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Recurrent miscarriage: causes, evaluation and management
  1. Carmen Garrido-Gimenez1,
  2. Jaume Alijotas-Reig2,3
  1. 1High Obstetric Risk Unit, Obstetric Department, Vall d'Hebrón University Hospital, Universitat Autónoma, Barcelona, Spain
  2. 2Systemic Autoimmune Disease Unit, Department of Internal Medicine I, Vall d'Hebrón University Hospital, Barcelona, Spain
  3. 3Department of Medicine, Faculty of Medicine, Universitat Autónoma, Barcelona, Spain
  1. Correspondence to Dr Carmen Garrido-Giménez, High Obstetric Risk Unit, Vall d'Hebrón University Hospital, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain; carmengagi{at}hotmail.com, cgarrido{at}vhebron.net

Abstract

Recurrent miscarriage is frustrating for the physician and a heartbreaking experience for the patient. Approximately 5% of couples trying to conceive have two consecutive miscarriages. Despite a thorough study of patients, the aetiology of this common obstetric complication is unknown in 50% of cases. Known causes include abnormal chromosomes, endocrinological disorders and uterine abnormalities. Although antiphospholipid antibodies have been demonstrated in miscarriages, the role played by alloimmune mechanisms remains unclear. New immunological approaches such as natural killer cells, regulatory T cells, tumour necrosis factor α, cell-derived microparticles, leptin, certain glycoproteins and cytokines should be considered. The management of thyroid diseases and immunological disorders is continuously evolving. Several genetic diagnostic procedures such as parental karyotyping and preimplantation genetic screening should probably not be used routinely. Antiphopholipid syndrome and some recurrent miscarriage-related endocrinological disorders can be effectively treated. Finally, new therapeutic approaches and the pleiotropic effects of old ones have led to improved fetal–maternal outcomes.

  • RECURRENT MISCARRIAGE
  • RECURRENT PREGNANCY LOSS
  • FETAL-MATERNAL TOLERANCE
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Introduction

Recurrent miscarriage is one of the most frustrating and difficult areas in reproductive medicine, since the aetiology is often unknown and evidence-based diagnostic and treatment strategies are scarce.

Recurrent miscarriage is classically defined as the loss of three or more consecutive pregnancies before the 20th week of gestation (molar, ectopic and biochemical pregnancies are not included), with or without previous live births. However, many experts consider two consecutive losses sufficient for diagnosis, and suggest an assessment after each loss with a thorough evaluation after three or more losses.1

The current classification of poor pregnancy outcomes is shown in figure 1. Recurrent miscarriage can be considered a primary or secondary process, depending on whether a live birth has occurred at some time. No specific term has been coined to describe women with non-consecutive pregnancy losses interspersed with normal pregnancies.

Figure 1

Spectrum of poor pregnancy outcomes. PE, pre-eclampsia; pPE, puerperal pre-eclampsia; SGA, small for gestational age; w, weeks.

Couples suffering recurrent miscarriage mainly want to know the cause and the risk of further recurrence. General aetiological categories of recurrent miscarriage include genetic, endocrine, anatomical, immunological, thrombophilic and environmental factors (box 1). When evaluating a patient, the physician should be aware of the current classification, determine the nature of previous pregnancy losses, and collect all possible risk factors. However, despite thorough investigation, no cause can be found in up to 50% of cases.2 Nevertheless, the prognosis for a successful future pregnancy is generally good: the overall live birth rates after normal and abnormal diagnostic evaluations for recurrent miscarriage are 77% and 71%, respectively.3

Box 1

Risk factors for recurrent miscarriage

  1. Chromosomal and gene disorders

  2. Endocrine abnormalities

    • Diabetes/thyroid dysfunctions

    • Prolactin disorders

    • Polycystic ovary syndrome

    • Luteal phase insufficiency

    • Androgen disorders

  3. Anatomical factors

    • Congenital anomalies

    • Uterine fibroids

    • Asherman's syndrome

    • Defective endometrial receptivity

  4. Immunological disorders

    • Autoimmune disorders

      • Thyroid dysfunctions

      • Coeliac disease

      • Antiphospholipid antibodies and antiphospholipid syndrome

      • Positivity for other autoantibodies

      • Reproductive autoimmune failure syndrome

    • Alloimmune factors (maternal–fetal tolerance)

