RIF Flashcards
Implantation failure definition
Good quality embryo has been transferred into the uterine cavity but has failed to establish a pregnancy evidenced by ultrasound visualisaiton of a intrauterine gestational sac.
Definition of RIF
No consensus definition.
ESHRE - RIF describes the scenario in which the transfer of embryos
considered to be viable has failed to result in a positive pregnancy
test sufficiently often in a specific patient to warrant
consideration of further investigations and/or interventions
ESHRE - The recommended threshold for the cumulative predicted
chance of implantation to identify RIF for the purposes of initiating
further investigation is 60%. When a couple have not
had a successful implantation by a certain number of embryo
transfers and the cumulative predicted chance of implantation
associated with that number is greater than 60%, then
they should be counselled on further investigation and/or
treatment options. This term defines clinical recurrent implantation
failure for which further actions should be considered.
Number of transfer to intervene with investigations in RIF
RIF specific investigations (after above threshold is met) that are recommended or could be considered
Recommended:
Reassessment of lifestyle factors (Male and female)
Reassessment of endometrial thickness
Assessment of APA or APLS in case of risk factors
Can be considered:
Chronic endometritis biopsy
Karyotype parents
Assessment of thyroid function
Endometrial function testing
3d ultrasound or hysteroscopy
progesterone levels (late follicular and midluteal)
Investigations NOT recommended for RIF by ESHRE
Natural killer cell testing (both peripheral and uterine)
HLA-C compatability testing
Vitamin D testing
Microbiome profiling
Uterine T lymphocyte assessment
Blood cytokine levels
Assessment of mtDNA testing
Sperm DNA fragmentation/FISH analysis
Lifestyle factors and RIF
Evidence from well designed intervention studies demonstrating an improvement in ART outcomes following lifestyle changes remains scarce.
BMI, smoking, illicit drugs, alcohol consumption and caffeine intake.
Vitamin D testing in RIF
Insufficient data to recommend the routine measurement of Vit D levels or treatment of deficiency.
Role in ART remains controversial. - some studies have shown improved outcomes with normal levels, others have shown the opposite.
Measuring levels may be inaccurate.
Widely applied in clinical practice but not recommended by ESHRE.
Parental karyotype
Higher rate of parental karyotype abnormalities in RIF group than general population but rates are low - 2.1%
Despite the low prevalence, karyotyping can be considered to confirm the absence of a chromosomal abnormality in parents.
If a chromosomal abnormality is detected, genetic counselling and, where relevant, preimplantation genetic testing (PGT), is recommended.
Non-invasive investigation of uterine cavity
3D ultrasound -no studies evaluating whether 3D USS improves outcomes in patients with RIF.
Given limited cost and non-invasiveness can be considered if not previously done.
Sonohysterography and HSG are techniques to diagnose uterine pathologies but are less well studied in RIF.
Hysteroscopy
Hysteroscopy can be considered, especially when there is a suspicion of a uterine anomaly visualized on transvaginal ultrasound.
TROPHY trial Lancet 2016 - Outpatient hysteroscopy in those with RIF prior to new cycle. No difference in LBR between control group.
Meta-analysis 2019 - improvement in LBR if OH done prior to further treatment cycle in those with RIF.
Not established if treatment abnormalities improves outcomes:
endometrial polypectomy, surgical removal of submucous fibroids, uterine septum resection, or removal of intrauterine adhesions. While the interventions are established for the treatment of symptoms, their impact on pregnancy or LBRs has, to our knowledge, not been evaluated in patients with RIF. Similarly, the effect of treatment of adenomyosis on pregnancy or LBR in women with RIF has not been evaluated.
Endometrial receptivity and function
While there are insufficient data to recommend the routine use of any commercially available test of endometrial receptivity to diagnose the cause of RIF, assessment of specific aspects of endometrial function by testing can be considered.
Actually good evidence to show pET no better than standard timing ET.
Doyle JAMA 2022 = large RCT showing no difference in LBR.
Simon 2020 drug funded and major trial design concerns, only PP showed improved outcomes with pET.
chronic endometritis and RIF
At present, conclusions regarding the value of the diagnosis and treatment of endometritis are significantly hampered by the lack of standardization. However, the investigation and treatment of CE can be considered in RIF. Revision of this recommendation may be indicated should studies using more standardized diagnostic techniques, including the emerging DNA-based tests, reveal a clearer benefit.
ESHRE - Assessment for chronic endometritis (CE) can be considered. If CE is diagnosed, treatment with antibiotics can be considered.
Endometrial thickness and RIF
A recent large retrospective study concluded that EMT at the time of ET does not seem to predict the chance of implantation in case of euploid frozen blastocyst transfer (Ata et al., 2023).
systematic review and meta-analysis investigating the association between endometrial thickness and LBR in fresh cycles reported that women with a thin endometrium (EMT<7mm) had a significantly lower LBR compared to women with EMT >7mm (OR 4.7)
Re-assessment of endometrial thickness is recommended. A review of the estradiol treatment regimen is recommended if the endometrium is noted to remain thin. Hysteroscopy to rule out Asherman’s syndrome can be considered.
Progesterone measurement during ART
Premature progesterone rises around time of trigger may cause endometrial/embryo asynchrony during fresh ET. Subsequent delay restores IR in a cohort study. Still debated.
Low midluteal P4 on serum assessment linked to worse outcomes for both fresh and frozen ET. Individualised p4 administration has been shown to restore implantation rates in cohort studies.
uNK cells and pNK cells
Peripheral NK cell testing is not recommended in RIF
Uterine NK cell testing is not recommended in RIF
Both NK cell types act as immunomodulators but demonstrate a different profile of secreted cytokines and receptor/gene expression.
Issues:
- pNK and uNK numbers don’t correlate, regarded as two individual markers.
- uNK cells undergo huge chage throughout a menstrual cycle, hormone dependent change in phenoytype, high levels in the luteal phase, need strict criteria for timing of testing.
- no agreed upon test in terms of time and means of testing for uNK
- references ranges vary widely.
- unknown if assessing number can be used to reflect their functional impact.
- functional tests such as constitution of receptors may have more clinical value
Studies;
- some have found higher uNK cells assoc with less favourable implantation milieu
- Meta-analysis of CD56bright uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women).
