Diagnosis and treatment of recurrent miscarriage

Recurrent miscarriage is defined as two or more consecutive miscarriages before the 20 week of pregnancy. Sporadic miscarriages can occur in 10-15% of all pregnancies in the first or second trimester and typically before the 12 week of pregnancy.

The risks of having subsequent miscarriages increases as follows:
24% after two miscarriages
30% after three miscarriages
40% after four consecutive miscarriages
The causes of miscarriages can be divided into six categories:

Genetic
In approximately 2-4% of couples with recurrent miscarriages, one partner will have a genetically balanced chromosomal abnormality. Balanced translocations account for the majority of chromosomal abnormalities. A blood test of both the husband and wife can detect these abnormalities.

Approximately 60% of miscarriages are due to chromosomal abnormalities in the fetus. The most common cause is an aneuploidy which is an abnormal number of chromosomes. Chromosomes can also be broken or have other abnormalities. A chromosomal analysis from the conceptus is obtained during a dilitation and curettage to rule out abnormalities in the fetus. PGD can often be used to rule out chromosomal abnormalities.

Hormonal and Metabolic Disorders
Luteal phase defect (LPD) - Occurs when the corpus luteum (The site of egg release) fails to produce sufficient progesterone to establish a mature endometrial lining suitable for proper placental attachment. This can be treated by progesterone supplementation post ovulation.

Polycystic Ovarian Syndrome (PCOS) :
Studies have shown that as much as 36-56% of women with recurrent miscarriages have PCOS. Women with PCOS who miscarry may have higher levels of androgens and a significant insulin resistance. The risk of miscarriages can be reduced with insulin lowering agents like metformin. Preconception management with lowering of insulin as well as androgens appears to be imperative for reducing miscarriages.

Other Metabolic Abnormalities
Type I insulin-dependent diabetes mellitus

Uterine Abnormalities
Congenital uterine abnormalities include the bicornuate (uterus with two cavities), septate (uterus with a midline wall) uterus or uterus didelphic (duplication of uterus and cervix). These abnormalities account for 10-15% of miscarriages. This is because the embryo cannot implant and get the nourishment it needs to survive. Most uterine abnormalities can be corrected surgically.
Uterine submucosal fibroids (fibroids in the uterine cavity) as well as scars inside the uterus can also be associated with recurrent miscarriages.

Infections
Listeria Monocytogenes
Mycoplasma Hominis
Ureoplasma Urealyticum
Chlamydia
Bacterial vaginosis has been associated with mid trimester pregnancy loss
Most often there are no symptoms, and when diagnosed, these infections can be treated very effectively with antibiotics.

Thrombophilia
(hereditary disorders can lead to blood clots)
Factor V leiden mutation
Prothrombin mutation
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency

Autoimmune Factors
Sometimes immunologic factors may be present which cause the female’s body to mistake the fetus for an invading pathogen. When this happens, her body makes antibodies to the fetus and attempts to destroy it. This antibody reaction causes increased clotting and is responsible for approximately 5% of miscarriages. The physician can perform a blood test to detect some of the immunologic causes of miscarriage:
▪    Lupus anticoagulant
▪    Anticardiolipin
▪    Platelet count
▪    Antiphosphotidylserine IgG and IgM
Treatment may include a combination of a baby aspirin and Lovanox (blood thinner)

Potential Therapies
As we learn more about genetics, embryology, immunology and blood clotting, we have developed better diagnostic tests into causes of miscarriage. While treatment of anatomic and hormonal abnormalities will clearly improve pregnancy outcomes. there are few definitive therapies that have been clearly shown to decrease miscarriage rates due to other factors.

Preimplantation genetic diagnosis (PGD)
Surgery
Depending on the type, uterine abnormalities can be corrected surgically. Surgical Correction of a uterine septum (where the uterine cavity is divided in half) has been shown to be extremely beneficial for RPL. Although overall rare in the general population, uterine septi can affect 10-15% of those who suffer from repeated pregnancy losses.

Thyroid and Prolactin medical therapies
Abnormalities with the thyroid and prolactin can be easily treated with simple medical therapy.

Immunotherapy
Immunology is the most hotly contested field of research for miscarriages. The basic theory is that an embryo consists of material from the mother and “foreign” material from the father. This foreign material is recognized by the mother’s hyper-immune system and is attacked. Research surrounds therapy to reduce the recognition of “foreign” material or inhibit the destruction of foreign material, in this case, the pregnancy.
Current immunotherapy, i.e. IV IgG, is considered experimental and there are no randomized studies that validate its usage outside of research protocols. Any immunotherapy available is considered “off-label” (FDA approved drug that is being used in an unapproved manner). FCI follows the American Society of Reproductive Medicine guidelines that warns that such therapy has no long-term data yet proving that it has any beneficial effect. Other “promising” therapies are often proven to be ineffective and therefore a conservative approach is warranted until more definitive data and research is complete.

Anticoagulant therapy
Those patient diagnosed with Antiphospholipid Syndrome (APL) may benefit from therapy. Antiphospholipid antibodies and anticardiolipin antibodies are auto antibodies that may lead to reduced blood flow to a pregnancy and cause an increase the tendency of the blood to clot.
Women with RPL have an increased risk of having APL and treatment with heparin and baby aspirin during early pregnancy can reduce a pregnancy loss by 50%.
Such therapy, although promising, on occasion has been applied to other medical situations such as unexplained Infertility without any definitive data regarding its benefit. Because heparin and aspirin are not completely risk-free and can have significant side effects, FCI believes that such therapy should be reserved for those with a definitive diagnosis of APL.

Anti-insulin therapy
Women with PCOS, a specific reproductive disorder that can result in irregular cycles and elevated male hormone levels, may benefit from a diabetic drug called metformin during early pregnancy.