"Recurrent miscarriage" (RM), also known as "repeated pregnancy loss" (RPL) and "habitual abortion," is the term used to describe three or more consecutive spontaneous miscarriages that occur at 20 weeks or less (24 weeks or less in Iraq, according to the Ministry of Health), or with fetal weights of less than 500 grams [1]. For women who are attempting to get pregnant, losing pregnancies repeatedly is physically and emotionally distressing. A range of 1% to 3% was calculated for the total frequency of RM [2].

        The prevalence of RM will depend on how it is defined. There is still no agreement on what constitutes RM with regards to the number of prior miscarriages and gestational age. The number of prior miscarriages in RM is three or more according to the European Society of Reproduction and Embryology, but the American Society for Reproductive Medicine defines it as two or more [3]. Recurrent miscarriage's etiology Since RM is a diverse illness, it is unlikely that RM is caused by only one specific pathogenic component. According to recent research, only 40% to 50% of instances of RM have a known cause. Idiopathic is the classification given to the remaining instances of RM[4]. Parental, prenatal, environmental and psychological factors have been identified as the identifiable causes of RM to date[4-6].

Parental Factors

Chromosomal Abnormality: 2%–4% of RM is caused by parental balanced structural chromosomal rearrangement [7]. The most frequent type of chromosomal rearrangement, known as a balanced reciprocal or Robertsonian translocation, can cause unbalanced gene translocations in the developing baby, which can cause miscarriage [8]. Chromosome inversion, insertions and mosaicism are further chromosomal abnormalities connected to RM.

Maternal Factors

Age

• It is well known that as a woman ages, her fertility declines and her chance of miscarriage, fetal trisomy 21 and monosomy XO increases. RM is a form of reproductive failure that is frequently affected by risk factors. Recurring losses and maternal age are two important predictors that a woman with RM would miscarry, according to studies [9]

• Features of AnatomyAnatomical aberrations account for 16 to 18% of RM cases [6]. Typical anatomic abnormalities include uterine adhesions, uterine fibroids, uterine polyps and congenital uterine deformities. These defects may cause insufficient endometrial vascularity when mbryos implant, which could ultimately result in placental abruption and miscarriage. Congenital uterine abnormalities such an arcuate, septate, or bicornuate uterus, among these natomic defects, may be more likely to cause second-trimester miscarriages than early pregnancy losses [10]

Endocrinological Factors

In between 8% and 12% of cases of RM, endocrinological disorders are to blame [2]. Luteal phase deficiency (LPD), polycystic ovarian syndrome (PCOS) and hyperprolactinemia are the three endocrinological conditions that affect RM the most frequently. When the endometrium develops more than two days later than its corresponding chronological date in a histological dating, it is said to have LPD [3].

Replacement therapy with progesterone or human menopausal gonadotropin (HMG) has been shown to lower the rate of miscarriage in RM patients with LPD, which has been connected to LPD [11].

According to case studies, RM patients with PCOS who had metformin and ovarian drilling treatments were able to have healthy live babies [12], suggesting a connection between RM and PCOS. Diabetes Mellitus: Women with insulin-dependent diabetes had higher incidence of spontaneous abortion and significant congenital malformations. The degree of metabolic control in early pregnancy seems to be correlated with risk [1].

Prothrombotic States

Prothrombotic conditions are thought to be responsible for 12.5% of RM (13) Both acquired and inherited disorders fit the bill for this ailment.2. Hereditary thrombophilia. 12.5% of RM may, according to estimates, be attributable to prothrombotic states [13] both inherited and acquired disorders fit the description of this ailment.Gene-based thrombophilia.

Antithrombin III Deficiencies

Antithrombin III is the most potent inhibitor of thrombin, factor Xa, IXa and XII an. A decrease in antithrombin III concentration or function results in an antithrombin III deficiency [14]. The risk of thromboembolism over the course of a lifetime is high because to this autosomal disease. Women with antithrombin deficiency have been found to have a substantially increased risk of miscarriage.

Protein C and Protein S Deficiencies

When protein S is present, protein C performs a larger role that inhibits the anticoagulant factors Va and VIIIa. When protein C activity or antigen levels are decreased, there is inadequate protein C available. A drop in protein S concentration or function causes protein S shortage [1]. Protein C plays a bigger role in inhibiting the anticoagulant factors Va and VIIIa when protein S is present. When protein C activity or antigen levels are decreased, there is inadequate protein C available. When its concentration or function decreases, Protein S becomes rare.

