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Evaluation and treatment of recurrent pregnancy loss: a ...

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 in uenced by maternal age. recurrent pregnancy loss (RPL) is de ned by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly de ned etiology. (Fertil Steril 2012;-:- -. 2012 Use your smartphone by American Society for Reproductive Medicine.) to scan this QR code Earn online CME credit related to this document at and connect to the discussion forum for this article now.*. Discuss: You can discuss this article with its authors and with other ASRM members at http://. * Download a free QR code scanner by searching for QR. scanner in your smartphone's app store or app marketplace.

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1 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 in uenced by maternal age. recurrent pregnancy loss (RPL) is de ned by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly de ned etiology. (Fertil Steril 2012;-:- -. 2012 Use your smartphone by American Society for Reproductive Medicine.) to scan this QR code Earn online CME credit related to this document at and connect to the discussion forum for this article now.*. Discuss: You can discuss this article with its authors and with other ASRM members at http://. * Download a free QR code scanner by searching for QR. scanner in your smartphone's app store or app marketplace.

2 C. linically recognized pregnancy cal Evaluation may proceed following agrees that genetic causes should be loss is common, occurring in two rst-trimester pregnancy losses. evaluated and appropriate treatments 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 rudimentary and rarely includes pregnancy LOSS. random numeric chromosome errors, molecular studies which show promise speci cally, 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 de ned by two or more failed clinical anomalies, thrombophilias, hormonal products of conception while the pregnancies (2).

3 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 not support de nitive conclusions The challenge for clinicians is to differ- primarily trisomies that are, in part, about the causes of RPL because most age related (1, 10, 11). In those losses entiate sporadic miscarriage from RPL. studies of pregnancy loss have focused Self-reported losses by patients may with a normal karyotype, gross on sporadic miscarriage and not RPL.

4 Morphological abnormalities in the not be accurate. In one study, only A putative diagnosis will be made and 71% of self-reported clinical pregnancy fetus diagnosed by transcervical treated in approximately 50% of 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 eld is in ux. appropriate, pregnancy is de ned 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).

5 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: 15) (Fig. 1). The risk of aneuploidy at each age is lower in women with RPL. Fertility and Sterility Vol. -, No. -, - 2012 0015-0282/$ than in those who undergo sporadic Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc. miscarriages (11). VOL. - NO. - / - 2012 1. 2. PRACTICE COMMITTEE. TABLE 1. Suspected causes of recurrent pregnancy loss. Cause Contribution to RPL (%) Recommended screening Supportive scienti c evidence Controversial scienti c 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.)

6 Anatomic (mean, ) Hysterosalpingography Congenital uterine Uterine broids, 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 CD16 NK cells, Circulating CD16 NK cells embryotoxic factor, cytokine pro les, blocking antibodies, HLA typing, anti-paternal leukocyte antibodies, circulating CD16 NK cells Environnmental, occupational, History Not related to recurrent or personal habits pregnancy loss Note: ANA antinuclear antibodies; aPL antiphospholipid. Practice Committee. recurrent pregnancy loss. Fertil Steril 2012. VOL. - NO. - / - 2012. Fertility and Sterility.

7 Carrier status. Currently, routine preimplantation embryo FIGURE 1. aneuploidy screening is not justi ed (20, 21). If the Evaluation of RPL identi es 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 ( , 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, re ex DNA extraction and analysis of a sample of maternal blood by means of microsatellite analysis can permit differentiation between a fetal source vs.

8 Maternal contamination (22). Kaplan-Meier plot showing percentage of women in the recurrent miscarriage cohort who have had at least one live birth after rst Antiphospholipid Syndrome consultation by number of miscarriages before rst 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.

9 Balanced reciprocal transloca- antibodies in laboratory-speci c 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 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 Classi cation 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 1.

10 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 direct examination of the fetus. management (de ned as natural conception and observation) b. One or more premature births of a morphologically normal for couples with RPL carrying a structural genetic abnormal- neonate before the 34th week of gestation because of ity, two systematic reviews have summarized the success rates eclampsia or severe pre-eclampsia or recognized features from the literature (16, 17). In these reviews, live birth rates of placental insuf ciency. c. Three or more unexplained consecutive spontaneous were estimated to be between 31% 35% per cycle for IVF/ abortions before the 10th week of gestation with maternal PGD and cumulative live birth rates were 55% 74% for anatomic or hormonal abnormalities and paternal and natural conception/medical management.


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