Is Recurrent Miscarriage a Form of Infertility?

For anyone who has experienced more than one miscarriage, the headline is striking: “Gene Linked to Repeat Miscarriages.” While the researchers themselves caution that their results are not enough to warrant special related treatment, the report offers another piece to the puzzle of recurrent miscarriage.

Losing a pregnancy, no matter how early, is difficult emotionally. For those who have struggled to conceive in the first place, it can be devastating.

Depending on who you talk to, “recurrent miscarriage” refers to the loss of more than one, two, or three pregnancies. It is also referred to with the terms:

  • Recurrent spontaneous abortion, or RSA
  • Habitual spontaneous abortion or loss
  • Repeat miscarriage

So, when headlines are made by researchers disclosing their latest findings, some infertility patients take notes.

Bearing in mind that nearly half of all miscarriages occur as the result of unknown or undetermined causes, what are the known causes of losing any given pregnancy?

Structural

The good news is that most structurally related miscarriages can be prevented with treatment of the underlying problem. Unfortunately, many women are unaware of the existence of these loss precursors:

  • Uterine fibroids
  • Congenital uterine malformations, such as septate or bicornuate uterus
  • Some other uterine conditions
  • Incompetent cervix, most notably in second trimester or later losses
  • Endometriosis

If you have any reason to suspect any of the above situations, ask your doctor before you conceive whether or not further exploration is warranted.

Hormonal

While hormonal dysfunction may cause miscarriage less frequently than genetic/chromosomal conditions (see below) in the general population, it may be of greater significance in those seeking fertility treatment.

Frequently, women who have hormonal imbalances which cause conception difficulty will also experience early miscarriage as a result of those same imbalances. Again, these situations are largely correctable, but often go undetected until loss has occurred:

  • Luteal phase defect, in which the body’s two primary reproductive cycles, the ovulatory and the menstrual, are not in-sync, thereby producing a situation in which the uterus is not ready to receive a fertilized egg
  • Untreated thyroid disease, most notably hypothyroidism
  • Poorly controlled diabetes, particularly in the first trimester

If you’re not sure about your own hormonal status yet, think about your family’s. Many endocrine conditions are inherited, and many occur without symptoms at first. An endocrinologist is the best specialist to help you detect a problem in this area.

Genetic/Chromosomal

Perhaps by far the most common cause of early miscarriage, there is still a lot of mystery surrounding chromosomal issues–but not for long. With completion of the Human Genome Project, scientists are able to learn more than ever before about our genetic makeup and effects on our lives.

It is believed that more than 60 percent of all first trimester losses are the result of abnormal chromosome structure (structural anomalies) or number (aneuploidies).

The mystery involves genetic testing (sometimes referred to as chromosomal testing or karyotyping) and whether or not it is performed. Unless testing on the actual embryo or fetus is done, it is impossible to determine that a loss was chromosomal related. Testing of the parents can help lead a couple in the direction of knowing, by shedding light on whether either or both of them have any chromosomal conditions that would create a non-viable conceptus.

In determining the need for genetic testing, a degree of risk (for example, high or low risk) will be assessed. The following should be considered:

  • Number and circumstances of previous miscarriages
  • Previously-born children with known congenital malformations or conditions
  • Extended family background and inheritable disorders
  • Maternal age
  • Other tests, such as ultrasound, indicating need for further investigation (for prenatal testing)
  • Maternal health or illness (for prenatal testing)
  • Known exposure to a teratogenic substance (for prenatal testing)
  • Risks and benefits for the patient of testing

Why isn’t genetic testing offered across the board, to every couple who is seeking infertility treatment? For several reasons, perhaps the most important being that all tests have a certain amount of inaccuracy and false results due to human error. So the risks and benefits of testing must be carefully weighed for each situation. Also, it simply would not be cost-effective to test the vast majority of individuals whose results will be normal.

That said, it should be possible for anyone to request genetic testing, regardless of known risks, if the patient is willing and able to pay for the tests and related counseling. Because of the enormous complexity of genetic testing and its results, counseling should always be a part of the process.

Environmental

As with any living being, embryos and fetuses are directly and indirectly impacted by what is around them. Environmental causes of repeat miscarriage may include:

  • Teratogens, such as certain chemicals or drugs
  • Maternal intake of substances that may lead to poor health, such as alcohol or tobacco
  • Maternal malnutrition

Because of the female body’s incredible ability to protect unborn children from environmental circumstances, they are not often the cause of miscarriage. Environment is certainly not often a cause of recurrent miscarriage, since that would require the mother be repeatedly impacted by the offending factors in more than one pregnancy.

