Causes of Miscarriage
Genetic
The majority of sporadic spontaneous miscarriages in the general population are due to genetic abnormalities of the conceptus. These are due in part to chromosomal abnormalities of the egg or sperm. Since it is now well established that a woman’s eggs deteriorate with age, it is not surprising then to see increased rates of miscarriages in older women. The etiology of this phenomenon is directly linked to the chromosomal deterioration of eggs with time. Normal fertilization and early embryo development in the humans can occur despite the presence of genetic abnormalities. Studies of 3 day old human embryos have shown chromosomal abnormalities in 20-60% of perfectly normal embryos. More than likely, most of these chromosomally abnormal embryos would arrest in early development and subsequently miscarry. Actually, in clinically recognized first-trimester miscarriages where fetal material is available, about 50-60% have chromosomal abnormalities. It is thought that certain couples are predisposed to such abnormal conceptions.
The evaluation of couples with recurrent miscarriages by Karyotype or chromosomal analysis, has demonstrated a small proportion (2-6%) have indeed abnormal chromosomal rearrangements. The most common is called "balanced translocation".
Factor V Leiden mutation is an inherited thrombophyllia which can lead to increased risk of blood clots and miscarriage. Patients can have one copy of the gene (heterozygous) or two copies(homozygous). Both forms can lead to miscarriages but the homozygous variant is worse. Patients who are diagnosed with this mutation should be on heparin during pregnancy.
PT G20210 mutation is another mutation that can contribute to an increased risk of miscarriage, especially if a homozygous form (2 copies of the gene) exists. The use of heparin for this mutation is controversial.
MTHFR mutation has not been definitely linked to an increased risk of miscarriage but in conjunction with other mutations, it may be contribute slightly to the risk of miscarriages. Patients who are homozygous for this mutation should take extra folic acid.
Anatomical
Several uterine abnormalities have been associated with recurrent miscarriages. Approximately 15% of patients have a uterine abnormality accounting for their fetal losses. Losses from anatomical causes are most commonly occurring in the second trimester.
These abnormalities could be secondary to congenital defects, i.e. the patient was born with the abnormality or acquired, i.e. develop it later in life such as fibroids.
Women can be born with an abnormal uterus with an abnormal shape. Examples of these abnormalities include unicornuate, didelphic or bicornuate uteri.
The normal uterus is a pear shaped organ with a triangular cavity. Some patients have a uterus with a smaller abnormal cavity or two adjacent attached cavities. Some can have a membrane sticking into the cavity from the top, called a septum which can interfere with conception or the normal maintenance of a pregnancy.
The mechanism in these cases is probably related to an insufficient blood supply to the septum resulting in inadequate nutritional support of the fetus that implants on the septum, or possibly to a mechanical pressure effect.
Uterine fibroids are benign tumors of the uterine musculature that forms its body and are more frequently found in Blacks than Caucasians.
Up to 20% of patients with recurrent miscarriages due to uterine anomalies have fibroids. Fibroids usually do not cause infertility or miscarriages unless they are located inside the uterine cavity or in very close proximity to the endometrial lining. Alterations in the blood supply of the lining are though to be the cause of the abnormal implantation. The presence of what we call "submucosal" fibroids may also cause distortion of the uterine cavity with damage to the overlying lining or endometrium and mechanical interference of fetal and placental growth resulting in recurrent miscarriages. An analogy that one could make is the following: The endometrium is like the soil and the embryo is like a plant seed. In order for the seed to grow, a good soil is needed. Rocks in the soil (or fibroids) can interfere with the normal growth of a plant or embryo.
Intrauterine adhesions or scarring are bands of fibrotic connective tissue which can partially or completely obliterate the uterine cavity. These scars can occur following surgical procedures such as a dilatation & curettage done for incomplete miscarriages, for abortions or abnormal bleeding.
