When IVF Doesn't Work: What the Evidence Really Says About Recurrent Implantation Failure

For couples who have been through multiple failed IVF cycles, the question that inevitably arises is a painful one: is something wrong that nobody has found yet? The instinct is to investigate further, to add more tests, more treatments, more add-ons. It feels like action, and action feels better than uncertainty. But according to the most authoritative guidance in the field, that instinct — however understandable — can lead patients down an expensive, emotionally draining, and evidence-free path.

In 2023, the European Society of Human Reproduction and Embryology (ESHRE) published its first comprehensive good practice recommendations on Recurrent Implantation Failure (RIF). What emerged was a document as notable for what it advised against as for what it recommended — a clear-eyed appraisal of a field where, in ESHRE's own words, investigations and interventions are frequently "applied in clinical practice without biological rationale or unequivocal evidence of benefit."

Defining RIF: Getting the Threshold Right

Before any investigation is considered, the question of whether a patient genuinely meets the definition of RIF matters enormously. For years, clinics worldwide used wildly inconsistent criteria, and a 2025 systematic review confirmed that the majority of published RIF research used definitions that didn't meet ESHRE's diagnostic threshold — casting doubt on the validity of much of the existing literature.

ESHRE's definition is deliberately individualised. Rather than applying a fixed number of failed transfers to everyone, it asks whether the cumulative probability of successful implantation should, statistically, have exceeded 60% — but hasn't. This depends on the patient's age, number of embryos transferred, and critically, whether those embryos have undergone preimplantation genetic testing for aneuploidies (PGT-A).

Without PGT-A (embryos of unknown chromosomal status), the threshold is three failed transfers in women under 35, and four in women aged 35–39. This higher bar reflects the well-established reality that chromosomal abnormality in the embryo — aneuploidy — is the single biggest driver of implantation failure, and becomes increasingly prevalent with advancing maternal age. Many failed cycles are the result of abnormal embryos, not anything wrong with the uterus or immune system.

With PGT-A (confirmed euploid embryos), the threshold falls to just two failed transfers, regardless of age. Once the major embryonic variable is removed, failure carries a stronger diagnostic signal. Even so, live birth rates after euploid embryo transfer range from approximately 40–65% depending on age and other factors. Failure after a euploid transfer is deeply frustrating, but it is not biologically inexplicable.

What Is Actually Causing RIF?

This is where intellectual honesty is essential. Despite decades of research, the precise mechanisms underlying implantation failure are still not fully understood. ESHRE identifies three broad contributing domains: embryo factors (primarily chromosomal abnormality, considered the principal determinant of implantation success); endometrial and uterine factors (structural anomalies, thin endometrium, chronic endometritis, the window of implantation); and systemic maternal factors (immunological, thrombophilic, hormonal, and lifestyle-related). In many cases, no identifiable cause will be found — and ESHRE is explicit that this reflects the limits of current scientific knowledge, not a failure of clinical thoroughness.

What Investigations Are Actually Supported?

ESHRE recommends a focused set of investigations with a clear clinical rationale. Hysteroscopy and 3D ultrasound are recommended to exclude structural uterine pathology — fibroids, polyps, septum, adhesions — though most RIF patients will have a structurally normal uterus. Thyroid function testing is recommended given the impact of thyroid dysfunction on implantation. Antiphospholipid antibody screening is recommended where there is clinical suspicion, such as a history of recurrent pregnancy loss or thromboembolism — but not routinely in all patients. Reassessment of lifestyle factors — smoking, alcohol, caffeine, and BMI — is recommended at every stage, given consistent (if low-quality) evidence of their impact on ART outcomes.

Screening for chronic endometritis via endometrial biopsy with CD138 immunohistochemistry can be considered, with antibiotic treatment if the diagnosis is confirmed. ESHRE is careful to note, however, that significant limitations in diagnostic standardisation affect the validity of existing data. Karyotyping of both partners can also be considered to exclude parental chromosomal abnormalities, particularly where PGT-A has not been performed.

