Recurrent pregnancy loss (RPL): definitions and etiology

Recurrent pregnancy loss (RPL): what is it?

Pregnancy loss is the most common adverse event of pregnancy.

However, the definition of recurrent pregnancy loss (RPL) is far from unambiguous: the Royal College of Obstetricians and Gynecologists (RCOG) defines RPL as three or more consecutive spontaneous miscarriages (RCOG 2011), while the American Society for Reproductive Medicine (ASRM) defines RPL as two or more consecutive miscarriages (Practice Committee of ASRM 2013). Finally, the European Society of Human Reproduction and Embryology refers to RPL as two or more consecutive or non-consecutive miscarriages (ESHRE Guideline Group on RPL 2018).

Globally, according to the aforementioned definitions, between 2% and 5% of couples experience RPL.

Recurrent pregnancy loss: which causes?

RPL may have a considerable impact on a couple's wellbeing and psychology. Understanding and identifying the causes of RPL is therefore pivotal. Said this, it's important to have in mind that, thus far, about 50% of all miscarriage events remain of unknown cause (idiopathic), meaning they may be caused by the interaction of several different factors. In the remaining half of the cases, a more precise cause can be identified:

  1. genetic causes (chromosomal and monogenic);
  2. immunological and inflammatory factors;
  3. anatomical alterations;
  4. endocrine abnormalities;
  5. environmental.

Genetic causes (chromosomal)

Chromosomal abnormalities are one of the most frequent causes of spontaneous miscarriage. They cause 50% -60% of all cases of first-trimester miscarriage. Chromosomal abnormalities may concern the number of chromosomes (as in the case of trisomies or monosomies) or their structure (as in the case of translocations and inversions). These anomalies, balanced in the parents, greatly increase the likelihood of having a genetically unbalanced gamete due to the complex mechanisms of segregation during meiosis. According to a recent study, in about 5% of couples with RPL, one of the partners has a balanced translocation or inversion. Similarly, the presence of these structural alterations is 10 times greater in couples with RPL than in the general population.

Genetic causes (monogenic)

Very recently (and very interestingly) it has been shown that not only chromosomal abnormalities can cause RPL. Actually, also point mutations can cause RPL (monogenic causes of RPL). For example, Fatemi and colleagues (2021) described frameshift mutations in the KHDC3L gene in a large family with RPL with or without hydatiform mass. The same group, in 2020, also identified a missense mutation in the CCNB3 gene that segregated in a family with RPL.

Immunological and inflammatory causes

It's well known that the mother's immune system develops a tolerance mechanism towards the fetus, which allows the pregnancy to go on. However, various immune factors can alter this mechanism (of which functioning is still poorly understood). These factors may promote the risk of multiple miscarriages. For example, antiphospholipid antibody syndrome (APLS), a heterogeneous autoimmune disease, can be diagnosed in approximately 5-20% of patients with RPL. APLS is one of the most important causes of pregnancy complications, leading to early miscarriages, eclampsia and reduced fetal growth. APLS is thought to cause a state of hypercoagulability leading to thrombosis of the placental blood vessels. Luckily, APLS is treatable.

Among other immunologic causes, there's increasing evidence about the role of NK cells (Natural Killer cells), which may be altered in their number or their cytotoxicity levels.

The control of inflammation also plays an important role in preventing RPL. For example, it is known that polymorphisms in numerous inflammation-related genes such as FOXP3, CLOCK, IL-10, TNF-α, and IL-17F may be associated with RPL. Similarly, polymorphisms in CRP, that affects circulating C-reactive protein in chronic inflammatory diseases, ma also be associated with RPL. However, we are talking here about polymorphisms that might be predisposing, although not being predictive.

Anatomical causes

Numerous studies indicate that up to 13% -19% of patients with RPL have a structural malformation of the uterine cavity. These malformations can be congenital or acquired. Congenital forms include arcuate uterus, septum, single or bi-horned, while acquired forms include intrauterine adhesions, polyps, and submucosal myomas. In one study, the uterus septum was found to be the most common congenital anomaly, being identified in about 5% of patients with RPL.

Endocrine causes

The involvement of the endocrine system in poliabortivity is widely debated. According to numerous studies, conditions such as hypothyroidism, insulin resistance, polycystic ovary syndrome, vitamin D deficiency, luteal phase deficiency and prolactin disorders can have an in influence on RPL. However, if it's known that overt hypothyroidism may cause reduced fertility, miscarriages, pre-eclampsia and preterm births, the association with other endocrine problems is still an open debate, given the conflicting results of several studies.

