Repeated İmplantation Failure

Despite all the advancements in technology and techniques, not all IVF cycles result in successful pregnancies. Understanding the causes of IVF failure can help couples explore their options and make better-informed choices for their fertility journey.

Repeated implantation failure (RIF) represents a further challenge for the couple and treating clinic. To understand and solve this problem, examining the factors contributing to failure surrounding this complex issue is essential.

There are no strict criteria defining the number of failed cycles or the total number of embryos transferred in these IVF attempts. Different centres practicing IVF may use different definitions for RIF. It is often defined as the failure to achieve pregnancy after the transfer of at least 3-4 good-quality embryos in 3 or more fresh or frozen cycles.

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Successful implantation depends on a well-functioning endometrium as well as a normal healthy embryo. This process might be challenged if either of these variables is abnormal. So, both sides should be carefully re-assessed.

It is important to have an open discussion with an IVF specialist to tailor the most appropriate management plan. Many interventions lack robust, high-quality evidence, and empirical treatments should be discussed in detail regarding potential benefits and risks.

Here is a sample management plan for RIF in IVF;

 

1. Re-evaluation and Patient Counseling

• Detailed History and Physical Examination:
  • Review previous IVF cycles in detail: stimulation protocols, number and quality of retrieved oocytes and embryos, endometrial thickness and appearance, embryo transfer technique.
  • Assess for any new medical conditions, changes in lifestyle, or new symptoms.
  • Thorough physical examination, including a pelvic exam.
• Psychological Support and Counseling:
  • RIF is emotionally draining. Provide empathetic counselling and discuss the emotional impact.
  • Set realistic expectations and explain the investigative and treatment pathways clearly.
  • Consider referral for psychological support or counseling.

1. Diagnostic Workup for RIF

The diagnostic workup aims to identify uterine, embryonic, parental, and systemic factors contributing to RIF.

1. Uterine Factors:

1. Anatomical Assessment:
   • Hysteroscopy: Gold standard for direct visualization of the uterine cavity.
     • Indications: Suspected space occupying lesions such as polyps, submucosal fibroids or adhesions (Asherman’s syndrome), chronic inflammation of the inner layer (endometritis).
     • Intervention: Surgical interventions (Polypectomy, myomectomy, adhesiolysis, septoplasty ) can be performed concurrently.
   • 3D Transvaginal Ultrasound: Excellent for assessing uterine morphology, fibroids, adenomyosis, and endometrial receptivity parameters.
   • Saline Infusion Sonohysterography (SIS) / Hysterosalpingography (HSG): Less invasive than hysteroscopy for initial screening of cavity abnormalities, but hysteroscopy provides direct visualization and allows for intervention.
2. Endometrial Receptivity Assessment:
   • Endometrial Receptivity Analysis (ERA) / Endometrial Receptivity Map (ERMap) / Window of Implantation (WOI) Testing: Biopsy-based molecular tests that analyze the expression of genes involved in endometrial receptivity to determine the optimal time for embryo transfer (personalized embryo transfer – pET).
   • Immunohistochemistry for Endometrial Markers: Assessment for markers like integrins, pinopodes (though their clinical utility is debated).
   • Chronic Endometritis (CE):
     • Diagnosis: Endometrial biopsy for histological examination (plasma cells via CD138 staining) or microbiology culture.
     • Treatment: Course of broad-spectrum antibiotics (e.g., Doxycycline for 10-14 days).

1. Embryonic Factors:

1. Preimplantation Genetic Testing for Aneuploidy (PGT-A):
   • Purpose: Screens embryos for chromosomal abnormalities (aneuploidy), which is a major cause of implantation failure and miscarriage.
   • Consideration: Highly recommended, especially for advanced maternal age, to ensure transfer of euploid embryos. However, it’s invasive and requires embryo biopsy.
2. Sperm DNA Fragmentation Index (DFI):
   • Purpose: High levels of sperm DNA fragmentation can negatively impact embryo development and implantation.
   • Intervention: If high, consider lifestyle changes, antioxidant supplements for the male partner, or advanced sperm selection techniques (e.g., PICSI, IMSI).
3. Embryo Quality Re-assessment:
   • Thorough review of embryology lab procedures, culture conditions, and embryo grading criteria.
   • Consider alternative culture media or extended culture to blastocyst stage (if not already done) to allow for natural selection of more viable embryos.

1. Parental Genetic Factors:

1. Parental Karyotyping:
   • Purpose: To screen for balanced translocations or other chromosomal rearrangements in either partner, which can lead to the production of aneuploid embryos.
   • Indication: History of recurrent miscarriages or severe male factor infertility.

1. Immunological Factors:

• The role of immunological factors in RIF is complex and debated, with evidence for and against various interventions.
• Thrombophilia Screening:
  • Inherited: Factor V Leiden, Prothrombin gene mutation (G20210A), MTHFR, Protein C, Protein S, Antithrombin III deficiencies.
  • Acquired: Antiphospholipid Syndrome (APS) – Lupus anticoagulant, anticardiolipin antibodies, anti-beta-2 glycoprotein I antibodies.
  • Treatment if positive: Low-dose aspirin and/or low molecular weight heparin (LMWH).
• Natural Killer (NK) Cell Activity:
  • Testing: Peripheral blood NK cells or endometrial NK cells.
  • Controversial: The clinical significance and appropriate treatment based on NK cell levels are not universally agreed upon. Some clinicians may consider corticosteroids or intralipids.
• Other Immunological Tests (Less Evidence-Based):
  • Cytokine profiling, HLA typing, anti-thyroid antibodies (ensure thyroid function is optimized).

