The efficacy of add-ons: selected IVF “add-on” procedures and future directions

Abstract

Since the advent of ART, technology has continuously evolved to improve embryology and pregnancy outcomes. However, not all technologies that are integrated into practice have convincing evidence of clinical effectiveness, and they often increase the financial burden of fertility care. We discuss here a selection of commonly utilized IVF “add-ons” and discuss the existing evidence for their utility. The procedures included in this review are time-lapse imaging of embryos, assisted hatching, EmbryoGlue, sperm DNA testing, egg activation with calcium ionophore, endometrial receptivity array, and physiological intracytoplasmic sperm injection (PICSI). While there is rather limited supporting evidence for nearly all IVF add-ons that we reviewed, there is strong demand from patients, physicians, and the biotechnology industry to continue further research and development in this arena. We propose that all add-on procedures should provide true efficacy for the patient, and reproductive endocrinologists should inform patients of the costs and benefits of utilizing various technologies before they undergo treatment. In the future, add-ons that show clear evidence of efficacy and justifiable cost should be incorporated into routine practice, while others that do not meet these criteria should be phased out entirely.

Introduction

Since its inception in the 1970s, in vitro fertilization (IVF) as a treatment for infertility has progressed from its earliest great achievement, the birth of Louise Brown, to a rapidly evolving field responsible for over 2.5 million IVF cycles globally each year [15]. Patients who are undergoing IVF are highly motivated to achieve a successful pregnancy, and new technologies are constantly developed with the intent to improve treatment outcomes.

While the basic steps of the IVF process are typically rather uniform, there are many “add-on” technologies that providers may offer to supplement standard practice in an effort to improve the odds of a cycle’s success [1, 2]. These technologies have varying levels of evidence for their validity, and many providers disagree about the utility of offering them given that they often come at increased personal financial cost to the patient. Here we aim to provide an overview of the evidence, costs, and potential risks associated with several common IVF add-ons, and discuss future directions for managing add-ons in our field.

The procedures included in this review are time-lapse imaging of embryos, assisted hatching, EmbryoGlue, sperm DNA testing, egg activation with calcium ionophore, endometrial receptivity array, and physiological intracytoplasmic sperm injection (PICSI). These interventions make up a small selection of the complete list of currently available add-ons, many of which are similarly rife with controversy. For example, there is still no unified scientific consensus on the utility of preimplantation genetic testing for aneuploidies (PGT-A) despite much attention on this topic in recent years and large, high-quality studies evaluating its use and efficacy [52, 64]. The varied patient populations, laboratory conditions, and myriad of other factors that may influence IVF outcomes add substantial difficulties to the study of add-ons. These issues have plagued the scientific process that is needed to draw accurate conclusions about each technology, and continue to do so today.

Methods

The specific add-ons that we selected for review were chosen because they are commonly practiced in the USA and have been identified as lacking in convincing evidence of clinical effectiveness. Most of the profiled add-ons are recognized by the United Kingdom’s Human Fertilisation and Embryology Authority (HFEA), which assigns a traffic light rating—green, amber, or red—to add-on procedures based on the level of currently available evidence of clinical effectiveness [1, 2]. None has yet received a green light, which indicates strong evidence for both effectiveness and safety. Rather, all evaluated add-ons were assigned either an amber light, indicating conflicting documentation of clinical effectiveness, or a red light, indicating evidence of clinical ineffectiveness [1, 2]. Both red and amber ratings indicate that the HFEA does not recommend routine use of the add-on. We then briefly outlined the supporting evidence for and against each of the add-ons using data gleaned from Cochrane review articles, when available, as well as meta-analyses and randomized controlled trials that have been carried out. We then addressed potential risks and cost associated with use of each technology. Finally, we discussed future directions and possible strategies for approaching these technologies at present time, given the current level of evidence available and financial realities of incorporating them into the laboratory and clinical setting.