      • Regulatory T cell and natural killer (NK) cell dysfunctions

      • ↑proinflammatory cytokine network (immunodystrophism)

  5. Inherited thrombophilic disorders

    • Antithrombin and protein C/S deficiency

    • Factor II, factor V Leiden and MTHFR mutations

    • Other gene mutations related to clot pathway proteins (ie, 4G/4G plasminogen activator inhibitor)

  6. Infectious diseases (rarely)

    • Bacterial

    • Viral

  7. Miscellaneous factors

    • Environmental/exercise/stress

    • Placental abnormalities

    • Medical illness

    • Male factors

    • Toxic habits

  8. New risk factors

    • Circulating cell-derived microparticles

    • Leptin

    • Human chorionic gonadotropin (hCG)

    • Glycodelin

    • NK cells

    • NK cell receptors (NK-KIRs, NKG).

A wealth of information has accumulated on this topic. However, this article aims to propose a correct assessment of couples with recurrent miscarriage and summarise the evidence of evaluation and management rather than provide an update on current understanding of the topic.

Search strategy and selection criteria

Data for this review were obtained through a comprehensive literature search using the relevant keywords (‘miscarriage’ or ‘recurrent miscarriage’, ‘abortion’ or ‘recurrent abortion’, ‘recurrent fetal loss’, ‘recurrent in-vitro fertilisation failure’; alone or in combination with: ‘idiopathic’, ‘spontaneous’, ‘diagnosis’, ‘treatment’ ‘immunology’, ‘autoantibodies’, ‘antiphospholipid antibodies’, ‘aspirin’, ‘low molecular weight heparin’, intravenous immunoglobulin’, ‘progesterone’ ‘parental cell inmunisation’, ‘thrombophilia’, ‘treatment’) to identify articles published in English from Medline, PubMed and The Cochrane Library (2000–January 2014). The initial search identified more than 5000 articles using the keywords (some were found in duplicate). We particularly selected randomised controlled studies or meta-analyses when possible, followed by prospective, matched or non-matched case–control, cohort studies and reviews. Short cohort studies, short reports, brief reports, editorials, opinion papers and letters to the editor were excluded. Finally, only 271 studies on recurrent miscarriage were considered adequate and were finally collected and discussed. Some relevant articles before 2000 focusing on general concerns about recurrent miscarriage were also included. Finally, following journal policy, 100 articles were selected for this review using our clinical and scientific judgement after a hard and accurate review and discussion between CG-G and JA-R.

Aetiology of and risk factors for recurrent miscarriage

Epidemiological factors

Miscarriage occurs in up to 15–20% of apparently normal couples and becomes recurrent in 2–3% of these couples.3 The risk of fetal loss rises steeply after the age of 35 years,4 from 9.5% at 20–24 years to 76% at 45 years and older. In clinical practice, the chances of a successful pregnancy in women ≥40 years are poor, when risks of miscarriage, pre-eclampsia, ectopic pregnancy and stillbirth increase.5

Reproductive history is known to be an independent predictor of future pregnancy outcome. Primigravidae and women with a history of live births have a lower risk of miscarriage in their next gestation than those whose most recent pregnancy ended in miscarriage.3 Nevertheless, women with a history of live births may still miscarry in future gestations; however, the prognosis for successful pregnancy is better with secondary recurrent miscarriage. Interestingly, it has been demonstrated that the risk of further miscarriage increases after each successive pregnancy loss, reaching 45–50% after three consecutive losses,6 and the prognosis worsens with increasing maternal age. Fortunately, 90% of women who have had one miscarriage subsequently have a normal pregnancy and a healthy baby; 50–60% are able to have a healthy baby after two miscarriages. Even a woman who has had three miscarriages in a row still has an approximately 40% chance of having a successful pregnancy the fourth time.