Factor V Leiden mutation

The Factor V Leiden mutation results in acquired protein C resistance and placental veins and spiral arteries thrombophilia. This could result in placenta abruption and, ultimately, miscarriage. The relationship between RM and Factor V Leiden has been discovered [15].

Prothrombin Gene Mutation (G20210 Mutation)

The most notable risk factor for venous thrombosis is the prothrombin gene mutation (G20210A), which is linked to an increased risk of thrombosis. Recent research has revealed a relationship between RM and the G20210A mutation [15].

Acquired Thrombophilia

The antiphospholipid syndrome (APS) is the most frequent form of acquired thrombophilia connected to RM. Antiphospholipid antibodies are autoantibodies that are directed towards negatively charged phospholipids. Primary APS (when it presents alone) and secondary APS (when it coexists with other illnesses like systemic lupus erythematosus) are the two subtypes of APS. The main factor causing RM has been identified as APS. In a cohort of 500 consecutive women with RM, Rai et al. looked at the prevalence of APS and discovered that 15% of them had APS [16].

Immunological Factors

The mother's immune system's capacity to adapt to fetal antigens determines whether or not the semiallogenic embryo survives during gestation. Loss of pregnancy could result from immune adaptive process dysregulation.

Thyroid Antibody

Thyroglobulin and thyroid peroxide antibodies were discovered to be related with RM, indicating that thyroid autoimmunity may not be functioning properly and contributing to RM [17].

Natural killer Cells

The natural killer (NK) cell has been the subject of the greatest research. NK cells are a crucial component of innate immunity and make up the majority of the endometrium's leukocyte population during implantation and the early stages of pregnancy. NK cells control the maternal adaptive immunity to the semi-allograft embryo by secreting cytokines, chemokines and angiogenic agents. Numerous studies have demonstrated that RM is linked to an increase in NK cells in endometrial tissue as well as peripheral blood [18].

H-Y antibodies

Prior to secondary recurrent miscarriage, boys are born far more frequently than girls and this is related to a lower likelihood of a future live birth. Girls are more likely to be born after secondary RM.Pregnancy losses have been linked to high-titer antisera that are specific for male antigens (H-Y) [19].

Cervical Incompetence

The phrase "cervical incompetence," also known as "cervical insufficiency," describes the cervix's dilation and shortening in the absence of labor contractions as a result of a problem with the cervical sphincter [20]. Repeated spontaneous miscarriages in the middle of the third trimester have been linked to cervical incompetence.

The Infections

It's unclear what part infection plays in RM. Herpes simplex virus (HSV), Listeria monocytogenes, Toxoplasma gondii, rubella and Chlamydia trachomatis are only a few of the microbes that have been linked to unforeseen miscarriage. More so than early pregnancy losses, bacterial vaginosis appears to be linked to early membrane rupture, which causes midtrimester loss and premature labor [21].

Paternal Factors

There hasn't been much research done on the relationship between RM and sperm shape and function, thus it's unknown at the moment. According to preliminary research, sperm DNA with aberrant integrity may increase the risk of miscarriage [22]. These studies, however, are more concerned with occasional miscarriages than RM.

Fetal Factors

The most frequent cause of fetal RM is a genetic abnormality. The most common chromosomal abnormalities of abortuses in RM are aneuploidy, or an abnormally large number of chromosomes [23]. Preimplantation genetic diagnosis (PGD) statistics show that after aneuploidy screening, women with RM had a higher rate of chromosomally defective embryos than women without RM [24]

Environmental Factors

Smoking and drinking coffee have been linked to an increased risk of miscarriage. Recent research has revealed that daily caffeine consumption has a dose-dependent effect on the risk of RM in females who are homozygous for the caffeine-metabolizing enzyme CYP1A2*1F [25]. According to other studies, women who drank wine and coffee while also being around tobacco smoke were more likely to spontaneously miscarry [1].

