Hormones play a key role in putting the fetus in the uterus, and changes can result in a risk of miscarriage. There is a need for a consensus on the tests and diagnostic criteria to be performed so that all experts can evaluate the couples equally. This way, it allows you to avoid further financial losses and emotional disturbance for these couples while you can evaluate the effectiveness of every available treatment. Endocrine factors in recurrent miscarriages are as follows:
Luteal Phase Insufficiency
Inadequate exposure to progesterone to maintain a secretory endometrium that would lead to normal embryo implantation and growth. The diagnostic criteria for luteal insufficiency are not well established, making it difficult to conduct studies that could show a causal link between luteal phase failure and RPL. Therefore, luteal phase failure testing is not recommended in patients with RPL. Its use for the treatment of progesterone or human chorionic gonadotropin (hCG) is different in the literature.
Studies on subclinical hypothyroidism and increased risk of RPL, defined as thyroid stimulating hormone (TSH)> 2.5 mU / L and normal free thyroxine, have low levels of evidence. The presence of anti-thyroid peroxidase antibodies (anti-TPO) in patients with RPL, including euthyroid, is an important gestational prognostic factor. Therefore, a TSH and anti-TPO dosage is recommended for women with RPL. And it suggests that T4 levels should be evaluated when detecting abnormal levels of the above examinations.
Patients with clinical hypothyroidism should be treated with levothyroxine. In women with RPL and subclinical hypothyroidism, the benefit of treatment should be evaluated as the evidence is conflicting. Additionally, euthyroid women who are anti-TPO positive should not be treated with levothyroxine.
Polycystic Ovary Syndrome and Insulin Metabolism Disorders
Various abnormalities observed in patients with polycystic ovarian syndrome (PCOS) have been independently associated with RPL, including insulin resistance, hyperinsulinemia, hyperandrogenemia, hyperprolactinemia, and obesity. There is a higher prevalence of insulin resistance among women with RPL than controls. However, no studies have confirmed the cause-effect relationship between insulin resistance and RPL.
Therefore, there is not enough evidence or metformin use in pregnancy to recommend PCOS, rapid insulin and rapid glucose, insulin and glycemia evaluation to prevent pregnancy loss and disturbances in glucose metabolism in women with RPL. The existence of an independent link between hyperandrogenemia and RPL is controversial. Therefore, it is not recommended to investigate androgen levels in women with RPL.
Most studies cannot establish a direct link between RPL and serum prolactin concentration. Therefore, prolactin testing is not routinely recommended in the absence of clinical signs of hyperprolactinemia. However, if hyperprolactinemia is detected, treatment with dopaminergic agonists may be considered in women to increase live birth rates. Most centers routinely test serum prolactin levels, as hyperprolactinemia is an easily treatable cause.
There are few studies evaluating the relationship between vitamin D deficiency and RPL. One of them showed an increased prevalence of hypovitaminosis D in women with RPL, but the cause-effect relationship could not be determined. Therefore, based on the significant prevalence of hypovitaminosis D in women with RPL and its possible association with obstetric and fetal complications, pre-consultation counseling in these women may include prophylactic vitamin D supplementation.
Chronic endometritis (CE) is defined as persistent inflammation of the endometrial mucosa caused by the presence of bacterial pathogens in the uterine cavity. Its prevalence in patients with RPL is approximately 12-13%. The impact of CE on reproductive capacity is controversial, but many authors suggest that CE may adversely affect embryonic implantation. Some studies indicate an infectious etiology with positive cultures in 75% of women with histologically confirmed CE; the most common bacteria are Escherichia coli, Enterococcus faecalis and Streptococcus agalactiae (77.5%)
Most patients are asymptomatic and pain in uterine or cervical mobilization is the most common clinical picture. CE is diagnosed histopathologically as lymphoplasmacytic infiltration in the endometrial stroma. Immunohistochemistry for the marker found in CD138 plasma cells is used to increase diagnostic accuracy. A diagnostic video hysteroscopy can help determine CE by direct visualization of the endometrial cavity, which usually occurs with mucosal edema, focal or diffuse endometrial hyperemia, or micro-polyps. The sensitivity, specificity and positive and negative predictive values of hysteroscopy in the diagnosis of CE are 86.36%, 87.30, 70.37 and 94.82%, respectively.