Environmental causes

Environmental and behavioral risk factors, such as maternal age, BMI index and cigarette smoking are considered risk factors for miscarriage.

Thrombophilias: myth or reality?

A special mention goes to thrombophilias, that is, those inherited or acquired diseases that cause an increased risk of deep vein thrombosis due to plasma hypercoagulability. The main inherited thrombophilia are the factor V Leiden mutation (G1691A), the prothrombin gene mutation (G20210A), protein C, protein S and anti-thrombin deficiency. Historically, hereditary thrombophilias have been associated with polyabortivity, as it was hypothesized that placental thrombosis events favored RPL. Although numerous studies published in the literature confirm and corroborate this hypothesis, a growing series of recent studies have been published that disprove this association and do not confirm the results. Therefore, routine screening for thrombophilia in patients with recurrent miscarriages is not currently recommended if they have not already had deep vein thrombosis events.

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References

Elhady GM, Kholeif S, Nazmy N. Chromosomal Aberrations in 224 Couples with Recurrent Pregnancy Loss. J Hum Reprod Sci. 2020 Oct-Dec;13(4):340-348. doi: 10.4103/jhrs.JHRS_11_20. Epub 2020 Dec 28. PMID: 33627985.

Manning R, Iyer J, Bulmer JN, Maheshwari A, Choudhary M. Are we managing women with Recurrent Miscarriage appropriately? A snapshot survey of clinical practice within the United Kingdom. J Obstet Gynaecol. 2020 Oct 19:1-8. doi: 10.1080/01443615.2020.1803241. Epub ahead of print. PMID: 33073655.

Che D, Fang Z, Pi L, Xu Y, Fu L, Zhou H, Gu X. The SERPINA4 rs2070777 AA Genotype is Associated with an Increased Risk of Recurrent Miscarriage in a Southern Chinese Population. Int J Womens Health. 2021 Jan 18;13:111-117. doi: 10.2147/IJWH.S290009. PMID: 33500667.

Pinar MH, Gibbins K, He M, Kostadinov S, Silver R. Early Pregnancy Losses: Review of Nomenclature, Histopathology, and Possible Etiologies. Fetal Pediatr Pathol. 2018 Jun;37(3):191-209. doi: 10.1080/15513815.2018.1455775. Epub 2018 May 8. PMID: 29737906.

Fatemi N, Ray PF, Ramezanali F, Shahani T, Amiri-Yekta A, Kherraf ZE, Cazin C, Almadani N, Varkiani M, Sarmadi S, Sodeifi N, Gourabi H, Biglari A, Totonchi M. KH domain containing 3 like (KHDC3L) frame-shift mutation causes both recurrent pregnancy loss and hydatidiform mole. Eur J Obstet Gynecol Reprod Biol. 2021 Apr;259:100-104. doi: 10.1016/j.ejogrb.2021.02.006. Epub 2021 Feb 10. PMID: 33639414.

Fatemi N, Salehi N, Pignata L, Palumbo P, Cubellis MV, Ramazanali F, Ray P, Varkiani M, Reyhani-Sabet F, Biglari A, Sparago A, Acurzio B, Palumbo O, Carella M, Riccio A, Totonchi M. Biallelic variant in cyclin B3 is associated with failure of maternal meiosis II and recurrent digynic triploidy. J Med Genet. 2020 Sep 16:jmedgenet-2020-106909. doi: 10.1136/jmedgenet-2020-106909. Epub ahead of print. PMID: 32938693.

Vomstein K, Feil K, Strobel L, Aulitzky A, Hofer-Tollinger S, Kuon RJ, Toth B. Immunological Risk Factors in Recurrent Pregnancy Loss: Guidelines Versus Current State of the Art. J Clin Med. 2021 Feb 20;10(4):869. doi: 10.3390/jcm10040869. PMID: 33672505

Hamulyák EN, Scheres LJJ, Goddijn M, Middeldorp S. Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome-What is the evidence? J Thromb Haemost. 2021 Mar 9. doi: 10.1111/jth.15290. Epub ahead of print. PMID: 33687789.

Carbonnel M, Pirtea P, de Ziegler D, Ayoubi JM. Uterine factors in recurrent pregnancy losses. Fertil Steril. 2021 Mar;115(3):538-545. doi: 10.1016/j.fertnstert.2020.12.003. PMID: 33712099.

Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol. 2019 Feb;59(1):36-44. doi: 10.1111/ajo.12920. Epub 2018 Nov 4. PMID: 30393965.

Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020 Dec 10;6(1):98. doi: 10.1038/s41572-020-00228-z. PMID: 33303732.

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