Analysis of Causes of IVF Failure in China: Embryo Factors, Endometrium & Chromosomal Abnormalities Explained

===== Opening: Scenario of Failure Cause Analysis =====

Reproductive Doctor Perspective Failure Cause Analysis

Not achieving clinical pregnancy after an IVF cycle, or experiencing embryo arrest or miscarriage after pregnancy, is not uncommon in clinical practice. From a reproductive medicine perspective, IVF failure is not a single event, but a group of clinical outcomes with different etiologies and mechanisms. A distinction needs to be made: whether the embryo did not implant at all (recurrent implantation failure), or whether a biochemical pregnancy or early miscarriage occurred after implantation. The investigation directions for these two situations differ significantly.

===== Module A: Direct Answer to the Question =====

Core Cause Classification of IVF Failure

According to clinical statistics and published Chinese assisted reproduction data, the main causes of IVF failure are concentrated in the following four areas:

• Embryo Factors: Chromosomal aneuploidy, poor embryo developmental potential, high fragmentation rate. This is the most frequent cause of failure, accounting for approximately 50% to 60% of all failure cases.
• Endometrial Factors: Poor endometrial receptivity, chronic endometritis, thin endometrium, intrauterine adhesions, polyps or fibroids affecting implantation.
• Maternal Endocrine and Immune Factors: Thyroid dysfunction, vitamin D deficiency, abnormal NK cell activity, positive antiphospholipid antibodies, etc.
• Male Factors: Elevated sperm DNA fragmentation index (DFI), abnormal sperm chromosome structure, which may be overlooked in routine semen analysis.

===== Module B: Why Does This Problem Occur =====

Why Embryo Chromosomal Abnormality is the Primary Cause

Chromosome nondisjunction during oocyte meiosis is the main source of embryo aneuploidy. Female age is the strongest independent influencing factor:

• Under 35 years: Embryo aneuploidy rate is approximately 30% to 40%
• 35 to 40 years: Increases to 50% to 65%
• 40 to 42 years: Can reach 70% to 80%
• Over 43 years: Exceeds 90%

Additionally, an elevated sperm DNA fragmentation index (DFI > 30%) can lead to embryonic genome instability, abnormal cleavage, and decreased blastocyst formation rate. Even if morphology is normal, developmental arrest or implantation failure is more likely after transfer.

Regarding endometrial receptivity, chronic endometritis (CE) is an easily overlooked cause. CE is caused by plasma cell infiltration into the endometrial stroma. It is difficult to diagnose with routine ultrasound or hysteroscopic visual inspection and requires CD138 immunohistochemical staining for confirmation. In untreated CE-positive patients, the probability of recurrent implantation failure is significantly increased.

===== Module L: Interpretation of Examination Indicators =====

Key Examination Indicators for Investigating Failure Causes

The following examinations have clear clinical significance after IVF failure. It is recommended to complete them systematically before planning the next cycle:

Examination Item	Key Indicator	Abnormality Indication
Embryo Chromosomal Analysis (PGT-A / Miscarriage Tissue CNV)	Chromosome number, structural variation	Aneuploidy, segmental duplication/deletion
Sperm DNA Fragmentation Index (DFI)	DFI < 15% normal; 15%~30% borderline; > 30% abnormal	Elevated DFI associated with decreased embryo developmental potential
Endometrial CD138 Immunohistochemistry	Plasma cell count ≥ 5/HPF	Chronic endometritis
Saline Infusion Sonography / Hysteroscopy	Endometrial morphology, adhesions, polyps, fibroids	Uterine cavity abnormalities affecting implantation
Thyroid Function + Autoantibodies	TSH, FT4, TPOAb, TgAb	Subclinical hypothyroidism, Hashimoto's thyroiditis
Vitamin D Level	25-OH-VitD < 30 ng/mL indicates insufficiency	Related to endometrial receptivity and immune regulation
Antiphospholipid Antibody Panel	LA, aCL, β2-GP1	Antiphospholipid syndrome increases miscarriage risk

Note: The above examinations are not all completed at once but are selected in layers based on the patient's age, number of previous cycles, miscarriage history, and embryo situation. For example, for a young patient (<35 years) with first-time transfer failure, prioritize investigating the uterine cavity environment and endocrine factors; for patients over 40 years, the probability of embryo chromosomal abnormalities is highest, and PGT-A should be considered first.

===== Module D: Differences Across Age Groups =====

Differences in Failure Causes Across Age Groups

Age is the most core variable in the stratified analysis of IVF failure. The following is a summary based on clinical observations:

• ≤ 35 years: Endometrial factors and endocrine factors account for the highest proportion. The embryo chromosomal abnormality rate is relatively low (about 30%), so the investigation focus should be on uterine cavity environment, immune and metabolic factors.
• 36~39 years: The embryo chromosomal abnormality rate begins to increase significantly (about 50%), along with a decline in endometrial receptivity. At this stage, it is necessary to investigate both the embryo and the endometrium.
• ≥ 40 years: The embryo aneuploidy rate exceeds 70%, making it the dominant factor in failure. Even with good endometrial conditions, the probability of obtaining a chromosomally normal embryo is greatly reduced. At this stage, embryo genetic screening (PGT-A) offers the highest value.

In clinical practice, for women over 42 using their own eggs, obtaining one chromosomally normal embryo requires an average of 3 to 4 blastocysts for biopsy, meaning multiple ovarian stimulation cycles are needed to accumulate embryos. This is an objective biological limitation, unrelated to medical technology.