Until a few years ago, the uterine cavity was thought to be a sterile environment. Recently, it has been discussed that an imbalance in the uterine microbiota could compromise embryonic implantation or cause an abortion. Endometrial biopsy and etiological agent search for next-generation sequencing (NGS) microbiota evaluation can now be done through commercial kits. However, more studies are needed to evaluate its diagnostic effectiveness on reproductive outcomes and treatment.
Some studies suggest that treatment is associated with increased live birth rates and low miscarriage rates. There are several treatment options; The main forms of treatment mentioned in the literature refer to doxycycline alone (100 mg, orally for 12/12 hours, for 14 days), metronidazole (250 mg, orally for 12/12 hours, for 14 days) and the combination of ciprofloxacin. (250 mg orally 12/12 hours 14 days).
Father Factors in Recurrent Miscarriages
There is a growing acceptance of male etiological factors for RPL. Screening consists of detailed sperm analysis. Excessive sperm DNA fragmentation is an important restriction for conception. Two meta-analyzes show that pregnancy losses are associated with a high rate of sperm DNA fragmentation. Available tests for the sperm DNA fragmentation index are the sperm chromatin structure test (SCSA), terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick end labeling (TUNEL), the Sperm Chromatin Dispersion test, and the comet test.
Some clinical conditions are related to increased breakdown of sperm DNA. High seminal plasma leukocyte concentration, systemic infections, varicocele, and smoking, among others, are associated with spermatic DNA damage. A Cochrane meta-analysis suggests that the use of antioxidants, including vitamins C and E, may have benefits for subfertile men and improve sperm DNA fragmentation for no apparent reason.
Generally, the recommended dose is 1 gram of vitamin C and 1000 IU of vitamin E per day for at least 2 months. However, this effect has not yet been established in patients with RPL. ESHRE specifies that sperm DNA fragmentation research should be evaluated for illustrative purposes for RPL. For couples indicated with intracytoplasmic sperm injection (ICSI), laboratory techniques can be applied to select sperm with a lower DNA fragmentation rate, such as physiological intracytoplasmic sperm injection (PICSI) and intracytoplasmic morphologically selected injection (IMSI).
However, the use of testicular sperm appears to improve fertilization, pregnancy and live birth rates compared to PICS and IMSI techniques. Also, more studies are needed to determine the best method for selecting sperm to reduce abortion rates. Morphological analysis of sperm is another point to consider in RPL cases. The presence of spermatozoa with structural anomalies may be associated with aneuploidy, which often results in aneuploid embryos that are not implanted or canceled. This is especially true in cases of globozoospermia and macropermia, which are monomorphic forms of teratospermia. (if all sperm have the same anomaly)
Infertility is often associated with these cases and the prognosis for IVF is hidden. Therefore, when associated with abortion, embryonic biopsy (PGT-A) may be an option for preimplantation genetic testing for aneuploidies following IVF. Recurrent spontaneous abortion is a condition with a multifactorial etiology and the cause of the loss has not been determined in approximately 50% of cases. This explains a great deal of controversy regarding the investigation and treatment of pathologies that cause recurrent casualties.
Despite so much debate, there are some points that experts agree on. Psychological support for couples is very important and is associated with a better prognosis in the next pregnancy. Undergoing periodic consultations and ultrasounds, especially in the period of previous losses, reduces the stress of these couples. The woman’s age and the number of previous losses are the most important factors in predicting the couple’s chance of having a live baby in the next pregnancy.
Recurrent spontaneous abortion is a condition with a multifactorial etiology and we could not identify the cause of the loss in approximately 50% of cases. This explains a great deal of controversy regarding the research and treatment of pathologies that cause recurrent casualties. Despite so much debate, there are some points that experts agree on. Psychological support for couples is very important and is associated with a better prognosis in the next pregnancy. Undergoing periodic consultations and ultrasounds, especially in the period of previous losses, reduces the stress of these couples. The age of the woman and the number of previous losses are the most important factors in predicting the couple’s chance of having a live baby in the next pregnancy.
There is a need for consensus among human reproductive societies on the tests and diagnostic criteria that should be ordered so that all experts can evaluate couples equally. In this way, you can evaluate the effectiveness of every available treatment, avoiding further financial burns, emotional disturbance and iatrogenesis for these couples.
Writer: Ozlem Guvenc Agaoglu