1. Systemic Factors:

1. Thyroid Function (TSH, free T3, free T4, anti-TPO antibodies):
   • Ensure optimal thyroid function (TSH ideally < 2.5 mIU/L for conception).
2. Prolactin Levels:
   • Hyperprolactinemia can interfere with implantation.
3. Vitamin D Levels:
   • Vitamin D deficiency has been linked to lower IVF success rates. Supplementation if deficient.
4. Glycemic Control:
   • For patients with diabetes or insulin resistance, optimize blood glucose levels.
5. Lifestyle Factors:
   • Diet: Encourage a balanced, anti-inflammatory diet (e.g., Mediterranean diet).
   • Weight Management: Optimize BMI (overweight/obesity or underweight can negatively impact implantation).
   • Smoking and Alcohol Cessation: Crucial for both partners.
   • Stress Reduction: Recommend stress management techniques (yoga, meditation, acupuncture).

III. Treatment Strategies for RIF

Based on the diagnostic workup, a personalized treatment plan is formulated.

1. Uterine Interventions:

• Surgical Correction: Hysteroscopic polypectomy, myomectomy, adhesiolysis, metroplasty as indicated.
• Treatment of Chronic Endometritis: Antibiotics.
• Personalized Embryo Transfer (pET): If ERA/ERMap indicates a displaced window of implantation.
• Endometrial Scratch/Injury (Endometrial Receptivity Assay):
  • Theory: Controlled injury to the endometrium in the cycle preceding IVF may improve receptivity.
  • Evidence: Mixed results, but some studies show benefit, particularly in patients with RIF. Can be performed during diagnostic hysteroscopy.

1. Pharmacological Interventions (often adjunctive):

1. Anticoagulants:
   • Low-dose Aspirin (LDA) (75-100 mg daily): Often initiated in cycles following RIF, especially if thrombophilia is suspected or as an empirical treatment.
   • Low Molecular Weight Heparin (LMWH): Used for confirmed thrombophilias, particularly APS, or sometimes empirically.
2. Corticosteroids (e.g., Prednisolone):
   • Indications: Suspected immunological issues, particularly elevated NK cells (though controversial) or autoimmune conditions.
   • Dosage: Typically low-dose (e.g., 10-20 mg daily) initiated around embryo transfer.
3. Immunomodulators:
   • Intralipids: Intravenous lipid emulsion, thought to modulate NK cell activity. Used by some clinicians, but robust evidence is limited.
   • G-CSF (Granulocyte-Colony Stimulating Factor):
     • Route: Uterine infusion or subcutaneous injection.
     • Purpose: May improve endometrial thickness and receptivity in some cases, especially in thin endometrium.
   • Platelet-Rich Plasma (PRP):
     • Purpose: Autologous PRP infusion into the uterine cavity to potentially improve endometrial receptivity and thickness. Emerging evidence but needs more research.
4. Gonadotropin-Releasing Hormone (GnRH) Agonist (long protocol/down-regulation):
   • Some clinicians advocate for a long GnRH agonist protocol in RIF patients to optimize ovarian stimulation and endometrial preparation.
5. Human Chorionic Gonadotropin (hCG) Wash/Infusion:
   • Infusion of hCG into the uterine cavity before embryo transfer, thought to improve endometrial receptivity. Evidence is still accumulating.

1. Embryo-Related Strategies:

• PGT-A: To select euploid embryos for transfer.
• Blastocyst Transfer: If not already performed, consider culturing embryos to the blastocyst stage to allow for natural selection and better synchronization with endometrial receptivity.
• Optimized Embryo Culture Conditions: Review and improve lab conditions.
• Assisted Hatching: May be considered in certain cases (e.g., thick zona pellucida), though its benefit is debated for RIF.

1. Ovarian Stimulation Protocol Modifications:

• Individualized Protocol: Adjust ovarian stimulation protocol based on ovarian reserve and previous responses to optimize oocyte quality.
• Dual Stimulation (DuoStim): In poor responders, performing two stimulations within the same menstrual cycle to potentially accumulate more oocytes and embryos.

1. Alternative Therapies (Less Evidence-Based, but sometimes considered):

• Acupuncture: Some patients find it beneficial for stress reduction and may contribute to overall well-being.
• Nutritional Supplements: CoQ10, DHEA (for poor responders under strict medical supervision), antioxidants.

1. Post-Transfer Management

• Continued Support: Psychological support throughout the two-week wait.
• Follow-up: Regular monitoring of any medications prescribed.

In brief, couples with RIF require psychological support and appropriate clinical investigation and intervention. Repeated failure can be due to several reasons including advanced maternal age, poor individual response to fertility medication, immunologic problems, thrombophilias, abnormal endometrial receptivity, anatomical abnormalities, deviations in microbiome, male factors, embryo aneuploidy, fluid collection in Fallopian tubes, insufficiency in the expertise of the embryology laboratory and sometimes unknown/unexplained factors.

The IVF failure sometimes turns into a blame-game. Some degree of disappointment or even anger is normal after an IVF failure. Immediate reaction is usually to find something or someone to blame. At first, the couple tend to blame the clinic, thinking it was their negligence somewhere along the line that caused harm to the embryos. However, it should be known that each fertility journey is unique, and the management of IVF is highly individualized and based on a thorough diagnostic workup, patient history, and current scientific evidence.

Finally, it should be remembered that there are lots of couples who hold their babies after repeated attempts. So do not give up and try again.

 

 

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