Recurrent Pregnancy Loss: Risk Factors and Recommended Treatments

Recurrent Pregnancy Loss (RPL) is an obstetric condition closely linked with an emotionally traumatic experience and further social implications. Despite extensive clinical and experimental research efforts, some of the core questions concerning contributory factors to RPL and effective treatment methods remain scientifically unanswered.

Key takeaways:
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    Recurrent pregnancy loss is a failure of two or more pregnancies with an estimated prevalence of 1 to 2%.
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    Despite extensive research and investigation efforts, the etiology of 50 to 75% of RPL cases remains unidentified.
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    Antiphospholipid antibodies, thyroid pathologies, and uterine anatomy abnormality assessments are recommended screening tests for identifying RPL etiology.
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    Despite various empirical management options, there is no high-quality evidence of the usefulness of any treatment in RPL prevention.
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    Vaginal micronized progesterone may have a beneficial effect on the live birth rate, although it is not a routine guideline recommendation.

According to the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), recurrent pregnancy loss is defined as the failure of two or more pregnancies diagnosed by ultrasonography or confirmed by histopathologic examination. The definition of pregnancy includes both conceptions achieved spontaneously and following assisted reproductive technologies, while ectopic and molar pregnancies and implantation failures are not considered in this category.

The estimated prevalence of RPL is 1 to 2%. Estimated rates of two and three and more consecutive miscarriages are 5% and 1%, respectively.

Risk factors

Despite extensive investigation efforts, in 50 to 75% of RPL cases, no causative factor is identified.

Maternal age. The risk of pregnancy loss is minimum between the ages of 20 to 35. This risk rapidly increases after the age of 40 years.

Smoking. Cigarette smoking may have an adverse effect on trophoblastic function, and cessation of smoking is recommended in women experiencing RPL.

Alcohol consumption. More than three to five drinks per week were found to be associated with increased miscarriage risk.

Weigh. Maternal obesity and being underweight may have a negative impact on the chances of live birth. Therefore, the normal BMI range (18 to 24.9 kg/m²) should be aimed for a healthy lifestyle.

The level of evidence supporting the direct effects of vitamin D insufficiency, stress, exercise, and caffeine intake on RPL is insufficient.

Investigation tests

Due to the uncertainties in the etiology of the condition, it is not uncommon for RPL patients to be tested for multiple genetic and immunological profiles. Recommendations are to limit the unnecessary use of multiple tests. These include using ESHRE Guideline group investigative tests as recommended, considered for research purposes, and non-recommended tests.

Antiphospholipid antibodies. Antiphospholipid syndrome (APS) contributes to 8 to 42% of RPL cases. Screening for lupus anticoagulant (LA) and anticardiolipin antibodies (ACA), and anti-β2 glycoprotein I is recommended after two pregnancy losses.

Thyroid abnormalities. It is recommended that women with RPL should be assessed for thyroid stimulating hormone (TSH) and thyroid-peroxidase (TPO) antibody levels. Moreover, cases with abnormal levels should be followed by thyroxine (T4) testing.

Uterine anatomy assessment. It is recommended that all women with RPL should have a uterine anatomy assessment, and the preferred method for evaluation is 3D transvaginal ultrasound. This method has a higher capacity to diagnose and differentiate uterine anatomy abnormalities, such as the septate uterus and bicorporeal uterus. The evidence supporting the effects of uterine surgery in the management of RPL is insufficient.

Tests to be considered for explanatory purposes or in a research context

Hereditary thrombophilia screenings, including factor V Leiden and prothrombin gene mutations, proteins C and S, and antithrombin deficiencies, are not among routinely recommended tests in RPL. It could be carried out in the research context or cases with additional risk factors for thrombophilia.

Genetic tests. Genetic analysis of miscarried pregnancy tissue and parental karyotyping is not routinely recommended. However, they could be performed for explanatory purposes and after an individual risk assessment.

Although fetal and parental karyotyping is not recommended in routine practice, couples should receive genetic counseling and be informed about possible treatment options in case of diagnosed abnormalities. The evidence proving the benefits of preimplantation genetic testing (PGT) is also limited.