Overview of add-ons

Time-lapse imaging (TLI)

Time-lapse imaging uses digital cameras built into an incubator to allow for continuous monitoring of embryos as they develop in culture media. Although TLI was initially introduced in a research setting in 1997 [44] and later work highlighted the potential use for TLI as a clinical tool in 2008 [28], no prospective randomized controlled trial evaluated this technology until 2014 [46], at which time it had already been in use for several years. The 2014 study by Rubio et al. reported an increase in implantation rate and ongoing pregnancy rate when embryos selected via TLI with EmbryoScope were transferred [46]. However, this study included both day 3 and day 5 transfers, and most cycles were double embryo transfers [26]. These limitations make it difficult to determine the cycle conditions in which TLI is beneficial, and whether the results hold true in the setting of single embryo transfer, which is the goal of most modern laboratories.

The proposed advantage of TLI is its capability to continuously monitor embryos to detect minute changes that may not otherwise be identified, which allows for optimal embryo selection with minimal disruption to culture conditions. However, the true clinical benefit of this technology remains unproven. A Cochrane review published in 2019 analyzed nine randomized controlled trials (RCTs) and found that all the available data comparing TLI to conventional incubation strategies is low to very low quality (Armstrong, Bhide, et al. 2019). At present, there is no good evidence that use of this intervention provides any advantage or disadvantage in regard to pregnancy, live birth, or miscarriage rates (Armstrong, Bhide, et al. 2019).

While investigation into the safety of TLI has been rather limited, one randomized retrospective cohort study concluded that use of TLI does not increase the risk of any obstetric or perinatal adverse outcomes, such as preterm delivery and low birth weight. However, this study was limited by a small sample size, and some have argued that given the lack of convincing data regarding efficacy and safety, use of TLI should be limited to research purposes [45]. Finally, there is little consensus on the appropriate morphokinetic parameters to use in embryo selection, and the various algorithms which have been developed to select the embryo with the greatest reproductive potential lack external validity [19]. Given that optimized embryo selection is one of the major proposed benefits of TLI, these issues will need to be addressed.

Use of TLI itself likely poses minimal risk to embryos, and limiting movement of embryos during culture may offer some protective effect. While TLI may be helpful in enhancing the role of the embryologist [43], the significant cost of this technology—implementing it into the clinical setting can cost hundreds of thousands of dollars [42]—has been reported as a barrier to its use [5, 43, 45]. In one survey of clinics that did not employ use of TLI, 50% of practitioners reported that one of the main reasons for not investing in this technology was its cost, and 37.5% reported a lack of data supporting its clinical value [5].

TLI has been assigned an “amber” rating by the HFEA, indicating conflicting evidence for its clinical effectiveness. Given TLI’s high cost and a dearth of evidence regarding its clinical utility for embryo selection at this point in time, this technology requires further development before it is a feasible investment for most fertility clinics to take on.

Assisted hatching (AH)

Assisted hatching involves the use of a laser to create a small hole in the zona pellucida. This intervention was first reported in 1988 [9] as a strategy to help embryos successfully achieve implantation, and has since been widely utilized. Despite implementation of AH in the early 1990s, it was not until 2006 that a prospective randomized study demonstrated improved implantation and pregnancy rates in patients undergoing FET cycles, but no additional benefit gained from AH in those undergoing fresh embryo transfer.

At present, it remains unclear whether this translates to any improvement in live birth rate [66]. A recent Cochrane review of 39 RCTs concluded that AH may slightly improve clinical pregnancy rate, but the quality of evidence is poor [27].

The same review concluded that AH may slightly increase the risk of multiples; this intervention has long been associated with an increased risk of multiple gestations, including higher order multiples [22], which places patients at greater risk of pregnancy complications. Additionally, it has been suggested that the process of disrupting the zona pellucida can cause damage to the embryo leading to chromosomal changes or congenital fetal anomalies [25]. However, a large population-based study showed no increased risk of fetal malformations in offspring resulting from embryos which had been treated with AH [25]. This intervention may also increase the cost of treatment for patients, as some clinics quote an additional fee that may vary between 200 and 1000 US dollars to perform the procedure [17].

Assisted hatching currently has a “red” rating assigned by the HFEA, indicating a lack of evidence for its clinical effectiveness. Given that this intervention has been in use for approximately 30 years, it is necessary to conduct well-designed studies to improve the quality of evidence regarding its clinical utility and efficacy. Alternatively, clinics should forgo its use until such evidence is available.

