Recurrent miscarriages are an important reproductive health issue, affecting 1-5% of couples. The purpose of this article is to summarize current knowledge about the genetic causes of recurrent miscarriage. The most common parental genetic disorders associated with recurrent miscarriage (karyotypic abnormalities, carrier status of recessive diseases, dominant diseases, and thrombosis) and studies of other possible genetic causes are presented.
This review also sheds light on the possibility that changes in the embryo/fetal genome can lead to miscarriage and discusses the methods used to assess abortion materials and their advantages and disadvantages. Understanding the genetic background of miscarriage is important for prognosis as well as for potential planning for prenatal diagnosis of later pregnancies.
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Miscarriage is the most common complication of pregnancy. While it is estimated that it can terminate 10-15% of clinically diagnosed pregnancies, the actual number may be 4-5 times higher. The Royal College of Obstetricians and Gynaecologists (RCOG) considers recurrent miscarriages to be three or more consecutive pregnancy failures, while the American Society of Reproductive Medicine defines recurrent miscarriages as at least two consecutive miscarriages. Recurrent miscarriages are an important issue for reproductive health, as it is estimated that 1-5% of couples will be affected by it. It may have a dual background of genetics and environment.
The purpose of this article is to summarize current knowledge about the genetic causes of recurrent miscarriage and to discuss the role of genetic diagnosis in determining the cause of pregnancy loss. Genetic causes may involve alterations in the mother's, father's, or fetus's genetic material. Genetic testing can be done on both parents or in miscarriage material (embryo/fetus).
Changes in the genetic material of parents
Changes in the genetic material of parents who contribute to an increased risk of miscarriage in successive pregnancies include chromosomal karyotype abnormalities, recessive and dominant disease carrier status, and mutations in genes responsible for coagulation and folic acid metabolism. The presence of karyotypic abnormalities in one of the parents is one of the most common causes of known recurrent miscarriages. The most common is balanced chromosomal aberration, i.e. it does not cause clinical symptoms in carriers, but may induce the production of abnormal germ cells containing an abnormal amount of genetic material.
In couples with recurrent miscarriages, at least in 3-5% of cases one party is confirmed to be a balanced translocation. The most common are mutual translocations, which are less common due to inversion and Robertson translocations. Balancing the condition of a carrier of chromosomal aberrations increases the risk of miscarriage in pregnancy, as well as the risk of chromosomal karyotype imbalance at birth. However, with the exception of some rare cases, most carriers of balanced chromosomal aberrations have a high chance of producing healthy offspring. The risk of recurrent miscarriage after a second birth or the risk of having a karyotype abnormality at birth varies depending on the type of chromosomal aberration. Genetic diagnosis is performed by evaluating two parental karyotes by using conventional cytogenetic methods based on light microscopy.
In both parents, the disease may be induced by mutations in single-gene recessive diseases, especially when the parents are close relatives. One case described by Kedar et al. is congenital methemoglobinemia. Other examples include the carrier state of mutations that cause congenital joint contractures or Smith-Lemli-Opitz syndrome. Interestingly, the incidence of Smith-Lemli-Opitz syndrome is lower than expected, which may be due to insufficient awareness by obstetricians and gynecologists of the widespread fetal defects associated with SLO syndrome. If the genetic problem is an autosomal recessive disorder, then the risk of recurrence of abnormalities in consecutive pregnancies is up to 25%. However, in practical clinical practice, it is difficult to diagnose and screen for the condition of carriers of hidden diseases.
Another class of disorders consists of autosomal dominant disorders that are transferred to offspring with a high probability (50%). Symptoms of these disorders may worsen (expected) in offspring, such as ankylosing muscular dystrophy, which primarily affects the muscular system and is associated with muscle rigidity, muscle stiffness, language impairment, and swallowing. Muscle rigidity can lead to obstetric complications, including miscarriage, premature birth, edema, fetal death in the womb, prolonged delivery, or intrapartum bleeding. Most often, this symptom is not observed in the ancestors. For example, when family history includes cataracts in younger years, dystrophy may be suspected of muscular ankylosing. In this case, it is particularly important to assess fetal development, as the disease may metastasize with the transfer of symptoms in the offspring, especially if inherited from the mother. Fetal ultrasonography may show decreased fetal movements and dysphagia, leading to hyperhydramnios and malformed feet. Although maternal symptoms may be discrete, mutations can lead to fetal death or stillbirth.
In the case of homozygote mutations, IUFD (intrauterine fetal death) is associated with the presence of autosomal dominant disorders in both parents, one example of which is cartilage hypoplasia. In this case, it is feasible to use targeted diagnostic methods in parents, and they should be provided with comprehensive clinical examination and pedigree analysis, followed by diagnostic molecular tests.
Genetic disorders associated with the X chromosome may cause IUFD in male fetuses. These disorders include congenital Bloch-Sulzberger disease, Goltz syndrome, Rett syndrome, and Aicardi syndrome. Because these syndromes are so rare, routine diagnostic tests for screening are not currently recommended.
Another cause of recurrent miscarriage is congenital thrombosis after maternal factor V gene G1691A (Leiden mutation) and prothrombin gene (G20210A mutation) are impaired. These mutations have been studied in depth, and the test is part of a routine diagnosis of recurrent miscarriages. In terms of factor V, both the Leiden mutations G1691A and T1328C mutations appear to be important in the pathogenesis of recurrent miscarriages, especially those observed before the 7th week of pregnancy. However, identifying factor V gene (Leiden mutation) and prothrombin II gene polymorphisms may not be sufficient to screen for congenital thrombotic risk factors. Obstetric failure may also be caused by genetically determined factor VII, factor XIII, or fibrinogen activity disorders. However, there are currently no studies that can definitively confirm the effect of these factors on recurrent miscarriage.
There is a relationship between recurrent miscarriage and congenital thrombosis in the father. Paternal factor V Leiden mutations were six times higher than in the control group. The mechanism of this phenomenon has not been properly studied.
However, other studies have shown that there is no significant difference in the frequency of specific thrombophilic susceptibility mutations in women with at least two miscarriages compared with women without a history of pregnancy miscarriage. This may indicate that obstetric failure may depend on the total number of mutations in the individual, rather than the presence of genetic mutations in the individual.
The effect of mutations in the MTHFR gene, a gene encoding proteins involved in folic acid metabolism, on recurrent miscarriage is controversial. Hyperhomocysteinemia has been reported to be not associated with reproductive failure. This may be due to folic acid supplementation, especially in the first trimester.
Other studies have addressed other genetic causes of obstetric failure. One of the diseases associated with the risk of recurrent miscarriage is obesity. There is evidence that BMI ≥30 kg/m is an independent risk factor for spontaneous and recurrent miscarriage. However, there are reports that even a genetic predisposition to obesity is associated with a greater probability of recurrent miscarriage.
Sinhalese women who have had multiple miscarriages have significantly higher variations in the single nucleotide polymorphism (SNP) rs9939609 allele in obesity-associated fats and obesity-associated genes (FTOs).
文献：Kacprzak M , Chrzanowska M , Skoczylas B , et al. Genetic causes of recurrent miscarriages[J]. Ginekologia Polska, 2016, 87(10):722-726.