Recurrent pregnancy loss (RPL) is defined as having a history of three miscarriages in the first trimester or a single loss in the second trimester. The basic work up of RPL is typically started after experiencing two consecutive losses in the first trimester, unless there are other identifiable causes for the miscarriages.
Genetic and Chromosomal Causes of RPL
The risk of miscarriage increases with the reproductive age and is estimated to be 10-15% between the ages of 20-30; 15-30% between 30 to 40 and 30-60% at 40-45. These percentages are based on clinically recognizable pregnancies and the rates may be higher if patients are monitored closely following fertilization, implantation and during early embryo development. Some of these pregnancy losses are not clinically recognized because the timing of the miscarriage may coincide with the expected period. In some cases, menses are late a few days to a week and may be due to a pregnancy loss that may go unrecognized because of lack of early monitoring with a pregnancy test. The outcome does not change even if monitoring is done early in such pregnancies, because they are mostly abnormal genetically and chromosomally; such are called biochemical pregnancies.
The main etiology (cause) of miscarriage in the first trimester is due to a numerical abnormality in the chromosomes of the conception (embryo). It’s estimated that between 70-90% of all miscarriages in the first trimester are due to genetic/chromosomal abnormalities such as trisomy (extra chromosome – 47), monosomy (lacking one chromosome – 45) or other numerical abnormalities (any number other than 46 chromosomes). In cases of repeated pregnancy loss compared to having a single miscarriage, the rate of chromosomal abnormalities may be just slightly lower because of other associated factors such as problems with the uterus, thyroid function, diabetes or immunological issues.
Specific genetic factors such as translocations of genes (4-8%) can be the cause of RPL aside from the numerical chromosomal abnormalities of the embryos (~80%). These genetic problems are called balanced or unbalanced translocations in the genes, where a piece of the chromosome may exchange places with another site on another chromosome. In such cases, genetic material is generally not lost, but there is exchange of the location for the specific genetic material (DNA), which is called balanced reciprocal translocation. In other cases, genetic material may be lost during the translocation resulting in abnormal chromosomal arrangement (unbalanced translocation).
In both of the above cases, carriers of such translocations (parents) are phenotypically normal and “genetically balanced”. When the egg and sperm of such individuals undergo meiosis (maturation and cell division) abnormal genetic makeup (egg and sperm) can form with normal, excessive or deficient genetic material. Normal, balanced or unbalanced genetic format can result in a normal pregnancy, a miscarriage occurs (or rarely a genetically abnormal fetus depending on the specific abnormality).
Anatomical Causes of RPL
Anatomical factors can impact on pregnancy outcome and include uterine malformations (abnormal development of the uterus from birth), fibroids and intrauterine adhesions (Asherman’s syndrome). Uterus forms by the elongation and unification of two embryonic tubes that eventually become the mature uterus and abnormalities during these developmental stages can result in uterine anomalies (Mullerian anomalies).
Uterine malformations include unicornuate uterus (only one tube forming into the mature uterus), septate uterus (excessive tissue [septum] at the center of the uterus), bicornuate uterus (heart shaped), didelphic uterus (two separate uteri with two cavities connected with two cervices), DES exposed uterus and various degrees of T-shaped uterus. Uterine anomalies can result in first and second trimester losses and preterm labor along with associated complications. The problem can be related to compromised blood vessel development with limited blood flow to the uterus. Additionally, endometrial cavity may be limited in its volume to accommodate a developing fetus. In such cases, the pregnancy can attach to a weaker area in the uterus, such as the “septum” and result in a miscarriage.
Among all of the above anomalies, septum of the uterus is the type of abnormality that can be corrected surgically with high success rates. Other abnormalities are best treated with a conservative approach, including close monitoring in early pregnancy, cerclage procedure for second trimester losses and very rarely by surgical correction of the uterus (metroplasty-rarely done).
Fibroids (myomas) are relatively common in women and generally asymptomatic (without pain, bleeding or pelvic pressure) throughout the reproductive years. In some women, the presence of such symptoms can necessitate an ultrasound examination of the uterus and fibroids can be diagnosed. Additionally, fibroids can be diagnosed with gynecological examination, if they reach a certain size and palpated through bi-manual examination. In most cases fibroids can be observed over time, but in others medical or surgical treatment is necessary.