===== Module G: Most Easily Overlooked Details =====

Most Easily Overlooked Details

In the investigation of IVF failure causes, the following details are often underestimated:

• Chronic Endometritis (CE): Cannot be diagnosed by routine ultrasound or hysteroscopic visual inspection; CD138 staining is mandatory. The detection rate of CE in the infertile population is about 30%~40%, and it is higher in those with recurrent implantation failure.
• Sperm DNA Fragmentation Index: Normal routine semen analysis (concentration, motility, morphology) does not guarantee normal DNA integrity. An elevated DFI directly affects embryo developmental potential and the ability to sustain growth after implantation.
• Vitamin D Level: Vitamin D receptors are expressed in endometrial and immune cells. Insufficient levels are associated with decreased endometrial receptivity and immune imbalance.
• Thyroid Autoantibodies: Even if TSH is within the normal range (<4.2 mIU/L), positive TPOAb or TgAb is associated with an increased risk of recurrent implantation failure and early miscarriage.
• Endometrial Microbiome: A reduced proportion of Lactobacillus and increased microbial diversity may affect endometrial receptivity, but clinical testing is not yet widespread.

===== Module H: Common Pitfalls in Cognition and Decision-Making =====

Common Pitfalls in Cognition and Decision-Making

Based on reviews of numerous failure cases, the following misconceptions frequently recur in patient decision-making:

• Misconception 1: Believing that "a good embryo morphology score means no problem." In reality, about 30%~40% of morphologically normal blastocysts still have chromosomal abnormalities (especially in older individuals).
• Misconception 2: Repeated transfers without investigating the cause. Some patients undergo 3~4 consecutive failed transfers before starting systematic testing, wasting precious embryos and cycles.
• Misconception 3: Ignoring the investigation of male factors. When all female tests are normal, elevated male DFI or chromosomal polymorphisms may be the hidden root cause.
• Misconception 4: Having overly high expectations for "immunotherapy." Immune factors account for only a small portion of failure cases. Using immunosuppressants (e.g., corticosteroids, TNF-α inhibitors) without a clear diagnosis offers limited benefit and carries potential risks.
• Misconception 5: Repeated transfers without ruling out uterine cavity pathology. Conditions like endometrial polyps, adhesions, and chronic endometritis can be resolved in one hysteroscopic procedure, but they need to be detected first.

===== Module M: Clinical Case Scenario Analysis =====

Clinical Case Scenario Analysis

===== Module R: Practitioner Observations =====

Practitioner Observations: A Systematic Approach to Investigating Failure Causes

In clinical work, the core task after IVF failure is to distinguish between "embryo cause" and "uterine cause", or a combination of both. The following investigation logic is commonly used in reproductive centers:

1. Step 1: Review embryo data. This includes embryo morphology score, developmental rate (day 3 cell number and fragmentation, blastocyst expansion degree and inner cell mass/trophoblast grading), and any available chromosomal analysis results from miscarriage tissue.
2. Step 2: Assess the uterine cavity environment. First choice is saline infusion sonography or hysteroscopy, along with endometrial CD138 staining to rule out chronic endometritis.
3. Step 3: Maternal endocrine and metabolic screening. Includes TSH, TPOAb, vitamin D, fasting glucose, and insulin resistance index.
4. Step 4: In-depth male examination. Includes sperm DNA fragmentation index, sperm morphology (strict criteria), and Y chromosome microdeletion (if necessary).
5. Step 5: Immune and coagulation tendency screening. Used to rule out antiphospholipid syndrome, abnormal NK cells, etc. (applicable for recurrent implantation failure or recurrent miscarriage).

It is important to emphasize that not all failures require a full set of tests. The core basis for stratified assessment is: the patient's age, number of previous failures, miscarriage history, and the quantity and quality of available embryos. For a patient with only 1 failure and age under 35, excessive testing is unnecessary and may increase psychological burden.

===== Module Q: High-Frequency Consultation Questions (Naturally Integrated) =====

High-Frequency Questions About IVF Failure

When is PGT-A suitable?

Female age ≥38 years; history of fetus with chromosomal abnormality or miscarriage; recurrent implantation failure (≥2 times); or when a larger number of embryos are available and there is a desire to prioritize transferring chromosomally normal embryos. PGT-A can screen out aneuploid embryos, reducing the risk of failure due to embryo factors.

When is repeated transfer not advisable?

It is not recommended to have consecutive transfers before the cause of failure is clarified. Especially when the patient is older (≥40 years) or has a limited number of embryos, each transfer consumes a precious embryo. Identifying the cause and adjusting the plan accordingly is more valuable than blindly repeating cycles.

How long should one wait after failure before the next cycle?

From a physiological recovery perspective, an interval of at least 1~2 menstrual cycles is recommended. If hysteroscopic surgery or immunotherapy is needed, the interval may be extended to 3~6 months depending on the specific situation. The core purpose of timing is to complete necessary tests and treatments, not just to wait.

How to determine whether the cause of failure is the embryo or the endometrium?

The most direct way to judge is: if a chromosomally normal blastocyst screened by PGT-A is transferred but still fails to implant, the probability of an endometrial factor exceeds 80%. If a morphologically high-scoring embryo without genetic screening is transferred, the probability of embryo chromosomal abnormality and endometrial factor each account for a certain proportion, requiring further investigation.

===== Ending: Risk Reminder =====

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