Recurrent miscarriage and infertility: a national service evaluation

Abstract The appropriate clinical care of women/couples with infertility experiencing recurrent miscarriage (RM) is overlooked in international guidelines. We sought to evaluate care provision for women/couples with RM and infertility across public (19 clinics providing RM care, five fertility clinics) and private sectors (nine fertility clinics) using adapted guideline-based key performance indicators (KPIs) for RM. An online survey comprised of multiple-choice/open questions was administered via Qualtrics from November 2021 to February 2022, encompassing: (i) structure of care, (ii) investigations, (iii) treatments, (iv)counselling/supportive care and (v) outcomes. Clinical leads for pregnancy loss and fertility and clinical nurse/midwife specialists within each unit/clinic were invited to participate. The response rate 73% (24/33), varied by provider: Public RM care (18/19; 95%), 2/5 public fertility (40%); private fertility (3/9; 33%). Access to fertility expertise was limited in public RM clinics (39%). While investigations and treatments provided mostly adhered to guidelines, there was uncertainty regarding immunotherapies. Educational needs identified included fertility counselling, informative and supportive care resources. Clinical outcomes were seldom audited (2/22; 9%). Greater engagement with the private sector is required to unify care across sectors and to ensure standardised evidence-based care. Audit and outcomes reporting should be mandated. Lived experience of current care structures should inform service improvements. Impact Statement What is already known on this subject? There is a paucity of research into the appropriate clinical care of women/couples with infertility experiencing recurrent miscarriage, with a resulting deficit within international RM guidelines. It is known that RM care is variable and often not in line with guidance. What do the results of this study add? This study demonstrates that while care is largely in line with clinical practice guidelines, there is variation in counselling, imaging and surgical treatments offered. Areas for education identified included fertility counselling and resources for information provision and supportive care. Clinical outcomes were seldom audited. What are the implications of these findings for clinical practice and/or further research? Fertility care must expand to ensure access for women with RM and infertility. Further research exploring barriers and facilitators to the delivery of evidence-based care for women/couples with infertility and RM is required. The lived experiences of service users must inform service improvements.