The ERA Test: Promising Theory, Uncertain Evidence

The Endometrial Receptivity Array (ERA) deserves specific attention because it has become one of the most widely offered — and most expensive — add-on tests in RIF management. The premise is that some women have a displaced "window of implantation," and that personalising transfer timing based on gene expression profiling of the endometrium will improve outcomes. Meta-analyses suggest around one in three RIF patients may have a displaced window. The theory is compelling.

The evidence, however, does not straightforwardly support routine use. When women with a non-receptive ERA result who underwent personalised embryo transfer were compared to those with a receptive result undergoing standard transfer, ongoing pregnancy rates were similar (approximately 40–50% in both groups). A large multicentre cohort study found live birth rates were actually higher after unguided transfer than ERA-guided transfer. ESHRE classifies ERA as something that can be considered, acknowledging a possible benefit in a subset of patients — but it falls well short of recommending it as standard practice.

Treatments Not Supported by Evidence

The treatment landscape in RIF is, frankly, characterised more by hope than by evidence. ESHRE's recommendations here should be read carefully by any patient being offered a menu of add-on treatments.

PGT-A, if not already performed, can be considered — particularly in older women with high aneuploidy rates — as it eliminates the primary driver of implantation failure. Blastocyst-stage transfer can be considered where it hasn't yet been attempted, as it allows further natural selection in the laboratory. Where confirmed chromosomal abnormalities are found in either partner, genetic counselling and PGT for structural rearrangements (PGT-SR) is recommended.

Beyond this, the list of treatments ESHRE explicitly does not recommend is extensive and includes many that are routinely and expensively offered to RIF patients: endometrial scratching (high-quality RCT evidence shows no benefit), intrauterine or subcutaneous G-CSF, intravenous intralipid infusion, intravenous immunoglobulin (IVIG), intrauterine PBMCs, intrauterine platelet-rich plasma (PRP), intrauterine hCG injection, low molecular weight heparin (except where APS or clinical thrombophilia is confirmed), GnRH agonist or aromatase inhibitor pre-treatment, and assisted hatching. Similarly, routine testing for uNK cells, vitamin D, inherited thrombophilias, and microbiome profiling (EMMA/ALICE) is not recommended in the absence of specific clinical indications.

The Core Message: Evidence-Based Care Is Better Care

The ESHRE guidance makes an important point that is worth stating plainly: more investigations do not equal better care. Every test carries a cost — financial, emotional, and sometimes physical. Many RIF add-ons command hundreds or thousands of pounds per cycle, with no robust randomised controlled trial evidence to support them. The absence of a clear diagnosis after appropriate investigation is not a failure — it is the honest reflection of where reproductive science currently stands.

What the evidence does support is a prognosis-centred conversation. Understanding an individual's cumulative probability of success across further transfers, factoring in age and embryo status, is far more valuable than an ever-expanding diagnostic workup. Most patients who do not yet meet the RIF threshold will go on to succeed with further treatment. Many who do meet it will still achieve a pregnancy with continued, evidence-guided care.

Good fertility medicine, as ESHRE affirms, is not about doing more. It is about doing the right things — with clarity, kindness, and an honest commitment to the evidence.

Reference: ESHRE Working Group on Recurrent Implantation Failure et al. ESHRE good practice recommendations on recurrent implantation failure. Human Reproduction Open. 2023;2023(3):hoad023. https://doi.org/10.1093/hropen/hoad023

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Medical Disclaimer This article is intended for general informational and educational purposes only. It does not constitute personal medical advice and should not be used as a substitute for professional medical consultation, diagnosis, or treatment. Every patient's circumstances are unique, and the investigations and treatments discussed may or may not be appropriate for your individual situation. If you are concerned about recurrent implantation failure or any aspect of your fertility treatment, please speak to your own fertility specialist, who can assess your personal history and circumstances in full. The recommendations summarised here are based on ESHRE good practice guidance current at the time of publication and are subject to change as new evidence emerges.