Psychological Factors

Experiences that may have psychological repercussions are referred to as stressful or tense [26]. When the hazards are greater than one's capacity to handle them, stress results. Stressors are the situations that can lead to stress. The two different types of stressors are acute stressors, which are short-term events like hunger or being in a vehicle accident and chronic stressors, which are long-term events like poverty or bad health [27]

Stress responses are the responses that stress causes [27]. Stress can affect a person's mental health by causing symptoms including anxiety, rage and aggression, apathy and despair and cognitive impairment. The physiological reactions to stress may include an increase in blood pressure, blood sugar levels, pupillary dilation, metabolic rate, heart rate, blood pressure, tense muscles and pupillary dilatation [27].

Researchers have so far suggested a number of models for the stress response. The 'fight-flight' model of stress reactions, initially introduced by Walter Cannon in 1932, is an essential illustration of these responses. The sympathetic nervous system and the endocrine system are described as being activated by a stress input, rousing and mobilizing the body. This arousal may be protective by enabling resistance to the threat or fleeing from it.

However, given that it eventually results in psychosomatic problems, it might be dangerous [27]. The "general adaptation syndrome," which explains a multitude of physiological changes in stress reactions, is another popular model of the stress response. There are three steps to it. The sympathetic nervous system is more active during the initial stage of alarm, consuming resources and diminishing threat resistance. The body fortifies itself against the threat and actively engages it by running away from or resisting it in the second stage of resistance. When the body runs out of physical resources, which results in decompensation and illness, the body enters the third stage of "exhaustion" [27].

Someone may become more prone to illness or disease if their sympathetic nervous system or neuro-immune-endocrine system are overstimulated for an extended period of time after being subjected to stress stimulation [27]. The cardiovascular, immunological and endocrine systems are negatively impacted by this excessive arousal, leading to health issues [26].

The Stress Following Miscarriages

Having children is a common goal of relationships for many couples. However, spontaneous miscarriages occur in 15% to 20% of pregnancies [28] Miscarriages are frequently described as traumatic by couples. Words like "grief," "mourning," "guilt," "anxiety," "depression," "coping," "loss of self-esteem," and "frustration" are frequently used to describe the psychological anguish brought on by miscarriages [29].

Despite a growing body of study on the subject, there are variations in the rate of psychiatric morbidity following miscarriages. This discrepancy may result from the conflicting stress measurements utilized in recent investigations. There isn't much agreement on the psychometric measures that should be used to assess stress associated to infertility, despite the fact that questionnaires are the most used stress assessment tools. In their research, many writers used various questionnaires to measure various psycho-parameters [27].

Stress (Physical and Emotional) Causing Miscarriages

Studies on animals have demonstrated that sound stress causes mice to miscarry by increasing inflammatory markers like TNF [30]. Human studies have indicated that stress (both physical and mental) reduces the possibility of conception and that stress is also associated with a higher risk of miscarriage [31].

For instance, a prospective epidemiological investigation was carried out by Boivin et al. [32] with a sizable cohort of 818 couples who received reproductive procedures. For instance, Boivin et al. [32] carried out a prospective epidemiological study with a sizable cohort of 818 couples who received reproductive procedures [32]. A large cohort of 1098 women was also examined by Arck et al. [33] and they discovered that higher stress levels were linked to a higher chance of future miscarriages in the first trimester of pregnancy [33]. In a significant epidemiological study, the first trimester miscarriages of 603 women in the UK population and 6116 people without a recent miscarriage were compared. They discovered [34], confirming that stress contributes to miscarriage, that stress raises the possibility of miscarriage. In contrast to the research described above, other studies revealed a harmful link between stress and miscarriage. For instance, a prospective study of 783 women revealed no relationship between anxiety or depression and the success rates of IVF treatment for conception [35].

Research also revealed that the risk of miscarriage in a subsequent pregnancy was not increased by psychological stress [36-37]. Furthermore, a study found a correlation between higher stress levels and a better pregnancy result as opposed to miscarriage [38] ⁽The following contradicting conclusions could be the result of different psychometric scores. measures for evaluating stress. 

