In round 1, the working group generated 50 unique ideas of items in fertility practice that are potentially unnecessary. Round 2 narrowed this to 28 items, round 3 to 14 items, and round 4 to 13 items, which were then evaluated in the national CFAS membership survey for the final round (Figure 1). One-hundred-and-twenty-nine CFAS members responded to this survey, which was distributed to approximately 600 members who agreed to be contacted by email correspondence, achieving a 21.5% response rate (Table 1). Results of the survey were reviewed by the working group, who created the final recommendations list based on those with the 5 highest content agreement scores, and the 5 highest aggregate scores for prevalence, cost, and potential for harm (Table 2). Supporting literature for each item was included in the descriptions in the final list (Table 3).
Table 1
CFAS Membership Online Survey Demographics
|
n (%)*
|
Professional Background
|
|
MD
|
46 (35.7)
|
Nurse
|
14 (10.9)
|
Embryologist
|
41 (31.8)
|
Counselor
|
8 (6.2)
|
Administrator
|
2 (1.6)
|
Other
|
21 (16.3)
|
Gender
|
|
Male
|
36 (27.9)
|
Female
|
92 (71.3)
|
Prefer not to share
|
1 (0.8)
|
Years Working in Fertility
|
|
0-5 years
|
31 (24.2)
|
6-10 years
|
29 (22.7)
|
11-20 years
|
29 (22.7)
|
>20 years
|
39 (30.5)
|
*Percentages are rounded to one decimal point, therefore, the sum of values in each category may not add to exactly 100. |
Table 2
CFAS National Membership Survey Results for the Top 5 Items
Item
|
Sum of Very Important & Moderately Important Responses
|
Issue Prevalence*
|
Cost*
|
Potential for Harm*
|
Aggregate Score (%) of issue prevalence, cost, & potential for harm
|
Recommended to Include in Top 5 List*
|
1. PGT
|
54 (69.2)
|
28 (50.91)
|
55 (94.83)
|
42 (73.68)
|
73.1
|
40 (69.0)
|
2. High dose gonadotropins
|
49 (64.5)
|
39 (70.91)
|
42 (76.36)
|
37 (67.27)
|
71.5
|
30 (53.6)
|
3. Assisted hatching
|
49 (62.8)
|
34 (59.65
|
37 (66.07)
|
33 (58.93)
|
61.6
|
29 (51.8)
|
4. Immune therapy
|
52 (67.5)
|
17 (30.36)
|
43 (78.18)
|
43 (75.44)
|
61.3
|
37 (66.1)
|
5. DNA fragmentation
|
54 (68.4)
|
30 (54.55)
|
46 (85.19)
|
13 (24.07)
|
54.6
|
31 (54.4)
|
*Expressed as n (%) of respondents who answered “Yes,” in a yes or no question about whether the issue is prevalent, costly, has potential for harm, or should be in the top 5 list; note that respondents were able to skip questions. |
Table 3
Final Recommendations List
Recommendation Number
|
Recommendation
|
1
|
Don’t routinely perform preimplantation genetic testing for aneuploidy screening on patients undergoing IVF
|
2
|
Don’t prescribe gonadotropins in doses of over 450 units daily for controlled ovarian stimulation in IVF
|
3
|
Don’t routinely perform laser-assisted hatching on fresh embryos prior to transfer
|
4
|
Don’t prescribe corticosteroids, IVIG, leukemia inhibitory factor, or lymphocyte immunization therapy for patients undergoing IVF, those with a history of recurrent implantation failure, or those with recurrent pregnancy loss
|
5
|
Don’t routinely perform sperm DNA fragmentation testing
|
Summary of Recommendations with Supporting Evidence
Recommendation #1: Don’t routinely perform preimplantation genetic testing for aneuploidy screening on patients undergoing IVF.
Aneuploidy is a well-established cause of implantation failure, miscarriage, and pregnancy anomalies, and is known to increase in frequency with advancing oocyte age [10-12]. Pre-implantation genetic testing for aneuploidy (PGT-A) was developed to select euploid embryos for transfer with the goal of increasing live birth rate [13]. Despite its common use in Canada and the United States, there are several randomized control trials (RCTs) looking at PGT-A using blastocyst biopsy with no clear evidence of benefit [14]. One study comparing single euploid embryo transfer with untested blastocyst transfer demonstrated no statistically significant difference in ongoing pregnancy rate when fresh and first frozen embryo transfer cycle were included in the analysis [15]. Likewise, an RCT comparing single euploid transfer with double embryo transfer of untested embryos showed no difference in live birth rate [16, 17]. While a higher live birth rate was demonstrated in one study of patients randomized to receive either a double euploid embryo transfer or a double untested embryo transfer, this study has been questioned for its applicability because double embryo transfer is not the standard practice in Canada due to the increased risk of multiple gestation [18]. Similarly, in patients with recurrent pregnancy loss (RPL), there are no RCTs demonstrating a benefit of in vitro fertilization (IVF) with PGT-A compared with spontaneous conception, and in fact there may be an increase in time to pregnancy [13].
In summary, while PGT-A may be an appropriate choice for select patients who are counselled on the indications, limitations, and risks, it should not be recommended routinely to all patients. In addition to there being no clear benefit of routine PGT-A, there are also potential harms including risk of false positive findings and embryo loss, as well as additional costs and increased time spent waiting for results [13, 14].
Recommendation #2: Don’t prescribe gonadotropins in doses of over 450 units daily for controlled ovarian stimulation in IVF.