Immunological tests

HLA testing is not recommended in routine clinical practice, as no specific treatment is available. Based on the study results by Nielsen et. al., only Scandinavian women experiencing RPL after the firstborn boy could be considered for HLA class II determination.

Antinuclear antibodies (ANA) testing also should be considered only for explanatory purposes.

Sperm DNA fragmentation test could be considered for the male partner for explanatory purposes.

Other immunological tests: Anti-HY antibodies, Natural Killer cell testing either in peripheral blood or in the endometrium, and anti-HLA antibodies are not recommended to use for RPL etiology investigation purposes.

Metabolic or hormonal tests, including cytokine testing, ovarian reserve and PCOS assessment, luteal phase insufficiency, LH, and androgen testing, fasting insulin and glucose, prolactin, and homocysteine plasma level testings are also should not be used for RPL screening.

There is no high-quality evidence on the usefulness of any treatment in preventing miscarriage. However, prevention and correction treatments should be considered based on the test results and diagnosed pathologies.

Anticoagulant treatment. Mainly being investigated in vitro studies, low-molecular-weight heparin (LMWH) was found to be associated with favorable immunological effects. Interestingly, a Swedish randomized controlled study investigating women receiving LMWH during pregnancy showed proinflammatory effects of LMWHs, especially in the second and third trimesters of pregnancy.

According to recent guidelines, women diagnosed with antiphospholipid syndrome and with a history of three and more pregnancy losses are recommended to receive low-dose aspirin (75 to 100 mg/day) starting before conception. Furthermore, a prophylactic dose of heparin (unfractionated or low molecular weight heparin) starting following a positive pregnancy test also could be considered. However, without antiphospholipid syndrome diagnosis, heparin or low-dose aspirin were not found to improve the live birth rate. Thus, ESHRE guidelines do not recommend routine use of aspirin and heparin in RPL patients.

Hypothyroidism treatment. Levothyroxine treatment should be initiated in women with overt hypothyroidism. The T4LIFE trial investigated euthyroid women with positive anti-TPO antibodies experiencing recurrent miscarriages. Study results did not find a difference in the live birth rate in women treated with levothyroxine. Thus, the authors do not recommend routine levothyroxine use in euthyroid women who are positive for TPO antibodies.

Progesterone and hormonal treatments. A meta-analysis from the Cochrane database reports that progesterone makes little or no difference in the live birth rate in women with recurrent miscarriages. Only vaginal micronized progesterone might increase the live birth rate in women with one or more previous pregnancy losses and early pregnancy bleeding. ESHRE guidelines find the evidence supporting the beneficial effects of progesterone insufficient for scientific recommendations.

Immunological treatment. According to ESHRE guidelines, immunological biomarkers should not be used to select RPL couples for immunological treatments except for antiphospholipid antibodies. Lymphocyte immunization therapy doesn’t have a significant effect on RPL and might be associated with severe side effects.

Intravenous immunoglobulin (IVIG). A recent meta-analysis, including non-randomized studies, found a twofold increase in the live birth rate with IVIG use in RPL cases. Later, a randomized-controlled study investigating women with unexplained four or more pregnancy losses reported that high-dose IVIG administration is associated with a more than two-fold increase in live birth rate compared to placebo. However, according to the last ESHRE guideline published before these studies, the use of IVIG is not recommended in the treatment of RPL.

Other approaches. Evidence supporting the beneficial effect of intralipid and granulocyte stimulating factor (G-CSF) is insufficient to make a scientific recommendation.

Paternal recommendations. Smoking cessation, limited alcohol consumption, keeping body weight within normal ranges, and normal exercise are recommended to couples with RPL. Antioxidant use for men has not been proven effective in improving live birth chances.

Psychological support. Pregnancy loss is a significant traumatic life event, and the recurrent nature of the condition increases the intensity of the grief period. Although most of the psychological care is focused on maternal mental health, the emotional impact of RPL on men and eventually on the integrity of couples’ life should also be considered.


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