Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, is usually a silent struggle. Despite the prevalence, many women do not share their stories with family or friends. Recent research shows that couples can experience high levels of stress and anxiety, as well as feelings of isolation, grief, and sadness. Informing patients about available testing may help to alleviate some of these emotions, as 78% of patients surveyed would like to know the cause of their miscarriage. The evaluation can help find answers by identifying potential causes that are unlikely to recur or issues that can be addressed and treated.
Causes of recurrent pregnancy loss
Approximately 15% to 25% of clinically recognized pregnancies end in loss and about 5% of women of reproductive age experience RPL.1 The incidence of miscarriage increases with both increasing maternal ageand paternal age. The risk of miscarriage is greatest in couples for which the woman is 35 years of age or older and the man is 40 years of age or older.4 It is now recommended that an evaluation including a physical exam and testing be performed following 2 first-trimester pregnancy losses, regardless of whether or not they are consecutive.1 The most frequent causes of RPL include chromosomal abnormalities, autoimmune disorders, hormonal abnormalities, and structural issues of the uterus. Following complete evaluations, the cause of RPL can be identified for approximately 75% of couples.
Testing for genetic causes of recurrent pregnancy loss
Genetic testing for RPL includes chromosome analysis or microarray analysis of the products of conception (POC, the miscarriage tissue), and/or blood chromosome analysis of the parents. A normal chromosome result usually includes 46 chromosomes. Extra or missing chromosomes or extra or missing pieces of chromosomes result in an incorrect number of genes, and this can cause a miscarriage. Approximately 41% of RPL is due to abnormal POC or fetal chromosomes.5 Microarray analysis is another method to look for chromosome abnormalities in the POC that does not require living/dividing cells, which are needed for chromosome analysis. The risk of no results due to growth failure, seen in 10 to 40% of POC samples for chromosome analysis, is eliminated with microarray analysis. Parental blood chromosome analyses can determine if a parent has a balanced rearrangement (translocation or inversion) of their chromosomes, meaning that the correct number of genes are present but arranged differently on the chromosomes than normal. This is associated with an increased risk of chromosomally abnormal pregnancies. The incidence of parental chromosome abnormalities is approximately 5% in couples with a history of 3 miscarriages. If a parent is determined to have a balanced chromosomal rearrangement, preimplantation genetic diagnosis to look for chromosome abnormalities in the embryo followed by in vitro fertilization can be offered for future pregnancy attempts.
Testing for other causes of recurrent pregnancy loss
Other conditions that cause recurrent pregnancy loss can be identified with appropriate testing and some are treatable, boosting a couple’s chances of achieving a successful pregnancy. Antiphospholipid syndrome (APS), occurring when the immune system produces antibodies which increase the risk of blood clots, is present in approximately 5% to 20% with women with RPL.7 This condition is diagnosed with blood tests and the presence of a clinical history of vascular thrombosis, which is a blood clot that blocks a blood vessel, or a poor pregnancy history with no other known cause. APS is treatable with low-dose aspirin and heparin.8 Endocrine abnormalities are present in approximately 6% of women with RPL5 and include luteal phase deficiency, elevated thyroid-stimulating hormone (TSH) levels, hyperprolactinemia, and uncontrolled diabetes. These conditions are also diagnosed with blood tests. Treatment options include hormonal treatments and diabetic control which may include diet, weight loss, and medication.8 Maternal anatomical anomalies are present in 16% to 23% of patients with RPL. Structural anomalies of the uterus are usually present from birth, while other anomalies such as adhesions, fibroids, and polyps are acquired. These anomalies can be diagnosed with imaging studies and treatment options include surgical correction.8
Outlook for the future
The outlook for patients with RPL is hopeful. Overall, 67% of women had a live birth within 5 years of their first consultation. When breaking down these patients into groups based on the number of pregnancy losses, 72% of women with a history of 3 miscarriages delivered a liveborn within 5 years of their first consultation for RPL and 50% of women with a history of 6 or more pregnancy losses had a live birth within 5 years.
Quest Diagnostics offers a recurrent pregnancy loss panel through ReproSource®, our specialty fertility diagnostic laboratory. Information about this panel can be found at https://www.reprosource.com/. These tests can also be ordered individually through Quest Diagnostics; more information is available at Quest Women's Health (questwomenshealth.com). You can also arrange to speak with a Quest genetic counselor by calling 866-GENEINFO (1.866.436.3463).
"ReproSource® is a national leader in specialty fertility diagnostic services. While ReproSource® is a Quest Diagnostics affiliate, ReproSource® and Quest are separate companies. As such, health plan access, test ordering, and billing processes may differ from those of Quest Diagnostics. Please note that ReproSource® is not a Medicare/Medicaid provider. For more information, please contact ReproSource® at 1.800.667.8893 or visit ReproSource®.com/Contact.
- Barbados J, Hercz D, Friedenthal J, Missmer SA, Williams S. A national survey on public perception of miscarriage. Obstet Gynecol. 2015;125:1313-1320. doi: 10.1097/AOG.0000000000000859
- Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320:1708-1712. doi: 10.1136/bmj.320.7251.1708
- De la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Human Reproduction. 2002;17:1649-1656. doi: 10.1093/humrep/17.6.1649
- Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Human Reprod. 2012; 27:2297-2303. doi: 10.1093/humrep/des179
- van den Berg MM, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta. 2012;1822(12):1951-1959. doi: 10.1016/j.bbadis.2012.07.001
- Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril. 2010;93(4):1234-43. doi: 10.1016/j.fertnstert.2009.01.166
- El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health. 2017;17(9):331-345. doi: 10.2147/IJWH.S100817
- Kutteh WH. Novel strategies for the management of recurrent pregnancy loss. Semin Reprod Med. 2015;33(3)161-168. doi: 10.1055/s-0035-1552586
- Lund M, Kamper-Jorgensen M, Svarre Nielsen H, Lidegaard O, Nybo Anderson A, Bajrne Christiansen O. Prognosis for live birth in women with recurrent miscarriage: what is the best measure of success? Obstet Gynecol. 2012;119(1):37-43. doi: 10.1097/AOG.0b013e31823c0413