One of the most devastating outcomes facing couples who are trying to have a child is miscarriage. Human reproduction is a relatively inefficient process and random miscarriages are found to occur in 15-20% of clinically recognized pregnancies. The vast majority of these losses are due to chromosomal defects within the Embryo. In 2-4% of couples of reproductive age, the losses are repetitive and frequently related to factors other than chromosomal abnormalities. A complete investigation may reveal a cause for the recurrent miscarriages in 60-70% of couples. In most cases, couples who experience repeated pregnancy losses (RPL) due to an identifiable cause, will benefit from intervention and have a successful outcome.
Traditionally, RPL has been defined as three or more consecutive pregnancy losses. Recent studies have shown that the causes of miscarriage are virtually the same after two losses as after three, so most experts now agree that an evaluation is warranted following two consecutive miscarriages. The underlying causes of recurrent miscarriages fall into six broad categories: hormonal, infectious, anatomic, genetic, immunologic and thrombophilic factors.

Hormonal Factors

Miscarriages that occur due to hormonal factors are estimated to account for roughly 10% of repeated losses and may be the result of a Corpus Luteum , leading to Progesterone levels that are insufficient to prepare and sustain theEndometrium for pregnancy. A Luteal Phase defect may be associated with hypothyroidism, hyperprolactinemia, or lifestyle issues such as high intensity exercise. Other hormonal factors associated with an increased risk of miscarriage include insulin resistance, often found in individuals with PCOS, uncontrolled diabetes and elevated baseline FSH levels, which suggest a decline in ovarian reserve and egg quality. With the exception of reduced ovarian function, correction of the underlying hormonal disturbance will dramatically improve pregnancy outcome.

Infectious Factors

Certain bacterial infections including Mycoplasma hominus, Ureaplasma urealyticum and chlamydia have been identified more commonly amongst individuals who have had a miscarriage. Although a clear association as a cause of recurrent losses has not been established, assessment for the presence of these organisms and treatment of both partners with antibiotics is often performed prior to the next pregnancy.

Anatomic Factors

Anatomic causes of miscarriage may be Congenital or acquired. Congenital uterine abnormalities occur as the result of incomplete fusion of the Mullerian ducts during the first twelve weeks of fetal development and are estimated to account for 10-15% of repeated losses. The anomaly most commonly associated with pregnancy wastage is a uterine septum. Retrospective studies have suggested that only 6-28% of individuals with an untreated septum will have a live birth and that surgical resection leads to dramatically improved outcomes. Uterine fibroids are found in up to 30% of women and may be associated with an increased risk of miscarriage possibly due to disruption of blood flow to the Fetus, or mechanical factors. Submucus myomas, large intramural myomas and multiple myomas are most commonly implicated as playing a role in repeated losses, although limited data is available. Removal of the myomas may be indicated depending on the history, sonographic findings and exclusion of other factors that might contribute to miscarriage. The presence of intrauterine adhesions that occasionally result from a prior D&C, or other intrauterine procedure, have been associated with an increased risk of miscarriage, possibly as a result of poor blood flow to the scarred endometrium. The outcome following hysteroscopic removal of adhesions is directly related to the extent of damage, although there is little prospective data regarding the role of adhesions as a cause of repeated miscarriages, or the benefit of surgical repair.

Genetic Factors

At least 50% of sporadic miscarriages are due to numeric chromosome abnormalities (Aneuploidy) that result from random errors in cell division and occur more commonly with advancing maternal age. Amongst couples with recurrent miscarriages, 2-8% are found to have structural chromosome rearrangements, most commonly balanced or Robertsonian translocations. Genetic counseling should be offered as the probability of having a healthy live birth is related to which chromosomes are affected and the type of abnormality. IVF with preimplantation genetic diagnosis (PGD) may be used to screen embryos that are normal, or that are carriers of the balanced translocation, in order to reduce the risk of another loss due to aneuploidy.

Immunologic Factors

Pregnancy is regarded as an “immune-privileged state” because the fetus possesses paternal antigens that are foreign to the mother and ordinarily would cause rejection. One proposed cause of pregnancy loss in some individuals is that there is an abnormal maternal immune response directed against the fetal-placental unit. Elevated natural killer cells in the endometrium may be associated with higher levels of cytotoxic T cells leading to a disturbance in immune tolerance and an increased risk of miscarriage. These types of immune dysfunctions have not been conclusively shown to be a cause of repeated losses and one proposed therapy which involves the intravenous infusion of Immunoglobin G (IVIG) is controversial and is generally considered experimental by most investigators.

Much less controversial is the association of elevated levels of antiphospholipid antibodies (APLs) with miscarriage. APLs include anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) and are found in 5-15% of women with repeated losses. Moderate to high titers (>20 PL units) of either IgG or IgM ACA are considered significant. Because levels may fluctuate, individuals with borderline levels should have testing repeated during pregnancy. Other types of APLs including antiphosphatidylserine and beta 2-glycoprotein may also be associated with an increased risk of miscarriage. These autoantibodies can lead to placental thrombosis later in pregnancy and probably interfere with attachment, invasion and development of the placenta during the first trimester. A meta-analysis demonstrates that treatment with heparin and low-dose (81mg) aspirin will significantly improve pregnancy outcome in individuals with APLs. Studies suggest that low molecular weight heparin (e.g. Lovenox) is as effective as heparin in reducing the risk of loss.

Inherited Thrombophilic Factors

The inherited thrombophilias are a group of coagulation disorders that lead to an increased risk of venous thromboembolism (VTE) and are found in approximately 15% of the western population. The most common mutations are Factor V Leiden, prothrombin gene (Factor II) and methylenetetrahydrofolate reductase polymorphisms (MTHFR). Other inherited thrombophilias include deficiencies in Proteins C and S and antithrombin. Several of these abnormalities have been linked to adverse obstetric outcomes including pregnancy loss (especially 2nd and 3rd trimester), preeclampsia, growth retardation and placental abruption, in addition to VTE. Current data concerning a link between the inherited thrombophilias and repeated early miscarriages is very controversial. Small retrospective studies and meta-analyses show the strongest association between recurrent losses and Factor V Leiden, prothrombin gene and activated protein C resistance. Most studies fail to show a consistent association between the presence of MTHFR mutations and recurrent miscarriages. Based on current studies, the use of heparin and low dose aspirin in women with a history of a later loss in association with Factor V Leiden, a prothrombin gene mutation or activated protein C resistance, is warranted. At the present time, there are no well controlled prospective studies that support the use of anticoagulant therapy in women with these abnormalities and repeated 1st trimester losses. The use of anticoagulant therapy in this population may be offered following discussion of the risks and theoretic benefits of the treatment, but should be considered empiric until more data becomes available.

In conclusion, the use of a comprehensive evaluation will help identify potential factors that may contribute to miscarriage in the majority of cases and helps guide therapy to address the underlying cause(s). Happily, the vast majority of couples who suffer from repeated miscarriages, ultimately, will be successful and have a live birth.