Hyaluronan-enriched media (EmbryoGlue)

It has been proposed that enriching transfer media with hyaluronan improves implantation rates and other pregnancy outcomes compared with other media formulations containing lower concentrations of this molecule [3],Schoolcraft 2002). Specialized commercial media, such as EmbryoGlue, arose after murine studies performed in the 1990s showed improved implantation rates when culture media were enriched with hyaluronan [20],the rationale for this outcome was that concentrations of hyaluronan in the reproductive tract increase at the time of implantation, and that embryos have increased expression of its receptor during the blastulation phase of development [20]. It has since been suggested that hyaluronan also promotes decidualization of the endometrial lining [3] and that higher concentrations of hyaluronan better mimic uterine fluid and the intrauterine environment (Schoolcraft 2002).

EmbryoGlue was brought to market and made available for clinical use in 2003. The first randomized clinical trial assessing the efficacy of using a transfer media with a higher concentration of hyaluronan was performed in 2002 with a small number of patients and found that implantation rates were slightly improved under these conditions but pregnancy rates were unchanged (Schoolcraft 2002). A randomized clinical trial conducted in 2006 then specifically investigated EmbryoGlue and reported that it improved both implantation and pregnancy rates in patients with tubal factor, and improved implantation rates in those with recurrent implantation failure [60]. Additionally, this study reported an overall increase in live birth rate resulting from all embryos treated with EmbryoGlue compared with controls, which were cultured in media containing a lower level of hyaluronan [60]. Further studies have since provided contradictory results, with some suggesting that EmbryoGlue is beneficial to pregnancy rates (Zborilova et al.; [59] and others reporting no significant differences in implantation rates, pregnancy rates, or live birth rates [21, 48].

A recent Cochrane review analyzed data from prior RCTs published up until January 2020 and found moderate-quality evidence that high concentrations of hyaluronic acid in transfer media increase the number of clinical pregnancies and live births compared with media that contain minimal or no hyaluronic acid [23]. It is worthwhile to note that this review included only patients up to age 35 [23], and some have suggested that EmbryoGlue and similar formulations have the greatest benefit in poorer prognosis patients, such as those over 35 years of age, those with poor-quality embryos, or those with previous failed cycles [3, 21].

While studies have suggested that EmbryoGlue increases the risk of multiple gestations [3, 23], much of the prior literature on this topic was published when transferring two or more embryos at a time was a common occurrence. Given the significantly increased number of single embryo transfers performed in recent years, it is possible that this association is no longer valid. EmbryoGlue is thought to have few other associated risks, but it may come at unnecessary increased cost to the laboratory or the patient (some clinics charge patients several hundred dollars for use of this media) if cheaper and equally effective media preparations are available [3].

EmbryoGlue currently has an “amber” rating assigned by the HFEA, indicating that evidence for its efficacy is conflicting and larger studies under more current laboratory conditions are needed.

Sperm DNA fragmentation testing

High-quality sperm is a critical component of success in the ART process, and it has been established that DNA fragmentation due to DNA strand breaks can negatively affect male sperm quality and contribute to infertility [40]. Through the use of various assays, sperm DNA can be tested for fragmentation or breaks. These tests, which include terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), sperm chromatin structure assay (SCSA), sperm chromatin dispersion (SCD), and the Comet assay, are proposed to assess sperm function and quality, which correlates with reproductive outcomes [56].

The initial basis for testing sperm DNA fragmentation emerged in the 1980s, when animal studies on mammals found that differences in sperm chromatin configuration were associated with decreased fertility [14]. In the mid-1990s, it was suggested that DNA strand breaks were one of the causal agents of altered chromatin structure [49], and in 1998, Lopes et al. reported that sperm with higher DNA fragmentation had worsened morphology and motility as well as decreased fertilization rates with ICSI [33].

