IVF Failure

Recurrent IVF Failure

An embryo may not implant either because there is something wrong with the embryo itself that it can’t implant, or there is something in the uterine environment that doesn’t allow a normal embryo to implant.

Problems with the embryo

The most common abnormality found in pre-implantation embryos is an abnormal chromosome complement. Data from preimplantation genetic diagnosis suggest that 30% to 90% of in vitro fertilized eggs depending on maternal age are chromosomally abnormal. Furthermore, it has been estimated that 75% of karyotypically normal pre-implantation embryos fail to implant. Other than chromosomal abnormalities, problems with the pregnancies can include abnormal genes or abnormal DNA contributing to their losses. While mutations in HLA G genes have been associated with post-implantation recurrent pregnancy loss, secretion of soluble HLA G protein by pre-implantation embryos has been used to predict implantation potential of in vitro fertilized eggs before embryo transfer into the uterus. Fragmented DNA from the sperm has also been associated with poor embryo quality and implantation failure.

Problems within the uterus

Problems within the uterine environment that inhibits the embryo from implanting have been classified as anatomic, hormonal and immunologic.
a. Anatomic abnormalities are lesions inside the uterus that mechanically inhibit implantation. These anatomic abnormalities act like an intrauterine device to prevent implantation of the embryo and include:

Endometrial polyps-- benign outgrowths of the uterine lining that protrude into the uterine cavity)
Submucous fibroids – benign tumors of the uterine wall that protrude into the uterine cavity
Uterine synechia - scarring or adhesions inside the uterine cavity

b. Hormonal responses of the lining of the uterus to both estrogen and progesterone are necessary for the uterus to be receptive to the embryo. Mutations in some of the genes encoding for the progesterone receptor have been associated with recurrent implantation failure.
c. Immunologic mechanisms involved in implantation are being identified. The uterus as well as the embryo has to be made amenable (receptive) to implantation. Uterine receptivity requires continuous interactions between the embryo and the mother. These interactions are communicated through proteins known as cytokines. Cytokines are secreted by the cells within the uterine lining including the immune cells. During the pre-implantation period preparation of the uterine lining for implantation involves stimulation expression of adhesion systems that hold the embryo to the uterus. If the immune cells don’t send proper signals through secretion of appropriate cytokines to the embryo or if these cells don’t respond to signals from the embryo, then adhesion and thus subsequent implantation will not occur.

Establishing the correct diagnosis is an important component in treating couples
with reproductive failure. Recurrent implantation failure occurs after fertilization and prior to implantation . Thus it can be the consequence of problems within the egg or the sperm that gives rise to an embryo that it can’t implant or problems within uterine lining that don’t allow an otherwise normal embryo to implant.
Problems within the egg can manifest clinically as diminished ovarian reserve or premature ovarian failure. Diagnostic tests useful in identifying individuals at greater risk for diminished ovarian reserve or premature ovarian failure include:

Follicle Stimulating Hormone (FSH), estradiol and inhibin B-- Ovarian Reserve describes the ovary's capacity to respond to gonadotropin stimulation by producing a sufficient number of good quality eggs capable of generating normal embryos. Anti Mullerian Hormone (AMH) serum concentration provides a new measure of ovarian reserve to accompany the measurement of day 3 Follicle Stimulating Hormone (FSH) and Estradiol (E2) concentrations. Since AMH is secreted by granulosa cells, it is a more direct measurement of assessing follicular function than FSH.
Antiovarian Antibodies (AOA) - Anti-Ovarian Antibodies (AOA) have been reported in women with premature ovarian failure, low ovarian reserve and unexplained infertility. Among women with infertility, those with evidence of ovarian autoimmunity appear to have poorer in vitro fertilization (IVF) treatment outcomes than women without antiovarian antibodies. Both reduced responsiveness to gonadotropin stimulation and reduced pregnancy rates are observed in women with ovarian antibodies. Women with antiovarian antibodies are less likely to become pregnant after IVF/ET than women without antiovarian antibodies. The predictive value of a positive antiovarian antibody for poor pregnancy outcome after IVF/ET is 82%.

Problems within the sperm not diagnosed by the standard parameters of semen analysis can be detected by:

Sperm DNA Integrity assay (DNA fragmentation) -- Results of recent research indicate that sperm quality influences not only rates of fertilization of eggs but also subsequent embryo development. In humans, these paternal effects have been shown to affect rates of embryo cleavage, blastocyst formation and implantation. The markers of sperm quality used to predict pregnancy outcome are not the parameters included in the standard semen analysis (sperm concentration, motility or morphology), but rather the results of the Sperm DNA Integrity assay that measures DNA damage in sperm reported as DNA fragmentation index (DFI) and high DNA staining (HDS).
Y chromosome microdeletion assay -- Microdeletions in the Y chromosome is a genetic condition that results in no or very low sperm counts. Estimates report that one out of five or 20% of men with no or very low sperm counts have one or more microdeletions. It is important to identify individuals who have Y chromosome deletions because these deletions are transmissible by intracytoplasmic sperm injection.

