In vitro fertilization (IVF) is a complex process with no guarantees. Even with high quality embryos, the success rate per IVF cycle ranges from 20-35% for women under 35 years old. Unfortunately, failed IVF cycles are common despite perfect embryos. There are several potential reasons why IVF fails despite good quality embryos.
Embryo quality
Embryo quality is graded based on morphology and developmental timing. However, appearance doesn’t always correlate with viability. Chromosomal abnormalities are common in embryos and cannot be detected by visual assessment. Genetic issues like Down syndrome, Turner syndrome, and trisomy 13/18 can impede development despite normal looking embryos. Embryo quality assessment remains subjective, so even “good” embryos may have underlying problems.
Embryo morphologic grading
Embryos are given quality scores during IVF based on physical characteristics:
| Grade | Description |
|---|---|
| Excellent/Good (4-5) | Even sized, symmetrical blastomeres with no fragmentation |
| Fair (3) | Slight asymmetry in blastomeres, up to 10% fragmentation |
| Poor (1-2) | Uneven sized blastomeres, significant fragmentation >10% |
However, studies show morphology correlates poorly with euploidy (normal chromosomes). Many “good” embryos are genetically abnormal while some poor quality embryos are chromosomally normal. Strict morphology grading fails to predict viability.
Timing of development
Embryo development is closely monitored during IVF. Ideal growth timing is:
- Day 1: Fertilization and formation of two pronuclei
- Day 2: 2-4 cells
- Day 3: 6-8 cells
- Day 4: Morula
- Day 5/6: Blastocyst
Faster developing embryos are preferred but rate of growth alone also fails to assess chromosome status. Genetic screening via PGT-A testing is necessary for accurate assessment.
Embryo chromosomal abnormalities
Up to 70% of IVF embryos have the wrong number of chromosomes, called aneuploidy. Examples include:
- Down syndrome – Trisomy 21
- Turner syndrome – Monosomy X
- Trisomy 13/18
Aneuploidy directly correlates with lower implantation and higher miscarriage rates. Unfortunately, most chromosomal issues cannot be identified by embryo morphology or growth rate. Only PGT-A/CCS genetic screening can detect abnormalities. Without biopsy and testing, genetically poor quality embryos are unknowingly transferred.
Incidence of embryo aneuploidy by female age
| Maternal age | Aneuploidy rate |
|---|---|
| Under 35 | 25-35% |
| 35-37 | 40% |
| 38-40 | 50-60% |
| Over 40 | Over 70% |
Older women produce more aneuploid embryos due to deterioration of egg quality. But even women under 35 have high rates of chromosome issues leading to IVF failure.
Lack of embryo-uterine synchronization
Successful implantation requires a dialogue between embryo and endometrium. This communication becomes disrupted in IVF cycles for various reasons:
Supra-physiologic hormonal levels
IVF uses higher hormone doses to stimulate the ovaries. Estrogen and progesterone levels far exceed natural levels to prepare the lining. However, supraphysiologic levels disrupt uterine receptivity markers needed for implantation. Too much hormone stimulation creates an unnatural endometrial environment.
Endometrial scratch procedure
Some clinics perform an endometrial biopsy or scratch to improve implantation. However, this causes inflammation and disrupts the endometrial lining. Any injury to the uterus negatively affects receptivity.
Embryo-uterine synchrony loss
The ideal implantation window is narrow. Transfer too early or late leads to failure. Labs estimate embryo stage and uterine status best they can to coordinate the two. But IVF disrupts natural synchrony between embryo age and endometrial timing. Mistiming implantation remains a major cause of IVF failure.
Poor endometrial receptivity
Implantation failure can arise from intrinsic endometrial disorders preventing embryo attachment:
Luteal phase defect
A luteal phase defect (LPD) happens when progesterone levels are too low after ovulation. This leads to premature sloughing of the uterine lining before implantation can occur. LPD often goes undiagnosed.
Chronic endometritis
Chronic endometrial inflammation like endometritis creates a hostile environment for embryos. Inflammation interferes with proper immune modulation and receptivity.
Submucosal fibroids
Non-cancerous fibroid tumors in the uterine cavity can impede implantation and blood flow to the endometrium.
Hydrosalpinx
Fluid-filled Fallopian tube cysts, or hydrosalpinx, allows fluid to leak into the endometrial cavity disrupting implantation.
Adenomyosis
Invasion of endometrial tissue into the uterine muscle layer called adenomyosis also reduces implantation and increases miscarriage risk.
Intrauterine adhesions
Scar tissue bands called adhesions inside the uterus disrupt normal development of the endometrium. Asherman’s syndrome is a severe form causing amenorrhea.
Endometrial polyps
Abnormal tissue growths inside the uterus, called endometrial polyps, can act as an implantation barrier and reduce IVF success rates.
Embryo transfer difficulties
Even a perfectly healthy embryo can fail to implant due to issues with the embryo transfer procedure itself:
Traumatic catheter insertion
Overly traumatic insertion of the embryo transfer catheter can trigger uterine contractions. This interferes with implantation.
Retained embryos in catheter
Sometimes embryos remain stuck in the catheter and fail to release into the uterus. The transfer needs to be smooth and unobstructed.
Embryo expulsion
Forceful transfers can cause embryos to be expelled or washed out through the cervix. Gentle technique is vital.
Suboptimal embryo placement
If embryos are deposited in a non-receptive location like near the cervix or fundus, implantation is much less likely. Ideal site is about 1.5-2cm from the uterine fundus.
