PRACTICE COMMITTEE Evaluation and treatment of recurrent pregnancy loss: a committee opinion The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology. (Fertil SterilÒ 2012;-:-–-. Ó2012 Use your smartphone by American Society for Reproductive Medicine.) to scan this QR code Earn online CME credit related to this document at www.asrm.org/elearn and connect to the discussion forum for Discuss: You can discuss this article with its authors and with other ASRM members at http:// this article now.* www.ASRM.org/fns-xx-x-xxx * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace. linically recognized pregnancy cal evaluation may proceed following agrees that genetic causes should be loss is common, occurring in two first-trimester pregnancy losses. evaluated and appropriate treatments C approximately 15–25% of preg- considered (4–6, 9).Unfortunately, nancies. The majority of sporadic losses ETIOLOGY OF RECURRENT clinical genetic testing remains ’ before 10 weeks gestation result from PREGNANCY LOSS rudimentary and rarely includes random numeric chromosome errors, molecular studies which show promise specifically, trisomy, monosomy, and Studies that focus on RPL have exam- in helping to elucidate mechanisms for polyploidy (1). In contrast, recurrent ined factors related to genetics, age, RPL. There is a very high frequency of pregnancy loss (RPL) is a distinct disor- antiphospholipid syndrome, uterine sporadic karyotypic abnormalities in der defined by two or more failed clinical anomalies, thrombophilias, hormonal products of conception while the pregnancies (2). It is estimated that or metabolic disorders, infection, incidence of karyotypic abnormalities fewer than 5% of women will experience autoimmunity, sperm quality, and life- in the parents is low. two consecutive miscarriages, and only style issues (Table 1). Several recom- Of the examined products of 1% experience three or more (3). mendations have been published (5, 6) conception, approximately 60% of early regarding the evaluation and man- pregnancy losses are associated with agement of RPL. These publications do sporadic chromosomal anomalies, WHO TO EVALUATE fi not support de nitive conclusions primarily trisomies that are, in part, The challenge for clinicians is to differ- about the causes of RPL because most entiate sporadic miscarriage from RPL. age related (1, 10, 11).Inthoselosses studies of pregnancy loss have focused with a normal karyotype, gross Self-reported losses by patients may on sporadic miscarriage and not RPL. not be accurate. In one study, only morphological abnormalities in the A putative diagnosis will be made and fetus diagnosed by transcervical 71% of self-reported clinical pregnancy treated in approximately 50% of fi embryoscopy have been described in losses could be veri ed in hospital re- patients with RPL (7, 8). The following cords (4). For the purposes of determin- 18% of patients (12). The risk of overview acknowledges that our sporadic miscarriage between 6 and 12 ing whether evaluation for RPL is understanding of this field is in flux. appropriate, pregnancy is defined as weeks of gestation in women less than a clinical pregnancy documented by ul- 35 years of age is 9% to 12% (13, 14). trasonography or histopathological Cytogenetic Abnormalities in The risk increases in women over examination. Ideally, a threshold of Pregnancy Loss 35 years of age due to the markedly three or more losses should be used Virtually every published set of recom- increased incidence of trisomic for epidemiological studies while clini- mendations and reviews on this topic pregnancies (10). In women older than 40 years of age, the sporadic Received June 22, 2012; accepted June 25, 2012. miscarriage rate approaches 50% (1, 14, Correspondence: American Society for Reproductive Medicine, 1209 Montgomery Highway, Birming- ham, AL 35216 (E-mail: [email protected]). 