An investigation into recurrent pregnancy losses (RPL) is warranted after two or more clinical miscarriages. Sporadic miscarriages occur in up to 15-20% of early pregnancies, but RPL are found in only 2-5%. A systematic evaluation will detect a possible underlying cause in roughly half of individuals who suffer from RPL and helps provide confidence that a livebirth can be achieved. Even without a specific diagnosis however, 50-80% will ultimately have a successful outcome, depending on maternal age and number of prior losses. This is an important fact to share with those who are faced with unexplained RPL in order to help maintain a sense of hope, as their next pregnancy is attempted.

Numerous factors have been implicated as causes of RPL, but evidence based data is lacking in most cases. This informational letter will review evidence related to genetic, anatomic and infectious causes of miscarriage.

Genetic Factors

Cytogenetic abnormalities are found to be the most common factor responsible for miscarriage, even in cases of RPL. The proportion of all losses that are due to chromosomal aneuploidy increases with age and is higher in losses that occur prior to 10 weeks.

Following miscarriage, testing of the products of conception (POC) provides insight for patients about their loss and helps determine whether to initiate further investigation. When a loss is found to be due to a chromosomal error, attempting to become pregnant again may be considered even without a full investigation. Alternatively, if a second miscarriage is identified as euploid, it is appropriate to complete an evaluation to help identify factors that may be associated with recurrent losses. Importantly, over 50% of results reported as a normal female (46XX) using routine cytogenetic analysis, are due to maternal cell contamination (MCC). When these specimens are analyzed using more specific single-nucleotide polymorphism (SNP) microarray technology, a significantly higher percentage of miscarriages are found to 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.

Recent studies using SNP and whole genome sequencing techniques suggest that certain single gene disorders and micro deletions or duplications may be responsible for otherwise unexplained losses. This is an emerging area of research in this field and as more data is gathered, it is likely to become an important addition to the investigation of RPL.

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.

Preimplantation genetic screening (PGS) of embryos is often recommended in cases of unexplained recurrent miscarriages, or in individuals who carry a structural chromosomal rearrangement. Several retrospective studies have found that the use of PGS in individuals with a history of idiopathic RPL reduces the rate of miscarriage. One large multicenter analysis demonstrated a miscarriage rate of only 6.9% following the transfer of a PGS normal embryo, compared to an anticipated rate of loss of 33.5% in a RPL population. There is conflicting data regarding the cost effectiveness of this strategy, compared to expectant management. Controlled studies are needed to determine if there are specific age groups of those with unexplained RPL that would clearly benefit from the use of PGS.

Anatomic Factors

Anatomic causes of miscarriage may be congenital or acquired. Congenital uterine abnormalities occur as the result of incomplete fusion or resorption of the Mullerian ducts prior to 20 weeks of fetal development and are estimated to be associated with up to 10-15% of repeated losses. The anomaly most commonly associated with pregnancy wastage is a uterine septum. One large retrospective study found that 41% of individuals with an untreated septum miscarried, compared to only 12% of controls. Most retrospective studies and meta-analyses suggest that surgical resection leads to dramatically improved pregnancy outcomes in individuals with a history of repeated losses.

Uterine fibroids are very common in women of reproductive age and are thought to contribute to 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 data is limited and difficult to interpret due to variations in size and location of myomas. Removal of the myomas may be indicated depending on the history, sonographic findings and exclusion of other risk factors.

The presence of intrauterine adhesions that occasionally result from a prior D&C, or another 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.

Infectious Factors

A 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. Other studies have shown a significantly higher percentage of chronic endometritis in patients with repeated implantation failure and RPL compared to the general population. An interesting paper published this year reports that sensitive molecular techniques have identified that the uterine cavity is not a sterile environment, but is instead normally colonized by symbiotic bacteria. This paper suggests that the presence of an abnormal endometrial microbiome, may contribute to implantation failure and miscarriage. Further study is recommended to determine if an endometrial biopsy should be included in the routine evaluation of patients with RPL.

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). There remain many controversial areas that require further randomized studies in order to define their role in maintaining pregnancy. Happily, even without a definitive diagnosis, the majority of couples who suffer from repeated miscarriages will ultimately achieve a live birth.


 

Selected References

The Practice Committee of the American Society of Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil Steril 2012; 98: 1103-1111.

Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, Munné S. Idiopathic recurrent miscarriage is caused mostly by aneuploidy embryos. Fertil Steril 2012; 98: 675-680.

Thorne J, Craffey A, Nulsen JC. Detection of an inherited deletion in products of conception in a patient with recurrent losses and a normal karyotype. Obstet Gynecol 2017; 130: 126-129.

Saravelos SH, Yan J, Rehmani H, Tin-Chiu L. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod 2011; 26: 3274-3279.

McQueen DB, Bernardi LA, Stephenson MD. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril 2014; 101: 1026-1030.

Moreno I, Franasiak JM. Endometrial microbiota-new player in town. Fertil Steril 2017; 108: 32-39.