Neither family history alone nor a history of prior term births is sufficient to rule out a potential parental chromosomal abnormality. Whereas the frequency of detecting a parental chromosomal abnormality is inversely related to the number of previous spontaneous losses, the chance of detecting a parental chromosomal abnormality is increased among couples who have never experienced a live birth (13). Abnormalities also may be detected upon parental karyotype analysis of some couples with a history of spontaneous abortions interspersed with stillbirths and live births (with or without congenital anomalies). Ultimately the use of parental karyotyping as a screening modality to evaluate the structural chromosomal etiologies of recurrent pregnancy loss may become insufficient. Evidence now suggests that, in some cases, paternal chromosomal abnormalities may be isolated within a particular fertilizing spermatozoon (16,17). Aneuploid spermatozoa may be particularly motile (18). Other structural chromosome anomalies, such as inversions and insertions, may also contribute to recurrent abortion, as can chromosomal mosaicism and single gene defects. X-linked disorders uncommonly result in recurrent abortion of male rather than female offspring (19).
Thrombophilias There is a great deal of interest in the role of inherited thrombophilias in recurrent pregnancy loss (20–22). This heterogeneous group of disorders increases venous or arterial thrombosis. Their associations with pregnancy loss remains controversial and is attributed to hypothetical alterations in placental growth and development, particularly to alterations in placental vascular development (23–28). Abnormal placental vascularization and inappropriate placental thrombosis would link these thrombophilic states to pregnancy loss. Although some thrombophilic states may be acquired, most are heritable. Those heritable thrombophilias most often linked with reference to recurrent pregnancy loss include activated protein C resistance associated with mutations in factor V, deficiencies in proteins C and S, mutations in prothrombin, and mutations in antithrombin III.
Like spontaneous pregnancy loss, inherited and combined inherited or acquired thrombophilias are also surprisingly common. Greater than 15% of whites carry an inherited thrombophilic mutation (21). The most common of these are the factor V Leiden mutation, a mutation in the promoter region of the prothrombin gene and mutations in the gene encoding methylene tetrahydrofolate reductase (MTHFR). These disorders are present in their heterozygous state in approximately 5%, 2% to 3%, and 11% to 15% of healthy white populations, respectively (22,29–31). These common mutations are associated with mild thrombotic risks. It remains controversial whether homozygous MTHFR mutations are associated with vascular disease at all (32). In contrast, more severe thrombophilic deficiencies, such as those of antithrombin and of protein S, are much less common in the general population. These epidemiologic data support the hypothesis that a selective genetic advantage may accompany carriage of common heritable thrombophilias. To this point, women with activated protein C resistance because of the factor V Leiden mutation have reduced blood loss at delivery and factor V Leiden carriage is reported to improve pregnancy rates in intracytoplasmic sperm injection or IVF, suggesting a positive role in implantation (33,34). It is important to note that the above epidemiology of factor V Leiden mutations is specific to white populations. Factor V Leiden and prothrombin gene mutations are rare in African and Asian populations, despite similar incidence of venous thromboembolic events (35–38). Protein C, protein S, and antithrombin mutations are the most important risk factors for venous thromboembolic events among many Chinese and other Asian populations (39). These ethnographic differences are important considerations when faced with decisions concerning diagnostic testing in patients with a history of recurrent fetal loss.