Review
Recurrent miscarriage: current concepts in diagnosis and treatment

https://doi.org/10.1016/j.jri.2009.12.006Get rights and content

Abstract

Although recurrent miscarriage (RM) affects only 1–3% of couples, it has a major influence on the wellbeing and psychosocial status of patients. Therefore, research into improved diagnosis and development of new treatment strategies is essential. In this review, we summarize current concepts on diagnosis and treatment in RM, drawing upon research reports and international guidelines to provide insights into the pathophysiology of pregnancy disrupted by repeated miscarriage. Anatomical malformations, infectious diseases, endocrine disorders, autoimmune defects as well as acquired and inherited thrombophilia are established risk factors in RM. In addition, our recent findings indicate an impact on miscarriage incidence of glycoproteins such as glycodelin, and nuclear hormone receptors such as the peroxisome proliferator-activated receptors (PPARs). Significantly reduced glycodelin expression is associated with miscarriage, whereas up-regulation of PPARs appears to compensate for either the activated immune response or the disturbed cytotrophoblast differentiation in RM patients. There is also evidence that circulating placental microparticles are increased in a subgroup of RM patients, indicating an acquired procoagulant state even outside pregnancy. Treatment strategies like aspirin and low molecular weight heparin (LMWH) are standard medications in RM, although only a few placebo-controlled trials have proven their benefit in respect to live birth rate. There is emerging evidence that new treatment options, including drugs like TNFα inhibitors and granulocyte colony-stimulating factor (G-CSF) might be beneficial in some cases of RM. However, larger clinical trials must be completed to further prove or disprove benefits of these drugs in the treatment of RM patients.

Introduction

Three or more consecutive spontaneous miscarriages with or without previous live births are defined as recurrent miscarriage (RM) and this condition affects about 1–3% of women during their reproductive years (Carrington et al., 2005). In the face of declining birth rates especially in Western Europe, there is a growing movement to offer extensive diagnostic procedures to patients suffering at least two spontaneous abortions. Primary RM refers to patients with consecutive losses and no prior successful pregnancy; secondary RM refers to losses following a live birth.

Known risk factors for RM are genetic disorders, uterine pathologies, endocrine dysfunctions, autoimmune diseases, acquired and inherited thrombophilia as well as environmental factors (Rai and Regan, 2006). Additionally, late pregnancy complications including intrauterine growth restriction (IUGR), preterm labor, and preeclampsia are associated with RM (Dolitzky et al., 2006). Still, in nearly 50% of RM patients the underlying cause remains unknown.

Normal pregnancies lead to haemostatic changes towards a procoagulatory state with an increase in concentrations of clotting factors and fibrinogen, and decreased levels of anticoagulant factors with reduced fibrinolytic activity (Brenner, 2004). It seems that a subgroup of RM patients is in a permanent “acquired” procoagulatory state as fibrin deposits are found in the intervillous space of their placentas (Rai et al., 2003). There is increasing evidence that in some RM patients, this “procoagulatory state” is linked to increased concentrations of circulating microparticles (Laude et al., 2001, Carp et al., 2004, Toth et al., 2008b, Toth, 2009).

Other possible new risk factors for RM include nuclear hormone receptors like peroxisome proliferator-activated receptors (PPAR) as well as leptin and the glycoprotein glycodelin (Toth et al., 2007, Toth et al., 2008c, Toth et al., 2009b). However, only preliminary data are available indicating a possible role of these factors in the pathophysiology of disturbed pregnancy. RM patients with acquired or inherited thrombophilia are currently treated with aspirin and/or low molecular weight heparin (LMWH), although only few placebo-controlled trials have proven their benefit concerning live birth rate in RM patients, especially in patients with antiphospholipid syndrome (APS). With regard to possible new treatment options, TNFα inhibitors and granulocyte colony-stimulating factor (G-CSF) seem to be two promising new drugs, although larger clinical trials have to be conducted to evaluate their potential benefits in the treatment of RM patients.

Section snippets

Chromosomal and single gene disorders

In 4% of couples suffering from RM, changes in the karyotypes including balanced reciprocal translocations, Robertsonian-translocations, gonosomal mosaic and inversions are found, compared to 0.2% within control couples (Franssen et al., 2005). Single gene disorders (e.g. alpha thalassemia major) can contribute to late (second and third trimester) pregnancy losses (Laurino et al., 2005). However, Stern et al. did not find any difference in incidence of abnormal karyotypes when comparing

Circulating microparticles

Circulating microparticles are increased during normal (Bretelle et al., 2003) and disturbed pregnancy conditions such as preeclampsia (Gonzalez-Quintero et al., 2004). Furthermore, there is evidence that a subgroup of RM patients is in a permanent prothrombotic state even outside pregnancy (Rai et al., 2003). Microparticles from circulating blood cells expose phosphatidylserine and thus are believed to induce coagulation (Vanwijk et al., 2003). Injection of artificial phospholipid vesicles

Summary

In developed countries, maternal age at the first pregnancy is increasing and birth rates are declining so that couples are increasingly focused on achieving one uncomplicated pregnancy. Clinicians can cope with these expectations by negotiation or by identifying any underlying problems. However, patients with miscarriages at the age of 35 years or older should seek proper diagnosis and treatment strategies even after two events. Therefore, known risk factors for RM should be excluded by

Acknowledgements

PD Dr. Bettina Toth was supported by the LMUexcellent Mentoring Program of the Ludwig-Maximilians University, Munich, Germany; by the “Friedrich Baur Scholarship” and by the “Universitätsgesellschaft” of the Ludwig-Maximilians University, Munich, Germany. U. Jeschke is supported by the Deutsche Forschungsgemeinschaft (DFG).

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