The mechanism of Stress Effect on RM

The following contradictory findings could be the outcome of various psychometric results. techniques for measuring stress. Stress can have an impact on the production of parvocellular neurons (PVN), arginine vasopressin (AVP), corticotrophin releasing hormone (CRH) and neuropeptides (NPs) as well as their release from the hypothalamus. The interaction of these mediators affects the anterior pituitary gland's ability to secrete adrenocorticotrophic hormone (ACTH), which in turn stimulates the adrenal cortex's ability to produce glucocorticoids. Parvocellular neurons (PVN), arginine vasopressin (AVP), corticotrophin releasing hormone (CRH) and neuropeptides (NPs) can all be produced and released from the hypothalamus in response to stress. Additionally, catecholamines and noradrenaline can be released by the sympathetic nervous system as a result of stress.

A variety of physiological responses can be triggered by these elevated neurohormones and sympathetic components, which may disrupt homeostasis and result in a number of harmful somatic abnormalities [39-40]. According to several studies, the combination of the psycho-neuroendocrine and immune systems causes a link between stress and pregnancy loss. Contrary to the findings of the studies listed above, other investigations have shown a negative relationship between stress and miscarriage. For instance, a prospective study of 783 women found that the likelihood of IVF conception was unaffected by anxiety or depression [35]. Furthermore, studies have demonstrated that experiencing emotional stress does not make a second pregnancy more likely to end in miscarriage [36-37]. Additionally, a study found that higher stress levels were associated with better pregnancy outcomes as opposed to miscarriages [38]

At Babylon Maternity and Pediatric Teaching Hospital's Department of Obstetrics and Gynecology, a prospective case-control research was carried out from December 2022 to April 2023.

Inclusion Criteria

Women who have unexplained RM but no reproductive issues were eligible for this study. They experienced three or more spontaneous miscarriages in a row. As long as the parity was limited to 1-3, RM was classified as either primary or secondary depending on whether or not there had been previous live births.

Since all of the patients are known cases of RM, examinations from their prior outpatient clinic visits previously included thrombotic studies. FSH, LH, estradiol, prolactin, thyroid function and mtiphospholipid antibody screening.Hysterosalpingography and ultrasonography.

Unaccounted-for RM was free of endocrinological issues, antiphospholipid monoclonal antibody testing was negative and coagulation tests were within normal limits. Both pelvic ulography and hysterosalpingography show no evidence of a structural uterine momaly.

Exclusion Criteria

Women with psychiatric diseases, pituitary issues and depression who were using anti-depressants were not included in this study. 100 women in our study, aged 20 to 40, were split into two groups: Fifty women with unexplained RM were part of one cohort; they were divided into two groups. First RM. There were 50 women in Group B (control) Secondary RM who had never had a miscarriage, infertility problems, or pituitary problems. At the outpatient clinic, depression and psychiatric problems were sought after. Only a history of miscarriage or infertility was thought to be a factor that might influence the level of stress connected to infertility.

Methods

On their first visits to the clinic, members of the population study who had been referred there were approached and a thorough history and examination were conducted. After the interview, the researcher determined which individuals were qualified, saw them and gave them information about the study's goals. The details of the study were further communicated to the women who participated in it. which included the quantity of visits, the kinds of samples that were needed from them and the invasive techniques used in these examinations. Written consent was obtained after assuring them of the confidentiality and anonymity of their data as well as their right to withdraw from the study at any time.

Procedure

First visit

The Questionnaire: Patients in the case group and control group had to complete a comprehensive questionnaire package at the start of the experiment to gauge their levels of psychological stress. The researcher double reviewed the questionnaire responses after collecting them from the participants to make sure that each question was addressed and that the response was understandable in order to avoid data invalidation caused by missing data. The bundle of pre-designed questionnaires included three individually validated instruments: The Fertility Problem Inventory, the Perceived Stress Scale and the Positive and Negative Affect Schedule (PANAS). The questions in these surveys were brief, straightforward, clear and simple to respond to. Numerous studies have demonstrated the validity, dependability and sensitivity of these approaches. To reduce discrepancies in comprehending the questionnaire, the researcher delivered it in a straightforward and clear manner (using an accurate translation into Arabic). The researcher also wrote the responses.

All qualified participants received instruction in the Low Dose Overnight Dexamethasone Suppression Test (DST) for blood cortisol measurement at their initial visit. About the DST, the investigator went into extensive detail. They were reassured that a single, low-dose exogenous glucocorticoid administration would not cause any harm. On the second day of their period, they had to take a Dexamethasone tablet at a dose of l mg at 23:00 and they had to go back to the hospital the next day.

