of the laboratory survey reflect the programs’ recognition to invest in equipment and commit to practices that provide an optimal environment for gametes and embryos. The integration of positive pressure, HEPA filtration and efforts to reduce volatile organic compounds in and outside the incubators agree with recommendations from an international consensus report on IVF laboratory air quality. (17) While reports of contamination cases in IVF laboratories are rare, Munch et al. reported a decline in fertilization, cleavage and blastocyst conversion rates when carbon filtration intended to remove volatile organic compounds (VOCs) from the laboratory’s HVAC system was inadvertently removed. (18,19) They noted that fertilization and embryo development markers quickly returned to their benchmark levels after resumption of VOC filtration. This report demonstrated that without environmental controls in place, additional efforts to optimize fertilization rates and support embryo development may be futile.

Laboratories have several options when selecting incubators for embryo culture. (20) While no specific incubator style has been shown to be superior over another, embryologists need to select incubators that will allow them to minimize incubator openings while satisfying the demands of their clinical caseload.(21) All but one laboratory responding to our survey opted to use benchtop incubators and everyone reported using reduced oxygen for at least a portion of their embryo culture. Benchtop incubators afford laboratories the ability to assign individual chambers to each case. The smaller chambers in benchtop incubators have been shown to facilitate faster temperature and atmosphere recovery after opening compared to larger chambers of the box style incubators.(22–24) In theory, reduced environmental stress on the embryos should lead to improved embryo development, but faster incubator recovery time has yet to be associated with better outcomes. Likewise, there is evidence that incubation in atmospheric oxygen levels has deleterious effect on embryo development, but studies have yet to prove use of a reduced oxygen atmosphere yields improved pregnancy outcomes. (25,26) Despite the lack of evidence that live birth rates are impacted incubation factors, embryologists must be proactive and utilize tools to optimize embryo quality in anticipation that these efforts will positively impact the reproductive potential of the IVF procedure.

The use of assisted hatching varied across programs with a third of the laboratories reporting PGT as the only indication for them to artificially breach the zona pellucida. As with other laboratory practice, assisted hatching has been shown to be associated with improvements in some outcome measures such as implantation rate and clinical pregnancy rate, but has yet to be shown to improve live birth rates. (27–29) The use of additional “add-on” interventions such as sperm selection aids for ICSI (PICSI and IMSI) and time-lapse imaging were rarely employed by the surveyed laboratories. Some have argued that the increasing range of IVF add-on’s available to clinicians and patients has created new ethical challenges requiring balance between recognition of patient autonomy and healthcare providers’ duty to deliver cost-effective, and safe care. (28,30)

It was not surprising there was no consensus among the laboratories regarding the type of embryo culture media and replenishing strategy. Numerous studies have been performed to compare embryo culture media, but there has been little evidence to show superior IVF outcomes using one culture medium and/or replenishing strategy versus another. (21,31) One could speculate that, provided environmental controls are in place, laboratories with a robust quality management program may be able to optimize culture conditions with a number of commercially available culture media. Due to the already long survey, we were unable to inquire about laboratory quality control practices associated with culture media management.

Vitrification has become the standard method of embryo cryopreservation in today’s fertility clinics. All high-performing clinics in this survey vitrify embryos at the blastocyst stage while applying different criteria and thresholds to determine embryos eligible for vitrification. The main factors are decent quality ICM and sufficient trophectoderm. In most cases, poor quality embryos are excluded from cryopreservation.

Routine measurement of key performance indicators (KPI) is a critical element of an fertility center’s quality management program. The factors a center selects to measure must be reliable, robust, relevant to internal and external factors and feasible to implement. We used the Vienna consensus report on IVF laboratory performance indicators to develop our questions regarding measures employed by the laboratories and clinics. (32) The majority of the laboratories monitor fertilization rate by insemination method, oocyte degeneration after ICSI and blastocyst development on days 5 and 6. Not surprisingly, cleavage stage assessments were only utilized by the programs that were compelled to remove the embryo from the incubator due to the laboratory’s use of sequential media or media replenishment. This illustrates the importance of not only monitoring the performance indicators, but selecting measures that are a component of routine patient care or laboratory practice. Additionally, programs must select measures that serve as early warning signals when fall below benchmarks. (33–35)

The strengths of this study include that all programs selected participated in this comprehensive survey. As in the previous publication, the decision was made not to reveal the names of the clinics as the objective of this was to summarize practice patterns and not advertise. The limitations of this study are the potential for survey volunteer bias as only 1–2 providers/lab personnel completed the questionnaire so there may be other practice patterns that were not captured. This was a descriptive study with no comparative group so it is possible that programs that are not performing as highly may still be functioning in a similar fashion. Other limitations include that these results/survey were not validated and that the sample size of the programs may not be representative of other programs. The practice patterns of IVF are large and not all practice patterns were able to be addressed due to the length of the survey that would be needed.

In conclusion, there is often consistency but also some variations in practice among the different high-performing fertility clinics. The high performing clinics are focusing on singleton delivery outcomes. As a field, IVF is evolving and it is imperative that we assess our progress and collaborate together for the good of our patients.

TABLE 2.

Categories of Personnel in 2017

Categories of Personnel for 2017	Number of programs	Per Egg Retrieval (egg retrieval/# of personnel)	Per Total Cycles (fresh + frozen)/# of personnel
Physicians	13	123(46–159)	259 (81–771)
Advanced Practice Providers	7	322(117–735)	749(310–1514)
Registered Nurses	13	83(20–113)	145 (54–367)
Medical Assistants	12	192(35–269)	374 (157–889)
Sonographers	7	197(70–530)	380 (108–551)
Lab Director (onsite)	11	657(222–3185)	1429(476–7162)
Embryologists	13	152(40–530)	273 (129–716)
Andrologists	12	309(218–716)	647 (218–2366)
Financial Counselors	12	251(50–530)	464 (97–931)
Psychological support	6	592(250–1062)	1440 (551–2387)

Capsule.

Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success.