L9: Embryo Implantation Disorders Flashcards
How is an embryo graded?
- Grade 1 to 4 (good to bad)
- Considers size distribution and level of fragmentation
How is a blastocyst graded?
- 1 - 4 according to degree of expansion
- If 3+ -> A-C for inner cell mass and trophectoderm
- A: tightly packed, many cells
- B: Loosely packed, several cells
- C: Very few cells
Define embryo:
- Discrete entities arising from the first completed mitotic division after fertilisation
- Develops from a zygote
List all of the stages that implanation encompasses:
- Free-floating blastocyst -> blastocyst hatching
- Apposition then adhesion (Start of WOI)
- Endometrial invasion
- Embryo differentiation and growth (End of WOI)
Embryo-endometrium communication once implantation is complete:
- Blastocyst, once implanted into epithelium of endometrium, secretes cytokines like IL-1
- This, in turn, stimulates LIF expression in the endometrium
Define implantation rate:
- Number implanted out of number transferred over a period -> KPI
- Usually measured by number of gestation sacs on scans
Fully define recurrent
implantation failure: (4 parameters)
- Failure to achieve clinical pregnancy after….
- Transfer of at least 4 embryos
- In at last 3 transfer cycles (fresh/frozen)
- Good quality embryos
- Woman under 40
Define implantation failure:
- Failure to reach a stage in which there is ultrasound evidence of intrauterine pregnancy
List 6 outcomes causing repeated IVF failure:
- Cycle cancellation (various reasons)
- Failed fertilisation
- Failed implantation
- Biochemical pregnancy
- Clinical miscarriage
- Ectopic pregnancy
What 5 lifestyle factors can impact embryo quality (women):
- Age
- Diet and supplements (folate and vitamin D both pro-implantation)
- BMI may reduce implantation (<18, >30)
- Smoking (increases FSH dose, reduce egg yield, embryo quality and implantation)
- Stress (cause-effect relationship difficult to establish)
What 4 factors contribute to poor sperm quality?
- Iatrogenic (surgery, radiation etc)
- Chromosomal / genetics
- Congenital / varicocele
- Lifestyle factors (including chemical exposure such as anabolic steroid use or occupational substance exposure)
- Note that a large proportion of poor sperm goes unexplained
What factors reduce egg quality? (x2)
- Reduced ovarian reserve (age, iatrogenic, chromosomal / genetic, congenital)
- Issues with cumulus cells
What factors in the laboratory might negatively impact implantation rate? (list 7)
- Stimulation protocol (serum Pr at hCG trigger)
- Handling of eggs (number of flushes, denuding etc, ICSI vs IVF)
- Aldehydes / noxious volatile organic compounds
- Cheap culture media, culture dish and embryo transfer catheters
- Exposure of embryos to light
- Incubator conditions (controlled pH, thermal environment)
- Embryo transfer technique (operator experience)
Give some examples of endometrial factors for implantation failure: (x7)
- Poor endometrial development
- Infection (e.g. after previous pregnancy or injury)
- Polyps
- Submucous fibroids
- Uterine synechia (uterine walls adhere)
- Adenomysosis (endometrial tissue grows into muscular wall)
- Congenital (e.g. uterine septa, can be caused by mullerian dysgenesis)
- N.B. Endometrial factors largely unexplained
Tubal factor for implantation failure:
- Hydrosalpinges (damaged tubes leak water)
- Blockage due to infection (gonorrhea, chlamydia)
List some immune factors for implantation failure: (x4)
- Poorly controlled thyroid disease (Hashimoto etc)
- Poorly controlled diabetes mellitus
- PCOS
- Premature ovarian failure
List some immune disorders which can cause implantation failure:
- Autoimmune thyroid disorders (hashimoto)
- Autoimmune gonadal diseases (addison’s)
- Abnormal endometrial cytokines (e.g. elevated NK cells in endometrium)
- Antiphospholipid syndrome (APS)/thrombophilia
Common chemical tests after implantation failure: (grouped by diagnosis/es)
- FSH, AMH, antral follicle count -> ovarian reserve, autoimmune ovarian disorders
- Testosterone, SHBG, Free androgen index -> PCOS
- Thyroid peroxidase antibody, TSH -> thyroid disorder, autoimmune disorder (hereditable/acquired)
- Lupus anticoagulant, Antiphospholipid Ab -> Lupus, APS aka thrombophilia
- Glycosylated haemoglobin (Hb A1C) -> diabetes
First line tests after implantation failure (anatomical): (x2)
- Pelvic ultrasound (TVS/TAS)
- Hysterosalpingography
Second line tests after implantation failure:
- Hysteroscopy and/or laproscopy (confirming uterine/endometrial/tubal or ovarian factor)
- Parental karyotyping (if strongly indicated only)
Give 3 further fertility tests with doubtful clinical value:
- Sperm DNA fragmentation test
- Endometrial sampling for natural killer (uNK) cells
- Blood for pNK cells
- Note: These tests are still informative in research setting
List some general measures to take in order to improve embryo quality:
- Encourage couple to try early
- Good diet
- Reduce/eliminate cigarette smoking
- Reduce alcohol
- Weight control (difficult in some cases e.g. PCOS, due to interaction of condition with metabolism)
Name two procedural measures that could improve embryo quality alongside embryo selection:
- Coculture with cumulus
- Assisted hatching
- In some cases, outsourcing the gamete is necessary -> donation (e.g. for parental aneuploidies)
- In sperm factors, issue may be circumvented using ICSI
When might TESA/TESE be applied:
- In cases where sperm DNA fragmentation is strongly suspected
Define APS (thrombophilia):
- A systemic autoimmune disease characterised by vascular thrombosis and/or pregnancy morbidity in the persistent presence of antiphospholipid antibodies (aPL)
How do we test for aPL? (x3)
- Lupus anticoagulant (LA)
- Abs against beta-2 glycoprotein I
- Abs against cardiolipin (aCL)
- Any positive results would need retesting over time before a diagnosis could be reached
How does aPL affect placentation and pregnancy outcomes?
