Genetic causes of miscarriage

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

According to Boue J. et al. (1975), chromosomal abnormalities were detected in 50-65% of abortions during cytogenetic testing. According to French F. and Bierman J. (1972), out of 1000 pregnancies registered from 5 weeks, 227 end in spontaneous abortion by the 28th week, and the shorter the gestation period, the more frequent the losses. Chromosomal abnormalities were detected in 30.5% of abortions, with 49.8% having trisomy, most often trisomy of chromosome 16, 23.7% having X-monosomy, and 17.4% having polyploidy. It is believed that trisomy of other chromosomes is also common, but they are lethal at very early stages of development, more often than clinical ones, and are not included in studies. The phenotype of abortions is highly variable - from anembryony or “empty fetal sac” to intrauterine fetal death.

Total reproductive losses in humans amount to approximately 50% of the number of conceptions, with chromosomal and gene mutations playing a dominant role in the genesis of losses.

With a high initial level of formation of chromosomally abnormal embryos, natural selection occurs, 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 chromosomal aberrations survive to the perinatal period.

Several prospective studies in large populations have found chromosomal abnormalities in 1 in 200 newborns. With more detailed examination, this figure is even higher, and only one in three have these abnormalities detected during clinical examination.

Human chromosomal pathology depends not only on the intensity of the mutation process, but also on the effectiveness of selection. With age, selection weakens, so with older parents, developmental anomalies are more common.

In most cases, chromosomal pathology appears as a result of a de novo mutation in the germ cells of parents with a normal chromosomal set, as a result of a meiotic disorder, or in germline cells as a result of a mitotic disorder.

The lethal effect of a mutation that occurs after implantation results in the cessation of embryo development, resulting in miscarriage.

About 30% of zygotes die due to the lethal effect of the mutation. Meiotic disorders can be caused by many factors that affect the fetal karyotype: infection, radiation, chemical hazards, medications, hormonal imbalance, aging of gametes, defects in genes that control meiosis and mitosis, etc.

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

In women with habitual miscarriage, significant structural karyotype abnormalities occur 10 times more often than in the population and account for 2.4%.

The most common chromosomal abnormalities are trisomy, monosomy, triploidy, and tetraploidy. Triploidy and tetraploidy (polyploidy) are usually caused by fertilization by two or more spermatozoa or by a disorder in 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 in termination of pregnancy.

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

The most common cytogenetic cause of repeated abortions is reciprocal translocation of chromosome segments. 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 a chromosomal segment is included in another place of the same chromosome or transferred to another chromosome, or an exchange of segments occurs between homologous or non-homologous 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, contributing to the occurrence of spontaneous abortions, infertility, or the birth of children with developmental anomalies.

With 2 spontaneous miscarriages in the anamnesis, 7% of married couples have chromosomal, structural changes. The most common is reciprocal translocation - when a 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 deficiency), as a result of this imbalance either a miscarriage occurs or the birth of a fetus with developmental anomalies. The risk of pregnancy loss depends on the specificity of the chromosome, the size of the translocation site, the sex of the parents with the translocation, etc. According to Gardner R. et al. (1996), if such an imbalance is present in one of the parents, the chance of having a miscarriage in a subsequent pregnancy is 25-50%.

The main cause of habitual abortion is reciprocal translocation, and its recognition requires analysis of chromosome segments. During the examination of 819 members of families with habitual abortions, 83 chromosomal abnormalities were identified, of which the most common were Robertsonian translocations (23), reciprocal translocations (27), pericentric inversions (3), and mosaic sex chromosomes (10).

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

Married couples with reproductive system disorders are found to have such disorders as "mosaicism" or "minor" changes in chromosome morphology, or even "chromosomal variants". At present, they are united by the concept of "polymorphism". Karetnikova N.A. (1980) showed that in spouses with habitual miscarriage, the frequency of chromosomal variants is on average 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 of S and satellite threads h of acrocentric chromosomes, the size of the Y chromosome - in parents contribute to an increased risk of chromosomal rearrangements, due to which the frequency of reproductive disorders and developmental anomalies increases.

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 frequency of miscarriage, stillbirth and birth of children with developmental anomalies is much higher than in the population. As our studies have shown, there are especially many spouses with "karyotype variants" in miscarriage of early gestation.

When transmitted from phenotypically normal, genetically balanced carriers, chromosomal variants relatively infrequently, but inevitably lead to the formation of chromosomal rearrangements in their gametogenesis, which results in genetic imbalance in the embryo and an increased risk of abnormal offspring. Minor chromosomal variants should be considered as a chromosomal load that may be responsible for miscarriage.

Apparently, with the decoding of the human genome it will be possible to identify the significance of such minor forms of karyotype disorders for humans.

If the spouses have a history of more than 2 spontaneous abortions, medical genetic counseling is necessary, which includes a genealogical study 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.

Secondly, cytogenetic testing of the spouses and counseling are necessary, which includes:

1. Explanation of what was found in the spouses (genealogy + cytogenetics);
2. Assessing the degree of risk for subsequent miscarriages or the birth of a child with developmental abnormalities;
3. Explanation of the need for prenatal diagnostics in subsequent pregnancies; the possibility of donating an egg or sperm if a serious pathology is detected in the spouses; the chances of not having a child in this family, etc.

Thirdly, if possible, cytogenetic testing of abortions, all cases of stillbirths and neonatal mortality.

Probably, until the human genome is fully deciphered, it is difficult to imagine what shortening or lengthening of chromosome arms gives to the genome. But in the process of meiosis, when chromosomes diverge and later in the process of forming the genome of a new person, these small, unclear changes can play their unfavorable role. We have not observed such a high percentage of karyotype abnormalities, even in the form of a "variant" of the norm, in patients with late pregnancy losses.

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