Do genetic factors explain recurrent pregnancy loss?
We are at the dawn of a new age in the identification of etiologies for both isolated and recurrent pregnancy loss
For the better part of the past 20 years I have consulted on or cared for well over 1000 patients with recurrent pregnancy loss (RPL) due to either stillbirths or miscarriages. So this is an area of obstetrics I have thought about quite a bit and it is fair to say that I have been very frustrated by my frequent inability to identify the cause of this tragic condition or to offer effective treatments.
A rough classification scheme for RPL
To grossly simplify this disorder based on 2 decades of personal observations, I would argue that there are 3 major patient populations affected by RPL. The first are older nulliparous patients who have delayed childbearing until their late 30s or early 40s and present with recurrent pre-embryonic (<5 weeks) or embryonic (<10 weeks) miscarriages with or without infertility. In rare cases, they also will have interspersed second- and third-trimester fetal deaths. When the products of conception (POCs) from these patients are accessible and can be karyotyped, they most often display aneuploidy (eg, trisomies, triploidy, or less commonly, deletions and insertions). We really do not understand the pathogenesis of maternal age-associated chromosomal instability and there is not much that we can offer to these patients beyond encouragement, and ultimately donor egg in vitro fertilization.
The second RPL population consists of patients with recurrent severe fetal growth restriction and stillbirths, which generally occur at progressively earlier gestational ages. These patients have a heterogeneous set of etiologies that ultimately involve severe uteroplacental vascular insufficiency. Some are due to antiphospholipid antibody (APA) syndrome, others are associated with severe chronic hypertension with associated decidual vasculopathy, and a few are associated with poorly understood alloimmune etiologies like chronic intervillositis.1 Treatment options are also limited in this population, except for APA syndrome patients, who often benefit from heparin and low-dose aspirin therapy.2
The greatest riddle to me is the third population of RPL patients. These women are generally younger, often multiparous, and prone to intermittent fetal loss at or after 10 weeks, although the occasional patient also presents with recurrent intermittent embryonic loss. As a general rule of thumb, these losses tend to occur around the same gestational age, or at least in the same trimester. Given the intermittent pattern of occurrence, genetic causes can be suspected. Indeed, in about 3% of RPL cases, usually involving early losses, a parental-derived unbalanced chromosomal translocation will be found.3
However, I have long suspected that most cases of intermittent RPL result from Mendelian disorders. For example, intermittent early losses may rarely be caused by homozygosity for the adult-onset polycystic kidney disease gene.4 In rare cases, later losses are caused by autosomal and X-linked recessive lethal multiple pterygium syndromes (aka fetal akinesia deformation sequence) that present as mid-pregnancy fetal death associated with hydrops, cystic hygroma, contractures of the extremities, and other anomalies triggered by mutations in neuromuscular junction genes.5 Of course, a number of other mutations associated with obvious congenital anomalies also can cause stillbirth, but the precise genetic etiology of the vast majority of cases of intermittent RPL, particularly in anatomically normal fetuses, has remained undiscovered.