New Understanding of the Causes of Miscarriage

Maria Leo^*

Department of Biological Science, University of Lisbon, Portugal

Received: 01-June-2023, Manuscript No. jlcb-23-103096; Editor assigned: 05-June-2023, Pre QC No. jlcb- 23-103096(PQ); Reviewed: 19- June-2023, QC No. jlcb-23-103096; Revised: 22-June-2023, Manuscript No. jlcb-23-103096(R); Published: 29-June-2023; DOI: 10.37532/ jlcb.2023.6(3).93-96

Abstract

The most common complication of early pregnancy is sporadic miscarriage. A less common occurrence is the loss of two or three pregnancies in a row; this is considered a separate disease entity. It is generally accepted that sporadic miscarriages are primarily the result of abnormal embryos failing to develop into viable embryos. Multiple factors, including maternal thrombophilic disorders, immune dysfunction, and a variety of endocrine disorders, are thought to contribute to recurrent miscarriage. However, neither of these conditions is always associated with repeated early pregnancy loss nor is it exclusive to recurrent miscarriage. New theories about the causes of sporadic and recurrent miscarriage have emerged in recent years. In addition to lifestyle factors and changes in sperm DNA integrity, epidemiological and genetic studies suggest a multifactorial background in which immunological dysregulation during pregnancy may play a role. The idea that the decidualized endometrium functions as a biosensor of embryo quality has been supported by recent experimental findings. If this biosensor is disrupted, it may result in the implantation of embryos that are designed to fail. These brand-new insights into the underlying mechanisms of miscarriage raise the possibility of novel and potent preventative measures.

Keywords

Sporadic miscarriage • Thrombophilia disorder • Immune disorder • Recurrent miscarriage • Epidemiological studies • Endocrine disorder

Introduction

Many early pregnancy complications are referred to as “miscarriages,” so it’s important to understand the terminology. The European Society of Human Reproduction and Embryology (ESHRE) defined early pregnancy events in a new way in 2005. A “biochemical loss” is defined as a pregnancy loss that occurs prior to ultrasound or histological verification but after a positive urinary Human Chorionic Gonadotropin (hCG) or raised serum -hCG. These typically occur before the sixth week of pregnancy. When an ultrasound examination or histological evidence demonstrates the existence of an intrauterine pregnancy, the condition is referred to as clinical miscarriage. Early clinical pregnancy losses (before gestational week 12) and late clinical pregnancy losses (from gestational week 12 to 21) are two types of clinical miscarriages. ESHRE guidelines define Recurrent Miscarriage (RM) as three or more consecutive pregnancy losses before 22 weeks of gestation. However, there is no consensus regarding the number of pregnancy losses required to meet the criteria for RM. It is acknowledged that the aforementioned terminology is not always clinically useful, despite its widespread use. In fact, a recent paper suggested categorizing pregnant women according to their developmental periods [1].

Early pregnancies frequently result in clinical miscarriage, which can be a distressing complication. Advances in cytogenetic and immunogenetics, as well as a better understanding of implantation and maternalembryo interactions, have provided new insights into the condition’s potential causes and opened up new research opportunities for its prevention and treatment [2].

The prevalence of both occasional and persistent miscarriages

Ineffectiveness is a characteristic of human reproduction. Only about one third of conceptions result in a live birth, according to prospective cohort studies using sensitive and specific daily urinary hCG assays on women trying to conceive. An estimated 30 percent of human conceptions fail before being implanted, and another 30 percent fail after being implanted but before the missed menstrual period, which typically occurs in the third or fourth week of pregnancy. Preclinical losses are a common name for these. Lastly, it is estimated that 15% of conceptions result in early clinical pregnancy loss, with significant age-related variation. Therefore, the incidence varies from 10% in women between the ages of 20 and 24 to 51% in women between the ages of 40 and 44. About 4% of pregnancies end in late losses between 12 and 22 weeks, which occur less frequently [3].

