Genetic causes of miscarriage

In connection with the use of genetic research methods, there are significant opportunities for expanding the understanding of the genesis of spontaneous abortion. Gamete losses start from the moment of ovulation. According to Weathersbee PS (1980) from fertilized eggs, 10-15% can not be implanted. According to Wilcox et al. (1988) preclinical pregnancy loss is 22%. These data suggest that preclinical loss is a kind of instrument of natural selection, as well as sporadic early pregnancy loss. Numerous studies have established a high incidence of chromosomal abnormalities in the fetus during spontaneous abortions. It is believed that chromosomal abnormalities are the main cause of this pathology.

According to Boue J. Et al. (1975), a cytogenetic study in 50-65% of abortus revealed chromosomal abnormalities. According to French F. And Bierman J. (1972), of the 1000 pregnancies recorded from 5 weeks, by the 28th week, spontaneous abortion 227 ends, and the less gestation time, the more frequent the loss. Chromosomal abnormalities were detected in 30.5% of abortus, with trisomy, in most cases trisomy of the 16th chromosome, in 23.7% in X-monosomy and in 17.4% in polyploidy. It is believed that trisomy of other chromosomes is also common, but they are lethal at very early stages of development, more often need clinical and do not fall into research. The phenotype of abortus is very variable - from anembrion or "empty fetal sac" to intrauterine fetal death.

Total reproductive loss in humans is approximately 50% of the number of conceptions, with chromosome and gene mutations dominating in the genesis of losses.

At a high initial level of formation of chromosomal abnormal embryos, a natural selection takes place, aimed at eliminating carriers of chromosomal mutations. In humans, more than 95% of mutations are eliminated in utero, and only a small portion of embryos and fetuses with aberrations of chromosomes survive to the perinatal period.

In several prospective studies conducted in a large population, the presence of chromosomal abnormalities in 1 of 200 newborns was identified. With a more detailed examination, this figure is even higher, and only in one out of three, these anomalies are revealed during clinical examination.

Chromosomal pathology of a person depends not only on the intensity of the mutation process, but also on the efficiency of selection. With age, the selection is weakened, so at an older age of parents, an anomaly of development is more common.

In most cases, the chromosomal pathology appears due to mutation de novo in the parental cells of parents with a normal chromosomal set, as a result of meiotic disturbance or in the cells of the germinal path, as a consequence of mitosis.

The lethal effect of the mutation, which arose after implantation, leads to the termination of embryo development, resulting in miscarriage.

About 30% of the zygotes die due to the lethal effect of the mutation. Infringements of meiosis can be caused by many factors that affect the fetal karyotype: infection, radiation, chemical hazards, drugs, hormonal balance disorders, gamete aging, defect in genes controlling meiosis and mitosis, etc.

In the case of chromosomal causes of a habitual miscarriage, more often than among sporadic spontaneous interruptions, such forms of chromosome rearrangements that do not arise de novo, but are inherited from parents, are determined. Can be determined by genetic disorders.

In women with habitual miscarriages, significant structural anomalies of the karyotype are 10 times more common than in the population and amount to 2.4%.

The most frequent chromosomal abnormalities are trisomy, monosomy, triploidy, tetraploidy. Triploidy and tetraploidy (polyploidy) are usually caused by fertilization with two or more spermatozoa or a violation during the ejection of polar bodies during meiosis. The embryo has an additional haploid set of chromosomes (69 XXY, 69 XYY, etc.). Polyploidy is a gross pathology, most often it ends with abortion.

Trisomy or monosomy is a consequence of the non-divergence of chromosomes in gametogenesis. With monosomy 45 X0, 98% of pregnancies end in miscarriage and only 2% result in childbirth with the development of the Turner syndrome in the child. This anomaly is almost always lethal to a human embryo, and survival is associated with mosaicism.

The most frequent cytogenetic cause of recurrent abortions is reciprocal translocation of segments of chromosomes. Carriers of aberrant chromosomes (heterozygotes for translocation, inversion, mosaic) are phenotypically normal, but they have a decrease in reproductive capacity. The most common type of chromosomal aberration is translocation - structural changes in chromosomes, during which the chromosomal segment is included elsewhere on the same chromosome or transferred to another chromosome, or segments are exchanged between homologous or nonhomologous chromosomes (balanced translocation). The frequency of translocation in spouses with miscarriage is 2-10%, i.e. Significantly higher than in the population - 0.2%.