In the infertility population as well as patients with recurrent miscarriages, fibroids are more common and generally result in the adverse outcome such as fertility treatment failures or miscarriages. Fibroids can be present within the uterine cavity where the pregnancy develops (submucous), in the muscle layer (intramural) or connected to the outside of the uterus (subserosal).
If the fibroids are small and on the outside of the uterus (still connected) or in the muscle layer, but far away for the endometrial cavity, most likely they do not result in any adverse outcomes. If such fibroids are very large and multiple, they may possibly impact on the pregnancy outcome even though they are not inside the uterine cavity. If the fibroids are impinging on the endometrial cavity or already growing into or inside the cavity, they may result in infertility or recurrent miscarriages. In such cases, surgical removal of these fibroids is recommended to improve pregnancy outcome. Each individual case may be different and depending on the number, extent, size and involvement of the fibroids, surgical treatment may be necessary. Patients need to be counseled about the treatment options of fibroids, especially those with infertility or recurrent pregnancy loss.
Intrauterine adhesions (IUA or Asherman’s syndrome) can form following dilatation and curettage (D&C) for abortions, miscarriages or for excessive bleeding following delivery. In other unusual cases, pelvic infections can result in the destruction of the endometrium (the cells inside the uterus/cavity). IUA are closely associated with miscarriages and hysteroscopic correction of the scar tissue results in high success rates.
Thrombophilias (Clotting Disorders) and RPL
Thrombophilias are a group of disorders that result in an increased risk of clot formation inside blood vessels. They most often result in clot formation in the lower extremities or the uterus and the placenta during pregnancy. These disorders may increase the risk of miscarriage overall and it is recommended that patients with a history of RPL undergo screening for thrombophilias.
Whereas there is no clear consensus on the extent of testing for these disorders, a panel including those most closely associated with RPL is generally preferred. The most established relationship between thrombophilias and RPL is the anti-phospholipid syndrome that includes patients with a history of blood clots, miscarriages and low platelets (cells that stop bleeding). Other commonly associated thrombophilias include protein S, protein C and Anti-thrombin III deficiency, hyperhomocysteinemia, Factor II mutation – prothrombin 20210 mutation, Activated Protein C Resistance and Elevated Plasminogen Activator Inhibitor-I Level.
Thrombophilias generally result in late first trimester miscarriages, in which the pregnancy may be established with an ultrasound and a strong heart beat can be present, but in the following few weeks, unexpectedly fetal demise may be diagnosed. In early miscarriages, chromosomal abnormality of the embryo is much more common than thrombophilia related losses.
Treatment of thrombophilias during pregnancy includes “blood thinners”. The recommended regimen is baby aspirin (81mg daily) and either heparin or Lovenox type of drugs, although heparin is the preferred option. In most cases, this regimen is continued until the end of the first trimester, but in others it may be prolonged until delivery, especially in cases with other risk factors.
Other associated diseases with RPL include thyroid dysfunction and diabetes, and patients with RPL should be screened for both. If there is uncontrolled diabetes or low/high thyroid function, the risk of RPL will be increased. The best treatment in such cases is the management of the underlying cause and close follow up during pregnancy.
In some cases, the cause of RPL may not be identified despite extensive testing. In such cases, close follow up with the next pregnancy with weekly ultrasounds and positive reinforcement is found to be helpful in improving the pregnancy outcome.
Finally, in cases of chromosomal abnormalities genetic testing of embryos created by IVF (in vitro fertilization) may be useful. Currently, preimplantation genetic diagnosis/screening (PGD/PGS) or comparative genomic hybridization (CGH) are the two tests available. PGS remains to be a limited test that evaluates 16 out of 46 chromosomes, whereas CGH evaluates 46 out of 46 chromosomes and provides more information. There are additional genetic tests being developed to screen the embryos for chromosomal abnormalities such as array CGH, 24-probe PGD or SNP analysis, but due to limited information and concerns with accuracy these tests are not routinely used. If chromosomally normal embryos are transferred into the uterus, pregnancy rates may be improved and risk of miscarriage decreased significantly. It is important to discuss such treatment options with patients who have a history of RPL. Gestational surrogacy is another option for patients with a significant history of RPL, especially for those with a uterine malformation.