By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: A small retrospective cohort study raises the possibility that advanced genetic techniques can be used to analyze the products of conception in women with recurrent pregnancy loss to identify those most likely to have treatable reasons for their miscarriages.
SOURCE: Maslow BS, et al. Single-nucleotide polymorphism microarray ploidy analysis of paraffin-embedded products of conception in recurrent pregnancy loss evaluations. Obstet Gynecol 2015;126:175-181.
Investigators at the University of Connecticut Health Center conducted a small retrospective cohort study including 42 women with at least two documented first-trimester losses who presented for new evaluation of recurrent pregnancy loss over a 2-year period. Paraffin-embedded products from 62 of the total of 178 losses suffered by these women were subjected to single nucleotide polymorphism (SNP)microarray ploidy analysis to identify all 24 different chromosomes (i.e., the 22 autosomes and X and Y). This technique successfully diagnosed fetal chromosome number in 44 of the 62 samples, with 43% (19/44) being euploid and 57% (25/44) being noneuploid. The most common chromosomal abnormalities were trisomy 15 (5/25) and monosomy X (4/25) and probably explain the loss of that pregnancy. Of note is that participants in this small study were significantly more likely to have an abnormality on routine screening for recurrent pregnancy loss (RPL) as recommended by the American Society for Reproductive Medicine if they had one or more euploid losses identified than those with only noneuploid losses (relative risk, 2.78; 95% confidence interval, 1.34-5.78; P = 0.028). This finding remained significant when adjusted for maternal age, number of losses, number of samples, and total pregnancies.
Five of the 14 women with one or more euploid analyses had abnormalities on RPL screening. Four of these had a uterine septum and one had antiphospholipid antibodies. In contrast, only one of 21 women with only noneuploid losses had any abnormality on screening, and this was the presence of uterine synechiae. One of seven women with no result on SNP microarray testing had an abnormality on screening (i.e., a submucous myoma).
Based on these findings, the authors suggest a new paradigm for evaluating women with RPL. If paraffin-embedded products of conception are available, they suggest SNP microarray testing and simultaneous evaluation of the uterine cavity. If the loss is aneuploid, no further evaluation is warranted unless there is a balanced translocation, thus justifying parental karyotyping. If euploid, modified screening with no parental karyotyping should be conducted. Only if SNP microarray testing cannot be performed is RPL screening justified.
COMMENTARY
Evaluation of women with RPL is frustrating for clinicians and their patients. The emotional and mental distress to these couples mandates that clinicians ensure adequate psychological counseling and support for those affected. This is made more imperative by the fact that no apparent cause is typically identified in more than half of couples presenting with RPL.1 Yet more than 50-60% of women with unexplained RPL eventually have a future successful pregnancy depending on maternal age and parity, with or without medical consultation.2
All authorities agree that more than half of all early pregnancy losses are associated with sporadic chromosomal abnormalities, primarily trisomies as well as monosomies and other polyploidies, that are at least partly age related.3,4 Although it is true that RPL may occur in those who are statistically unlucky and have multiple genetically abnormal pregnancies, authorities concur that evaluation is warranted whenever a woman has two or more failed clinical pregnancies.5 The real question is just what tests should be included in that evaluation because aneuploidy is not usually the cause of RPL in those in whom a cause can be identified. Genetically, a balanced translocation in one of the parents is a cause that must be excluded.
In an opinion published in 2012, the Practice Committee of the American Society for Reproductive Medicine recommended that evaluation of RPL could proceed after two consecutive pregnancy losses.1 The Practice Committee further suggested that screening might include:
- Assessment of the uterine cavity by sonohysterogram, hysterosalpingogram, and/or hysteroscopy.
- Screening for lupus anticoagulant, anticardiolipin antibodies, and anti-ß2 glycoprotein I.
- Screening for thyroid or prolactin abnormalities.
- Peripheral karyotypic analysis of the parents.
Lastly, the Committee noted that karyotypic analysis of the products of conception might be useful, but noted that “clinical genetic testing remains rudimentary and rarely includes molecular studies, which show promise in helping to elucidate mechanisms for RPL.”1
The authors of this small study suggest that there is no need to proceed with expensive karyotypic testing of the parents if SNP microarray testing of the products of conceptions reveals any genetic abnormality save for a balanced translocation. The authors of this study also point out that fresh tissue is not needed to perform the analysis, but rather the DNA can be extracted from chorionic villi embedded in paraffin blocks and identified by examining the stained sections made from the blocks.
While SNP microarray analysis was used in this study, other molecular genetic techniques, such as comparative genomic hybridization (CGH) array analysis, might be utilized as well, even though CGH analysis alone cannot identify maternal cell contamination.6 As these techniques (and others) become more available, simpler to perform, and less costly, then the evaluation scheme suggested by the authors becomes more and more feasible. At present, even the authors point out that the cost of SNP microarray testing alone is more expensive than all of the tests currently recommended for the evaluation of RPL.
This small study, like so many others, identified uterine anomalies in several of the women with RPL, with uterine septa being most common by far. Several retrospective studies have documented that a uterine septum is found more commonly among women with early pregnancy losses. In one of the larger studies, the incidence of a history of first trimester loss was 41.1% in 689 women with a septate uterus diagnosed on screening 3-D ultrasound in an infertility clinic compared to 12.1% in the control of more than 15,000 women in the general pregnant population.7 Meta-analyses of the effects of repair of the septum indicate that the incidence of miscarriage falls dramatically after the septum is incised or resected hysteroscopically.8
There is no question that no changes in the current recommendations regarding evaluation of RPL are warranted on the basis of such a small retrospective study. However, this thought-provoking study should give us pause and cause us to ask patients to place products of conception from any losses in water in the refrigerator and bring them to us so that they may be embedded in paraffin. Should the patient later be diagnosed with RPL, the paraffin blocks can be retrieved and analyzed. In the future, we may be better able to provide couples with RPL with explanations for their losses. Even if we are unable to increase the percentage who ultimately take home babies, such information will provide comfort and closure to those with lingering questions.
REFERENCES
- Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil Steril 2012;98:1103-1111.
- Lund M, et al. Prognosis for live birth in women with recurrent miscarriage: What is the best measure of success? Obstet Gynecol 2012;119:37-43.
- Hassold T, Chiu D. Maternal age specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet 1985;70:11-17.
- Stephenson MD, et al. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: A case-control study. Hum Reprod 2002;17:446-451.
- Van den Boogaard E, et al. Consecutive or non-consecutive recurrent miscarriage: Is there any difference in carrier status? Hum Reprod 2010;25:1411-1414.
- Kudesia R, et al. Rescue karyotyping: A case series of array-based comparative genomic hybridization evaluation of archival conceptual tissue. Reprod Biol Endocrinol 2014;12:19-26.
- Kupesic S, et al. Screening for uterine abnormalities by three-dimensional ultrasound improves perinatal outcomes. J Perinatal Med 2002;30:9-17.
- Venetis CA, et al. Clinical implications of congenital uterine anomalies: A meta-analysis of comparative studies. Reprod Biomed Online 2014;29:665-683.
A small retrospective cohort study raises the possibility that advanced genetic techniques can be used to analyze the products of conception in women with recurrent pregnancy loss to identify those most likely to have treatable reasons for their miscarriages.
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