Immunology in Infertility

Despite very effective treatment options, not every fertility treatment is successful. It happens that women become pregnant, but repeatedly suffer miscarriages. The causes of so-called recurrent pregnancy loss (also called recurrent miscarriage or habitual abortion), which usually occur in the early stage of pregnancy, are complex. In about half the cases, it is not possible to give a clear reason for the habitual abortions. If genetic disorders, infections and tumours can be excluded as the cause, there is the possibility that infertility is caused by immunological problem.

Pregnancy is a unique situation in which the placenta (recognizable as ‘non-self’, or separate from the mother) invades the lining of the womb and is a potential threat to the well-being of the mother. The mother’s immune system must recognize that threat, but also respond in such a way that does not eliminate it. The mother’s immune system is critical in establishing the relationship between the mother and the fetus that allows both to flourish.

Your immune system is responsible for fighting harmful microorganisms through the production of antibodies that recognize and attack foreign cells, such as bacteria and viruses.

The immune system has two main mechanisms: cellular (type 1) and antibody (type 2).

In normal pregnancy, substances produced by the placenta (particularly progesterone) cause a shift in how the mother’s immune system behaves, so that it becomes ‘type 2 dominant’. This is because type 1 responses are potentially more dangerous for the pregnancy. This shift means that some autoimmune diseases that are predominantly cellular, such as rheumatoid arthritis, tend to get better during pregnancy. But it also means that antibody autoimmune diseases such as Lupus (SLE) can get worse, and specific antibodies can have their own harmful effects too – on both the placenta and the foetus.

Anti Sperm Antibodies (ASA):

Women with immune infertility produce antisperm antibodies, ASA, in their reproductive tracts. These antibodies neutralize sperm by clumping them together and poking holes in their membranes. ASA also coats over receptors involved in sperm-egg binding and fertilization.

In men, immune infertility has several causes, including vasectomies. After a vasectomy, the body can no longer release sperm and produces antibodies to help engulf and clear them. ASA persists for years in the circulation of vasectomized men and may cause reduced fertility in those who have the procedure reversed (vasovasostomy).

There is no clearly defined treatment for immunological infertility. Historically, the best results seem to follow a trial of ovulation induction and insemination followed by in vitro fertilization with sperm washing and intra-cytoplasmic sperm injection, ICSI (a process that involves injecting a sperm directly into an egg).
Attempts to prevent the exposure of the female genital tract to spermatozoa for a period of some months by the use of condoms has been used in the hope that the immune response will diminish and then exposure will lead to fertilization before an immune response occurs. Of course, this treatment will frustrate many who are anxious to conceive as soon as possible. Immunosuppressive therapy with corticosteroids has been reported anecdotally with some success. Undoubtedly, the most successful treatments are intrauterine insemination or IVF.

Antiphospholipid syndrome (APS):

In the antiphospholipid syndrome (APS), women have antiphospholipid antibodies measured as either ‘anticardiolipin antibodies’ or a ‘lupus anticoagulant’. If these antibodies occur in women with reproductive failure and no other clinical problems then this is termed the primary APS, and if there are other autoimmune diseases (e.g. systemic lupus erythematosus (SLE) or Sjogren’s syndrome) it is called the secondary APS.

Antiphospholipid antibodies are reliable predictors of adverse outcome in pregnancy and are associated with early and late fetal loss, pregnancy-induced hypertension, intrauterine growth retardation, prematurity, and both venous and arterial thrombosis occurring during pregnancy. It must, however, be firmly emphasized that these associations are not observed in every woman, nor in every pregnancy.

Some women with phospholipid antibodies will deliver successfully. However, treatment with aspirin 75 mg and Enoxaparin  20-40mg a day has proved safe and effective in women with recurrent pregnancy loss. It is unknown if such treatment improves implantation in IVF, although women with APS undergoing IVF should still be treated to reduce the risk of miscarriage. It is also not known whether or not this therapy reduces the risk of pre-eclampsia or intrauterine growth retardation.

Antibodies affecting fetus:

Another way in which autoimmunity can affect the fetus is by passive transfer of an antibody that has pathogenic effects. Examples include neonatal thyrotoxicosis, neonatal lupus, and neonatal myasthenia gravis. All improve as the level of maternal antibody declines. Women with SLE need screening for particular antibodies which can cause fetal heart block and heart failure.

The indications for testing are:

  • Two miscarriages or two IVF or GIFT failures after age 35 or three miscarriages or IVF or GIFT failure before age 35
  • Poor egg production from a stimulated cycle (less than 6 eggs)
  • One blighted ovum
  • Unexplained infertility
  • Previous immune problems (ANA positive, rheumatoid arthritis, and/or lupus)
  • Previous pregnancies that have shown retarded fetal growth
  • One living child and repeated miscarriages while attempting to have a second child

Treatment of Immunological causes of Infertility:

In pregnancy the options include:

  • progesterone
  • Enoxaparin
  • prednisolone
  • Intravenous immunoglobulin (IVIG)

Prednisolone is a corticosteroid and anti-inflammatory that is normally taken prior to conception and is used to treat women who have antinuclear antibodies.

Immunoglobulin G infusion (IVIG) is a preparation of human antibodies injected intravenously. It works in the same way as the antibodies that a healthy body produces naturally. They are administered to support and/or regulate the immune system, as is done with auto-immune diseases.

Enoxaparin is an anti-coagulant used to prevent miscarriage due to anti-phospholipid antbodies.

Low-dose aspirin is an anti-inflammatory used to suppress the innate immune response to the presence of a foreign body such as sperm or an embryo. It is also an anti-platelet agent useful for anti-phospholipid antibodies.


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