Recurrent Early Pregnancy Loss

Mary D. Stephenson, M.D., M.Sc.

Miscarriage is the most common complication of pregnancy. With the inclusion of preclinical pregnancies, ∼30 to 50% end in miscarriage. Approximately 50 to 70% of early (<10 weeks of gestation) miscarriages are associated with lethal numeric chromosome errors, such as trisomy, monosomy, and polyploidy, of which trisomy increases dramatically with advancing maternal age. In addition, based on embryoscopy studies by Philipp et al, lethal embryonic developmental defects are found in more than half of clinically recognized miscarriages, some of which have euploid chromosome results.[1] One of the major challenges for clinicians is to determine whether an evaluation for other factors associated with recurrent pregnancy loss, including endocrine, uterine, and thrombophilic factors, is justified. With advancing genetic technologies, such as microarray comparative genomic hybridization (CGH) single-nucleotide polymorphisms (SNPs), the evaluation of the whole genome, at resolutions much higher than with conventional cytogenetic analysis, is possible. With microarray CGH, Rajcan-Separovic et al have recently published a preliminary study that identified genomic submicroscopic deletions and duplications in euploid miscarriages of couples with idiopathic recurrent pregnancy loss, termed copy number variants (CNVs), which may contain disrupted genes integral to early pregnancy.[2] Further investigation may lead to the identification of miscarriage genes that could be causative in recurrent pregnancy loss.

Early pregnancy terminology and definitions vary widely in the literature; therefore, the authors in this issue have attempted to be consistent, as much as possible, with the use of such terms. Whether an evaluation should begin with two or three early (<10 weeks of gestation) miscarriages, not necessarily consecutive, is still controversial, as is whether biochemical pregnancy losses should be included. Some clinicians are using chromosome testing of the second miscarriage to decide on whether testing of the couple is indicated. It is generally accepted that evaluation is required with a history of one fetal demise, based on a gestational age of at least 10 weeks. In this issue, recurrent early pregnancy loss is defined as two or more early miscarriages, not necessarily consecutive, unless otherwise stated.

Lathi et al discuss the importance of the miscarriage evaluation and how the information can be used to determine whether evaluation of the couple is necessary. In addition, the information can be useful for the patient and her partner with respect to their grieving process and then deciding whether to try again.

Hirshfeld et al provide a systematic review of management strategies for carriers of a reciprocal chromosomal translocation with a history of recurrent pregnancy loss. The results will be useful to the clinician for evidence-based counseling of patients with this most frequent structural chromosome rearrangement.

Endocrine disorders associated with recurrent early pregnancy loss are summarized in the article by Smith and Schust, along with recommendations and treatment of such patients. In particular, up-to-date information about subclinical hypothyroidism and thyroid autoimmunity is provided. The subsequent article by Patel and Lessey discusses the clinical assessment of the endometrium and some of the new diagnostic tests and therapeutic interventions presently being studied. Subsequently, Boots and Stephenson provide a systematic review of the impact of obesity on the rate of miscarriage in spontaneous conceptions. With obesity becoming an epidemic in the United States, this is an important area for further exploration.

Sugiura-Ogasawara et al describe the diagnostic evaluation of the uterus for the detection of uterine anomalies, followed by a summary of evidence-based management. As with many surgical-based treatments, randomized trials or even prospective studies are lacking in patients with a history of recurrent pregnancy loss.

The next two articles deal with thrombophilias in reproduction. Ernest et al provide an update on the latest diagnostic criteria and clinical management of the antiphospholipid syndrome. De Jong et al discuss the controversies surrounding the testing for inherited thrombophilias in recurrent pregnancy loss and the strength of the evidence on the use of anticoagulants to improve subsequent pregnancy outcomes.

Patients often inquire about assisted reproductive technology (ART) as a treatment for recurrent pregnancy loss. Vissenberg and Goddijn tackle this question by reviewing publications in which intrauterine insemination, in vitro fertilization, oocyte donation, and preimplantation genetic diagnosis and screening were offered. Little evidence presently supports the use of ART in such patients.

The final article by Saravelow and Regan is an important contribution on the role of preconception counseling in couples with a history of recurrent pregnancy loss. Lifestyle changes, reduction of stress, and review of medications taken by patients are especially important in couples with recurrent pregnancy loss. Close monitoring in the first trimester has repeatedly also been shown to improve pregnancy outcome.

This issue of Seminars in Reproductive Medicine provides comprehensive updates on recurrent pregnancy loss. I am indebted to all of the contributors from around the world for their thorough reviews. I hope you will find these contributions useful in your clinical practice.

REFERENCES

• 1 Philipp T, Philipp K, Reiner A, Beer F, Kalousek D K. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies.  Hum Reprod. 2003;  18 (8) 1724-1732
• 2 Rajcan-Separovic E, Diego-Alvarez D, Robinson W P et al.. Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss.  Hum Reprod. 2010;  25 (11) 2913-2922