Since then, increased sperm DNA fragmentation has been tied to poor embryo quality, decreased pregnancy rates, and increased miscarriage rates [7], but high-quality evidence is lacking [13]. While some have suggested that DNA fragmentation correlates with pregnancy outcomes after IVF, but not ICSI [67], others have reported that pregnancy outcomes after both IVF and ICSI are affected [40], although the effect of high DNA fragmentation on those undergoing ICSI appears to be less significant compared to IVF [13].

Furthermore, the varying assays have differing degrees of accuracy in predicting pregnancy outcomes with IVF or ICSI [7],a 2016 meta-analysis including 30 studies concluded that the ability of the SCD and SCSA tests to predict pregnancy after ART was poor, and the ability of the TUNEL and Comet tests to do so was fair [7]. The same study found that all four sperm DNA fragmentation assays are poorly predictive of pregnancy outcomes in patients undergoing ART when they are administered to all-comers, and routine use of the tests in that setting provides little clinical benefit [7].

While there is clear consensus that DNA fragmentation is a contributing factor to male infertility, there is not yet a clearly identified patient population or clinical circumstance in which DNA fragmentation assays should be utilized. Recent recommendations from the European Association of Urology suggest that testing should be performed in couples who have suffered recurrent pregnancy loss—after either spontaneous conception or ART—or those with unexplained male fertility (Salonia 2020). Other guidelines have additionally suggested testing those with environmental or medical risk factors that increase their risk for higher sperm DNA fragmentation, such as exposure to toxins or varicocele, as well as those with multiple failed IVF/ICSI cycles [13].

These tests are associated with essentially no additional risk to the patient, given that they can be performed from sperm gathered in routine semen collection. However, it is worth noting that the treatment for a positive result may be significantly more invasive if the male partner must then undergo a testicular sperm extraction (TESE) procedure. Testing for DNA fragmentation can range widely, from 170 to 250 USD on average [35, 51], which is significantly more costly than routine semen analysis. Additional procedures that may then be undertaken—such as TESE—further contribute to a higher total cost of treatment, but if these interventions are successful, they may decrease the need for further oocyte retrievals and result in more efficient and inexpensive treatment overall [12].

The HFEA has not currently assigned a traffic light rating to DNA fragmentation testing. This intervention may provide worthwhile benefit in a select group of patients, but is unlikely to be useful as a screening tool for sperm quality among all couples undergoing treatment.

Artificial oocyte activation (AOA)—calcium ionophore

Calcium ionophore is a chemical compound that is used to facilitate oocyte activation and thereby fertilization. The scientific basis for this intervention arose from animal studies performed in the 1970s [18, 55] which showed that calcium injection into mammalian oocytes induces their activation via calcium-induced calcium release that is necessary for intracellular signaling [11]. Similar results were seen when this experiment was carried out in human oocytes in 1991 [62], and animal studies performed in the early 1990s reported that fertilization after ICSI was improved when calcium ionophore was supplemented [58].

In 1995, one study reported that treating oocytes that had failed to fertilize after ICSI with calcium ionophore led to improved fertilization rates compared with oocytes treated with a control solvent [58]. Since then, further studies have continued to demonstrate a benefit to AOA after ICSI, particularly in the context of couples who have had prior cycles with suboptimal fertilization rates [16].

While much of the literature has consistently demonstrated improved fertilization rates with AOA, there remains some conflicting data regarding its impact on pregnancy and live birth rates. One study found that while AOA did not increase pregnancy or live birth rates in couples without any history of poor fertilization with conventional ICSI, it significantly improved these parameters in couples who had a history of one or more prior cycles with low fertilization rates [38]. More recent work has continued to support this. A 2017 meta-analysis including 14 studies concluded that treatment with calcium ionophore after ICSI improves fertilization, blastocyst, implantation rates, and live birth rates [39], and a randomized clinical trial performed in 2018 studied couples with severe male factor or prior ICSI cycles demonstrating poor fertilization and similarly concluded that AOA after ICSI improved clinical pregnancy, ongoing pregnancy, and live birth rates compared with ICSI alone [16].

While interpretation of the prior body of work has been often limited by small sample sizes and differing methods of performing AOA [54], the meta-analysis found that among higher quality studies with less bias, the beneficial effect of AOA was actually more pronounced [39]. Overall, the existing quality of evidence remains of low to moderate quality, and larger, well-designed studies are necessary.

