Evaluating fertility preservation interventions for alignment with ASCO Guidelines for reproductive aged women undergoing cancer treatment: a systematic review

Purpose While cancer treatment advancements have increased the number of reproductive-aged women survivors, they can harm reproductive function. Despite national guidelines, oncofertility service uptake remains low. This review explores interventions for fertility preservation alignment with American Society of Clinical Oncology (ASCO) guidelines and consideration of a multilevel framework. Methods We systematically reviewed literature from 2006 to 2022 across four databases. Identified interventions were assessed and scored for quality based on CONSORT and TREND statement checklists. Results were synthesized to assess for intervention alignment with ASCO guidelines and four multilevel intervention framework characteristics: targeted levels of influence, conceptual clarity, methodologic pragmatism, and sustainability. Results Of 407 articles identified, this review includes nine unique interventions. The average quality score was 7.7 out of 11. No intervention was guided by theory. Per ASCO guidelines, most (n=8) interventions included provider-led discussions of treatment-impaired fertility. Fewer noted discussions on fertility preservation approaches (n=5) and specified discussion timing (n=4). Most (n=8) referred patients to reproductive specialists, and few (n=2) included psychosocial service referrals. Most (n=8) were multilevel, with five targeting three levels of influence. Despite targeting multiple levels, all analyses were conducted at the individual level. Intervention strategies included: educational components (n=5), decision aids (n=2), and nurse navigators (n=2). Five interventions considered stakeholders’ views. All interventions were implemented in real-world contexts, and only three discussed sustainability. Conclusions This review identifies key gaps in ASCO guideline-concordant fertility preservation that could be filled by updating and adhering to standardized clinical practice guidelines and considering multilevel implementation frameworks elements. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-023-08133-3.


