What are the possible reasons for declining beta-hCG (human chorionic gonadotropin) levels in a female patient with primary infertility, significantly diminished ovarian reserve (Anti-Mullerian Hormone (AMH) of 0.04), who underwent a donor egg In Vitro Fertilization (IVF) cycle with a history of cancelled embryo transfer due to inadequate endometrial thickness, subsequent hysteroscopy showing a normal uterus with a slightly long posterior wall, and endometrial ploughing, followed by a failed pregnancy after transfer of two blastocysts?

Declining Beta-hCG After Donor Egg IVF Transfer

The most likely reason for declining beta-hCG in this case is biochemical pregnancy loss (early miscarriage), and your patient's severely diminished ovarian reserve (AMH 0.04) significantly increases her miscarriage risk even with donor eggs, suggesting a uterine or systemic factor rather than egg quality as the primary issue.

Primary Reasons for Declining Beta-hCG

Embryonic Aneuploidy

• While donor eggs typically have lower aneuploidy rates, chromosomal abnormalities remain the leading cause of early pregnancy loss 1
• However, in this case with donor eggs from presumably younger donors, this is less likely the primary factor

Diminished Ovarian Reserve as a Risk Factor

• Your patient's AMH of 0.04 ng/ml places her at substantially elevated miscarriage risk (OR 1.91; 95% CI 1.40-2.60) compared to women with normal AMH levels 2
• Women with severely low AMH (<0.7 ng/ml) face 91% increased odds of miscarriage, and this risk persists even with donor egg cycles 2, 3
• The association between diminished ovarian reserve and miscarriage may not be exclusively mediated by the oocyte—a common pathogenic insult could affect both the ovary and the uterus, impairing its capacity to receive embryos 1

Endometrial Factors

• The "ill-defined endometrial-myometrial junction (EMJ)" noted on ultrasound is concerning and may indicate:
  • Adenomyosis or subclinical endometrial pathology
  • Suboptimal endometrial receptivity despite adequate thickness
  • Chronic endometritis (not ruled out by hysteroscopy alone)
• The endometrial ploughing procedure itself may have caused inflammation or altered endometrial receptivity 1

Inadequate Luteal Support

• Day 13 endometrium of 9.2mm with ill-defined EMJ suggests possible suboptimal endometrial preparation
• Beta-hCG of 22 mIU on day 12 post-transfer is low for a dual blastocyst transfer, suggesting poor implantation from the outset

How to Proceed Further

Immediate Workup

• Obtain comprehensive thrombophilia panel: Factor V Leiden, prothrombin gene mutation, protein C/S, antithrombin III, lupus anticoagulant, anticardiolipin antibodies 1
• Test for chronic endometritis: Endometrial biopsy with CD138 immunohistochemistry (hysteroscopy alone is insufficient to diagnose this)
• Thyroid function tests and diabetes screening: Systemic conditions independently affect miscarriage risk 1
• Karyotyping of both partners: Though less likely with donor eggs, structural chromosomal abnormalities can contribute

Endometrial Assessment

• Consider endometrial receptivity array (ERA) testing to assess optimal progesterone timing for transfer
• Repeat hysteroscopy with directed biopsies if chronic endometritis suspected
• MRI pelvis to definitively rule out adenomyosis given the ill-defined EMJ finding

Next Cycle Modifications

• Extend estrogen priming phase before starting progesterone to achieve optimal endometrial thickness (>8mm) and trilaminar pattern
• Consider GnRH agonist suppression in the cycle prior to FET to improve endometrial receptivity
• Increase progesterone supplementation: Consider intramuscular progesterone in addition to vaginal, or increase vaginal dosing
• Add low-dose aspirin (81mg daily) starting with estrogen phase if thrombophilia workup negative 1
• Consider adjuvant therapies:
  • Granulocyte colony-stimulating factor (G-CSF) intrauterine infusion if chronic endometritis confirmed
  • Vitamin D supplementation if deficient
  • Prednisone 5-10mg daily if autoimmune factors identified

Embryo Management

• Strongly recommend preimplantation genetic testing (PGT-A) for future donor egg cycles to exclude aneuploidy as a factor 1
• Transfer single euploid embryo rather than two untested blastocysts to reduce confounding variables and optimize implantation conditions

Critical Pitfalls to Avoid

• Do not assume donor eggs eliminate all risk: Your patient's severely diminished ovarian reserve (AMH 0.04) indicates a systemic or uterine factor that persists regardless of egg source 1, 2
• Do not repeat transfer without addressing the ill-defined EMJ: This finding requires investigation before proceeding 1
• Do not overlook chronic endometritis: Standard hysteroscopy has poor sensitivity for this diagnosis; specific immunohistochemistry is required
• Do not cancel cycles prematurely for endometrial thickness alone: The initial cancellation at 11mm on day 9 may have been premature, as thickness can continue to increase 1

Counseling Points

• Be explicit about elevated miscarriage risk: Even with optimal management, her baseline miscarriage risk remains 27% absolute (versus 20% baseline) due to severely diminished AMH 1
• Set realistic expectations: Women with AMH <0.7 ng/ml have persistently elevated pregnancy loss rates even with donor eggs, suggesting the issue extends beyond oocyte quality 1
• Consider gestational carrier consultation if multiple failed transfers occur despite optimization, as uterine factors may be insurmountable 1