Although AOA has been in use for decades, there remains some controversy regarding its safety; it has been suggested that the manipulation of gametes involved in performing this intervention may increase rates of birth defects, or other adverse neonatal outcomes such as preterm delivery or intrauterine growth restriction [37]. However, a recent meta-analysis concluded that use of AOA did not result in any significant increase in either chromosomal anomalies or congenital birth defects [32], and an earlier study on a small number of patients found no difference in any adverse neonatal outcome analyzed [37].

AOA may also come at additional cost to the patient, and has been quoted at approximately 270 USD [6]. The HFEA has assigned AOA a traffic light rating of “amber,” indicating that there is conflicting evidence at this time.

Endometrial receptivity arrays (ERA)

Adequate endometrial receptivity is a critical component of achieving successful implantation after embryo transfer. Attention may turn to the endometrium in cases of recurrent implantation failure, when clinicians are searching for an explanation. Endometrial receptivity is defined as the intrauterine conditions that are favorable for embryo implantation [31]. While the window of implantation (WOI) typically occurs over a 2–3-day period [61] during the luteal phase, for various reasons this time period may be shifted or narrowed in some patients undergoing IVF [31, 34]. Therefore, there is much interest in developing a test to help predict optimal endometrial receptivity.

The endometrial receptivity array (ERA) was developed to analyze the molecular make-up of the endometrium and attempt to identify the window of implantation so that patients undergo embryo transfer at the proper time [34]. The ERA was initially introduced in 2011 and included 238 genes related to endometrial receptivity [10]. The patient’s endometrial tissue was analyzed and the transcriptomic profile was paired to a computational model to predict that individual’s unique WOI [10]. The ERA’s reported specificity and sensitivity for identifying the WOI were 0.88 and 0.99 [10], respectively, which made for a promising diagnostic test. However, further studies to evaluate its effectiveness in the clinical setting have produced mixed results.

A 2018 study performed on good prognosis patients found no difference in ongoing pregnancy rates when the ERA was used to personalize the timing of FET [4], suggesting that it has little clinical benefit. Some have argued that the correct population for this test is those with recurrent implantation failure (RIF), as they may be more likely to have a displaced WOI that may explain prior failed cycles. To this effect, a study done in 2013 by the same group who developed the ERA demonstrated that in a small group of patients with RIF, use of the ERA improved implantation and pregnancy rates [47]. However, attempts to replicate these results have often been unsuccessful. A recent retrospective analysis of 97 patients with a history of RIF showed that ERA was often discordant with histologic sampling of the endometrium, and its use did not correlate with improved pregnancy rates [8]. Another recent retrospective review found that personalized ET after use of ERA resulted in a trend towards improved implantation and pregnancy rates, but the effect was not statistically significant [57]. The existing literature is largely comprised of studies with small sample sizes, and larger prospective studies are needed.

While the ERA is simple enough to perform—tissue collection is the equivalent of an endometrial biopsy—use of this test does require an additional invasive procedure that may be painful for the patient and is associated with a small risk of intrauterine injury or infection. Furthermore, the ERA is costly—it can run between 800 and 1000 USD [24]—and is not covered by insurance providers.

The ERA is assigned a “red” traffic light rating by the HFEA. Personalized medicine and genomics-based tests certainly hold great potential and may be an important part of reproductive care in the future. However, at present there is not sufficiently clear-cut evidence that the ERA offers a justifiable benefit for its cost.

Physiological intracytoplasmic sperm injection (PICSI)

Physiological intracytoplasmic sperm injection involves identifying sperm that bind well to hyaluronic acid (HA) as a way to select for sperm with high genomic integrity and thereby decreases aneuploidy and miscarriage rates [63]. This theory is based on the concept that sperm with chromatin breakdown and higher rates of DNA fragmentation are unable to effectively digest HA, which is a key component of the oocyte-cumulus cell complex that is present prior to fertilization [63].