Background
Approximately one million women are diagnosed with cancer each year in the USA.As of 2020, 10% of these cancer cases occurred among women under the age of 40, with more than 48,000 new cancer diagnoses in adolescent and young adult (AYA) women ages 15 to 39 [1].Substantial advances in early detection (e.g., screening uptake, genetic testing) and treatment (e.g., radiation therapy) for cancer has dramatically increased survivorship with greater than 85% of women diagnosed under age 45 surpassing 5-year survival rates [1][2][3][4].
To achieve these impressive outcomes, cancer treatments typically comprise extensive chemotherapy, radiotherapy, 689 Page 2 of 18 hormone therapies, and/or surgical procedures.While life-saving, these therapies can damage reproductive function [5][6][7].For women, commonly used cancer treatments accelerate follicle and oocyte depletion, leading to impaired reproductive endocrine function and infertility.It is estimated that over 100 million women worldwide are at risk of cancer treatment-related ovarian impairments and may seek fertility preservation by 2025 [8].
Moreover, loss of endocrine support for hormonally responsive tissues can trigger a cascade of long-term medical problems in addition to infertility [9].For example, existential psychosocial concerns and poor quality of life is prevalent and persistent in cancer patients and survivors [10,11].A recent review found factors such as early-onset menopause and unfulfilled desire for biological children are associated with poorer mental health outcomes in survivorship [12].Some patients even view the loss of the ability to have biological children as more distressing than the cancer diagnosis itself [9,12,13].One study found that approximately 50% of young cancer patients ages 18-45 who wished to have children in the future required some psychological support with regard to fertility and future parenthood after a cancer diagnosis [12,14].
In 2006, the American Society of Clinical Oncology (ASCO) endorsed evidence-based clinical practice guidelines on fertility preservation for healthcare providers, publishing subsequent updates in 2013 and 2018.Aligning with other national and international recommendations, ASCO guidelines recommend that all patients undergoing potential gonadotoxic treatments should receive information and counseling about the impact of their disease or treatment on future fertility and fertility preservation options as part of their initial comprehensive care plan.Specifically, the guidelines encourage (1) provider discussion of potential impairment to fertility, (2) provider discussion of fertility preservation approaches, (3) all discussions occurring as early as possible prior to beginning treatment, (4) patient referral to reproductive specialists for fertility preservation, (5) documentation of fertility-related discussions, and (6) patient referral to psychosocial services for additional support [13].
To further facilitate care of patients at risk of exposure to gonadotoxic agents, fertility preservation options are outlined as part of these guidelines.Standard fertility preservation options vary based on several factors including patient's biological sex, age and cancer type [5].For example, guidelines recommend sperm cryopreservation or testicular tissue freezing for adult men.All of these procedures can be conducted quickly prior to the beginning of treatment.The only fertility preservation options recommended by the most recent ASCO guidelines for prepubertal children include ovarian or testicular cryopreservation, both of which are currently investigational procedures.
Finally, fertility preservation options for reproductive age women include oocyte cryopreservation, embryo cryopreservation, ovarian shielding and transposition, ovarian tissue transplantation, etc.For most of these procedures, ovarian stimulation requires an average of 12 days to harvest oocytes prior to initiation of cancer treatments [3,13].
Accordingly, many fertility preservation interventions have been implemented in recent years to increase the uptake of fertility preservation.However, approximately 30-50% of patients do not receive adequate information regarding infertility risks and preservation options prior to beginning cancer treatments [1].A recent study reported that only 4 to 41% of females undergo preservation procedures [14].Further, health care providers' awareness of the need to talk about risks to fertility, fertility preservation options, and referral to reproductive specialists in a guideline concordant manner continue to remain low.Research to explore provider awareness of and adherence to ASCO guidelines has been limited and is somewhat dated.One study published in 2009 showed that of the approximately 60% of oncologists who reported awareness of ASCO guidelines, less than 25% reported following the guidelines on a regular basis, distributing educational materials, or referring patients for further discussions on fertility preservation [15,16].Another study published in 2011 found that of the oncologists who provided care to pediatric patients reported, only 44% were familiar with ASCO recommendations for fertility preservation [1,17].
As envisioned by ASCO, guideline-concordant fertility preservation care is inherently multifaceted and influenced by a complex and interconnected set of barriers and facilitators operating at individual, interpersonal and organizational level.For example, in addition to the patient, various family members (e.g., parents and/or intimate partners) may need to be involved with decision-making.Further, a variety of health care providers (e.g., primary care, oncology, reproductive endocrinology, nursing, surgery, mental health) are also involved to address patients' needs [7].At the organizational level, variations in access, availability, and insurance coverage for reproductive healthcare additionally contributes to health-system barriers to fertility preservation.Additionally, social barriers such as structural racism mean that patients of color are less likely to be seen in cancer specialty settings, have access to and undergo fertility preservation when compared to White patients [14].
To evaluate the range of evidence-based interventions being used to implement ASCO guideline-concordant fertility preservation care, we conducted a systematic review assessing: (1) strategies and outcomes aligned with ASCO 2018 practice guidelines, (2) consideration of multilevel influences on service provision, and (3) sustainability of the evaluated interventions for healthcare system integration.To

Defining intervention
In this review, we define interventions to include those testing strategies to increase consideration of and access to fertility preservation.Further, only articles in which interventions were evaluated relative to a comparison group are included.

Data sources and searches
In conducting the review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRSMA) guidelines [18].We completed systematic literature searches in four electronic databases (PubMed, Embase, Web of Science, Scopus) for intervention studies published between January 2006 (to align with publication of first ASCO guidelines related to fertility preservation [13] to January 2022.Keywords included: cancer, oncology, fertility preservation, oncofertility, intervention, healthcare utilization, and healthcare delivery.Full search terms can be seen in Appendix 1.We also hand searched any protocol papers to identify new articles subsequently published that were not captured in the initial search.We used Covidence to organize and manage the review database.

Intervention study selection
The intervention study inclusion criteria were: English language, published between 2006 and 2022, that described an intervention including women of reproductive age (ages 13-49) with a cancer diagnosis and/or the providers that care for them.Recent data show the average age for the onset of menarche is at 12.4 years old.Thus, we selected 13 years old as the lower age limit to identify women of "reproductive age" [19].Additionally, given that fertility preservation options vary by sex and age, we focused on reproductive age women.Excluded intervention studies (henceforth, "interventions") were those that only included males or pediatric patients, were not accessible in full text, conference abstracts, study protocols, and reviews.
Using these criteria, we conducted initial title searches to identify articles for initial abstract review.Keywords were clarified to ensure that all relevant articles appeared in the search.Next, one author (SP) reviewed all titles and abstracts to identify articles for full-text review.Finally, we completed full-text reviews to determine the interventions to be included.Two authors (SP, CMM) completed data abstraction on all full-text review articles.All discrepancies were resolved through discussion to reach consensus.