Treatment?
- aPL is able to interact with both sides of the placenta
- At the decidual level, it is proinflammatory with neutrophil infiltration, secretion of cytokines and complement activation
- At trophoblast level, it downregulates hCG, integrins and cadherins resulting in reduced trophoblast proliferation and growth
- APS is thus strongly linked to recurrent miscarriages, but not with implantation failure
- Treat with LMWH and aspirin
What is thyroid autoimmunity and how is it treated?
- Presence of autoantibodies against thyroid peroxidase (TPO) and/or thyroglobulin (TG)
- Associated with recurrent implantation failure
- Treated with thyroxine supplements
What are uNK cells?
- Related to natural killer cells (subpopulation of lymphocyte in peripheral blood)
- uNK found in in uterine lining at implantation
- Function essentially unknown but suggested to regulate placentation and trophoblast cell invasion
- Consequently, uNK tests have no agreed range of normality and there is no agreed treatment protocol
What can cause excess fluid in endometrium:
- Excess ovarian stimulation -> high dose oestrogen
- Low dose oestrogen
- Tubal factors (hydrosalpinges)
- Endometrial factors (poylp/fibroid/synechia. cervical stenosis/infection)
- Other/unknown
Why might diagnostic hysteroscopy be used in a clinic?
- Geographical difference in success rate of other tests (particularly reliability of USS)
- e.g. UK, not justified
- e.g. developing countries (Nigeria) where USS less reliable
- In cases of recurrent implantation failure
How are polyps managed before vs during fertility treatment?
- If detected before further IVF: Remove (see below)
- If detected during stimulation: Freeze all
- If detected during egg collection or after: If >1cm, freeze all, if very small and poor embryo, transfer
- Research provides mixed evidence for clinical value
- Convincing evidence shows that hysteroscopic polypectomy is significantly more effective than diagnostic hysteroscopy + biopsy only prior to IVF
Management of fibroids before and during IVF treatment:
- If detected before IVF: Remove using hysteroscopic myomectomy -> convincing research evidence
- If detected during stimulation: Freeze all
- If detected during egg collection or after: If significant distortion of endometrium, freeze all, If very small, low and type-2 - consider transfer
- N.B. Skillfull and cautious removal is key as can have iatrogenic impact on fertility
Effect of uterine septum on pregnancy:
- Doesn’t prevent pregnancy itself but does affect miscarriage rates
Treatment for hydrosalpinges, efficacy:
- Salpingectomy/tubal clipping
- Before: 15% LBR -> after: 30% LBR
- Rate of pregnancy and implantation also improved by treatment
What are some diagnoses that may result in poorly developed endometrium?
- Poor ovarian reserve / POF (age or otherwise e.g. FXPOI)
- Iatrogenic (medical, radiation)
- Endometrial (asherman’s synechia, chronic infection)
- Uterine fibroids
- Adenomysosis
- Other
Quality of evidence for hysteroscopic surgery of asherman synechia:
- Relatively convincing
What are fibroids, polyps and adenomyosis?
- Polyps: Benign proliferation of endometrial tissue which is not removed in menses
- Fibroids: Proliferation of connective tissue/muscle
- Adenomyosis: endometrial tissue growing into myometrium
Effect of smoking on fertility on various processes/organs:
- Ovary: early menopause and poor quality oocytes
- Steroidogenesis: Decreased oestrogen and progesterone, increased androgens
- Oviduct: Increased ectopic pregnancy, effects on oviductal smooth muscles
- Uterus/implantation: delayed implantation, decreased uterine receptivity
- Menstrual cycle: increase oligomenorrhea, dysmenorrhea, heavy bleeding