High doses of gonadotropins during IVF has significant potential for harm without evidence of benefit. Ovarian Hyperstimulation Syndrome (OHSS) is a well-known potential harm of high-dose gonadotropin stimulation with the potential for life-threatening complications in severe forms [19, 20]. An RCT from 2007 of patients under the age of 38 was terminated prematurely when an interim analysis demonstrated a lower embryo aneuploidy rate in patients with lower-dose stimulation (150 units daily) compared with higher-dose stimulation (225 units daily), with a similar number of chromosomally normal embryos created despite fewer oocytes retrieved, and a similar pregnancy rate per cycle start [21]. In a retrospective population-based study of 77,956 IVF cycles and 36,270 consecutive transfers from frozen/thawed embryos, the live birth rate in fresh IVF cycles improved as the number of eggs retrieved increased up to 11 oocytes, at which point the live birth rate plateaued around 30% [22]. When this same study included analysis of both fresh and frozen embryo transfers, the cumulative live birth rate increased per oocyte retrieved up to approximately 20 eggs where it plateaued at 45.8%; however, the incidence of severe OHSS increased significantly by the number of oocytes, particularly if more than 18 oocytes were retrieved [22]. While thromboembolic events were rare, a total of 16 events in 14 patients were observed, and occurred only when 15 or more eggs were retrieved [22].
Other potential risks of high-dose gonadotropin stimulation in pregnancies achieved through IVF with fresh embryo transfer is an association with higher rates of small for gestational age and low birth weight neonates in those with high estradiol levels in the late follicular phase [20]. In summary, balancing the limited benefits of obtaining a high number of oocytes with the increasing risk of OHSS as gonadotropin doses increase, gonadotropins should not be prescribed over 450 units daily.
Recommendation #3: Don’t routinely perform laser-assisted hatching on fresh embryos prior to transfer.
Laser-assisted hatching (AH) is a process by which the zona pellucida of the embryo is breached or thinned out prior to transfer with the goal of facilitating improved embryo expansion for increased pregnancy rates [23]. Risks of AH include embryo injury, unknown effects on fetal and childhood development and disease, and increased rates of monozygotic twinning [24]. A 2012 Cochrane Review of AH looked at 31 trials including 1,992 clinical pregnancies in 5,728 patients [23]. They demonstrated a slightly improved pregnancy rate with AH in analysis of all 31 trials, but when only the 9 RCTs that included information on live birth rate were analyzed, there was no significant difference in rates of clinical pregnancy or live birth [23]. Since this analysis, there have been prospective clinical trials demonstrating no benefit to AH in those undergoing fresh embryo transfer for advanced reproductive age (35-42 years old), male factor infertility, and endometriosis [25-27]. Furthermore, the National Institute of Clinical Excellence (NICE) guidelines recommend against AH because it has not been proven to increase pregnancy rates [28]. Given a paucity of literature indicating a clear benefit of AH for fresh embryo transfer, in addition to the potential risks and increased costs, it should not be routinely applied.
Recommendation #4: Don’t prescribe corticosteroids, IVIG, leukemia inhibitory factor, or lymphocyte immunization therapy for patients undergoing IVF, those with a history of recurrent implantation failure, or those with recurrent pregnancy loss.
There is a lack of convincing evidence that immunological medications improve pregnancy rates, and there are significant potential side effects. While there is biological plausibility behind the theory that suppressing the immune system can improve outcomes for patients with a history of implantation failure or RPL, meta-analyses have failed to demonstrate improvement in pregnancy or live birth rate with the use of steroids, granulocyte colony-stimulating factor, leukemia inhibitory factor, or immunoglobulin in those undergoing IVF [29, 30]. Additionally, there is potential for harm, as these immunosuppressive medications may lead to a host of possible side effects including increased susceptibility to infection, venous thromboembolism, and fracture, and often pose added financial strain [31]. For patients with RPL, the literature is more conflicting with a few small studies showing there may be some benefit with specific immune therapies; larger clinical trials exploring the impact on live birth rate are needed to demonstrate effectiveness before these medications are routinely offered [30]. In the context of RPL, the recommendation is to avoid IVIG and lymphocyte immune therapy, where the literature clearly demonstrates a lack of benefit of these medications [30]. Given the absence of clear evidence supporting immunological therapies in improving pregnancy rates across a variety of patient contexts in addition to the aforementioned potential side effects, these medications should not be prescribed outside of a research setting.
Recommendation #5: Don’t routinely perform sperm DNA fragmentation testing.
Sperm DNA fragmentation testing is a commonly performed test for which abnormal results have been associated with lower fertilization and pregnancy rates, poorer embryo quality, and higher miscarriage rates [32]. Despite these associations, abnormal results often do not lead to a change in management [32]. Various testing methods for sperm DNA fragmentation exist with inconsistent cut-off values for abnormal results, making evaluation of the literature difficult to generalize; furthermore, there are no studies in which the rate of spontaneous conception is compared with the rate of conception after assisted reproductive therapy (ART) in those with high DNA fragmentation. Sperm DNA fragmentation testing has been traditionally recommended for many indications including for patients with varicocele and abnormal semen parameters, unexplained infertility, RPL, intrauterine insemination (IUI) failure, and IVF or intracytoplasmic sperm injection (ICSI) failure [33]. In a meta-analysis of 30 studies on pregnancy rates associated with sperm DNA fragmentation testing in patients undergoing IVF with ICSI, regression analysis revealed little predictive value for the tests included in the studies (including Sperm Chromatin Structure Assay, TUNEL, and Comet assay) in terms of predicting pregnancy outcomes [32]. In summary, based on a paucity of evidence supporting the clinical application of sperm DNA fragmentation testing, it should not be routinely applied.