During the washing processes, unbound components are removed. The substrate (4-Methyl-umbelliferone phosphate) cycles in and out of the SPR during the final detection neps. The cjogate enzyme breaks down this substrate into a fluorescent product called (4-Methyl-uhelliferone), whose fluorescence may be detected at 450 nm. Fluorescence intensity is directly correlated with cortisol concentrations in the sample. Results are automatically generated by the device based on a calibration curve saved in memory at the conclusion of the assay and are then printed. The morning serum cortisol level must be suppressed to less than 50 nmol/l in order for the I mg Dexamethasone Suppression Test to be considered valid.

Prolactin Measurement

At the infertility lab's second visit, a Prolactin assay was conducted using a Biomerieux Mini Vidas Automated Immunoassay Analyzer (Marcy I'Etoile, France). Department in Babylon Maternity and Pediatric Teaching Hospital using the same principle mentioned earlier using SPR coated with monoclonal anti-prolactin immunoglobulins (mouse). On the same day, blood samples were collected for research into plasma prolactin. reference lab The typical range for follicular prolactin is (43.44-451.84 mlU/l).

Statistical Analysis

The Statistical Package for the Social Sciences (SPSS) version 21 of IBM was used to conduct the statistical analysis. The Mean and SD for age, BMI, serum prolactin and cortisol were displayed using descriptive analysis. FSH.LH. The intergroup and intragroup scores of the stress assessments were examined using independent testing. The Pearson correlation efficient test was used to look at the relationship between the results of psychometric tests and plasma prolactin concentrations. To examine differences in cortisol levels between instances with various conception outcomes or various pregnancy outcomes, independent T was utilized.

Cortisol readings and psychometric evaluations were compared using the Spearman's rank correlation coefficient test. With the Kolmogorov-Smirnov test, the prolactin value's normal distribution was examined. Plasma prolactin concentrations were compared using the T test between women who miscarried later and those who were over 24 weeks pregnant. The Pearson x2 test was used to assess how much the miscarriage rate varied between the two groups. The 0.05 p value was chosen as the threshold for statistical significance.

Psychometric Analysis

Demographic Characteristics of the Study Population: There were 100 women in the study population: 50 with RM that was not explained and 50 controls. At the time of the baseline evaluation, they all filled out questionnaires. Table 1 displays the demographics of these 100 women (controls and cases). In these 50 cases, the miscarriage rate difference between the two groups was measured using the Pearson x2 test. The cutoff point for statistical significance was set at 0.05 p.

Measurements of Stress in Cases versus Controls Differ in the Following Ways

The study population consisted of 100 women: 50 with RM that could not be explained and 50 controls. The subscale for sexual anxiety, yearning for parenthood, rejection of the childfree lifestyle and social concerns all displayed the same pattern p 0.05. Additionally, cases significantly outperformed controls in the Perceived Stress test and the PANAS Positive Affect tests, respectively p 0.05 Table 2.

Each value falls within the range of the Mean or SD. p value 005 was chosen as the threshold for statistical significance.

Table 1: Demographic Information of the Population was Examined

Unless otherwise stated, all data is presented as Mean SD

Table 2: The Relationship between the 50 Cases' Demographics and Psychometric Tests

Statistical significance was set at p value <0.05

Table 3: Differences in the Standards of Psychometric Measurements between Cases and Controls

The Relationship between Stress and Pregnancy Outcomes

Out of the 50 patients, 14 failed to conceive and 36 went on to give birth throughout the research period. Table 3 presents the results of the stress measurements for these two categories. In the psychometric test, there was no discernible difference in the levels of stress between the pregnant group and the non-pregnant group p>0.05. There was no appreciable difference in the number of previous miscarriages between the pregnant group and the non-pregnant group p>0.05. Age was the only significant factor that was linked to successful conception. In comparison to those who did not, younger women had subsequent pregnancies p 0.05.

Age, place of residence, socioeconomic level, education, marital status, kind of contraception used, presence and type of vaginal secretions, medications consumed and a history of other STDs are all factors considered in the epidemiology of T. vaginalis infection. Various risk factors may have an impact on infections [22]. 

