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Implantation Failure

Implantation failure is a significant cause of infertility (and the reason given for about 70% of IVF failures) but is rarely considered as the reason for not getting pregnant. There are, of course, differences between IVF cycles and natural conceptions, and a variety of reasons for healthy embryos not becoming babies. Implantation is a complex process requiring communication and then connections between embryo and mother.

IVF has pushed scientific boundaries and our knowledge of conception, and implantation failure is a significant cause of unsuccessful cycles.  A small percentage of women experience repeated implantation failure (RIF) with IVF where ten or more good-quality embryos over 2-6 IVF cycles fail (RIF has no formal definition, but this makes it more or less definite). i When three unsuccessful cycles involving the transfer of 1-2 good embryos are unsuccessful it should merit specialist analysis. ii 

Implantation failure treatment options vary with causes, and we highlight what issues the different Fertility Profiles tend to experience, testing options, plus research on self-help strategies that seem to work.

14 Reasons for implantation failure

1. Abnormal structure of the endometrial lining

Physical alterations or obstructions of the womb lining reduce implantation rates and include uterine polyps, fibroids, Asherman’s syndrome, or endometrial hyperplasia. iii It’s important to know these abnormalities are often missed during an initial diagnosis, even when a hysteroscopy or hysterosalpingogram (HSG) is performed.

When women have further examinations due to repeated implantation failure or repeated miscarriage, an abnormal structure in the womb is found 25% of the time.

2. The endometrium is too thin

The womb’s lining needs to be at least 7mm on the 7th day after ovulation to support implantation. v A lining of less than 8 or 9mm is so thin embryo’s have difficulty burrowing into it and implanting. Endometrial growth is stimulated by the release of estrogens from large follicles in the ovary and women who have few large follicles in a cycle produce fewer estrogens, and typically have thinner womb linings. A natural consequence of lower ovarian reserve is fewer large follicles reaching the end of “recruitment” each cycle, and this affects older women most.

Other causes:

    1. Long-term use of the oral contraceptive pill thins the endometrium
    2. Clomid use thins the womb lining and increases the risk of ectopic pregnancy, and the higher the dose, and the longer Clomid is given, the thinner the endometrium is likely to become. [i] [ii]
    3. The diet doesn’t contain sufficient nutrients to grow the womb lining
    4. Over-exercising reduces the availability of nutrients to build the womb lining
    5. Poor blood circulation in either the ovaries or the uterus reduces the transport of estrogens to the womb

Testing is usually done with ultrasound scans that measure the thickness of the endometrium.

3. Poor blood flow

The uterus requires a healthy supply of blood to support healthy function, and if blood flow is low it restricts the nutrient supply needed for a healthy womb lining or pregnancy.

Blood flow in the uterine arteries needs to be above 30 cm/s (3.0 Pl) for healthy lining growth that can support implantation (with a Doppler ultrasound). The blood flow in the uterine arteries of women who have repeated miscarriage (RP) is lower than in other women, and it’s particularly bad if they have ANA. [iii]

Causes of low uterine blood flow:

    1. Restrictions to the uterine artery
    2. Psychological stress reduces blood flow and can cause small babies [iv]
    3. Elevated testosterone levels [v]

iv

4. Hydrosalpinges

A hydrosalpinx is a grossly distorted Fallopian tube, that’s usually caused by inflammation from sexually transmitted infections. The far end of the tube gets blocked and fills with fluids which turn the tube into a “sausage” and the tube often fills with blood and mucus, which is toxic to sperm and embryos. This fluid can flow into the uterus, creating a hostile womb environment that makes implantation much less likely when a healthy embryo arrives from the other tube. Other causes of a hydrosalpinx are:

  1. Endometriosis
  2. Surgery to the tubes or lower abdomen
  3. Insertion of an IUD contraceptive
  4. An ectopic pregnancy
  5. Tuberculosis

5. Endometrial development dysfunction

The endometrium structure changes for about two days in the luteal phase and creates a “window of implantation” when the proteins on the surface of the womb encourage bonds. There are significant differences in these protein bond changes between women and evidence is emerging that women who experience RIF (repeated implantation failure) have relatively “down-regulated” bonding. This contrasts with women who have RM (repeated miscarriages), who have “up-regulation” of bonding that may encourage the implantation of sub-standard embryos and explain their subsequent loss. [vi]

The timing of the endometrial changes to coincide with the arrival of the embryo is another issue because if the womb isn’t at optimal receptivity when the embryo arrives, bonding is less likely to occur. Endometrial receptivity seems the greatest limiting factor in establishing a pregnancy with IVF in many gynaecological diseases (including PCOS), [vii] and causes include:

  1. Endometriosis.
  2. Psychological stress
  3. PCOS

6. Genetic abnormalities

A high percentage of embryos have abnormal genetic make-ups, which cause most implantation failures and early miscarriages. There are two causes; either major chromosomal problems (aneuploidy) that cause conditions like Down’s Syndrome or high levels of DNA fragmentation that create too much disorder in the developing embryo. vi

7. Heightened immune response

There are immune conditions such as elevated natural killer cells where the mother’s immune system is too active, and when this happens, her immune system removes embryo cells, preventing implantation or causing miscarriage. Both sides of the immune system need to respond to pregnancy for it to succeed, but an overly aggressive system will remove any unfamiliar cells, including potential babies.