Whether or not biochemical losses are included, the prevalence of RM is significantly lower than that of sporadic miscarriage. The prevalence ranges from 0.8% to 1.4% when clinical miscarriages are included. However, the prevalence is estimated to be between 2% and 3% if biochemical losses are taken into account. It is considered to be a disease entity that is defined by a series of events and has a number of possible etiologies because the incidence of RM is greater than would be predicted by chance [4].

The “physiological” causes and mechanisms of early pregnancy loss

It is a widely held belief that sporadic pregnancy losses that occur before an embryo has developed are a “physiological” phenomenon that prevents conceptions with serious structural malformations or chromosomal aberrations that are incompatible with life from developing to viability. Clinical studies that used embryoscopy to evaluate the morphology of the fetus prior to uterine evacuation support this idea. 85 percent of cases presenting with early clinical miscarriage had fetal malformations. An abnormal karyotype was found in 75% of the fetuses, according to the same study. Common are non-inherited and non-disjunctional causes of fetal chromosomal aneuploidies. Indeed, more than 90% of preimplantation human embryos were found to have at least one chromosomal abnormality in one or more cells in a recent comparative genomic hybridization study of the chromosomal complement of all blastomeres. It is still unclear what clinical implications minor, mosaic, and possibly “transient” aneuploidies have. However, despite the fact that the majority of fetuses with severe developmental defects will die in utero, some aneuploidies may allow them to live to full term. Trisomy 21 is the most common, but 80% of affected embryos die in utero or during the neonatal period. The majority of the time, the extra chromosome comes from the mother and is brought on by a mal segregation event during the first meiotic division. This may be considered a biological rather than a pathological phenomenon because the risk increases with maternal age. Although fetal chromosomal aberrations can be found in 29% to 60% of women with RM, the incidence decreases as the number of miscarriages rises, pointing to other mechanisms as a possible cause of miscarriage in RM couples who have experienced multiple losses [5].

Prenatal chorion villus sampling and amniocentesis will probably be replaced by diagnostic tests using fetal genetic material isolated from maternal plasma in the not-toodistant future for the diagnosis of fetal genetic diseases. From seven weeks of pregnancy, cellfree fetal DNA can be isolated from the mother’s blood, and numerous studies using nextgeneration sequencing techniques to identify fetal aneuploidies in cell-free fetal DNA have already been published. New insights into both chromosomal abnormalities and single gene disorders as a cause of sporadic and recurrent miscarriage will be gained as a result of the upcoming ability to sequence the entire fetal genome from free fetal DNA in the maternal circulation [6].

The reasons are immunological and genetic

Despite carrying allogeneic proteins encoded by paternal genes, it has long been a mystery how the implanting embryo and trophoblast survive maternal immunological rejection in the uterus. The majority of pregnancies are thought to be rejected by a set of mechanisms regulating maternal immune recognition and fetal antigen expression; however, when these mechanisms fail, they may result in RM [7].

It is likely that redundant mechanisms have developed to prevent immune rejection of the embryo, and RM will only occur when multiple mechanisms fail in a woman because reproductive success is crucial to a species’ survival. The ongoing debate regarding which immunological factors contribute to the pathogenesis of RM is exacerbated by this complexity [8].

There is general agreement that a number of autoantibodies, including those against phospholipid, nuclear, and thyroid, are more common in RM patients and may have a negative impact on prognosis. In any case, in people there is no confirmation that the antibodies essentially hurt the pregnancy; they could simply be indicators that these women are more likely to disrupt their immunological self-tolerance and pro inflammatory responses. Contrarily, a study found that pregnant mice injected with human IgG from a patient with anti-phospholipid antibodies significantly increased fetal resorption rate and decreased fetal weight, whereas antibodies blocking activation of the complement cascade prevented fetal resorptions and growth retardation completely when administered concurrently. In addition, mice lacking various complement factors were found to be resistant to fetal injury caused by injection of anti-phospholipid antibodies in this and other studies. This suggests that antiphospholipid antibodies may, at least in mice, exert their harmful effect on pregnancy through immunological mechanisms (complement activation) rather than a direct pro coagulant effect. However, there is less convincing evidence that humans with anti phospholipid syndrome are also subjected to complement activation by anti-phospholipid antibodies.It is debatable whether measurements of these biomarkers in peripheral blood reflect conditions at the feto-maternal interface. However, a number of studies have shown that women with RM and euploid sporadic miscarriage can have higher concentrations of pro inflammatory or T helper cell type I cytokines or higher frequencies of subsets of Natural Killer (NK) cells in the blood. Although a systematic review of relevant studies did not find that peripheral blood or uterine NK cell density or activity were predictive of pregnancy outcome in patients with RM, there is some evidence that uterine NK cells regulate angiogenesis in the non-pregnant endometrium and may therefore also play a role for implantation and early pregnancy [7].

