Rehan Salim MD MRCOG
Consultant Gynaecologist & Subspecialist in Reproductive Medicine
Wolfson Fertility Centre - Hammersmith Hospital
What is Recurrent Pregnancy Loss?
In a situation where there have been three or more failed pregnancies before the fetus reaches viability, i.e. 24 weeks, it is called recurrent pregnancy loss.
In cases when the cause of miscarriages is unknown, each pregnancy loss merits careful review to determine whether specific evaluation is appropriate or not. After three or more losses, a thorough evaluation is warranted. There are different causes for recurrent miscarriage, unfortunately very often no cause can be diagnosed. However, several tests can be conducted to identify a possible cause of recurrent miscarriage.
How common is Recurrent Pregnancy Loss?
It is estimated that approximately 25% of all recognised pregnancies result in miscarriage. Out of this less than 5% of women are at risk of having two consecutive miscarriages, and only 1% would experience three or more.
What are the causes of Recurrent Pregnancy Loss (RPL)?
The most common cause of pregnancy loss is genetic abnormalities in the fetus. Additional issues that me be causative include uterine problems, immunologic factors, hormonal disorders (such as thyroid dysfunction and diabetes mellitus).
Lifestyle factors such as smoking, excessive alcohol consumption, caffeine consumption, exposure to toxic products and obesity may also contribute to recurrent pregnancy loss. Unfortunately, at least in 50% of the cases, a specific cause cannot be found, and the RPL remains unexplained.
Uterine factors can predispose a woman to recurrent pregnancy loss, and it might be found in approximately 10% to 15% of the affected patients. Those are e.g. congenital uterine anomalies, such as a uterine septum, submucosal fibroids (fibroids which indent into the uterine cavity), polyps and Asherman’s syndrome (scar tissue in the uterine cavity). Diagnostic screening tests include hysterosalpingogram, sonohysterography, ultrasound or hysteroscopy. Surgery maycorrect some of these conditions and hence reduce risk of further miscarriages.
Genetic Factors (Aneuploidy)
One of the most common causes of miscarriage is a genetic problem of the embryo, and many early miscarriages are due to the random (by chance) occurrence of a chromosomal abnormality in the embryo. In fact, 70% or more of early miscarriages may be caused by a random chromosomal abnormality, usually a missing or duplicated chromosome. Often the patients are not aware of an early pregnancy since the pregnancy loss occurred very early.
A normal egg and sperm have 23 chromosomes each. After fertilisation the resulting embryo will have the normal total of 46 chromosomes. But sometimes the egg or the sperm doesn´t contain the correct number of chromosomes, or during the process of fertilisation the genetic material is not transferred correctly.
In certain cases (less than 5% of couples) a chromosome analysis test is done on a blood sample taken from the parents, This can help identify if there is an inherited genetic cause.
Translocation i.e.: the most common inherited chromosome abnormality, is when part of one chromosome attaches to another chromosome. The risk is that a healthy parent with a translocation passes the additional genetic information to the offspring. This will result in an affected baby because this will have an inadequate amount of genetic material.
Although, there may be a case that a healthy parent carries a translocation, their embryo receives inadequate genetic material.
This is one of the many reasons why a miscarriage usually happens. Pre-implantation genetic diagnosis along with in vitro fertilisation is an approach that may benefit couples with translocations or other specific chromosome defects.
Patient with thyroid dysfunctions and uncontrolled diabetes mellitus are also at risk for RPL. Moreover, due to changes in the endocrine profile including hyperinsulinemia and overexpression of androgen, also PCOS patients have a higher risk of pregnancy loss.
A condition with abnormal tendency to develop blood clots, and this might have a role in recurrent miscarriage. The most frequent problem is the factor V Leiden and prothrombin G20210A mutation. It should be mentioned that only 15 percent of patient with recurrent abortion are diagnosed with thrombophilia.
Hence, it does not make any sense to treat all patients with recurrent abortion, without the diagnosis of thrombophilia with anticoagulants like aspirin or low weight molecular heparin. Furthermore, the administration of anticoagulants in a patient with recurrent abortion needs to be validated in properly conducted clinical studies.
Antiphospholipid syndrome is responsible for 3% to 15% of recurrent miscarriages. Blood tests for anticardiolipin antibodies and lupus anticoagulant are done, in women who have this syndrome. A second blood test will be performed at least six weeks later, which will confirm the diagnosis. Use of heparin and aspirin is known to improve pregnancy outcomes in women who have high levels of antiphospholipid antibodies.
This is a controversial area. There is a theory that the mothers immune system is able to recognise an embryo as genetically foreign and attack it causing both infertility and miscarriage. The evidence so far is mixed with some studies showing that this is the case and others showing that it is not. The tests for immune factors essentially look at some of the cells involved in this process and some of the chemical that these cells produce. The results are then interpreted to allude that there is or is not an immune issue. Treatment remains varied from Intralipid infusions to more potent immunosuppressive drugs.
A detailed discussion around the evidence for this is absolutely necessary before embarking on these tests and/or treatment.
Defective Luteal Phase
To achieve and maintain a healthy pregnancy, progesterone, a hormone produced by the ovary after ovulation, is necessary. But whether or not low progesterone levels, often called luteal phase deficiency, cause repeated miscarriages, is unclear. Although the effectiveness of treatments in such cases is not clear, they include ovulation induction, progesterone supplementation or injections of human chorionic gonadotropin (hCG).
Some types of infections (Ureaplasma urealyticum, Mycoplasma hominus, Chlamydia, Listeria monocytogenes, Toxoplasma gondii, Rubella, Cytomegalovirus, Herpes virus) have been identified more frequently in vaginal and cervical cultures, and serum from women with sporadic miscarriages. But there is no convincing data, which says infections cause recurrent pregnancy loss. Therefore, there are no clear indications for routinely testing for these organisms, and also any use of antibiotics.
How is Recurrent Pregnancy Loss evaluated?
Women with recurrent pregnancy loss are evaluated initially with a thorough history and physical examination. Followed by a series of diagnostic tests, which includes blood work on both partners, an evaluation of the uterus, to look for anomalies or acquired factors such as fibroids, and scar tissue or polyps/ adhesions that may compromise embryo implantation for a if future possible pregnancy. Couples may also be offered genetic testing, to determine genetic diseases that could impair their reproductive success.
It has to be noted, that in approximately 50% to 75% of couples with recurrent pregnancy losses no explanation or cause is found. We have the ability to perform a genetic compatibility testing on the couple, to evaluate and predict possible genetic malformation in the embryo.
How is Recurrent Pregnancy Loss treated?
Up to 70 percent of patients being diagnosed with RPL can able to achieve a normal pregnancy without any treatment. The rest of the patients who are diagnosed with an abnormal finding will be treated according to their diagnosis. Empiric treatment of recurrent pregnancy loss with aspirin, (low molecular) heparin, gamma globulins, etc. is not recommended, and it is currently against evidence-based medicine.
However, there are lifestyle factors that may be contributing to a poor reproductive outcome, such as smoking and obesity, which are discussed.