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    Recurrent pregnancy loss


    Single-gene disorders

    The single-gene disorders associated with pregnancy loss are more closely associated with fetal than with embryonic loss. The hemoglobinopathies are one example. Alpha thalassemia is a genetic disorder in which the hemoglobin alpha chain is abnormally configured and does not function. There are 4 genes for the alpha chain within the human genome. If both members of a couple have 2 abnormal copies, and both of those abnormal copies reside on the same chromosome 16 (cis configuration) then 25% of their offspring will inherit only abnormal genes, and will suffer from Hemoglobin Bart’s, leading to fetal hydrops and death.

    Other single-gene disorders include the multiple pterygium syndromes, which can be inherited in an autosomal-recessive or X-linked fashion, but in either case can result in mid-pregnancy fetal loss. Crotti et al. recently reported on an association between the genes linked to cardiac cycle QT prolongation and stillbirth.14 If losses occur most often in male fetuses, one must consider the possibility of an X-linked genetic disease such as Rett syndrome. This is not a comprehensive list; in general these disorders cause intermittent mid-gestational losses but may present as mid-pregnancy RPL.

    Newer genetic technologies such as chromosomal microarray and whole-exome or whole-genome sequencing are demonstrating promise as tools for further investigation of causes of RPL. There have been reports of copy number variants representing small duplications or deletions, and their relationship to pregnancy loss.8,9

    Abnormalities of coagulation

    Hypercoagulable states

    This is an area in which there was much interest, but a growing number of prospective cohort studies have failed to demonstrate an association between inherited thrombophilias such as Factor V Leiden, Prothrombin 20210A mutation, or MTHFR C766T mutation and RPL. Furthermore, studies of heparin to prevent such losses have not demonstrated benefit.15-17

    Acquired thrombophilias, namely antiphospholipid antibody syndrome (APAS), have long been associated with RPL. Specific criteria exist for pregnancy-related diagnosis of APAS as well as for diagnosis in nonpregnant individuals related to thrombosis. When women meet both the clinical and laboratory criteria for APAS, treatment in the periconceptional period with heparin and aspirin has been shown to decrease the rate of pregnancy loss and adverse pregnancy outcome.18-20

    Of note, the validity of including recurrent early (<10 week) miscarriage as an obstetric criterion for APAS has recently been called into question.21 Careful review of the literature that established this association reveals several methodological weaknesses. A task force has been assembled, and it is hoped that new information will be made publicly available in the near future.20

    Bleeding disorders

    Rare diseases such as dysfibrinogenemia and factor XIII deficiency have been associated with mid-pregnancy hemorrhagic pregnancy loss.22 

    Some case reports exist of improved pregnancy outcomes in affected women after treatment with exogenous fresh frozen plasma. The typical presentation is a history of abruption or heavy vaginal bleeding preceding the loss, and these women often have a family history supportive of the diagnosis of inherited bleeding disorder.

    Uterine anomalies

    Some authors have demonstrated an association between the presence of a uterine septum or bicornuate uterus and RPL.23 Others have demonstrated an association between uterine cavity-distorting leiomyomas or polyps and RPL.24 While this body of literature is small, observational, and subject to significant ascertainment bias, imaging of the uterus by sonohysterography or hysterosalpingogram is still a standard practice.

    Removal of uterine septi, adhesions, submucous myomas, and polyps is recommended until randomized trials better inform clinical practice.

    Charles J. Lockwood, MD, MHCM
    Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...


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