15) (Fig. 1). The risk of aneuploidy at each age is lower in women with RPL Fertility and Sterility® Vol. -, No. -, - 2012 0015-0282/$36.00 than in those who undergo sporadic Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.06.048 miscarriages (11). VOL. - NO. - / - 2012 1 PRACTICE COMMITTEE 2 TABLE 1 Suspected causes of recurrent pregnancy loss. Cause Contribution to RPL (%) Recommended screening Supportive scientific evidence Controversial scientific evidence Not recommended Cytogenetic 2–5 Balanced reciprocal translocations aPL syndrome 8–42 (mean, 15) Lupus anticoagulant, IgG and IgM antibodies, IgG or IgM anti-annexin A5, ANA, antithyroid antibodies anticardiolipin IgG aPL testing for other anti-factor XII, anti- or IgM antibody, phospholipids and b2 prothrombin, IgA aPLs anti-b2-glycoprotein I glycoprotein I Anatomic 1.8–37.6 (mean, 12.6) Hysterosalpingography Congenital uterine Uterine fibroids, polyps Cervical incompetence Sonohysterography abnormalities Hormonal or metabolic Prolactin Uncontrolled diabetes Polycystic ovary syndrome and TSH or thyroid disease, prolactin insulin resistance, luteal Hemoglobin A1c phase progesterone Infectious None Bacterial vaginosis, endocervical infections Male factors None Abnormal sperm DNA Psychological None Psychological effects on uterine receptivity Alloimmune None Mucosal CD16À NK cells, Circulating CD16À NK cells embryotoxic factor, cytokine profiles, blocking antibodies, HLA typing, anti-paternal leukocyte antibodies, circulating CD16À NK cells Environnmental, occupational, History Not related to recurrent or personal habits pregnancy loss Note: ANA ¼ antinuclear antibodies; aPL ¼ antiphospholipid. Practice Committee. Recurrent pregnancy loss. Fertil Steril 2012. VOL. - NO. - / - 2012 Fertility and Sterility® carrier status. Currently, routine preimplantation embryo FIGURE 1 aneuploidy screening is not justified (20, 21). If the evaluation of RPL identifies a remediable cause, cy- togenetic analysis of subsequent losses can be employed to evaluate whether the event was random and not a treatment failure per se. Testing of the products of conception may also be of psychological value to the couple (6). There are pitfalls to this approach, however, including: the possibility of maternal tissue contamination of the specimen; failure to seek other causes of RPL if cytogenetic assessment reveals an abnormal karyotype; and the occurrence of non-cytogenetic embryonic abnormalities (e.g., dimorphic fetal development has been documented via hysteroscopy prior to dilatation and evacua- tion in the setting of normal fetal karyotype) (12). In the event that cytogenetic analysis of the products of conception re- veals a 46,XX karyotype, reflex DNA extraction and analysis of a sample of maternal blood by means of microsatellite analysis can permit differentiation between a fetal source vs. maternal contamination (22). Kaplan-Meier plot showing percentage of women in the recurrent miscarriage cohort who have had at least one live birth after first Antiphospholipid Syndrome consultation by number of miscarriages before first consultation. (Lund et al. Recurrent miscarriage and prognosis for live birth. The antiphospholipid syndrome is associated with recurrent Obstet Gynecol 2012.) pregnancy loss. The diagnostic criteria are outlined in Practice Committee. Recurrent pregnancy loss. Fertil Steril 2012. Table 2 (23, 24). Although it is generally agreed that between 5% and 20% of patients with recurrent pregnancy loss will test positive for antiphospholipid antibodies (aPLs), In the evaluation of RPL, parents should undergo periph- the actual reported range varies between 8% and 42% (24, eral karyotyping in order to detect any balanced structural 25). Several groups of investigators have characterized these chromosomal abnormalities. Balanced reciprocal transloca- antibodies in laboratory-specific assays that have not been tions and Robertsonian translocations (6) are observed in standardized (23). The most widely accepted tests are for lupus about 2%–5% of couples with recurrent miscarriage. Genetic counseling is important when a structural genetic fi factor is identi ed. The likelihood of a subsequent healthy live TABLE 2 birth depends on the chromosome(s) involved and the type of rearrangement. When one of the partners has a structural International Consensus Classification criteria for the genetic abnormality, preimplantation genetic testing (PGT), antiphospholipid syndrome (APS) (23, 24). amniocentesis, or chorionic villus sampling are options to APS is present if one of the following clinical criteria and one of the detect the genetic abnormality in the offspring. Treatment laboratory criteria are met. options include preimplantation genetic diagnosis (PGD) Clinical criteria fi 1. Vascular thrombosis for speci c translocations, with transfer of unaffected 2. Pregnancy morbidity embryos, or the use of donor gametes. While data are limited a. One or more unexplained deaths of morphologically normal comparing in vitro fertilization (IVF)/PGD versus medical fetuses after the 10th week of gestation by ultrasound or management (defined as natural conception and observation) direct examination of the fetus.