Genetic studies in spontaneous pregnancy loss

When a couple is trying to conceive, gestational losses are a problem that can be a one-time occurrence or can be repeated in successive pregnancies. This situation creates uncertainty for both parents and health professionals, who in many cases are looking for answers so that they can take action if necessary.

Unfortunately, about 25% of pregnancies end in unintended pregnancy loss, generally caused by a genetic alteration in the fetus. In these cases, it is important to identify it in order to determine the risk of recurrence in future pregnancies or the need to perform genetic studies on the parents. Currently, the incorporation of NIPT (Non-Invasive Prenatal Testing) technology in the study of the chromosomal causes of miscarriages has been a milestone for parents and couples.

Unintended pregnancy terminations usually occur in the first weeks of pregnancy, but can occur at any time during gestation. When 2 or more losses occur in consecutive gestations, they are considered recurrent gestational losses. Despite recurrent gestational losses, the possibility of conceiving a viable pregnancy and delivering a healthy baby is not ruled out. In many instances, knowing the underlying cause of these gestational losses can provide valuable information for taking steps to increase the chances of a viable pregnancy and a healthy delivery.

Factors that may affect the viability of the pregnancy

The causes of spontaneous terminations of pregnancy are highly variable and in some cases it is not possible to identify the reason, however, there are anatomical, genetic, lifestyle or previous conditions that are well established as factors that can affect pregnancy.

Anatomical factors

Anatomical causes that can result in gestational loss include abnormalities in the uterine cavity such as septate uterus which occurs when the uterine cavity is separated by a septum. Uterine fibroids can also cause miscarriages, especially when they are located inside the uterine cavity, since they do not allow the placenta to develop properly. The diagnosis of some of these alterations is usually ultrasound ultrasound or uterine radiography.

Immunologic factors

Immunological causes can be divided into autoimmune and alloimmune. Among the autoimmune causes are some alterations that generate a state of hypercoagulability of the maternal blood, creating clots that can reach the placenta and affect blood flow to the fetus. An example of this is the antiphospholipid syndrome, a type of acquired thrombophilia, which produces a rejection of the mother’s immune system towards the fetal tissues.

On the other hand, gestational losses of alloimmune origin occur when the mother’s immune system reacts to the fetus and produces antibodies to reject it. For example, Rh incompatibility occurs when the mother’s Rh-negative blood and the fetus’ Rh-positive blood come into contact. This type of incompatibility does not harm the first pregnancy, however, at the time of delivery the bloods come into contact and the mother’s immune system generates antibodies that in a second pregnancy could cause a gestational loss due to rejection of the fetus.

Genetic factors

Most miscarriages have an underlying genetic component. The presence of aneuploidies in the fetus is the main cause of miscarriage, these anomalies are the result of gametes with a higher or lower number of chromosomes than expected. Aneuploidies in the fetus are usually associated with the mother’s age; from 35 years of age the risk increases exponentially. When the cause of a miscarriage is an aneuploidy, the risk of recurrence in future pregnancies need not be high, but the mother’s age should always be a factor to be considered.

In addition to aneuploidies, about 4% of gestational losses are caused by other types of genetic variations: deletions and duplications along the fetal genome. In many cases, these partial aneuploidies in the fetus occur due to the presence of undiagnosed balanced translocations in one of the parents. In the event that these are transmitted to the offspring, they generate an unbalanced chromosomal rearrangement that can cause spontaneous abortion.

When a deletion or duplication is detected as the cause of a miscarriage, it is important to perform karyotyping of the parents to rule out the presence of balanced translocations, since their risk of recurrence is higher in subsequent pregnancies.

Studies in cases of gestational loss

Until now, in order to determine whether there is a genetic cause behind the gestational loss, the collection of the abortive remains or a chorionic biopsy is performed for later analysis. This type of study provides very relevant information, but has some limitations. The success rate of these studies is limited, around 53%, since they generally require prior cell culture and there is the possibility of fetal DNA contamination with maternal DNA, which alters the results of the study.

In addition, the collection of these types of samples requires specific containers and preservation conditions, and in the case of chorionic biopsy, the procedure must be performed in specialized centers with specific equipment. If the study fails, the major drawback is that a second sample could not be taken, so the failure rate is even more relevant. Given the complexity of sampling and the failure rate of the studies, until now it was not generally considered to perform genetic studies on fetal remains until the second or third miscarriage.

Currently, thanks to technological advances, it has been possible to adapt the technology used for non-invasive prenatal testing (NIPT) to the study of fetal chromosomal alterations in the case of gestational losses, in order to establish whether there is a genetic cause. This type of test substantially improves the success rate of such tests and also simplifies sample collection, since only a single maternal blood sample is required.

This methodology allows the detection of aneuploidies in all chromosomes and the analysis of deletions and duplications in autosomal chromosomes even if the loss occurs during the first weeks of gestation, since free fetal DNA increases its concentration in maternal blood when fetal development stops. Maternal blood collection should be performed prior to curettage to maximize the chances of obtaining a result.

By simplifying the sample collection, it is possible to perform the test even after a first gestational loss, especially in older women or women who have difficulty conceiving.

Interpretation of the results

If the test determines that the cause of the miscarriage is a trisomy, the risk of recurrence is low (always considering the maternal age), whereas, if the cause is a deletion/duplication, there may be a balanced rearrangement in the parents that increases the risk of recurrence in future pregnancies, so it is necessary to study the parents.

Genetic studies are transforming our understanding and approach to recurrent miscarriages. By identifying the underlying causes, we can move towards prevention and more effective treatments, providing better possibilities for those facing this emotional challenge.

At Veritas, we are experts in prenatal genomic medicine and are committed to researching and developing new solutions that improve care in this area. For this reason, we have pioneered the development and launch of PregnancyLoss, a test for cases of involuntary termination of pregnancy that allows us to determine if there is a chromosomal cause, with the objective of performing complementary studies.