Problems within the uterine environment in that result in failure of implantation of an embryo giving appropriate signals have been classified as anatomic, hormonal and immunologic.
Anatomic abnormalities of the uterus can be diagnosed by:

Hysterosonography (ultrasound evaluation of the uterus after fluid is injected) or
Hysterosalpingography (x-ray with instillation of dye into the uterus and fallopian tubes) or
Hysteroscopy (telescopic evaluation of the uterine cavity)

Hormonal response of the uterus can be diagnosed with the aid of the ultrasound:

Transvaginal ultrasound examination of the lining of the uterus around the time of ovulation
Color Doppler flow studies to evaluate blood flow to the lining of the uterus

Immunologic malfunction can be diagnosed with immunologic testing. Such tests include:

Antiphospholipid Antibody (APA) Panel-Antiphospholipd antibodies have been shown to kill pre-implantation embryos
Antinuclear Antibody (ANA) Panel-Antinuclear antibodies have also been shown to be embryotoxic
Antithyroid Antibody (ATA) Panel-Antithyroid antibodies have no direct effect on pre-implantation embryos, but are a marker of activated T cells in the lining of the uterus
Reproductive Immunophenotype (RIP)-measures circulating levels of NK cells. Elevation of circulating NK cells may be associated with implantation failure
Natural Killer cell Activity (NKa) assay-measures killing activity with NK cells. Elevated NK killing activity (greater than 10%) has been suggested to be associated with implantation failure
NK cell (CD56) numbers in endometrium, during the implantation of the embryo are increased in women who have recurrent implantation failures or miscarriages.
Embryotoxicity Assay (ETA)-measures circulating substances that kill preimplantation embryos
Immunoglobulin (Ig) Panel-Elevated levels of immunoglobulin, particularly immunoglobulin M, have been associated with implantation failure. Also the immunoglobulin panel will detect deficiencies in IgA which can be a contraindication to the use of IVIg if anti IgA antibodies are present.

An unlicensed medicine is one that does not have a product license. For example:

If only a very small number of people would use a medicine, there may be little commercial interest in marketing that medicine in the UK.
You may have agreed to receive an unlicensed medicine as part of a clinical trial.
The medicine may be waiting for approval from the MHRA.
Your doctor may prescribe your medicine in a form that’s not readily available, for example, to be made up as a special preparation by your local pharmacy.

Your doctor may prescribe a liquid medicine that’s only licensed in tablet form.

A good example for an unlicensed product which is widely prescribed is the vaginal progesterone that we regularly use following an IVF cycle. The particular brand of pesseries that is used in most clinics in the UK is not licensed for use in IVF or pregnancy. Although other brands with the same/similar ingredients are licensed.

For more information please check NHS(http://www.nhs.uk/chq/Pages/1004.aspx?CategoryID=73&SubCategoryID=101)

Steroids
Corticosteroids are a type of drug (a synthetic hormone) that can suppress immune responses, and are routinely used in the treatment of arthritis, asthma and other autoimmune disorders.

However, there is no proven advantage in using steroids in the first three months of pregnancy, and the risks to you and your baby outweigh any possible benefits. The National Teratology Information Service recommends that pregnant women avoid all drugs at this stage unless they are likely to benefit your health. The Committee on Safety of Medicines says that corticosteroids taken in pregnancy can carry a small risk of poor fetal growth, though there is little other risk to the fetus.

A clinical trial in Canada tested the effect of giving pregnant women, who had previously suffered two or more unexplained miscarriages, a corticosteroid (prednisolone). The study found that prednisolone did not prevent miscarriage, and increased the risk of high blood pressure, diabetes and premature birth.

Intravenous immunoglobulin (IVIg)
Intravenous immunoglobulin (IVIg) is the only medication that has been shown in randomized placebo controlled trials to be effective in the treatment of implantation failure (Heilmann et al, 2010; Winger et al, 2009). The usual dosage for implantation failure is 40mg prior to embryo transfer and 40mg after the first positive pregnancy test. In some instances it may be necessary to repeat IVIg infusions every three to four weeks until the end of the first trimester of pregnancy.

IVIg is made from antibodies extracted from the blood plasma of many different donors. It is mainly given by intravenous drip as a treatment for immune deficiencies and autoimmune diseases. It carries varied and sometimes unpredictable risks: Side effects can include headache, muscle pain, fever, chills, low back pain, thrombosis (blood clots), kidney failure and anaphylaxis (a bad reaction to the drug), though these effects are generally mild and occur in less than one in 20 patients.