While this is considered the most common immune-based cause of implantation failure, the “suppressive” side of the immune system is sometimes at fault when it fails to protect the embryo from a normal healthy recognition response by the “aggressive” side.

8. The parents’ immune systems are too similar

The immune system relies on the ability to distinguish cells that are “self” from “non-self”, and this involves HLA-DQα markers on our cells that flag up “self” to the immune system. If the two partners have exactly the same HLA-DQα markers, their embryo will look like “self” to the mother’s immune system, and while this sounds fine, in practice, her immune system has to recognise a pregnancy to make the necessary adaptations and accommodate it.

9. Uneven Endometrium

Incomplete shedding of the womb’s functional lining during a period leaves an uneven functional layer behind. The functional layer regrows during the follicular phase, and the womb ends up with both new and old tissue at the surface, where implantation occurs. The age, depth and health of the functional layer affect its ability to bond with an embryo, and implantation is less likely in old tissue. Many women with this condition experience dysfunctional uterine bleeding, with heavy periods, clotting or periods that vary greatly from month to month, but other causes of an uneven functional endometrial lining are:

  1. Endometriosis
  2. Endometrial hyperplasia
  3. Infection or inflammation of the endometrium
  4. Endometrial cancer
  5. Fibroids and polyps

10. Excessive blood clotting

Thrombophilia is a significant issue for women during their pregnancy as it increases the risk of miscarriage, but what’s less well-known is that thrombophilia is more common in women with Repeated Implantation Failure (RIF) or “unexplained infertility” than in the general population. vii The various causes of thrombophilia include:

  • Genetics such as factor V Leiden and prothrombin G20210A
  • Autoimmune conditions like anti-phospholipid syndrome and lupus anticoagulant that are acquired
  • Sedentary lifestyles
  • Reactions to the drug Heparin can cause Heparin-induced thrombocytopenia(HIT)
  • Nephrotic syndrome
  • Estrogens in the combined birth pill or HRT increase the risk of thrombosis 2-6x
  • Obesity more than doubles the risk of thrombosis

We recommend thrombophilia testing for all women who experience RIF, RM or unexplained infertility.

11. High “aromatase” levels

Aromatase (also called estrogen synthase) is an enzyme that’s needed to produce estrogens, specifically the conversion of testosterone into estrogens. Abnormally high aromatase levels in the womb lining are associated with lower implantation rates. viii The causes of high aromatase include:

  • Psychological stress
  • Inappropriate diet
  • Endometriosis
  • Excess alcohol
  • Inflammation and pain
  • Type II diabetes
  • Medications including some antibiotics and Phenothiazines
  • Genetic predisposition [viii]

12. Low “integrin” levels

Integrins are receptors on cell membranes that regulate the attachments between a cell and its surroundings. Their presence allows cells to make rapid and flexible responses on their surface and act like glue, which is extremely important for implantation.

The crucial integrin appears to be β3 integrin which is vital for clotting and bonding between cells. Low integrin levels in the lining of the womb are associated with low levels of implantation and IVF success ix, and low integrin levels are thought to be more likely when the woman has hydrosalpinx, endometriosis or low progesterone levels. Testing for integrin levels requires an endometrial biopsy 8-10 days after ovulation and further lab assessment.

13. Hormones used in ART

The hormones used in Assisted Reproductive Techniques can affect the structure of the endometrium after ovulation. In one study, only 30% of women taking Clomid (clomiphene citrate) had a normal structure to their luteal phase endometrium, compared to 48% of women given human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG). x

14. Abnormal uterine microbiome

Abnormal microbiome environments in the womb are thought to contribute to abnormal implantation processes, but traditionally, women with bacterial vaginosis were the only cases investigated. The recent explosion of research into the microbiome has questioned this narrow connection with fertility and an IVF study of 130 women found significant differences in pregnancy rate between the 28% of women with an abnormal microbiome, and women whose microbiome was “normal”:

  • 9% of women with an abnormal microbiome got pregnant
  • 43% of the women with healthy microbiomes got pregnant xi-xii

Tests for implantation failure

    1. Blood tests for hormonal, immune and blood clotting disorders
    2. Transvaginal ultrasound can detect:
      • The thickness and pattern of endometrial development
      • Polyps or fibroids that can physically obstruct implantation
      • Follicle development and confirmation of the egg’s release from the follicle
    3. Ultrasound Doppler can measure blood flow in the uterine artery
    4. Biopsy of the endometrium to:
      • Analyse the immune status of the endometrium (e.g. for NK cells CD57)
      • Determine preparation for implantation, for the proteins known to increase the likelihood of attachment, including “beta-3 integrin” (a “biomarker test” for this is now available). Biopsies need to be taken within two days of the standard developmental curve to be accurate; however, biopsy dating of the endometrium is controversial and isn’t advised in routine infertility evaluation xiii
  1. Chromosomal ‘karyotype’ testing of the partners (including their HLA-DQ match) is a reasonable option for couples with RIF
  2. Microbiome testing of the vagina, gut (or semen)