Blood or mucus on catheter tip
Any cervical mucus or blood carried on the transfer catheter along with the embryo can interfere with implantation. The catheter tip should be clean and clear.
Undiagnosed uterine issues
Standard fertility evaluations often miss subtle uterine problems. Further testing should be considered in women with recurrent IVF failure such as:
- Hysteroscopy – direct visualization of the uterine cavity
- MRI – detailed images identifying structural issues
- Endometrial biopsy – histological analysis of uterine lining
- Immune testing – check for elevated antibodies like natural killer cells
- Thrombophilia testing – assess for clotting disorders impeding blood flow
Uncovering hidden uterine factors maximizes chances for IVF success before another transfer.
Genetic compatibility factors
Embryo viability relies on intricate cell-to-cell communication and suppression of maternal immune response. Implantation failure may arise from subtle genetic incompatibilities between partners.
Sperm DNA fragmentation
Sperm contribute half the embryo’s genetics. High sperm DNA damage linked to male infertility can undermine embryo quality and early development.
HLA matching
Normal pregnancy requires specific matching of parental HLA genes regulating immunity tolerance. A combination of incompatible HLA markers in couples can negatively impact implantation and increase risk for recurrent pregnancy loss.
Proteins essential for placental development
Certain paternal proteins interact with maternal uterine receptors to facilitate embryo attachment and trigger angiogenesis. Particular protein profiles may determine IVF success.
Research on immunogenetic mechanisms affecting embryo selection and transfer outcomes is still ongoing.
Non-receptive endometrial microbiome
The endometrium hosts a complex microbiome essential for reproductive health. Dysbiosis and imbalance of key microbes may contribute to IVF failure by creating a hostile microenvironment.
Low Lactobacillus levels
Lactobacillus species support implantation through beneficial metabolic and immune interactions. Insufficient Lactobacillus allows detrimental bacteria to proliferate leading to inflammation.
High pathogenic bacteria load
Harmful microbes like Streptococcus, Staphylococcus, Enterococcus, Escherichia, and others trigger inflammation shown to inhibit embryo implantation. Their overgrowth from lack of Lactobacillus causes dysbiosis.
Changes after ovarian stimulation
Hormonal stimulation for egg retrieval suppresses Lactobacillus and enriches pathogenic species. This unfavorable shift in microbiome balance further hampers IVF success.
Treatment protocol issues
Suboptimal IVF treatment protocols can undermine implantation and pregnancy outcomes despite quality embryos:
Over-suppression of pituitary
Excessive suppression of natural hormones FSH and LH using GnRH agonists creates unfavorable uterine conditions.
Under-suppression of pituitary
Incomplete suppression allows premature LH surges detrimental to IVF success. Precise hormonal regulation is critical.
Premature trigger of final oocyte maturation
Too early administration of hCG trigger fails to maximize the egg cohort, limiting availability of high quality embryos.
Delayed trigger of final oocyte maturation
Late trigger timing allows follicles to overmature resulting in lower quality eggs and embryos.
Over/under dosing of FSH
Inappropriate FSH dosage leads to poor ovarian response and impaired endometrial receptivity.
Suboptimal progesterone exposure
Insufficient progesterone hormone during luteal phase fails to prime the endometrium for embryo implantation.
Lifestyle and environmental factors
External influences including diet, exercise, weight, toxins, and stress affect reproductive outcomes:
Obesity
Women with BMIs over 30 have lower implantation and clinical pregnancy rates from poor oocyte quality and hormonal disruptions.
Tobacco smoking
Cigarette toxins accumulate in follicular fluid and impair development. Embryos from smokers have 29% lower implantation rates per transfer.
Alcohol consumption
As little as 1 drink per day reduces IVF success by 50% compared to abstainers, mediated by effects on oocyte and embryo development.
Caffeine intake
Caffeine crosses the placenta impairing embryo metabolism. Women consuming >500mg daily (5 cups coffee) have significantly lower pregnancy rates.
Environmental pollutants
Pesticides, plastics, heavy metals, and other toxins disrupt hormonal balance and increase oxidative stress interfering with implantation.
Psychological stress
Stress triggers immune and inflammatory responses that adversely affect fertility and embryonic development through complex mechanisms.
Optimizing preconception lifestyle habits improves IVF outcomes.
Unexplained implantation failure
Despite extensive testing, the exact cause of IVF failure remains unknown in many cases. Some theorized mechanisms may involve:
- Impaired embryo-derived signals needed for cross-talk with the endometrium
- Defective endometrial cellular adhesion molecules preventing embryo attachment
- Dysfunctional angiogenesis blocking development of placental vasculature
- Abnormal epigenetic modifications of endometrial receptivity genes
- Mitochondrial DNA defects affecting embryonic metabolism
- Other intricate implantation pathways yet to be discovered
The molecular details underlying implantation remain poorly understood. Research continues to uncover novel pathways that may explain unresolved implantation failure.
Conclusion
Despite transferring euploid embryos, IVF success is never guaranteed because intricate cell signaling regulates implantation. Comprehensive testing and personalized treatments to optimize every aspect of fertility are key to overcoming implantation failure. Identifying any subtle reproductive issues in both partners, enhancing endometrial receptivity, and improving IVF protocols can help achieve pregnancy in difficult cases. With an integrative approach and patience, IVF success is still possible for many patients with recurrent implantation failure through emerging solutions like endometrial microbiome modulation, uterine artery vasodilation, hysteroscopy, and more.