Introduction
The traditional definition and care model for recurrent miscarriage (RM) whereby three consecutive miscarriages are the threshold for investigation, treatment or supportive care has been challenged recently (Bhattacharya et al. 2010, Van Dijk et al. 2020, Coomarasamy et al. 2021).This move to implement care after any two pregnancy losses before viability (Practice Committee of the American Society for Reproductive Medicine 2020, ESHRE Early Pregnancy Guideline Development Group 2023) has been driven, in part, by women's experiences (Bardos et al. 2015, Dennehy et al. 2022) and identification of a need for greater support after miscarriage (Musters et al. 2011, 2013, Bailey et al. 2019).Increasingly, miscarriage is recognised as a risk factor for both future pregnancy outcomes and maternal cardiovascular disease (Quenby et al. 2021).
The need of women/couples to understand why a miscarriage has occurred has been linked to subsequent psychological wellbeing (Bardos et al. 2015).It is unsurprising that in an examination of clinical practice in the UK, a proportion of investigations and treatments for RM outside of Royal College of Obstetricians and Gynaecologists (RCOG) guidance were requested by women (Manning et al. 2021).Other factors attributed to deviation from clinical practice guidelines (CPGs) included the acceptability of guidelines and the lowquality evidence underpinning them (Manning et al. 2021).Reduced compliance to CPGs has previously been demonstrated internationally (Franssen et al. 2007, Van Den Boogaard et al. 2013).Advanced maternal age and higher order miscarriage were also highlighted as driving factors for performing investigation and treatment outside of CPG recommendations (Van Den Boogaard et al. 2013).
These studies did not consider the fertility history of the couple in applying CPGs, although gamete donation was considered by over a third of Dutch gynaecologists as a treatment for RM (Franssen et al. 2007).Updated clinical guidance has not considered couples who experience RM and concurrent infertility (Regan et al. 2023), reflecting their exclusion from studies in the wider literature (Linehan et al. 2021).An international evaluation of RM CPGs showed that recommendations for the management of RM, including supportive care, do not incorporate the fertility history of women/couples experiencing RM (Hennessy et al. 2021).This oversight is not insignificant; RM and infertility share risk factors such as maternal age, have a reciprocal association and are independent risk factors for adverse pregnancy outcomes (Linehan et al. 2021).Moreover, the psychological impact of the dual experience results in differing supportive care needs (Freda et al. 2003).
In the Republic of Ireland (ROI), several factors complicate the care of women with RM and infertility.Primarily, to date there has been no national RM guideline, rather the RCOG guideline was adopted by most Obstetricians and Gynaecologists (Hennessy et al. 2022a(Hennessy et al. , 2022b)).Public fertility care is limited in capacity and geographical location; therefore, most fertility care is provided by private or not-for-profit healthcare operatives (Timoney 2022).Fertility services in the private and not-for-profit sector currently encompass nine main providers, some with multiple clinics nationwide (HPRA 2022).While clinics that handle human tissue are registered and monitored (HPRA 2022), there is no other fertility care register or mandatory outcomes reporting (Timoney 2022).A review of websites providing RM information found smaller clinics or individual fertility specialists provide a variety of investigations and some treatments, including artificial reproductive technologies (ARTs), in a more limited capacity (O' Regan et al. 2022).Without a national miscarriage or pregnancy database, or a requirement for fertility clinics to publish outcomes data, it is unknown how many women and couples in Ireland experience RM and infertility.The clinical pathways within private services or between public and private are also unclear.Furthermore, how care is delivered to women and couples with RM and infertility within the ROI or how this care varies nationally is unknown.
This study sought to evaluate care provision for women/couples with RM and infertility within the current framework across public and private sectors, using adapted guidelinebased key performance indicators (KPIs) for RM.
This online survey on RM and infertility was administered via Qualtrics and modelled on guideline-based KPIs for RM care developed within the RE:CURRENT Project through a sixphase consensus study (Hennessy et al. 2022a(Hennessy et al. , 2022b)).The survey comprised 41 questions, mainly multiple choice, across five sections pertaining to the care of women/couples with RM and infertility: (i) structure of care, (ii) counselling/supportive care, (iii) investigations, (iv) treatments and (v) outcomes (Supplementary File 1).
The survey was distributed alongside a national service evaluation on RM care.Respondents to the RM service evaluation in each of the 19 maternity hospitals/units in Ireland (named lead clinician, and/or clinical midwife/nurse specialist (CMS) in bereavement and loss, or director of midwifery), were asked to complete the survey (Hennessy et al. 2022a(Hennessy et al. , 2022b)).Additionally, the named lead clinician for fertility in maternity units that had a public fertility service was approached (n ¼ 5).The survey was also distributed to the clinical lead or specialist with an interest in RM each private fertility clinic (n ¼ 9).The survey algorithm was constructed such that questions were tailored towards those working in the public RM service, public fertility or private fertility sectors accordingly.Only one response per service was required.
Participants were invited to complete an online survey between 15 November 2021 and 18 March 2022.To facilitate recruitment, individual invites were emailed to potential participants, and clinic managers, where applicable.Participants provided informed consent prior to survey commencement.They were advised that the survey would take about 45-60 minutes to complete and reassured that reported findings would not identify individual participants, clinics or hospitals.Alternative modes of completion included telephone, or inperson, completion with a research team member.Regular (n ¼ 3) email reminders were used to maximise the response rate.Data were analysed in Microsoft Excel using descriptive statistics.

Structure of care
Responses to questions for structure of care in both public and private sectors are laid out in Table 2.
In half of cases, the consultant with training in RM management was the respondent.Reasons for referral from private clinics to public or private RM clinics included to obtain investigations not available within a particular clinic, to avoid costs of investigations for women/couples, or for expertise in the interpretation of results or further management.Regarding referral for surgical treatments, 11/19 (58%) respondents referred within or to public and private services, seven referred within or to public services only (7/19; 37%), with one stating no referral pathway existed (1/19; 5%).

Counselling and supportive care
Respondents were asked what topics they regularly discussed with women with RM and infertility; these results, in addition to the guidance employed, are presented in Table 1.
Additional sources of education and guidance cited included the Human Fertility and Embryology Authority (HFEA) (n ¼ 1) and colleagues working in other jurisdictions (n ¼ 1).Written information on RM and infertility or related topics was provided by four providers (4/24; 17%); one respondent cited a local leaflet, the remainder directed women to the websites of international bodies such as ESHRE, RCOG, NICE, ASRM or BFS.
Eleven respondents (11/20; 55%) provide information to women/couples about reputable sources of support for infertility and RM, both within the hospital and externally, while nine answered no (9/20; 45%).Sources of support included national support groups for miscarriage or pregnancy loss (n ¼ 5), local leaflet (n ¼ 4), bereavement midwife contact details (n ¼ 3), national websites (n ¼ 2) and international bodies (n ¼ 2).