The initial prospective studies on PICSI were carried out in the late 2000s, and in 2010 Parmegiani et al. published results suggesting that this method of sperm selection may lead to higher embryo quality [41]. Several years later, Miller et al. performed a randomized clinical trial and found that when standard ICSI was compared with PICSI, there was no difference in live birth rate [36]. A Cochrane review analyzed this study and seven additional RCTs to determine the efficacy of PICSI and similarly concluded that PICSI confers no additional benefit over conventional ICSI when live birth rate is the primary outcome [30]. A meta-analysis was also performed to evaluate miscarriage rate and concluded that PICSI is associated with a reduction in miscarriage rate, although the quality of evidence was determined to be low [30].

Although there is likely minimal added cost or risk associated with PICSI, it is futile to perform an intervention that does not improve pregnancy outcomes. PICSI has been assigned a “red” traffic light rating by the HFEA, as well-designed studies indicate there is no evidence that it improves live birth rates. At this time, it should not be incorporated into routine clinical practice and should be offered to patients only in a research setting.

Discussion

The advent of IVF add-on technologies is driven by physician and patient demand for improved ART outcomes, and yet this must ultimately be reconciled with safe, effective, and financially sensible treatment options. The newness of ART as an area of scientific inquiry allows great potential for innovation, but as summarized in Table 1, the add-ons we have profiled here are lacking in strong evidence for clinical effectiveness.

Table 1.

Add-ons profiled in this article as well as all those rated by HFEA

Add-on	HFEA Rating	Current Evidence (Cochrane Review or Best Available)	Quality of Evidence	Cost*
Time-lapse imaging (TLI)	Amber	No advantage or disadvantage in pregnancy rate (PR), live birth rate (LBR), or miscarriage rate	Low to very low	$$$$
Assisted hatching (AH)	Red	May slightly improve PR	Low to very low	$$
EmbryoGlue	Amber	Slightly improves PR and LBR	Moderate	$$
Sperm DNA fragmentation testing	None	Poorly predictive of pregnancy outcomes when administered to all patients	Unclear	$$
Artificial oocyte activation (AOA)	Amber	Improves PR and LBR	Low to moderate	$$
Endometrial receptivity assay (ERA)	Red	No advantage or disadvantage in PR	Low	$$
Physiological ICSI (PICSI)	Red	No advantage or disadvantage in LBR	Low	$
Preimplantation genetic testing for aneuploidies (PGT-A)	Red	No advantage or disadvantage in cumulative LBR, LBR after first embryo transfer, or miscarriage rate with polar body biopsy or with use of FISH for genetic analysis (Cochrane review does not comment on outcomes after blastocyst biopsy or next-generation sequencing)	Low to moderate	$$$
Intrauterine/Intravaginal culture	Red	No improvement in LBR	Low to very low	$$$
Intracytoplasmic morphologic sperm injection (IMSI)	Red	Uncertain if this intervention improves PR and LBR, or decreases miscarriage rates	Very low	$
Immunological tests and treatments (steroids, intralipids, IVIG, TNF-α blockers)	Red	No evidence supports the use of these agents in improving LBR; patients may experience significant adverse effects	Low to very low	$$
Endometrial Scratching	Amber	Unclear effect on PR or LBR, no impact on miscarriage rate	Moderate	$
Elective freeze all cycles	Amber	May increase PR and LBR; reduces risk of ovarian hyperstimulation syndrome	Moderate	$$

Other authors have similarly described concerns regarding the widespread use of certain add-on treatments for which there is little to no conclusive evidence of effectiveness [29]. Some have advocated for use of add-on treatments only in experimental settings, such as RCTs [29]. While these suggestions are certainly valid, it is difficult to reverse course on routine practice once an add-on has already been in long-term use. For example, despite HFEA’s clear critiques of most add-ons, 74% of patients in the UK undergoing fertility treatment in 2018 received at least one add-on [29]. However, a concerted effort should be made by practices to evaluate laboratory and treatment protocols currently in place and, if add-ons are included, to determine if their use is appropriate.

