The loss of even a single desired pregnancy is heartbreaking, but when this happens repeatedly, it is devastating and can lead to feelings of despair and overwhelming grief.  Fortunately, a careful review of the circumstances surrounding miscarriage, in conjunction with a comprehensive evaluation, can often lead to a successful strategy to help overcome this distressing diagnosis.

Recurrent pregnancy loss (RPL) has historically been defined as having three or more consecutive miscarriages.  For many years, couples would be faced with the recommendation to “just try again” before any investigation was initiated.  Studies have now clearly demonstrated that similar causes of miscarriage are found with nearly equal frequency whether an evaluation is undertaken after two or three losses.  Based on this information the American Society for Reproductive Medicine (ASRM) recommends that a clinical evaluation is completed after two consecutive first trimester losses.

Although random miscarriages are very common, only 1-5% of couples will suffer from repeated losses.  Chromosomal aneuploidy remains the most common factor responsible for miscarriage, even when they occur repeatedly.  The proportion of all losses that are due to aneuploidy increases with age.  One recent study demonstrates that it is more cost effective to check the genetic make-up of the products of conception (POC) from the second loss, than to complete a miscarriage evaluation without this information. If the loss is found to be due to a chromosomal error, then attempting to become pregnant again is appropriate even without initiating an investigation.  It is possible that IVF with preimplantation genetic screening (PGS) may improve outcomes in couples having repeated losses due to aneuploidy, but randomized studies have not been completed to verify the efficacy of this strategy.

When testing POC to determine whether to initiate an investigation, it is important to recognize that over 50% of results reported as a normal female (46XX) using routine cytogenetic analysis, are due to maternal cell contamination (MCC).  More specific single-nucleotide polymorphism (SNP) microarray technology identifies those specimens reported as normal female using conventional analysis and demonstrates that a significantly higher percentage of miscarriages are the result of chromosomal aneuploidy than originally reported.  It is therefore important to consider additional testing on POC reported as 46XX using conventional cytogenetics, or to utilize SNP technology as the initial step in the analysis of POC.

If a second miscarriage is identified to be euploid, it is appropriate to complete an evaluation to help identify other factors that are associated with recurrent losses.

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.

Hormonal Factors

Miscarriages that occur due to hormonal factors are estimated to account for roughly 10% of repeated losses and although controversial, may be the result of a corpus luteum deficiency, leading to progesterone levels that are insufficient to prepare and sustain the endometrium for pregnancy.  A luteal phase defect may be associated with hypothyroidism, hyperprolactinemia, or lifestyle issues such as high intensity exercise. Recent studies suggest that TSH levels that are greater than 2.5mIU/L are associated with a higher risk of miscarriage and warrant treatment.  Other hormonal factors associated with an increased risk of miscarriage include insulin resistance, often found in individuals with PCOS and uncontrolled diabetes. Correction of the underlying hormonal disturbance will dramatically improve pregnancy outcome.

Immunologic Factors

There is a clear association between recurrent miscarriage and individuals who have the antiphospholipid syndrome (APS) found in 5-20% of patients with RPL.  These individuals are identified by the presence of a circulating antiphospholipid antibody (lupus anticoagulant, anticardiolipin antibodies, anti-beta 2 Glycoprotein I) in conjunction with a history of thrombosis, repeated first trimester miscarriages, a single loss after 10 weeks gestation, or the onset of severe pre-eclampsia before 34 weeks gestation.  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 APS.  Studies suggest that low molecular weight heparin (e.g. Lovenox) is as effective as heparin in reducing the risk of loss.

In addition to APS, the presence of thyroid antibodies even in the face of normal thyroid function has been shown in a meta-analysis of 31 studies to be associated with an increased risk of miscarriage in women with recurrent losses.  One small randomized trial showed an improvement in pregnancy outcome when levothyroxine supplementation is provided.

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.

One recent study found chronic endometritis in 9% of women with repeated losses and demonstrated a significant improvement in live birth rate following treatment with antibiotics. Further study is recommended to determine if an endometrial biopsy should be included in the routine evaluation of patients with RPL.

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.  Data concerning a link between the inherited thrombophilias and repeated early miscarriages is very controversial.  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 first 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.