The most persuading proof for the significance of the safe framework in unsuccessful labor and RM comes from hereditary/epidemiologic examinations showing that hereditary biomarkers of conceivable significance for immunologic dysregulation in pregnancy are found with expanded recurrence in ladies with RM and show an adverse consequence on the visualization. Maternal homozygosity for a 14-base-pair insertion in the human leukocyte antigen (HLA)-G gene, maternal carriage of HLA class II alleles predisposing to immunity against male-specific minor histocompatibility antigens found on male embryos, specific maternal NK cell receptor genotypes in combination with fetal HLA-C genotypes that may be associated with aberrant maternal NK cell.

Prednisone, allogeneic lymphocyte immunization, intravenous immunoglobulin infusion, and injections of Tumor Necrosis Factor (TNF) antagonists or Granulocyte Colony-Stimulating Factor (G-CSF) are among the proposed treatment options for RM where immunologic dysregulation is thought to be involved. Due to the fact that the majority of these treatments have either only been tested in a few or small number of randomized controlled trials, there is a lot of debate surrounding their efficacy [8].

Epigenetic causes and polymorphisms in the HCG gene

The two subunits that make up the glycoprotein hCG are known as and. During the first trimester, an increasing amount of the syncytiotrophoblast’s secretion binds to the corpus Luteum’s Luteinizing Hormone (LH)/ hCG receptors, preventing its regression. It is common knowledge that low or inadequately increasing hCG levels are typically linked to early miscarriage. There are two possible interpretations for the link between miscarriage and low hCG production: 1) embryonal aneuploidy, immune or thrombophilic disturbances, and low hCG production are secondary causes of delayed trophoblast growth; or 2) the fetoplacental unit may secrete insufficient hCG due to a primary failure of the trophoblast to produce hCG, resulting in insufficient progesterone production and embryonic death. The latter condition may be treated with external hCG or progesterone, whereas the former condition would theoretically not benefit from it. If the trophoblast’s primary failure to produce hCG is the reason for some miscarriages, it could be genetic. On chromosome 19, four duplicate Chorionic Gonadotropin (CGB) genes code for the hCG subunit, with CGB5 and CGB8 being the most active. Tissue from RM appears to have lower levels of hCG-mRNA than from either ectopic or normal first trimester pregnancies, and there is a correlation between plasma hCG levels and trophoblast mRNA transcript levels. Some miscarriages in RM couples may be caused by polymorphisms in the CGB genes, as certain polymorphisms in the promoter region of the CGB5 gene have been found to have a lower prevalence in RM couples than in fertile couples. Couples with these polymorphisms might benefit from taking hCG supplements, but prospective trials are needed to verify this [9, 10].

Conclusion

Some cases of early pregnancy loss may be caused by epigenetic disruptions, according to recent evidence. The process of DNA demethylation and remethylation that embryos go through during implantation is crucial to their health and development. DNA methyltransferase1, an enzyme involved in maintaining methylation, was found to be expressed at lower levels in villi derived from embryos lost in early pregnancy in a study comparing methylation in embryos from medically terminated pregnancies to those from spontaneous losses. However, it remains unclear whether this is a causal rather than an associated phenomenon with miscarriage. There are currently a number of candidate genes that have been linked to a slight increase in the risk of early pregnancy loss. The majority of these genetic polymorphisms carry a low relative risk of miscarriage, depending on the patient’s clinical and genetic background; consequently, screening for the polymorphisms is not clinically useful.

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