Investigations
Respondents were asked if they performed additional investigations outside of routine fertility testing (e.g.full blood count, liver, renal and thyroid function tests, prolactin, diabetic screen, day 2 FSH/LH, day 21 progesterone, pelvic US, ovarian reserve testing, male partner semen analysis and hysterosalpingogram (HSG)) which feature in the KPIs; results are presented in Table 3.

Treatments
Respondents were asked which treatments within the KPIs they would provide to women with RM and infertility, which are shown in Table 3. Hysteroscopy and laparoscopy are included as treatments as they require placement on a surgical operating list, in addition to the potential to 'see and treat'.
Embryoscope was mentioned by one provider as a potential add-on treatment for this cohort.Progesterone therapy was also examined, with notable variety in the duration of prescriptions (N ¼ 14): up to the end of the 12th week (n ¼ 6), up to eight weeks (n ¼ 2), up to the 10th week (n ¼ 1), up to 16 weeks (n ¼ 2) and variably according to history (n ¼ 1).Reasons cited for varying progesterone regimes included use of donor oocytes, frozen cycles or a preterm birth history.
Two respondents (2/22; 9%) indicated that audit of subsequent pregnancy outcomes is performed in their unit (no audit; 20/22 (90%); no response, n ¼ 2).Both providers recorded livebirth rates, while just one examined the subsequent pregnancy rate and first-or second-trimester miscarriage rate.

Discussion
This national service evaluation of care for women/couples with RM and infertility demonstrates that while management mostly adhered to the relevant KPIs, there was variation in counselling, investigations and surgical treatments offered.to conceive again and seek fertility treatments.Certainly, information provided was variable, with less than half of women provided with information on all potential fertility treatment options.The risks and benefits of such treatments, including success rates, are important to relay to, and discuss with, women/couples (Ethics Committee (ASRM) 2022).Notably, the 2011 RCOG guideline predominated as an educational resource, suggesting a possible reluctance to follow international guidelines, alongside the need for updated education and guidance.Interestingly, half of respondents indicated that they used national guidelines to inform practice; however, there was neither a national RM nor fertility guideline available.An Irish guideline on RM has since been published (Linehan et al., 2023b), alongside updated ESHRE and RCOG guidelines, identifying this educational deficit is important to secure resources and training supports for successful implementation.Details of continuing professional development attended or online resources employed were not provided by respondents, despite the opportunity to do so.
There was limited awareness of available national resources for women/couples, with international sources cited more often.Awareness of these national educational and supportive resources must increase to direct women to the most relevant information and accessible supports, as online resources are not always reliable or wholly informative (O' Regan et al. 2022).Identifying women's/couples' needs could also inform more applicable resources.Investigations routinely performed varied, similar to other studies (Franssen et al. 2007, van den Boogaard et al. 2013, Manning et al. 2021, Hennessy et al. 2022a, 2022b).This may reflect the adaptation of practice in line with updated evidence, as some previously recommended investigations are not recommended in updated guidance (e.g.thrombophilia screening) (ESHRE Early Pregnancy Guideline Development Group 2023, Regan et al. 2023).Some investigations while demonstrating a clear association with RM, such as ANA and thyroid peroxidase antibodies, do not have subsequent evidence-based treatments, which may deter from inclusion in routine practice (Cavalcante et al. 2020, Dong et al. 2020).Most respondents did not perform unorthodox immunological investigations routinely, in line with CPGs.While 25% of respondents were unsure of unorthodox immunological investigations, a considerable proportion were unsure of standard investigations (13%), e.g.anti-phospholipid antibodies, indicating a need for greater education, extended to all involved HCPs.Counselling women/couples on not performing unnecessary investigations such as HVS is important as almost half of couples with RM feel under-investigated (Flannery et al. 2023).Endometrial scratch or biopsy was performed against CPGs by a proportion of respondents, in addition to unrecommended tests for uterine natural killer cells and chronic endometritis.They would also treat chronic endometritis, which is not shown to be of benefit (Kato et al. 2022).As it was beyond the scope of this study, it is unknown what laboratories perform these immunological tests or what the parameters and subsequent treatment thresholds are.Such standardisation is important in determining a true clinical effect and the absence of protocols for immune profiling, particularly for natural killer cells, has been flagged in systematic reviews of immunological treatments (von Woon et al. 2020).Immunological treatments employed such as intralipid therapy and LIT continue to not be recommended within updated guidance, despite some reported benefits, due to the heterogeneity of study populations and protocols, and methodological quality (Cavalcante et al. 2021(Cavalcante et al. , 2022)).
While sperm DNA fragmentation testing is to be considered (ESHRE Early Pregnancy Guideline Development Group 2023), it is not widely available as our findings show, and implementation would require significant investment in andrology services within the ROI.In addition to structural constraints in ART provision, PGT-A remains a 'code red' addon due to a lack of high-quality evidence to demonstrate a benefit in RM treatment (HFEA 2023).Similarly, there is no strong evidence to support treatment for male factors in RM (Linehan et al. 2023b).
Surgical interventions were mostly performed in line with CPGs.Few respondents performed complex surgeries such as metroplasty.Again, the publication of outcomes data for women undergoing these surgeries would contribute to the limited available literature.Such treatments should be ideally within the context of a randomised control trial (Regan et al. 2023) and undertaken by a multi-disciplinary team (MDT) (NICE 2015).Given the small numbers of women likely to experience a major Mullerian abnormality annually and the absence of an international guideline on management (Grimbizis et al. 2016), consideration should be given to establishing such an MDT with clear protocols within the new public fertility framework.
Medical treatments for unexplained RM were not widely prescribed with most reserved for certain clinical circumstances.Greater consideration could be given to prescribing aspirin given the results of the EAGeR trial and the benefits in reducing pre-eclampsia and preterm birth (Poon et al. 2017, Naimi et al. 2021) particularly in a cohort of women with infertility or of AMA.Similarly, there is evidence to suggest progesterone is of benefit in those with a history of miscarriage and bleeding (Coomarasamy et al. 2020) and it could be offered in the absence of bleeding as there is a benefit, albeit not statistically significant (Coomarasamy et al. 2021).Again, a proportion of respondents were unsure of prescribing medications.This study identifies a clear need for a national clinical guideline with accompanying education, combined with adequate resources and supports for implementation among all HCPs.

