13:39 25th January 2019 | Pregnancy Loss
Evaluation and treatment of recurrent pregnancy loss
Miscarriage, also known as spontaneous abortion and pregnancy loss is a common occurrence in approximately 15-25% of pregnancies. The majority of sporadic losses before 10 weeks gestation result from random numeric chromosomal errors. On the other hand, recurrent pregnancy loss (RPL) is a distinct disorder characterised by two or more failed pregnancies. Less than 5% and 1% of women experience two and three consecutive pregnancy losses. The definition, investigations, and management of RPL are one of the most argued topics in gynaecology.
Who to evaluate
The challenge for clinicians is to differentiate a sporadic miscarriage from RPL. Self-reported pregnancy losses by patients may not be accurate. For the academic purposes of determining whether evaluation for RPL is appropriate, pregnancy is defined as a clinical pregnancy documented by ultrasonography or histopathological examination. Ideally, three or more losses should be used for epidemiological studies while clinical evaluation may proceed following two first-trimester pregnancy losses.
Aetiologies and evaluation for recurrent pregnancy loss
1. Cytogenetic Abnormalities
About 60% of sporadic early miscarriages are thought to be due to chromosomal abnormalities (aneuploidies). Genetic abnormalities, including chromosomal aberrations (numerical and structural), and gene mutations can lead to pregnancy loss. Amongst them, the most common parental abnormality is balanced translocations, found in 3-5% of cases of RPL compared to 0.7% in the general population. Almost all published recommendations and reviews on this topic agree that genetic causes should be evaluated, and appropriate treatments considered. Unfortunately, clinical genetic testing remains rudimentary and rarely includes molecular studies which show promise in helping to outline mechanisms for RPL.
2. Structural Uterine Defects
Congenital uterine abnormalities are associated with second-trimester pregnancy loss. Other complications include preterm labour, fetal malpresentation and increased rates of cesarean delivery. Although the role of uterine malformations in first-trimester RPL is controversial, assessment of uterine anatomy is widely recommended.
In about 19% of women with RPL, uterine anomalies are seen and are acquired or congenital. Congenital Uterine Anomalies are found in 8.4-12.6% of women with RPL compared to 1-1.5% in the general population. The septate uterus is the most common CUA associated with spontaneous miscarriages. Acquired uterine anomalies include leiomyoma (fibroids), polyp and intrauterine synechiae (adhesions). Their clinical significance for RPL is however unclear. Submucosal myomas and polyps are found in 4.5% of women and 2-3% of women with RPL. Cervical incompetence usually causes second-trimester losses, and it can be acquired following surgical trauma or associated with congenital anomalies.
3. Immune Disorders
An immunological modification is necessary to prevent immune rejection as a foetus is genetically not identical to the mother only. Multiple immunogenic causes have been proposed. The autoimmune condition of importance for RPL is Antiphospholipid Syndrome (APS), which is an acquired thrombophilia. It accounts for 5-20% of cases of RPL, though it varies widely (5-42%). The clinical criteria for the diagnosis of APS in RPL is an occurrence of three or more consecutive pregnancy losses before the 10th week of gestation, in the absence of parental chromosomal, anatomic and hormonal abnormalities. The antiphospholipid antibodies are acquired, which damages the trophoblast leading to impaired trophoblast mediated functions like spiral artery formation, secretion of growth factors and human Chorionic Gonadotrophin (HCG), early apoptosis of trophoblasts and abnormal inflammatory response leading to impaired pregnancy support.
4. Endocrine and Metabolic factors
It is generally believed that maternal diabetes and thyroid abnormality are associated with RPL. Uncontrolled diabetes increases the risk of miscarriage, whereas an adequate pre-conception glycemic control significantly reduces the risk. A direct correlation is seen between the level of glycosylated haemoglobin and early abortion. Subclinical and clinical hypothyroidism is shown to be associated with RPL. Polycystic Ovarian Syndrome (PCOS) is also associated with an increased risk of miscarriage. A full endocrine and metabolic workup are therefore needed for management of RPL.
5. Unexplained RPL
Despite detailed investigations, 50-60% of cases with RPL remain unexplained. These unexplained cases include genuine RPL by chance and unexplained pathologic RPL which are not identified by any available investigative protocol.
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