At present, we often hear “so-and-so colleague had another miscarriage! , “so-and-so relative had another embryo stop!”. It’s true.
Indeed, recurrent miscarriages or embryonic arrests are a common occurrence among women of childbearing age and are on the rise. While these patients are actively looking for female factors, the gynecologists or fertility center doctors also recommend that the husband of the patient come to the male clinic to look for male causative factors. This is because the embryo is formed by the male partner’s sperm and the female partner’s egg together to form a fertilized egg, and factors on either side can lead to recurrent miscarriage and embryonic arrest.
What is recurrent miscarriage and embryonic arrest?
Recurrent spontaneous abortion (RSA) is defined as two or more consecutive spontaneous abortions, the incidence of RSA is about 2% to 5%.
The term “embryonic arrest” refers to the cessation of the development of the embryo in the early stages of pregnancy for some reason, which is customarily referred to as embryonic arrest. This is a clinical category of miscarriage or stillbirth, which used to be called premature abortion or indolent abortion.
What factors can cause it?
1, genetic factors including autosomal and Y chromosome color abnormalities. This is a clear cause of miscarriage and embryonic arrest for the woman, which is why we need to check the chromosomes. Humans contain 23 pairs of chromosomes, chromosomes 1~22 are called autosomes, and the difference of chromosome 23 determines the sex of men and women. It has been reported that 22% to 61% of aborted embryos have chromosomal abnormalities.
(1) Abnormalities in the number of autosomes: one type of chromosomal aneuploidy, in which spontaneous abortions occur and few fetuses survive. The other type of chromosomal aneuploidy includes haploid, trisomic, and polysomic abnormalities, and the surviving offspring often have obvious clinical manifestations of the abnormality, including trisomy 21 and Creutzfeldt-Jakob syndrome. These males are mostly combined with low fertility or infertility.
(2) Structural abnormalities of autosomes: This is caused by chromosome breakage, loss and improper recombination during the process of inheritance. The most common are translocations, followed by inversions. Carriers of balanced chromosomal translocations have unbalanced gametes produced by their germ cells during meiosis, which can lead to adverse outcomes such as miscarriage and malformations. The high miscarriage rate is associated with males carrying abnormal karyotypes, and the probability of miscarriage caused by males with reciprocal translocations is 61.1%, and the probability of miscarriage caused by inversions is about 28% to 42.9%; for embryonic arrest, the karyotype abnormality rate is 5.22%, of which autosomal abnormalities account for 14.6%.
(3) Y chromosome: Y chromosome length variation has genetic effects and is associated with miscarriage and embryonic arrest. Y chromosome integrity plays an important role in embryonic development and maintenance of pregnancy. There are two conditions: a large Y chromosome, which is defined as a Y chromosome length > chromosome 18 in the same karyotype. The detection rate of large Y chromosome in consecutive miscarriages can be 40.05%; the other is small Y chromosome, which refers to Y chromosome length < chromosome 21 in the same karyotype. The incidence of RAS due to small Y chromosome ranges from 3.26% to 26.32%, with a large variation.
The gene that regulates spermatogenesis, called AZF gene, is present on the long arm of Y chromosome. Its deletion, which we call microdeletion of the Y chromosome, not only affects spermatogenesis, but may also affect the continued pregnancy of the partner.
Treatment principles.
In general, there is no specific treatment for most patients due to genetic factors. For some of these translocations, the resulting unbalanced embryos end in miscarriage – repeated miscarriages and births of chromosomally abnormal offspring can be avoided by third generation IVF (PGD) techniques. Sperm donation may be a hopeless choice for patients.
2. Sperm DNA damage Sperm quality is associated with fertilized egg development to the blastocyst stage and implantation capacity, and paternally expressed genes regulate trophoblast cell proliferation and invasiveness and subsequent placental proliferation. Sperm DNA integrity is extremely important for sperm-egg interaction, fertilization, and early fertilization oogenesis. Studies have shown that RSA and embryonic arrest are significantly elevated with sperm DNA damage.
Treatment principles.
There is no specific treatment available, and all possible causes of sperm DNA damage need to be sought and treated for the cause. For example, inflammation of the reproductive tract, high temperature in the testis, varicocele, smoking, environmental factors, drugs and radiotherapy, chemotherapy, etc. Symptomatic treatment of the cause and complementary antioxidant drugs, etc. Some studies have shown that antioxidant therapy: vitamin C, vitamin E, etc. have the effect of improving sperm DNA. Chinese medicine may have a role in this part of the patients, clinically effective for some patients, but there is a lack of scientific research.
3. Anti-sperm antibodies Normal men do not produce anti-sperm antibodies due to the protective effect of the blood-testis barrier. Some studies have shown that men with RAS have a higher rate of positive antisperm antibodies than normal men. The possible mechanisms are.
