Recurrent Unexplained Failure of IVF

Unexplained failure is regarded as an IVF cycle that does not result in implantation despite successful egg retrieval and fertilization. The embryos appear to be of good quality and appropriate state. Recurrent failure is failure of 2-6 cycles.

HFEA data suggests that the 2 most important factors for IVF success are firstly female age and secondly the number of attempts. Pregnancy rates go down slightly by the 5th attempt.

There are likely to be a number of possible causes

Embryo effects

Chromosomal abnormality

The most common cause of failure is chromosomal abnormality. Mostly this is caused by either egg or sperm inherent abnormality. It is known that up to 25% of oocytes are not normal rising to 40% in the over 40 year old women.

Rarely (approx. 2.5%) women have abnormalities in their genetics such as balanced translocations so it would be worth testing for this if there are 3 or more failures.

It appears that increased DNA damage in sperm may also be relevant in cases where patients’ chromosomes are normal. This is still subject to further research.

It was hoped that embryo biopsy would identify normal and abnormal embryos. Most recent data has failed to show improvement in pregnancy rates from prenatal genetic screening (PGS) although it may identify a number of people where many or all embryos are genetically not normal. These people would have a lower chance of pregnancy than expected.

Suboptimal development

Embryo culture and selection is improving all the time but is still trying to mimic the intrauterine environment

Zona Hardening

The zona naturally hardens after fertilisation. This prevents further entrance of sperm which is appropriate. The hardening may affect the chance of the developed embryo (blastocyst) from expanding and hatching prior to implantation. Assisted hatching may help this situation. A small incision is made in the zona weakening it and therefore assisting the hatching process. It is unclear as to the clinical outcomes however and is not recommended before a diagnosis of recurrent implantation failure is reached.

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Uterine effects

Embryo transfer

Suboptimal transfer technique may affect implantation. Traumatic transfer, causing the uterine cavity to bleed and blind transfer may all adversely affect the uterine cavity. Most research suggests a mid-cavity transfer is the most successful technique. Transfer under ultrasound control can also be carried out when there is doubt. It visualises the position but adds time especially if the only purpose is to demonstrate the position to the patient. It may also traumatise the endometrium if the catheter has to be ‘waggled’ to demonstrate its position.

Uterine cavity

The presence of adhesions or polyps adversely affects transfer. Inflammation in the cavity (endometritis) also may have a negative effect. We would recommend a hysteroscopy prior to a third transfer in the event of 2 unsuccessful transfers.

Endometrial Scratch

There is some evidence that traumatising the endometrium deliberately in the cycle immediately before IVF/ICSI increases implantation. The mechanism is that it is thought to stimulate endometrial growth in the treatment cycle or it may provoke a helpful pro-inflammatory response. This can be done either at hysteroscopy or using an endometrial sampler (pipelle) in the outpatient department. It is not known how long the effect is supposed to last.

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Patient effects

Systemic illness will reduce implantation. If you have a temperature when you have a transfer your core temperature will be even higher. In this case it would be best to freeze embryos and replace them later

Obesity

Reduces the chance of implantation. It is probably due to an effect on the endometrium as there is no increase in chromosomally abnormal embryos (in fact there are slightly more normal ones).

Smoking

Reduces the chance of implantation. The cause is probably egg and/or sperm damage caused by heavy metals such as cadmium, or hydrocarbons. In the female, the effect is immediate so stopping smoking shortly before trying to conceive will improve things. In the male it may take 72 days for an improvement to happen.

Immunological issues

This is a highly controversial area. Studies show conflicting results about the effect of abnormal results and also about the results of treatments. The commonest tests are for both hereditary and acquired thrombophilia. Antiphospholipid syndrome is the commonest acquired condition. It is higher in infertility patients but the effect on fertility outcome is disputed. Currently both the British fertility society, the European society and the American society are of the opinion that Anti-phospholipid antibodies (APA) do not affect IVF success. The effect of factor V Leiden and other hereditary conditions is likewise controversial.

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Investigation of recurrent unexplained failure of IVF

1. Antiphospholipid antibodies are not associated with a reduction of pregnancy rates in IVF, and testing is not helpful.
2. Ovarian antibodies are associated with ovarian failure and unexplained infertility only.
3. Thyroid and antinuclear antibodies do not appear to influence IVF outcome.
4. Data on antisperm antibodies is contradictory on both their prediction of natural conception and the outcome of IVF. Recent prospective data suggests that their presence does not influence the outcome following IVF.
5. There is no peer-reviewed data to suggest that assessment of TH1 and 2 or peripheral blood NK cells is helpful in predicting outcome of IVF.
6. Data on the association of HLA sharing in IVF failure is conflicting and the association remains to be confirmed.
7. High uterine NK cells may be associated. Unlike peripheral blood NK cells there is a plausible biological role.
8. Timing of transfer-gene expression may be delayed suggesting delaying or accelerating transfer may help. At present there appears to be too much variation in the results (ie different menstrual cycles in the same person give differing results) for this to be a truly useful tool yet.

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Treatment of recurrent unexplained failure in IVF

1. There have been no peer-reviewed studies showing a benefit for LIT in this group.
2. Uncontrolled studies have reported some benefit using IVIG therapy in this group with increased NK cell activity. A randomised controlled trial showed no benefit with IVIG.
3. There is no evidence to support the use of steroids in this group. Steroids can have significant side effects associated with diabetes, high blood pressure in pregnancy and premature delivery.
4. The place for aspirin is controversial. Two randomised controlled trials have shown conflicting results; one showing improved results and the other showing no difference.
5. There is no peer reviewed research showing benefit for anti-TNF drugs in this group.
6. While the hypothesis of a relationship between immune disorders and failed implantation is attractive, with the exception of antiphospholipid syndrome in recurrent miscarriage there is a paucity of good data to support it. Practitioners should therefore be cautious when recommending such interventions outside ethically approved research studies or until peer-reviewed research provides support for their use.

This information may help in deciding whether you have a reduced chance or not and therefore whether you plan to continue with treatment, but will not improve your chance of pregnancy.

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