The results of the study show that there are considerable differences between infection and abortion, with the infection rate being highest among women who did not have an abortion, reaching 34.09%, as opposed to 12.35% for those who did. 2008. Women who had normal pregnancies (non-abortions) had the highest infection rate, which was 5.82%, while women who had abortions had the lowest infection rate, which was 4.67%, according to Al-Kazragee. The results of this study conflicted with those of other investigations, such as the one carried out in Najaf by Al-Ziyadi, in which high infection rates—at a rate of 19 percent—were discovered in women who had abortions. 10% of pregnant women who were healthy were found to have the greatest infection rates, which is 6.67% greater than the percentage identified in cases of abortion. Trichomoniasis can carry a number of dangerous organisms that cause infections and infertility into the Fallopian tubes.

There are many different causes of miscarriage, including ones that have embryonic roots. The membranes surrounding the fetus may become inflamed and release the prostaglandin hormone as a result of a placental infection, or early uterine activity may result in miscarriage.

The results of the current study also showed that there were notable variations in the distribution of parasite infection between pregnant and non-pregnant women, with the pregnant women having the lowest infection rate (27.35%) and the non-pregnant women having the highest infection rate (35.71%). The infection rate among non-pregnant women was 25.79% higher than the infection rate among pregnant women, which was 13.69%, similar to Al-Saeedi. The prevalence of parasite infection was higher in non-pregnant women than in pregnant women. Pregnant women may not be as successful at fighting off disease and the development of infection in those women may be related to changes in the vaginal environment brought on by changing acidity conditions. Trichomoniasis progresses from moniliasis in animals. The abnormalities of the vagina as well as the individual's state of health are blamed for the rise in the infection rate in non-pregnant women. A favorable environment for parasite development and reproduction is produced by pregnancy-related hormonal changes, vaginal epithelial enlargement, high levels of estrogen and glycogen, as well as the presence of an infection.

According to Dahab et al. and Al-Ibrahimi, non-pregnant women had the highest infection rates of 5.6% and 13.3%. The need of routine clinical tests for the early detection and treatment of these illnesses in female patients is highlighted by this study. Pregnant women are advised to often visit health facilities for a pregnancy check-up, according Adeoye and Akende.

The results of the current investigation demonstrated that there was a substantial difference in the level of LTB4 between the trichomonasis-infected women and the healthy control women. Compared to control women, the proportion of the LTB4 immunological criteria in the serum of infected women was 19.14.7.14. This is consistent with a spike in leukotriene brought on by parasite infection, which prompted the lining tissues to acquire immunity This is in line with an increase in leukotriene caused by parasite infection, which caused the lining tissues to develop immunity. Due to the abundance of monocytes in the vagina, LTB4 production is also abundant. The findings of this analysis are consistent with those of an earlier experiment by Eida et al. which found that women with symptoms of T. vaginalis infection had higher levels of the leukotriene LTB4. T. vaginalis secretes LTB4, a leukotriene stimulator. By interacting with the leukotriene LTB4 and the leukotriene receptors BLT on host cells, Nemati et al. show that T. vaginalis has the capacity to communicate directly with immune cells, changing the host immune response and activating neutrophils. Through the interaction of the leukotriene LTB4 with the leukotriene receptors BLT of host cells, Nemati et al. show that T. vaginalis has the capacity to communicate directly with immune cells. As a result of this communication, the host immune response has been altered and neutrophils have been activated. According to Min et al., these results are consistent with earlier animal research that showed leukotrienes LTB4 were produced in organisms with different worms and parasites. Aspergillus histolytica. Radhi and others. According to the current study's findings, pregnant women had the lowest infection rate (27.35%), while non-pregnant women had the greatest infection rate (35.71%). These differences in parasite infection distribution between pregnant and non-pregnant women were quite noticeable.: Women with unexplained recurrent miscarriage feel more pressure to respond to the survey than women whose recurrent loss has a known etiology.

Compared to control women, recurrent miscarriage women experienced higher levels of stress. When women experience recurrent miscarriage, there is no connection between cortisol levels and the likelihood that they may conceive. Women who experience unexplained recurrent loss have a higher chance of miscarriage when their prolactin levels are low. It seems likely that maintaining successful pregnancies necessitates a suitable level of prolactin concentration, even though the exact source of the observation is unknown.

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