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.
Lethal fetal arrhythmias caused by ion channel mutations
Recently Crotti and associates tested the hypothesis that mutations leading to long QT syndrome (LQTS)—a cause of unexpected death in infants, children, and young adults—might also cause fetal death after 13 weeks.6 They conducted postmortem anatomic studies and karyotype, toxicological, microbiologic, and biochemical analyses on a series of fetuses that died in utero, followed by an analysis for genes causing (or strongly associated with) LQTS. A total of 91 cases were evaluated (51 females, 40 males) with an average gestational age of 26.3 weeks (range, 14-41 weeks) at demise. The investigators identified 8 cases (8.8% [95% CI, 3.9%-16.6%]) where there were mutations associated with dysfunctional LQTS-associated ion channels (2 in losses at <20 weeks and 6 in losses at ≥20 weeks). This high frequency stands in stark contrast to the reported frequency of LQTS in adults (1/5,500 to 1/10,000)7 suggesting that lethality might be greatly enhanced during fetal life.
The authors theorize that high levels of circulating progesterone, a hormone that prolongs the QT interval, may contribute to higher lethality of these mutations in affected fetuses.6 Other factors that may contribute to lethality in an affected fetus include immaturity of the cardiac conduction system, volatility of the fetal autonomic nervous system with large physiological swings in sympathetic tone, and cord compression leading to sequential parasympathetic and sympathetic stimulation. Perhaps some losses associated with nuchal cords may have this underlying disorder. Of note, the prevalence of LQTS mutations is also greatly increased in infants who die of SIDS (10%) compared with adults.8
Clearly, additional studies are needed to confirm these observations. Moreover, because more than 300 mutations contribute to LQTS,9 expanded genetic surveys are needed. It will also be important to learn what percent of such mutations occur de novo and what percent reflect cryptic parental disease. Confirmation of inheritance also presents the opportunity for prevention in future pregnancies through maternal beta-adrenergic blockade therapy and detection of adults at risk for sudden death.9
You may suspect that I am obsessed with genetics and you may be wondering why I have not mentioned the role of other putative causes of RPL, including luteal-phase defects, infections, uterine anomalies, and inherited thrombophilias. The bottom line is that I think that, with rare exceptions, these conditions are either unrelated to RPL or they are serendipitous findings. Indeed, we are at the dawn of a new age in the identification of etiologies for both isolated and recurrent pregnancy loss. However, future discoveries concerning RPL are unlikely to come out of relatively crude genome-wide association studies, which, as in the case of many common diseases, have led to only modest correlations with single nucleotide polymorphisms (SNPs).10 Rather, breakthroughs will likely require examination of whole exome and/or genomic sequences of affected POCs with subsequent targeted studies of parental DNA. This approach should lead to identification of a host of autosomal and X-linked recessive causes of intermittent losses, as well as autosomal-dominant disorders of variable penetrance.
Whole exome and/or genomic sequencing may also commonly detect de novo germ line mutations and copy number variants in the POCs of women with maternal-age-associated recurrent losses found to be “euploid” by karyotype analysis. This would be analogous to the observation of increased rates of genetic abnormalities detected in stillborn specimens using chromosomal microarray studies, which detect far smaller (50 to 100 kb) deletions or duplications, compared with traditional karyotype analysis.11 Exome and genomic sequencing would increase this resolution down to the base pair level. In fact, I would argue that such women have age-induced genetic instability in their oocytes of which karyotype-detected aneuploidy is just the tip of the “genetic” iceberg.
Many possible RPL genes may be found to code for proteins crucial to early embryonic and fetal development as well as those, as reported above, associated with lethal arrhythmias. Epigenetic and even microRNA abnormalities may also be involved.12 Eventually, relatively inexpensive multi-gene panels and other high throughput screens may be used to screen for genetic causes of isolated and recurrent pregnancy loss providing closure to patients as to the cause of heartbreaking losses and eliminating often irrational impulses of guilt and anger that can have professional liability consequences. It will also dissuade physicians from employing aggressive, expensive and/or unproven treatments in an effort help desperate patents. In the interim, additional studies should be initiated to determine the prevalence of arrhythmogenic mutations as a cause of otherwise unexplained fetal losses. This approach has the added advantage of identifying affected parents who can then be offered life-saving interventions.
1. Contro E, deSouza R, Bhide A. Chronic intervillositis of the placenta: a systematic review. Placenta. 2010;31(12):1106-1110.
2. Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 132: Antiphospholipid syndrome. Obstet Gynecol. 2012;120(6):1514-1521.
3. Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod. 2006;21(4):1076-1082.
4. Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y. Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2002;40(1):16-20.
5. Vogt J, Harrison BJ, Spearman H, et al. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008;82(1):222-227.
6. Crotti L, Tester DJ, White WM, et al. Long QT syndrome-associated mutations in intrauterine fetal death. JAMA. 2013;309(14):1473-1482.
7. Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis. 2008;3:18. doi:10.1186/1750-1172-3-18.
8. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007;115(3):361-367.
9. Chiang CE. Congenital and acquired long QT syndrome. Current concepts and management. Cardiol Rev. 2004;12(4):222-234.
10. Huang JY, Su M, Lin SH, Kuo PL. A genetic association study of NLRP2 and NLRP7 genes in idiopathic recurrent miscarriage. Hum Reprod. 2013; 28(4):1127-1134.
11. Reddy UM, Page GP, Saade GR. The role of DNA microarrays in the evaluation of fetal death. Prenat Diagn. 2012;32(4):371-375.
12. Wang X, Li B, Wang J, et al. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod Biomed Online. 2012;25(4):415-424.