These adhesions can be detected by an x-ray test called HSG or Hysterosalpingogram, whereby a dye is injected through the cervix and it flows through the uterine cavity and tubes followed with x-rays. Intrauterine scarring may cause miscarriages due to lack of sufficient endometrium or lining for implantation, poor blood supply or mechanical restriction of the uterine cavity expansion during pregnancy. Symptoms associated with these adhesions depend on the extent and location of the scarring. In extreme cases, called Asherman’s Syndrome, the whole cavity is taken over and the patient will usually have very scant periods or total absence of menses.
Another common abnormality is the presence of uterine polyps which are benign growths (like skin tags) of the lining of the uterus.
Polyps usually present as abnormal bleeding or spotting and are usually easily treated by removal in the office.
Endocrine
Endocrine or hormonal causes have also been implicated as causes of recurrent miscarriages, such as Luteal-Phase Deficiency, Hypothyroidism and Diabetes mellitus.
Luteal-Phase Deficiency
Progesterone production by the ovary is essential for the maintenance of early pregnancy up to 6-7 weeks’ gestation. After this time, the placenta makes sufficient Progesterone to maintain the pregnancy. It has been demonstrated that in a small subset of patients, the inadequate production of this hormone results in infertility or recurrent losses. The second half of the menstrual cycle starting from ovulation and until the initiation of the menses, is called the Luteal phase. Progesterone deficiency can result in an abnormally shortened luteal phase and thus could lead to infertility or miscarriages. The diagnosis is usually made in women a luteal phase of less than 11 days and an abnormal endometrial biopsy result. If indeed the diagnosis is made, Progesterone supplementation should theoretically treat this condition successfully.
Other Hormonal Causes
Both hypothyroidism and diabetes mellitus have been associated with early pregnancy loss.
In diabetes, it is thought the elevated blood sugar level is directly responsible for the miscarriage while with hypothyroidism, the cause is still not entirely clear. Regardless, every patient suffering from recurrent miscarriage should be checked for a history of these illnesses.
Thrombophylias
Antipholspholipid syndrome is a condition that can lead to miscarriages and increased risk of blood clots. The diagnosis is made when patients have elevated levels of anticardiolipin antibodies or test positive for Lupus Anticoagulant. For a proper diagnosis the test should be positive twice, 6 weeks apart. Patients who have this disease should receive heparin during pregnancy.
Protein C, Protein S and Antithrombin III deficiency can also be associated with an increased risk of blood clots and miscarriages. Patients who are diagnosed with these should see a hematologist and may need heparin in pregnancy. These tests should be checked 6 weeks after a pregnancy for accurate results since pregnancy can interfere with results.
Immunologic
Despite the fact that the fetus is a "foreign body", its rejection does not normally occur. The mechanism of this protection is thought to be secondary to protective maternal serum blocking antibodies or the local secretion of protective (immunosuppressive) chemicals. These antibodies are thought to bind to the implanting and growing fetus and mask it from an immune response. Couples who share genetic markers are more prone to recurrent miscarriages because of the lack of these protective antibodies. This concept is very controversial however and its treatment is considered experimental and speculative at best.
The presence of maternal autoimmune disease or antibodies has also been implicated as case of recurrent miscarriages. Some of these illnesses include lupus, thyroid disease, diabetes and other common immunologic diseases. It is thought that the problem arises from the presence of a hypercoagulable state, i.e. "thickening of the blood" which results in blood clots in the placenta which eventually prevents the normal blood flow through the placenta and to the fetus.
Infectious
A variety of infectious organisms have been implicated in miscarriages. It is unusual however for a patient to have different such infections in subsequent pregnancies. Some of these organisms include Ureoplasma, Toxoplasma, Chlamydia and Herpes. The precise role of these infections is not well established but testing for some of these is warranted in some cases.
Unexplained
If after extensive evaluation the cause of the recurrent miscarriages is not elucidated, then the term "Unexplained" is used. unfortunately, 50% of patients will end up in this category of patients. Typically, it is recommended that these couples continue trying or to resort to IVF with Preimplantation genetic diagnosis or surrogacy as the ultimate treatment.