Strengths and limitations
This is an original study using guideline-based KPIs developed with a diverse stakeholder group to examine care provision nationally for women/couples with RM and infertility.This topic had not been covered previously nationally or internationally, and this work, like previous studies, provides insights on how current practice compares to current CPGs.CPGs are limited by the quality and currency of evidence underpinning recommendations, with a notable scarcity of high-quality randomised control trials in RM and infertility treatments (Cavalcante et al. 2021, Cavalcante andBarini 2022).Moreover, the RCOG and ESHRE guidelines used for KPI development have been updated and an Irish guideline on RM published; these will need to be incorporated into revised KPIs for future audit.
This study is timely, providing evidence for service improvements in advance of the introduction of publicly funded fertility treatment in the ROI (Women's Health Action Plan 2023).The 73% response rate incorporates an excellent response rate from RM services (95%), but poor response rates from public (40%) and private (33%) fertility clinics.This was despite three reminders and efforts associated with higher response rates such as small sample size, personalisation and reworded reminders (Sauermann andRoach 2013, Wu et al. 2022).Potentially, this excludes meaningful insights into fertility structures and management practices.It is a potential limitation that just one clinic from each fertility group was surveyed as there may have been inter-responder/regional variation.A proportion of surveys were answered by CMS who may not have experience of ART and this may be a contributory factor in the not insignificant proportion of blank/don't know responses.

Conclusions
This national service evaluation identified practice largely in line with CPGs.However, staff education is required, especially regarding counselling, information provision and resources to better inform and support women.Care structures must improve to allow better access to fertility services and ameliorate referral processes.Investigations should align with updated guidance.A small number of providers offer unorthodox investigations and treatments, which warrants further attention.There needs to be greater engagement from the private fertility sector and an onus to report outcomes data as well as treatments and interventions used.The lived experience of women/couples currently using RM and infertility services must be obtained to direct service improvements.

Table 1 .
Respondent demographics and counselling/supportive care.
a More than one response possible.

Table 2 .
Structure of care.