References

i ’Investigation and current management of recurrent IVF treatment failure in the UK’. Tan BK, Vandekerckhove P, Kennedy R, Keay SD. BJOG. Jun 2005;112(6):773-80.
ii ’Investigation and treatment of repeated implantation failure following IVF-ET’. Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T Human Reproduction 21(12):3036-43.
iii “Asherman’s syndrome: a critique and current review”. Klein SM, Garcia C-R (1973). Fertility and Sterility 24 (9): 722–735.
iv By BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=46604060
iv ’Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure’. Demirol A, Gurgan T. Reprod Biomed Online May 2004;8(5):590-94.
v ’Endometrial thickness appears to be a significant factor in embryo implantation in in vitro fertilisation.’ Noyes N, Liu HC, Sultan K, Schattman G, Rosenwaks Z. Hum Reprod Apr 1995;10(4):919-22.
vi’ Chromosome abnormalities identified by comparative genomic hybridisation in embryos from women with repeated implantation failure.’ Voullaire L, Wilton L, McBain J, Callaghan T, Williamson R. Mol Hum Reprod Nov 2002;8(11): 1035-41.
vii ’Increased rates of thrombophilia in women with repeated IVF failures’. Azem F, Many A, Yovel I, Amit A, Lessing JB, Kupferminc MJ.  Human Reproduction February 1, 2004;19(2): 368-70.
viii ’High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome’ Jan Brosens et al. Hum. Reprod. (2004) 19 (2): 352-356.
ix ’Endometrial receptivity defects during IVF cycles with and without letrozole’ Paul B. Miller et al. Hum. Reprod. (2012) 27 (3): 881-888.
x “In vitro fertilisation: the degree of endometrial insufficiency varies with the type of ovarian stimulation”. Sterzik K. et al. University of Ulm, Department of Obstetrics and Gynaecology, West Germany. Fertility and Sterility [1988, 50(3):457-62]
xi Implantation failure of endometrial origin: what is new? Bellver, José; Simón, Carlos. Current Opinion in Obstetrics and Gynecology: August 2018 – Volume 30 – Issue 4 – p 229–236
xii Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Haahr T et al. Hum Reprod. 2016 Apr;31(4):795-803. doi: 10.1093/humrep/dew026.
xiii ’Histological dating of timed endometrial biopsy tissue is not related to fertility status.’ Coutifaris C et al. Fertil Steril. 2004 Nov;82(5):1264-72.
xiv ’Endometrial receptivity defects during IVF cycles with and without letrozole’ Paul B. Miller et al. Hum. Reprod. (2012) 27 (3): 881-888.
xv ’Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.’  Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BW. Cochrane Database Syst Rev (1): CD002125.
xvi “Endometrial growth and uterine blood flow: a pilot study for improving endometrial thickness in the patients with a thin endometrium”. Takasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino N (April 2010). Fertil. Steril. 93 (6): 1851–8.
xvii ’Effects of ascorbic acid supplementation on serum progesterone levels in patients with a luteal phase defect.’ Henmi H, et al.  Fertility and Sterility (2003;80:459–61)
[i] Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium.’ Yasuhiko Nakamura M.D. Et al. Fertility &Sterility Vol. 67, No. 2, February 1997
[ii]Clomiphene citrate causes aberrant tubal apoptosis and estrogen receptor activation in rat fallopian tube: implications for tubal ectopic pregnancy’ R Shao, Et al. Biology of Reproduction 80(6):1262-1271. 2009
[iii] T. Habara et al. Elevated blood flow resistance in uterine arteries of women with unexplained recurrent pregnancy loss. January 2002 Human Reproduction 17(1):190-4
[iv] Helbig, Anne et al. “Does antenatal maternal psychological distress affect placental circulation in the third trimester?.” PloS one vol. 8,2 (2013): e57071. doi:10.1371/journal.pone.0057071
[v] Kathirvel Gopalakrishnan et al. Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats. March 2016. Hypertension. Vol. 67, Issue 3
[vi]</sup Huang, J., Qin, H., Yang, Y., Chen, X., Zhang, J., Laird, S., Wang, C. C., Chan, T. F., & Li, T. C. (2017). A comparison of transcriptomic profiles in endometrium during window of implantation between women with unexplained recurrent implantation failure and recurrent miscarriage, Reproduction153(6), 749-758.
[vii] Ione Lopes, et al. Endométrio na janela de implantação em mulheres com síndrome dos ovários policísticos,
Revista da Associação Médica Brasileira, Volume 57, Issue 6, 2011, Pages 702-709,
[viii] CYP19A1 gene: MedlinePlus Genetics