What are the possible reasons for a failed pregnancy or biochemical pregnancy in a patient with primary infertility, low Anti-Mullerian Hormone (AMH) levels, who underwent donor egg In Vitro Fertilization (IVF) with a positive beta-human Chorionic Gonadotropin (hCG) that declined after 48 hours, and how to proceed with further treatment?

Biochemical Pregnancy After Donor Egg IVF with Declining β-hCG

Your patient experienced a biochemical pregnancy (early pregnancy loss), most likely due to embryo aneuploidy or implantation failure, despite using donor eggs—this suggests either compromised endometrial receptivity related to your patient's severely diminished ovarian reserve (AMH 0.04) or technical/embryo quality issues unrelated to egg quality.

Understanding the Biochemical Pregnancy

Your patient's declining β-hCG after initial positivity (200 mIU on day 12, then falling) represents a biochemical pregnancy—implantation occurred but failed to progress. While donor eggs should theoretically eliminate oocyte quality concerns, several factors remain relevant:

Role of Diminished Ovarian Reserve in Pregnancy Loss

• Women with severely low AMH (<0.7 ng/ml, which includes your patient's 0.04) have significantly increased miscarriage risk even with donor eggs (OR 1.35; 95% CI 1.10-1.66), suggesting that diminished ovarian reserve reflects systemic factors beyond just egg quality 1.

• The mechanism likely involves endometrial factors rather than embryo quality when donor eggs are used, as the uterine environment in women with premature ovarian insufficiency may have compromised receptivity despite hormone replacement 1.

• Your patient's "ill-defined" endometrial-myometrial junction (EMJ) at 9.2mm on day 12 suggests suboptimal endometrial development, which could contribute to implantation failure 1.

Specific Causes in Your Case

Endometrial Factors (Most Likely)

• Inadequate endometrial preparation: The ill-defined EMJ indicates possible asynchrony between embryo development and endometrial receptivity, even with HRT protocol 1.
• The posterior wall abnormality noted during hysteroscopy may represent subtle anatomical issues affecting implantation 1.
• Endometrial "ploughing" (scratching) has inconsistent evidence for benefit and may have caused inflammation rather than improvement 1.

Embryo Quality Issues

• Even with donor eggs, blastocyst quality varies—if embryo grading was suboptimal or if the donor had unrecognized factors affecting egg quality, this could explain the outcome 1.
• Technical handling during transfer accounts for approximately 50% of early embryo losses in IVF cycles 2.

Biochemical Pregnancy Pattern

• β-hCG of 200 on day 12 post-transfer that fails to double in 48 hours indicates failed implantation or very early embryonic demise 3.
• This pattern (positive then declining) occurs in 15-20% of IVF cycles and represents true implantation followed by arrest 2.

How to Proceed Further

Immediate Workup Before Next Cycle

Endometrial Assessment:

• Perform endometrial receptivity array (ERA) testing to determine optimal timing for embryo transfer, as your patient may have a displaced window of implantation 1.
• Repeat hysteroscopy to reassess the posterior wall abnormality and ensure no intrauterine pathology developed post-procedure 1.
• Consider 3D ultrasound or MRI to better characterize the posterior wall finding noted as "a little long" 1.

Thrombophilia and Immunologic Screening:

• Test for antiphospholipid antibodies, lupus anticoagulant, and inherited thrombophilias, as these can cause early pregnancy loss even with donor eggs 1.
• Consider natural killer cell testing and thyroid antibodies, though evidence for treatment is limited 1.

Embryo Quality Optimization:

• Request preimplantation genetic testing for aneuploidy (PGT-A) on future embryos to ensure only euploid embryos are transferred 1.
• Review embryo grading from the failed cycle—if quality was suboptimal, consider different donor or laboratory protocols 1.

Modified FET Protocol for Next Attempt

Endometrial Preparation:

• Extend estrogen priming phase to ensure endometrial thickness ≥8mm with trilaminar pattern and well-defined EMJ before progesterone initiation 1.
• Add low-dose aspirin (81mg daily) starting with estrogen phase, as this may improve endometrial blood flow in women with diminished ovarian reserve 1.
• Consider adding vaginal sildenafil if endometrial development remains suboptimal, though evidence is mixed 1.

Progesterone Optimization:

• Ensure adequate progesterone supplementation (intramuscular progesterone 50mg daily or vaginal progesterone 600-800mg daily) as women with POI may have impaired corpus luteum function even with HRT 4, 5.
• Check serum progesterone levels on day of transfer to confirm adequate luteal support (target >10 ng/ml) 3.

Transfer Strategy:

• Transfer only one PGT-A tested euploid blastocyst rather than two untested embryos, as this improves live birth rates while reducing multiple pregnancy risk 1.
• Consider assisted hatching if not already performed, particularly given your patient's age and ovarian reserve status 6.

Long-term Considerations

Contraception Counseling:

• Despite AMH of 0.04, spontaneous pregnancy remains possible in 5-10% of POI cases, so contraception is mandatory if pregnancy is not desired between cycles 4, 5.

Systemic Health:

• Ensure your patient is on appropriate hormone replacement therapy for bone and cardiovascular health, as POI increases long-term morbidity risk 4, 5.
• Bone density screening (DEXA) should be performed if not already done 4.

Prognosis and Counseling

• With optimized protocol and PGT-A tested embryos, live birth rates with donor eggs should approach 50-60% per transfer despite your patient's diminished ovarian reserve 1, 6.
• The biochemical pregnancy indicates that implantation can occur, which is prognostically favorable compared to complete implantation failure 2, 3.
• Plan for 2-3 transfer attempts before considering alternative strategies, as cumulative success rates improve significantly with multiple cycles 6.