Balanced translocations can be transmitted from generation to generation by phenotypically normal carriers, promoting the occurrence of spontaneous abortions, infertility or the birth of children with developmental anomalies.

At 2 spontaneous abortions in the anamnesis of 7% of married couples have chromosomal, structural changes. The most common is reciprocal translocation - when the segment of one chromosome changes place with a segment of a non-homologous chromosome. As a result of meiosis, there may be an unbalanced number of chromosomes in the gamete (duplication or lack), as a result of this imbalance, either miscarriage or fetal birth with developmental anomalies occurs. The risk of losing pregnancy depends on the specificity of the chromosome, the size of the site of translocation, the sex of parents with translocation, etc. According to Gardner R. Et al. (1996), if there is such an imbalance in one of the parents, the chance of having a miscarriage during subsequent pregnancy is 25-50%.

The main reason for habitual abortion is reciprocal translocation, and for its recognition it is necessary to analyze segments of chromosomes. In a survey of 819 family members with habitual abortions, 83 chromosomal abnormalities were identified, most often Robertson translocations (23), reciprocal translocations (27), pericentric inversions (3), and mosaic sex chromosomes (10).

In addition to translocations, another type of chromosome anomaly - inversion - is found in couples. Inversion is an intrachromosomal structural rearrangement, accompanied by a reversal of the chromosome or chromotide segment by 180 °. The most common is the inversion of the 9th chromosome. There is no generally accepted point of view on the significance of inversions in the interruption of pregnancy. Some researchers consider this as a variant of the norm.

In married couples with a violation of the reproductive system, violations such as "mosaicism" or "small" changes in the morphology of chromosomes, or even "chromosome variants" are detected. At present, they are united by the term "polymorphism". Karetnikova NA (1980) showed that in spouses with habitual miscarriages, the frequency of chromosome variants averaged 21.7%, i.e. Significantly higher than in the population. It is not necessary that karyotype anomalies always include gross violations. The presence of C-variants of heterochromatin, short arms of acrocentric chromosomes, secondary constrictions on chromosomes 1, 9, 16, satellite regions S and satellite strands h of acrocentric chromosomes, Y chromosome sizes in parents contribute to an increase in the risk of chromosome rearrangements, reproductive disorders and developmental abnormalities.

There is no consensus on the significance of chromosome polymorphism in reproductive losses, but a more detailed examination of individuals with "chromosomal variants" showed that the incidence of miscarriage, stillbirth and the birth of children with developmental abnormalities are much higher than in the population. As our studies showed, especially a lot of spouses with "karyotype variants" in case of miscarriage of early gestation.

Transmitted from phenotypically normal, genetically balanced carriers, chromosome variants are relatively uncommon, but inevitably lead to the formation of chromosomal rearrangements in their gametogenesis, resulting in a genetic imbalance in the embryo and an increased risk of an abnormal offspring. Small chromosomal variants should be considered as a chromosomal load, which can be responsible for miscarriage.

Apparently, with the deciphering of the human genome it will be possible to reveal the importance for a person of such small forms of karyotype disorders.

If there are more than 2 spontaneous abortions in the anamnesis, it is necessary to provide medical genetic counseling, which includes genealogical research with attention to the family history of both spouses, including in this analysis not only miscarriages, but also all cases of stillbirths, intrauterine growth retardation , congenital anomalies, mental retardation, infertility.

Second, cytogenetic research in spouses and counseling is needed, which includes:

1. An explanation of what is found in the spouses (genealogy + cytogenetics);
2. Risk assessment for subsequent miscarriages or childbearing with developmental abnormalities;
3. Clarification of the need for prenatal diagnosis in subsequent pregnancies; the possibility of donation of the egg or spermatozoa in detecting a gross pathology in the spouses; chances of not having a child in this family, etc .;

Thirdly, if possible, a cytogenetic examination of the abortus, all cases of stillbirth and neonatal mortality.

Probably, while the human genome is not completely deciphered, it's hard to imagine what the shortening or lengthening of chromosomal arms gives in the genome. But in the process of meiosis, with the discrepancy of chromosomes and further in the process of formation of the new man's genome, these small, not clear values, changes can play their dysfunctional role. Such a high percentage of karyotype disorders, even in the form of a "variant" of the norm, we did not observe in patients with late pregnancy loss.

[1], [2], [3], [4], [5]