(1) The antibodies adhere to the sperm surface thus causing sperm to agglomerate with each other and affecting sperm motility;
(2) When the complement activity in seminal plasma is high, it also causes complement-mediated attack and damages spermatozoa;
(3) Affects the activity of spermatozoa enzymes and inhibits the dispersal effect of the radioactive crown;
(4) Closure of the antigenic sites of the acrosome membrane and inhibition of sperm attachment to and penetration of the zona pellucida;
(5) Affects the binding of sperm and egg;
(6) It can affect the development of embryo.
Treatment principles.
For the treatment of antisperm antibodies, the application of hormones is not too common due to the side effects of hormones and the development of assisted reproduction techniques. Chinese medicine is useful for the conversion of anti-sperm antibodies and improving the conception rate. For those who are ineffective in medication, assisted reproduction techniques, such as washing of sperm, IUI, IVF-ET, ICIS, etc., can be used to help conception.
4. Sperm morphology The World Health Organization (5th edition) describes normal sperm morphology as normal if it is greater than 4%. Although this criterion is more controversial at present, the relationship between poor semen quality and poor embryo development has been widely confirmed.
Abnormal sperm morphology is associated with abnormal sperm nucleoprotein histotype conversion, abnormal chromatin structure, sperm nucleoprotein defects, and DNA breaks. Sperm with chromatin abnormalities mostly show abnormal head morphology (e.g. large-headed sperm) with a significantly higher likelihood of miscarriage; abnormal acrosome in the head of sperm can cause sperm to lose the ability to fertilize leading to infertility or even cause miscarriage; mitochondria in the tail of sperm provide energy and normal morphology of microtubule structure is the basis of sperm motility sperm with tail abnormalities can cause sperm motility impairment, leading to reduced fertility.
Treatment principles.
Actively search for the cause and treat the cause (e.g. infection, sperm curvature, external physical and chemical factors, etc.). Antioxidant therapy is the most common treatment, and there is room for Chinese medicine to play a role, although there are few studies reported on whether Chinese medicine can improve the rate of sperm malformation, but it can improve the conception rate, probably related to the role of multiple targets to improve sperm motility and improve the quality of semen through multiple links. For those for whom drug treatment is ineffective, sperm can be treated (e.g. upstream method, etc.) for assisted reproduction.
5. Infection factors Currently, Chlamydia trachomatis (CT) and Ureaplasma trachomatis (UU) infections are considered to be important pathogens causing RSA. UU attached to the surface of sperm can secrete neuraminidase substances, and when they enter the oocyte with the sperm, the embryo will die and abort; they can cause an inflammatory response in the endometrium, affect the regulatory mechanism of the maternal autoimmune system to protect the embryo, interfere with embryo implantation or They can cause an inflammatory response in the endometrium, affecting the regulatory mechanism of the maternal immune system to protect the embryo, interfering with embryo implantation or damaging the growing embryo to induce miscarriage; the infection destroys the blood-testis barrier, which can lead to an immune response, producing ASAB, which in turn affects the development of early embryos and leads to miscarriage. In addition, the DNA damage rate of spermatozoa from patients infected with UU or CT is 3.2 times higher than that of controls, which can be reduced after antibiotic treatment. Of course TORCH (eugenics system) infection can also cause miscarriage and embryonic arrest.
Treatment principles.
Anti-infective treatment, for the most common UU and CT infections, firstly macrolide antibiotics and secondly quinolone antibiotics. For the male partner of RAS and embryonic arrest patients, microbial culture and drug sensitivity should be done routinely.
6.Unknown causes
(1) Age As men age, there is an increase in atypical spermatogonia, abnormal sperm cells, interstitial fibrosis of the germinal tubules, and shedding of immature germ cells, resulting in decreased sperm quality, decreased conception rate, increased miscarriage rate, autosomal regional dominant genetic disorders in the offspring, and increased fetal mortality. It was found that the rate of structural aberrations of sperm chromatin was significantly higher in men aged 59-74 years compared to men aged 23-29 years.
(2) Environmental factors Male sperm continue to be produced from pubertal development and the testes are superficially located, making them susceptible to external exposure factors during spermatogenesis, which can induce mutations or produce aneuploidy, etc. High temperature, air pollution, ionizing radiation, radiotherapy, mercury, and dibromochloropropane can all increase the mutation rate of sperm DNA.
Treatment principles
Age is an irresistible factor. From the perspective of eugenics, it is recommended that couples who have high expectations for their “career” should conceive a baby at an appropriate time. For environmental factors, we can only try to avoid them under certain conditions.
In conclusion, numerous studies have shown that male factors can affect embryogenesis, implantation, birth defects and miscarriage. Genetic mutations, advanced age, infections and any paternal genetic abnormality affecting the placenta suggest a risk of miscarriage and embryonic arrest. Therefore, active management of male factors is important for the prevention of RSA and embryonic arrest and for eugenic reproduction.