Gestational age at the time of pregnancy loss should be considered, since recurrent miscarriage typically occurs at a similar gestational age in consecutive pregnancies.7 Most women with recurrent miscarriage have early losses, a significant proportion of which are due to chromosomal aneuploidies, although these are less common than in sporadic miscarriages.8 Few women with recurrent miscarriage have late miscarriages, which are often attributable to other causes and are rarely due to chromosomal aberrations. Furthermore, late pregnancy complications, including fetal growth restriction, preterm labour and pre-eclampsia, are associated with recurrent miscarriage.9

Genetic abnormalities

Genetic factors are the most common cause of early spontaneous miscarriage (50–60%). However, it is important to distinguish between the genetic abnormalities in parents and the genetic alterations of the conceptus.

Parental chromosomal rearrangements

In approximately 2–4% of couples with recurrent miscarriage, one partner—more often the woman—will have a genetically balanced structural chromosome rearrangement, the most common being a balanced translocation (60% reciprocal and 40% Robertsonian, involving two homologous or non-homologous acrocentric chromosomes).10 Chromosome inversions are also associated with a higher risk of miscarriage,11 and the risk of miscarriage is influenced by the size and genetic content of the rearranged chromosomal segments.

The likelihood of a subsequent live birth in couples with an abnormal karyotype and recurrent miscarriage is poorer than in couples with normal chromosomes (66% vs 78%);12 however, an abnormal karyotype might not be the cause of the recurrent miscarriage, and parental karyotype is not particularly predictive of a subsequent pregnancy.13 Recently, many genetic polymorphisms14 and genes responsible for impaired cyclic decidualisation of the endometrium,15 apoptosis and inflammatory processes16 have also been found to be associated with recurrent miscarriage, and this is an active area of investigation.

Furthermore, the sperm of male partners in recurrent miscarriage appears to have a higher incidence of DNA damage and worse motility.17 Although increased numbers of sperm chromosome abnormalities have been described in couples with recurrent miscarriages, only 7% of fetal trisomies have been shown to be associated with paternal meiotic errors.18 Interestingly, the live birth rate in couples with structural chromosome abnormalities who conceive spontaneously is higher (50–65%) than that currently achieved after in vitro fertilisation (IVF) and preimplantation genetic screening (29–38%) per embryo transfer.19

Abnormal embryonic karyotypes

Fetal aneuploidy is the leading cause of spontaneous miscarriage in the first 10 weeks of gestation. At least 50% of all miscarriages are probably associated with cytogenetic abnormalities—trisomy, polyploidy and monosomy X.20 In couples with recurrent miscarriage, chromosomal abnormalities of the embryo account for 30–57%. Evidence shows that the higher the number of miscarriages, the less probable it is that they are related to chromosomal anomalies, so conceptus chromosomal abnormalities are more common in sporadic miscarriages than in recurrent miscarriage.21 A low proportion of these women have late recurrent miscarriages, usually before weeks 15–16, and chromosomal aberrations as a cause are rare.

Endocrine abnormalities

Endocrine dysfunction may account for 15–20% of all cases of recurrent miscarriage. Mild endocrine disease is not associated with recurrent miscarriage; however, poorly controlled diabetes mellitus and significant thyroid dysfunction have been associated with recurrent miscarriage.22

Thyroid autoimmunity is also linked to recurrent miscarriage, including those that are euthyroid. Interestingly, women with high levels of anti-thyroid antibodies do not suffer more miscarriages than those with low antibody concentrations.23 ,24 An apparent interaction between antiphospholipid antibodies (aPLs) and anti-thyroid antibodies in the risk of recurrent miscarriage has been reported.25 Vitamin D levels have been found to be lower in women with thyroid autoimmunity, and this deficiency is linked to infertility and miscarriage.26

Between 8% and 10% of women with recurrent miscarriage have polycystic ovary syndrome (PCOS), which is also related to hyperandrogenaemia, obesity and hyperinsulinaemia.22 The underlying mechanisms of recurrent miscarriage related to obesity and insulin resistance may include impairment of the fibrinolytic response, a leading player in the tissue remodelling that accompanies embryonic implantation.27

The role of other hormonal abnormalities remains controversial. Convincing evidence is lacking that elevated prolactin levels or a luteal phase defect are associated with recurrent miscarriage. However, it has been shown that bromocriptine and cabergoline may significantly reduce the rate of miscarriage in some women with recurrent miscarriage.28

Anatomical factors

Congenital uterine malformations are detected in approximately 10–15% of women with recurrent miscarriage. The most common congenital uterine malformation associated with recurrent miscarriage is septate uterus (figure 2) (35%), which is due to vascular insufficiency in the septum.29 The longer the septum, the worse the prognosis. Conversely, women with arcuate uterus tend to miscarry more often in the second trimester, so the contribution in recurrent miscarriage is controversial.30

Figure 2

Septate uterus shown on transvaginal three-dimensional volumetric ultrasound in sagittal (A) and coronal (B) plane. The arrow indicates the septate area itself. Image courtesy of Juan José Gómez Cabeza, Department of Gynecology, Vall d'Hebrón University Hospital.