Quality assessment and data extraction
We applied the CONSORT [20] and TREND [21] statement checklists to assess intervention quality and the extent to which articles aligned with quality and reporting guidelines.If articles mentioned any of the concepts included on our checklist, we considered the criteria fulfilled.All articles were then scored for fulfilled criteria on a scale ranging from 0 (lowest quality)-11 (highest quality).Abstracted data were organized based on assigned quality score from highest to lowest.
We used the population, intervention, comparator, outcomes, timeframe, and study design (PICOTS) framework [22] to select which intervention characteristics were extracted.General intervention characteristics included: intervention study design, sample targeted, unit of analysis, intervention time period, in what country or geographic region the intervention took place, intervention setting (e.g., oncology clinic, fertility clinic), sample size, and general sample characteristics.In this review, healthcare providers included oncologists, reproductive specialists, surgeons, and nurses.
For each intervention, we determined the alignment of intervention targets and relevant outcomes with the ASCO guidelines for fertility preservation prior to cancer treatment.A "yes" was assigned for the following guideline elements were targeted as an intervention strategy or assessed as an outcome: (1) provider-led discussion of potential impairment to fertility, (2) provider-led discussion of fertility preservation approaches, (3) timing of discussions occurring prior to beginning treatment, (4) patient was referred to reproductive specialist for fertility preservation, (5) fertility-related discussion was documented, and (6) patient was referred to psychosocial services for additional support [13].
We coded interventions for their alignment with a parsimony-based operational framework based on complexity theory and pragmatic trials [23].The framework considers four characteristics: socioecological levels of influence targeted, conceptual clarity, methodologic pragmatism, and sustainability.We noted the inter-level mechanisms implied at each level of influence that were targeted by the fertility preservation intervention and whether this was based on stakeholder input.For methodological pragmatism, we evaluated whether interventions took place in real world contexts and what background factors were considered in the evaluation of the intervention to enhance the generalizability of effectiveness findings.We also examined whether the interventions had any discussion or consideration of sustainability factors.Lastly, we noted whether the intervention 689 Page 4 of 18 outcome assessment showed significant benefit of the intervention for the proscribed outcomes.

Data synthesis and analysis
Extracted data were organized by quality assessments for: general intervention characteristics, alignment of intervention strategies and outcomes with ASCO guidelines and consideration of multiple levels of influence.Within each category, we rated intervention quality from 0 to 11.

Results
We identified 438 articles from four electronic databases, after removing duplicates, there were 407 unique articles, 32 were eligible for full-text review after title and abstract screening, and 11 articles fit inclusion criteria for final data abstraction (see Fig. 1).All articles were published between 2012 to 2021.Among the 11 articles included, we identified nine unique interventions.The remainder of the results will be reported by intervention.

Intervention study characteristics
Descriptions of the interventions are detailed in Table 2.
Most interventions utilized a quasi-experimental design (n=7) [24,27,28,[30][31][32][33][34] without randomization to a comparison group .Two interventions were randomized control trials [25,26,29].The majority of the interventions focused on educational components to increase patient and/or provider knowledge regarding fertility preservation options and to assist in discussions and the decision-making process.This primarily targeted the individual and interpersonal levels of influence.Two interventions utilized decision aids to assist patients further in their ability to have discussions around fertility preservation options and to prevent decisional regret in the future [25][26][27].Two interventions also leveraged the support of a nurse/patient navigator [24,31].Three took place in the USA [24,28,29].Other settings included: Austria, Australia, Canada, the Czech Republic, Germany, Poland, and Switzerland.The majority of interventions were implemented in specialty cancer centers or healthcare practices, with one in regional fertility centers [25,26].Two interventions included patients as young as 12 [24,32,33].Three interventions included males in the target sample [28,30,32,33], one included patients' parents [32,33], and one specifically targeted breast surgeons [34].
Borgmann-Staudt A, et al (2019) [32] Warner E, et al (2020 Interventions typically did not focus on a particular cancer type, but when they did, breast cancer was most commonly included (n=6) [24-27, 29, 31, 34].Five interventions did not report race/ethnicity of the sample [27,[30][31][32][33][34]; among those that reported the majority of participants were White.Most participants were in a relationship, had a college education, and were childless or had one child.

