Recurrent pregnancy loss (RPL) is defined as two or more losses with a gestational age of less than 20-24 weeks. Its prevalence varied between 0.8 and 1.4% when only patients with clinical pregnancy were considered. The pathogenesis is multifactorial and in only 50% of cases the causative factor can be identified: it is immunological, endocrine, genetic, metabolic and anatomical, among others. It is not always possible to determine the etiology, and recurrence of miscarriages negatively affects the psychological profile of the couple. Therefore, it is essential to understand the diagnostic methods that can define etiological factors and treatments that can improve outcome for the follow-up of couples with RPL.
Human understanding is a vulnerable event, a large part of all concepts are cytogenetically abnormal, and most such pregnancies turn into abortion. In couples with RPL, research can be divided into two main categories: genetic analysis of conception products and parental genetic analysis.
Genetic analysis of conception products
Studies in which conception products are analyzed have shown that genetic changes, especially aneuploidies, contribute to a significant part of the causes of pregnancy losses, constituting 50% of recurrent losses. Despite the importance of genetic changes as causes of miscarriage, there is still no consensus on whether a routine evaluation of pregnancy tissue should be performed. ASRM does not recommend the genetic evaluation of conception products.
In contrast, ESHRE suggests that this analysis should not be done routinely, but may be encouraged to clarify the etiological factor and assist in deciding whether further investigation or treatment is required. However, other studies and guidelines have proposed new algorithms for the assessment of pregnancy recurrence losses to be initiated by chromosome testing in conception products.
New chromosomal tests, such as chromosomal microarray analysis (CMA), have the potential to reduce costs because costly and unnecessary evaluations will not be used in the presence of modified examinations. Additionally, once a cause has been identified, the trend is towards reducing the use of empirical treatments with no scientific evidence. Studies have shown that couples with prior embryonic aneuploidy have a higher probability of child birth in subsequent pregnancies than patients with a previous karyotype of normal conception products (44% versus 71%). The pain experienced by the couple without knowing the etiological factor alone may justify investigating the existence of genetic changes as the cause of the events.
Parental genetic analysis
In about 5% of all couples that experience two or more fetal losses, a partner carries a balanced chromosomal rearrangement, representing an approximately eight-fold increase compared to the general population. Guidance for this double genetic counseling is important because the likelihood of a healthy child being born will depend on the type of rearrangement found and the chromosomes involved – for example, gestational losses are more in stable translocation and inversion carriers than Robertsonian carriers. Translocations. Although a partner carries chromosomal rearrangement, the cumulative live birth rate is important even with natural conception – 63.4%, despite the increased risk of miscarriage.
As for current guidelines on parental cytogenetic examination, ESHRE specifies that such assessment should not be done routinely, but rather after individual risk assessment in specific situations. However, ASRM recommends routine parental karyotyping as the information obtained can aid in counseling about the prognosis of future pregnancies, including guidance for performing preimplantation genetic testing (PGT), amniocentesis, or chorionic villus analysis.
Couples with structural cytogenetic changes have an increasing number of gametes with chromosomal imbalances, so implantation of embryos selected with PGT is expected to increase the live birth rate. However, in spouses carrying chromosomal rearrangement with RPL, the live birth rate, duration of subsequent conception, and miscarriage rates were similar in both natural conception and in vitro fertilization associated with preimplantation diagnosis (IVF-PGD). Other articles showed discordant results. Similar live birth rate and time to new pregnancy were reported; however, the miscarriage rate was significantly lower in the IVF-PGD group. Therefore, there is no consensus showing the benefit of such a strategy in this population, and no randomized controlled trials have been conducted to date to confirm possible benefits.
Thrombophils are inherited and / or acquired conditions that predispose individuals to thrombosis, and there are various prevalences in the general population. The most common hereditary thrombophils, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism 4-16%, factor V Leiden mutation 1691G A (heterozygous, 1-15%; homozygous, <1%), prothrombin mutation 20210G A (heterozygous, 2--5%; homozygous, <1%), antithrombin deficiency (0.02%), protein C deficiency (0.2-0.4%), protein S deficiency (0.03-0.13%) and sprinkle gene polymorphism. On the other hand, acquired thrombophilia is mainly antiphospholipid antibody syndrome (APS) 2%. A successful pregnancy requires adequate endovascular implantation and remodeling as measured by the trophoblast, and these prothrombotic conditions will be the target of research and intervention with anticoagulant therapy to prevent miscarriage.
Screening of hereditary thrombophilia even in the context of thrombosis is still being questioned. Factor V Leiden mutation (1691G A) and prothrombin mutation (20210G A) are associated with recurrent miscarriage. However, the lack of evidence that treatment alters pregnancy outcome leads to questioning the feasibility of investigating such mutations. Other thrombophilia such as protein C deficiency, protein S deficiency, and antithrombin deficiency were not associated with RPL, although they were associated with the thromboembolic event. MTHFR gene polymorphisms are no longer considered risk factors for thrombophilia.
The relationship between RPL and hereditary thrombophilia is weak or absent. Therefore, thrombophilic screening should be limited to patients with a family history of thrombophilia or a previous thrombotic event. There is no recommendation to screen for hereditary thrombophilia in patients with RPL without other risk factors. Screening tests may be affected by physiological / pathophysiological changes during pregnancy-puerperium, thrombotic event or anticoagulant use. Delivery should take place within 6 weeks or more after the miscarriage or thrombotic event, or early if necessary.
The use of anticoagulant therapy with low molecular weight heparin and / or aspirin has no benefit in preventing early (<10 weeks) or late (10 weeks) RPL. Therefore, the ineffectiveness of treatment, risk exposure and increased cost does not justify treatment with anticoagulants in patients with RPL without hereditary thrombophilia and other thrombosis risk factors.
APS is indicated in patients with RPL as well as those with an unfavorable pregnancy outcome or thrombosis episode for no apparent cause. The diagnosis of APS is based on a combination of at least one clinical criterion that includes thrombotic events and / or pregnancy morbidity and a laboratory criterion that includes three antibodies: lupus anticoagulant, anticardiolipin, and anti-2 glycoprotein 1 (anti-2GP1).
In cases of late pregnancy loss, lupus anticoagulant was more closely associated with RPL than any of the other antibodies. Anticardiolipin (IgG and IgM) has been associated with early and late pregnancy loss. The relationship between anti-2GP1 and late pregnancy loss seems controversial. ESHRE recommends that patients with two losses, whether consecutive or not, do a search for lupus anticoagulant antibodies and anticardiolipin, and the research should consider anti-2GP1.
Combined therapy, the use of low molecular weight heparin at prophylactic dose and low dose of aspirin (75-100 mg / day) increased the live birth rate from 10% to 70-80% in patients with APS and RPL. Therapeutic doses of heparin may be used in treatment failure, although there is no evidence of benefit. Other treatment regimens with limited evidence are the use of hydroxychloroquine or low-dose prednisolone in the first trimester. The use of immunoglobulin is questioned as studies are limited and there is no increase in live birth rate.
Author: Ozlem Guvenc Agaoglu