Recurrent pregnancy loss (RPL): definitions and etiology

RPL may have a considerable impact on a couple’s wellbeing and psychology. Understanding and identifying the causes of RPL is therefore pivotal. Said this, it’s important to have in mind that, thus far, about 50% of all miscarriage events remain of unknown cause (idiopathic), meaning they may be caused by the interaction of several different factors. In the remaining half of the cases, a more precise cause can be identified:

1. genetic causes (chromosomal and monogenic);
2. immunological and inflammatory factors;
3. anatomical alterations;
4. endocrine abnormalities;
5. environmental.

Chromosomal abnormalities are one of the most frequent causes of spontaneous miscarriage. They cause 50% -60% of all cases of first-trimester miscarriage. Chromosomal abnormalities may concern the number of chromosomes (as in the case of trisomies or monosomies) or their structure (as in the case of translocations and inversions). These anomalies, balanced in the parents, greatly increase the likelihood of having a genetically unbalanced gamete due to the complex mechanisms of segregation during meiosis. According to a recent study, in about 5% of couples with RPL, one of the partners has a balanced translocation or inversion. Similarly, the presence of these structural alterations is 10 times greater in couples with RPL than in the general population.

Very recently (and very interestingly) it has been shown that not only chromosomal abnormalities can cause RPL. Actually, also point mutations can cause RPL (monogenic causes of RPL). For example, Fatemi and colleagues (2021) described frameshift mutations in the KHDC3L gene in a large family with RPL with or without hydatiform mole. The same group, in 2020, also identified a missense mutation in the CCNB3 gene that segregated in a family with RPL.

It’s well known that the mother’s immune system develops a tolerance mechanism towards the fetus, which allows the pregnancy to go on. However, various immune factors can alter this mechanism (of which functioning is still poorly understood). These factors may promote the risk of multiple miscarriages. For example, antiphospholipid antibody syndrome (APLS), a heterogeneous autoimmune disease, can be diagnosed in approximately 5-20% of patients with RPL. APLS is one of the most important causes of pregnancy complications, leading to early miscarriages, eclampsia and reduced fetal growth. APLS is thought to cause a state of hypercoagulability leading to thrombosis of the placental blood vessels. Luckily, APLS is treatable.

Among other immunologic causes, there’s increasing evidence about the role of NK cells (Natural Killer cells), which may be altered in their number or their cytotoxicity levels.

The control of inflammation also plays an important role in preventing RPL. For example, it is known that polymorphisms in numerous inflammation-related genes such as FOXP3, CLOCK, IL-10, TNF-α, and IL-17F may be associated with RPL. Similarly, polymorphisms in CRP, that affect circulating C-reactive protein in chronic inflammatory diseases, may also be associated with RPL. However, we are talking here about polymorphisms that might be predisposing, although not being predictive.

Numerous studies indicate that up to 13% -19% of patients with RPL have a structural malformation of the uterine cavity. These malformations can be congenital or acquired. Congenital forms include arcuate uterus, septum, single or bi-horned, while acquired forms include intrauterine adhesions, polyps, and submucosal myomas. In one study, the uterus septum was found to be the most common congenital anomaly, being identified in about 5% of patients with RPL.

The involvement of the endocrine system in poliabortivity is widely debated. According to numerous studies, conditions such as hypothyroidism, insulin resistance, polycystic ovary syndrome, vitamin D deficiency, luteal phase deficiency and prolactin disorders can have an influence on RPL. However, if it’s known that overt hypothyroidism may cause reduced fertility, miscarriages, pre-eclampsia and preterm births, the association with other endocrine problems is still an open debate, given the conflicting results of several studies.

Environmental and behavioral risk factors, such as maternal age, BMI index and cigarette smoking are considered risk factors for miscarriage.

A special mention goes to thrombophilias, that is, those inherited or acquired diseases that cause an increased risk of deep vein thrombosis due to plasma hypercoagulability. The main inherited thrombophilias are the factor V Leiden mutation (G1691A), the prothrombin gene mutation (G20210A), protein C, protein S and anti-thrombin deficiency. Historically, hereditary thrombophilias have been associated with polyabortivity, as it was hypothesized that placental thrombosis events favored RPL. Although numerous studies published in the literature confirm and corroborate this hypothesis, a growing series of recent studies have been published that disprove this association and do not confirm the results. Therefore, routine screening for thrombophilia in patients with recurrent miscarriages is not currently recommended if they have not already had deep vein thrombosis events.