Alignment of intervention strategies and outcomes with ASCO guidelines
We assessed the extent to which the intervention strategies and relevant outcomes aligned with ASCO guidelines' six expectations of fertility preservation service provision (See Table 3).
Guideline Element 1: Health care providers should initiate discussion of the potential impairment to fertility.The majority of the interventions (n=8) included strategies to assist providers in initiating discussion of potential treatment effects on fertility and measured the occurrence of these discussions as an outcome [24,[27][28][29][30][31][32][33][34].To facilitate these discussions, one intervention included a 24-h fertility preservation hotline available to providers [24].Additionally, the electronic medical record (EMR) was modified to prompt oncologists initiate discussions with their patients and required them to document discussion before the patient chart could be closed [24].
Guideline Element 2: Providers discuss fertility preservation with patients.Over half (n=5) of the interventions noted discussions regarding fertility preservation approaches [24][25][26][27][28][29], with one targeting discussion as an 689 Page 6 of 18  to patients.The navigator documented all activities and services in the nursing section of the EMR [31].
Guideline Element 6: Refer patients for psychosocial services.This was noted in only two interventions [29,31] with only one including referral as a measurable outcome [29].As secondary outcomes, Partridge AH, et al (2019) examined attention to psychosocial concerns including noting emotional health, distress, referral for psychosocial support, etc. [29].

Intervention framework alignment: levels of influence, inter-level mechanisms, stakeholder inclusion, methodological pragmatism, intervention effectiveness, sustainability
All interventions except one [27] were multilevel, with three targeting two levels (individual and interpersonal) [25,29,32,33] and five targeting three levels (individual, interpersonal, and intervention strategy without measuring it as an outcome [25,26].The two most common intervention strategies to guide these discussions was providing patients with educational materials on fertility preservation [25][26][27] and providing patients with decision aids to review the options [24,28,29].
Guideline Element 3: Provide fertility preservation services as early as possible prior to the patient beginning treatment.Only four interventions specified that discussions occurred prior to treatment, and all four mentioned this as part of an intervention strategy but not as an outcome [25,26,28,29,31].None of the interventions actually measured when the treatment discussions were occurring or provided description of what was done to promote early discussions.
When considering inter-level mechanisms for conceptual clarity, approximately half of the interventions included stakeholders' views on the assumed process chains being targeted (n=4) [27,28,30,31,34].Examples of stakeholder inclusion were utilizing multidisciplinary expertise to develop and pilot survey instruments, conducting focus groups with the patient population prior to the intervention, pilot testing decision aids, conducting a provider needs assessment to develop education tools and intervention materials, and establishing an interdisciplinary steering committee to guide intervention development and implementation.
When considering methodologic pragmatism, all interventions were implemented in real world contexts as they took place in cancer centers, healthcare practices, and fertility clinics.Across the targeted levels of influence, seven interventions considered the sociodemographic characteristics of the patients as background factors [24-29, 31, 34], one intervention considered literacy level differences by region [30], with only one intervention making no mention of background factors [32,33].
Only three of the 11 interventions discussed sustainability [25][26][27][28].Examples of sustainability included easily updating and/or transitioning to online decision aid materials and considering strategies to increase physician use of resources.Two interventions explored ideas for how they could make the intervention more sustainable in the future [24,31].All components of the multilevel framework are outlined in Table 4.