Because immunoglobulins come from donor blood, there is the possibility of introducing blood-borne infections, such as hepatitis, HIV or CJD. IVIg contains antibodies. During pregnancy, antibodies cross the placenta into the bloodstream of the fetus. Therefore, in theory, IVIg antibodies could enter the fetal bloodstream, where they might react against some of the baby´s cells. However, this has not been seen in practice.

A detailed review of the risks associated with IVIg states "the practitioner considering IVIG for an unproven use must seriously weigh the potential benefit versus potential harm because of its varying and sometimes unpredictable immunomodulatory effects".

TNF-a blocking agents
Tumour necrosis factor (TNF) is a chemical produced by immune system cells, such as NK cells, which promotes inflammation and allows the immune system to attack the source of infections. TNF-a blocking agents are drugs used to block the effect of TNF - stopping inflammation but making the attack on infection less effective - and are routinely used in the treatment of arthritis, asthma and other immune disorders. There is evidence to suggest that treatment with TNF-a blocking agents improves pregnancy rates in women undergoing IVF treatment (Clark, 2010; Winger et al, 2009).

Several clinics offer the use of TNF-a blocking agents (Enovel, Remicade and Humira). However, there are risks: The makers of Remicade (infliximab) warn that using it may increase the risk of septicaemia; chronic infections such as tuberculosis; cancer of the lymphatic system; liver problems; white blood cell disorders; and strong reactions to the drug.

The British National Formulary says infliximab should not be used in pregnancy.
Humira (adalimumab) is not licensed for use in implantation failure (when the embryo fails to embed itself in the lining of the womb). Its effects on reproduction and fetal development are unknown.

Intralipids
Evidence from both animal and human studies suggest that intralipid administered intravenously may enhance implantation (Roussev et al, 2008). Intralipid is a 20% intravenous fat emulsion used routinely as a source of fat and calories for patients requiring parental nutrition. It is composed of 10% soybean oil, 1.2% egg yolk phospholipids, 2.25% gylcerine and water. Intralipid stimulated the immune system to remove “danger signals” that can lead to pregnancy loss. The appeal of Intralipid lies in the fact that it is relatively inexpensive and is not a blood product.

Phosphodiesterase Inhibitors
The phosphodiesterases are responsible for enzymatic degradation of molecules within the cells involved in generating energy for the cell to function. They have anti-inflammatory effects. Two phosphodiesterase inhibitors—Sildenfil (Viagra) and Pentoxiphylline (Trental) have been shown to increase blood flow to the uterus. Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. Significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who had previously experienced repeated IVF failures and who responded to the Viagra. Similar results were obtained when Trental was used in 400mg twice a day doses alone with vitamin E to treat women experiencing implantation failure associated with thin endometrium and elevated uterine NK cells. Efficacy of pentoxifylline for treatment of recurrent pregnancy loss in human beings remains to be established.

You can read more in the following sources:

1) For a review of the latest research please refer to the latest Cochrane Collaboration review of this field (Porter et al, 2006)

The Cochrane Collaboration is a group of over 11,500 volunteers in more than 90 countries who apply a rigorous, systematic process to review the effects of interventions tested in biomedical randomised controlled trials. Cochrane reviews are considered to be a reliable source of evidence in healthcare.

This review of immunotherapy for recurrent miscarriage concluded that:
"Neither immunization with paternal leukocytes nor treatment with intravenous immune globulin (IVIG) improve the live birth rate in women with unexplained recurrent miscarriage. Both are expensive and have potential serious side-effects. Moreover, women should be spared the pain and grief associated with false expectations that an ineffective treatment might work. These therapies should no longer be offered as treatment for unexplained recurrent pregnancy loss. Furthermore, immunological laboratory tests which have been previously advocated as justification for immunotherapies have no predictive value for pregnancy success and should be abandoned."

2) The Royal College of Obstetricians and Gynaecologists (RCOG) Scientific Advisory Committee have published an opinion paper (2008). The opinion papers states that “measurement of peripheral blood NK (PBNK) cell numbers or activity as a surrogate marker of events at the maternal-fetal interface is inappropriate…. A recent large UK study reported PBNK cell levels in predicting IVF cycle outcome to be ‘little better than tossing a coin’.” It concludes that “With the exception of aPL [anti-phospholipid antibodies] testing among women with recurrent miscarriage, there is little evidence to support any particular test or immunomodulatory treatment in the investigation and treatment of couples with reproductive failure. These tests and treatments should be restricted to those entered into formal research studies.”

3) The British Fertility Society (BFS) have published a review of evidence for use of medical adjuncts (supplementary procedures) in IVF, which covers a range of immunological tests and treatments (Nardo et al., 2009)

4) Two papers reviewing the science of NK cells in pregnancy are freely available (Moffett et al, 2004; Rai et al., 2005)

New studies and views in this field are continually being published. The Cochrane Collaboration review and the RCOG opinion paper and the BFS review do not take into account studies that have gone to press since they were written.

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