New technologies are often created by physicians, embryologists, or other fertility specialists, and are then marketed to both patients and other professionals in the field. Novel ideas that have the potential to improve outcomes for patients or otherwise improve quality of care are necessary for the advancement of the field and should be encouraged. However, physicians, embryologists, and other fertility specialists who help develop these technologies or otherwise may stand to profit from their success have a clear conflict of interest that should not be ignored. Many of the add-ons discussed here were integrated into the clinic or laboratory based on the results of a few small studies with significant bias, and not until years later were they retroactively studied in large groups of patients to assess for clinically significant improvements in outcomes. In the future, a greater effort should be made to reverse this sequence of events so that new technologies are studied much more thoroughly in a research setting prior to being widely offered to patients. This would result in a safer and more reasonable approach for patients, who are often absorbing the additional cost and, in some cases, additional risk that is associated with add-ons.

Furthermore, use of some add-ons generates increased revenue for fertility clinics, which may be privately owned by physicians or, as is becoming increasingly common, by venture capital funds. We propose that the physicians in ownership or leadership positions within a practice should set a clear, evidence-based standard for acceptable and justifiable use of add-ons so that physicians and/or embryologists who are trying to provide care in this way are not at odds with the clinic’s bottom line.

To this point, it is well known that the cost of infertility care can be a significant burden to patients, and there is little justification for utilizing any technology that adds cost to care but does not have a well-demonstrated benefit. Increased overall cost of treatment may decrease the number of cycles a patient can afford to undergo, and may ultimately decrease their chances of having their desired family size. Greater costs also increase the financial burden of fertility treatment on the healthcare system as a whole, and decrease access to care within the population. Within the USA, there is no central organization such as the HFEA which serves to evaluate the risks versus benefits of add-on technologies. The formation of such a group would facilitate the development of a clear consensus on the evidence for or against these technologies, and may help to clarify their role in the clinical setting. Additionally, a centralized group might act as a source of financial support towards funding research into the efficacy of add-ons so that costs are not passed on to the patient before there is good evidence for their use. This would allow for well-designed clinical trials to investigate add-ons prior to approving their use in the clinic.

Another potential driver for the continued use of add-ons is a desire from both physicians and patients to achieve a positive outcome as quickly as possible. In an effort to improve results, physicians may offer add-on technologies to all patients—even those with a good prognosis, and without prior failed cycles. This may result in an unnecessarily high financial cost to obtain a pregnancy that could have been achieved without add-on technologies. We believe that routinely incorporating add-ons in this manner should be strongly discouraged.

Alternatively, patients may present for care having researched their treatment options and may request certain technologies specifically. This situation may be particularly relevant when a patient has not become pregnant after multiple IVF cycles or has seen several different providers. In this case, a strategy of thoroughly informed consent should be undertaken to ensure the patient understands that there is limited evidence for the intervention, and may actually be some degree of risk and/or additional financial cost. It is critical that the physician advise the patient based on the available evidence, rather than what a certain technology may promise. If the patient still strongly wishes to proceed with using the add-on after thorough counseling and informed consent, we feel this is acceptable. Counseling should include a discussion of what the add-on is, what it is used for, possible side effects, currently available evidence for and against its effectiveness, how it improves the patient’s chances for pregnancy and/or live birth, and any associated extra cost.

Some limitations of this opinion article should be considered. We did not perform an exhaustive review of the literature, and relied primarily on evidence from Cochrane review articles, when available. We did not include all currently existing add-on treatments, as this list is too great to cover in a thorough manner. We instead attempted to include a selection of procedures and treatments that we believe are commonly used despite a lack of significant evidence for their effectiveness.

Conclusions

While there is a plethora of currently available IVF add-ons, most offer rather limited demonstrated efficacy in improving pregnancy outcomes. We believe that in the future, add-on procedures that survive will be those which provide true efficacy for the patient and are widely accepted as a justifiable cost by patients and/or insurance companies who drive reimbursement. Some existing add-ons will be perfected and become an integral part of routine practice, while others will be phased out entirely as their utility is called into question. In the meantime, both laboratories and clinical practices should take a critical eye to the add-on treatments they have incorporated to assess if they are producing true benefit to patients and are therefore justifiable interventions.

Declarations

Conflict of interest

The authors declare no competing interests.