Discussion
We reviewed fertility preservation intervention studies targeting reproductive-aged women to assess their alignment with ASCO practice guidelines; and whether they considered multilevel influences on service provision, effectiveness, and sustainability for healthcare system integration.Previous studies have shown that not adhering to evidence-based guidelines leads to practice variation and subsequently to a suboptimal quality of care and quality of life in survivors [34].
We found very few fertility preservation interventions included comparison groups which limits the rigor of the current evidence base.This review additionally identified gaps in the provision of ASCO guideline-concordant care.Our review suggests that while most interventions targeted some elements of the ASCO guideline, overall guideline adherence was limited and variable.Moreover, some interventions employed guideline relevant strategies but did not assess related outcomes.In these cases, it was unclear whether the interventions were effective in promoting guideline adherence.
The variability in alignment with ASCO guidelines may be associated with health care provider specialty and practice setting.Cancer care is provided by an interdisciplinary team of providers who see patients at varying points in the diagnosis and treatment process.Mapping fertility preservation intervention strategies to the standard course of care and the interchange between different care providers should be considered and tested in future interventions.
Additionally, greater attention should be given to specifically linking intervention strategies and evaluation outcomes to clinical practice and national guidelines.For example, Anazodo et al (2019) suggested the following: that the role and scope of practice for fertility care be defined for all healthcare providers, communication paths between different healthcare providers be mapped, discussions be initiated in a specified time frame, patients receive high quality communication to convey fertility risk and preservation options in different formats and at appropriate literacy levels; and that all communications and referrals to supportive care be documented [35].Interventions that target these steps and measure related outcomes are needed to establish evidencebased care and standardized provision of fertility preservation services.
Provision of fertility preservation services also must be contextualized as it relies on individual (e.g., patient decision-making), interpersonal (e.g., family involvement and health care provider), organizational systems (e.g., staffing, electronic medical records), and societal (e.g., structural barriers to access).Thus, fertility preservation interventions must consider multilevel frameworks in developing strategies and evaluating outcomes.While we found that most interventions targeted at least two levels of influence, all analyses were conducted at the patient-level.Future intervention trials should be designed to report hierarchical outcomes.For example, applying innovative implementation science frameworks for intervention development, analysis, and evaluation efforts would be useful in this endeavor.
In considering the multilevel complexity of fertility preservation, it was surprising that very few interventions reported engaging stakeholders at any level of influence in guiding intervention development.Among the few that did, some engaged patient focus groups and structured interviews, others targeted health care providers.Further, stakeholder input was often considered prior to intervention implementation not during and after.Without continued stakeholder engagement to assess intervention progress and whether modifications need to be made, this could limit sustainability.To develop interventions that are relevant, feasible, and sustainable, a more integrated and multi-level stakeholder engagement effort will be needed to identify linkages between levels of influence and mechanisms that might be amenable to intervention [23].For example, a recent study found national guidelines often do not advise on the skills required for adherence.Building oncofertility competencies as outlined in the International Oncofertility Competency Framework will rely on integrating patient and family perspectives, provider resources, and organizational supports [7].Thus, stakeholders at all levels have perspectives that will be important for an intervention to be sustainable.
There are some limitations to this review that warrant attention.First, we based our guideline alignment on ASCO clinical practice guidelines.It is notable that there are not yet a single set of unified guidelines for oncologists and fertility specialists for addressing fertility preservation [36].Several other national and international organizations (e.g., ASRM, NCCN) have developed recommendations and guidelines to support cancer patients in preserving their fertility.There are common elements across these guidelines (e.g., timeliness of provider discussion, informed decision-making) that we felt were consistent with the ASCO guidelines.Moreover, we also focused on the broad categories that arise in the clinical process of care for fertility preservation and exclude those more distal to care such as provider encouragement of patients to participate in clinical registries.By narrowing the scope, we may have missed some of nuances of adherence to guidelines aimed to support the research process.Finally, there is additionally a possibility that our key words did not catch all intervention studies available in the literature.

Conclusion
By 2023, the WHO estimates that 1.4 million reproductiveaged women will be diagnosed with cancer annually.As a result of scientific advances, increases in cancer survival rates have also led to the rising recognition for the field of Oncofertility and the need for fertility preservation.As seen in the literature, fertility preservation is still relatively new and evolving clinical area at the intersection of the fields of oncology and reproductive endocrinology.Yet, we can anticipate based on other new treatment implementation that systematic processes for delivering these services equitably will be needed [36].This review identified key gaps in ASCO guideline-concordant care provision and the emphasized the importance of utilizing multilevel implementation frameworks for effective and sustainable interventions.The results of this review will allow future research to improve access, advancing research, educating oncofertility service providers, and collaborating with transdisciplinary members of the field to develop standardized processes of care [37,38].

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Table 1
Quality assessment of interventions *Articles are shown in order of quality assessment **Total out of 11 categories

Table 2
General intervention characteristics

Table 3
Alignment of ASCO guideline components with interventions strategies and outcomes* * I denotes intervention strategy; O denotes relevant outcomes that were measured