Recurrent pregnancy loss
Recurrent pregnancy loss (RPL) is defined as 2 or more consecutive failed pregnancies.1 Although sporadic pregnancy loss is relatively common, complicating up to 50% of pregnancies,2,3 only 5% of couples will be diagnosed with RPL.
There are many possible etiologies for both recurrent and sporadic pregnancy loss. The most common by far are genetic abnormalities (accounting for >50% of cases). Genetic abnormalities can reflect whole-chromosome abnormalities (trisomy, monosomy, triploidy, etc.), partial-chromosome abnormalities (eg, macro- and microdeletions and insertions, unbalanced translocations), single-gene disorders affecting exons, introns, and promoter regions, as well as micro-RNA defects and changes in gene function reflecting epigenetic changes.
Other putative causes of RPL include disorders of thrombosis and hemostasis, uterine anomalies, immunologic disease, endocrine diseases, infectious etiologies, and other factors including environmental influences such as cigarette smoking.3,4 The causes and workup of RPL differ widely depending on the gestational age of the loss.
Thus, it is helpful to consider losses as pre-embryonic (“chemical pregnancy” or anembryonic gestation detected by ultrasound), embryonic (<10 weeks’ gestation), or fetal (10 or more weeks’ gestation).5
The goal of this article is to provide a thorough but concise understanding of the etiologies of pregnancy loss, and strategies for evidence-based workup and treatment of couples with a diagnosis of RPL.
Cytogenetic abnormalities such as trisomy, monosomy, and polyploidy are noted in 50%–60% of specimens obtained from first-trimester pregnancy losses.2,3 Some suspect the rate may be even higher, given the challenges of separating maternal decidua from products of conception, particularly at the earliest gestational ages.6,7 If there is maternal cell contamination, the euploid maternal cells can outgrow the aneuploid fetal cells in culture and the resulting 46, XX karyotype will reflect the maternal genotype, not that of the conceptus. This challenge can be overcome by using microarray rather than traditional karyotype, since microarray does not rely on cell culture.8-10 It is well established that the rates of aneuploidy increase with increasing maternal age.2,11 Observational studies have shown that increased consumption of folic acid in the periconceptional period may reduce this risk.12,13
Rates of whole chromosome abnormalities seen in pre-embryonic and embryonic gestations are listed in Table 1. The most common autosomal trisomy in early abortus specimens is trisomy 16. Chromosomal abnormalities have been reported as many as 90% of anembryonic gestations; this number decreases to 50% in the embryonic period, and to 30% in the early fetal period. Approximately 6%–12% of stillbirths beyond 20 weeks are associated with chromosomal abnormalities. At later gestational ages, the most common aneuploidies are trisomies 21, 18, and 13.2
Another cytogenetic abnormality associated with RPL is an unbalanced translocation. Approximately 3%–5% of couples with RPL will have one partner with an unbalanced translocation. This would be expected to lead to unbalanced translocation in up to 50% of offspring, leading to an increased risk of loss (Figure 1).