Still, in cases of repeated miscarriage where no other cause is being found, environmental possibilities should be explored.

Immunological

Another common cause of recurrent miscarriage, immunological loss refers to problems that the mother’s body has with allowing a pregnancy to thrive. The embryos may be perfectly healthy and growing normally, but the mother may have a blood protein or platelet coagulation defect that causes either

  • vascular thrombosis (blood clotting), or
  • a hemorrhagic (bleeding) tendency.

In the case of hemorrhagic tendency, there is inadequate fibrin (a protein which acts as a clotting agent) formed which leads to improper implantation of a fertilized egg. The following uncommon defects may lead to inappropriate hemorrhage:

  • factors XIII, X, VII, V, and II (prothrombin) deficiencies
  • fibrinogen defects including afibrinogenemia
  • those dysfibrinogenemias associated with hemorrhage

Of the two types of coagulation defects, hemorrhagic tendencies are less common.

In the case of thrombosis, this clotting then essentially cuts off or severely diminishes the supply of oxygen and nutrients between mother and baby after implantation. Maternal defects associated with this type of inappropriate clotting are:

  • lupus anticoagulants and anticardiolipin antibodies (often referred to as antiphospholipid syndromes or APA)
  • factor XII deficiency
  • dysfibrinogenemias associated with thrombosis
  • protein C deficiency
  • antithrombin deficiency
  • heparin cofactor II deficiency
  • fibrinolytic defects (plasminogen deficiency, tissue plasminogen activator deficiency, and elevated plasminogen activator inhibitor type 1)

Thrombotic-related loss usually occurs in first trimesters, but may also happen later in pregnancy.

Dr. Alan Beer, a pioneer in reproductive immunology, recommends inquiring about testing for immunological loss issues in the following cases:

  • two or more miscarriages or IVF failures
  • low ovulatory response to drug stimulation
  • a blighted ovum pregnancy
  • unexplained infertility
  • previous known immunity issues, such as rheumatoid arthritis or lupus
  • previous pregnancies in which fetal growth was inhibited
  • secondary infertility with repeat miscarriage as the primary issue

Some testing (DQ Alpha, specifically) in the realm of reproductive immunology is DNA-related (see “Genetics/Chromosomal” issues above.) In short, if a woman and man are too closely related in genetic terms, the woman’s body will likely treat a resulting embryo as a foreign invader and reject the pregnancy. In some cases, a normal first pregnancy may result, but with the interesting feature of creating a maternal cellular response that is negative to subsequent pregnancies.

Antibody issues involve the response of a woman’s body to any pregnancy and testing should include:

  • Natural killer cells (NK cells)
  • Antinuclear antibody (ANA)
  • Anti-DNA/Histone antibodies
  • Antiphospholipid antibodies (APA)
  • TJ6 protein
  • Lupus anticoagulant antibody
  • Hormone antibody assay
  • APTT (a blood clotting test)
  • Antithyroid antibodies

It should be stated that diagnosis and treatment of immunological causes is relatively new. Some physicians are skeptical about requiring of patients the amount of testing involved in reproductive immunology, and some plainly disagree with theories on its incidence and treatment. Consumers would be wise to just be aware of this common skepticism when they ask their own providers about immunological causes of recurrent miscarriage.

Headlines

As referenced earlier, news headlines about causes of recurrent miscarriage are attention-getting among those who struggle with the ongoing devastation and future fears. One of the most recent findings by Austrian researchers has linked a gene variation to repeat loss.

Specifically, they saw more losses in women with two copies of a particular variation (allele 2) of a gene that is involved in creating a cytokine. Cytokines work to regulate a body’s inflammation response, and earlier research has linked high cytokine levels to women with more than one miscarriage.

In effect, this finding at a genetic level is a step toward greater understanding of the immunological causes of miscarriage.

For the vast number of individuals and couples who are experiencing recurrent loss without explanation, there is hope through advancing science. It would bode them well to try and stay on top of published research. It is also crucial to work with a medical team that is as interested as you are in finding the causes of your previous losses, in order to hopefully treat and prevent any more in the future.