Regarding fibroids, submucous leiomyomata that deform the endometrial cavity can impede normal implantation and cause recurrent miscarriage.31 However, the relationship between miscarriage and intramural and subserous myomas remains the subject of debate.32 ,33

Classically, adenomyosis was not associated with infertility; however, recent studies point to an immunological mechanism by which adenomyosis might interfere with successful embryo implantation and could cause recurrent miscarriage.34 ,35 Whether Asherman's syndrome/intrauterine synechiae, endometrial polyps and endometriosis contribute to recurrent miscarriage remains controversial.36

Cervical insufficiency is a recognised cause of late recurrent miscarriage, although the true incidence is unknown. Women at risk include those with a history of cervical trauma (eg, conisation), collagen disorders, or congenital anomalies of the uterus/cervix.

Immune factors

Antiphospholipid syndrome (APS)

APS refers to the association of aPLs with venous and/or arterial thrombosis, and with embryo–fetal morbidity. It manifests in 5–15% of women with recurrent miscarriage, and is associated with other obstetric complications such as preterm delivery, intrauterine growth restriction, early pre-eclampsia, HELLP syndrome and subchorionic haematoma/placental abruption.37 ,38 It should be noted that ‘obstetric’ APS refers to women with only obstetric aPL-related complaints and no history of current thrombotic events at the time of diagnosis.39 In cases of recurrent miscarriage related to aPLs, placental injury produces inflammatory and prothrombotic changes that involve trophoblasts and endothelial and blood cells.40

To be considered to have APS, patients must fulfil the currently accepted Sydney criteria41 (box 2). Although Gris et al42 suggested that anticardiolipin antibodies (aCLs) might be dropped from the laboratory battery, others have shown that all categories defined in the Sydney criteria are needed to avoid a false-negative APS diagnosis.43 More recently, several authors have argued in favour of flexibility and/or extending clinical and laboratory categories.44 ,45 Several ongoing studies should help to clarify this topic in the near future.

Box 2

Revised classification criteria for the antiphospholipid antibody syndrome (Sydney criteria)*

Clinical criteria (one or more)

  1. Vascular thrombosis: one or more objectively confirmed episodes of arterial, venous or small-vessel thrombosis occurring in any tissue organ.

  2. Pregnancy morbidity:

    • (a) one or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or by direct examination) at or beyond the 10th week of gestation; OR

    • (b) one or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia, pre-eclampsia defined according to standard definitions or (ii) placental insufficiency; OR

    • (c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Laboratory criteria (one or more, present on two or more occasions at least 12 weeks apart)

  1. Lupus anticoagulant, detected according to the guidelines of the International Society on Thrombosis and Haemostasis.

  2. Anticardiolipin antibody of IgG and/or IgM isotype, in serum or plasma, present in medium or high titre (>40 GPL or MPL, or >99th centile), measured by a standardised ELISA method.

  3. Antibody to β2-glycoprotein I of IgG and/or IgM isotype, in serum or plasma in titres (>99th centile), measured by a standardised ELISA method according to recommended procedures.

*See Miyakis et al.41

†In studies of populations of women who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of women as listed in (a), (b), (c).

‡Patients with antiphospholipid syndrome should be classified into one of the following laboratory categories: I, more than one laboratory criterion present; IIa, LA present alone; IIb, anticardiolipin antibodies present alone; IIc, anti-β2-glycoprotein I antibody alone.

Alloimmune dysfunction

During pregnancy, the maternal immune system must undergo changes to tolerate the semi-allogeneic conceptus. Since maternal alloreactive lymphocytes are not fully depleted during pregnancy, local and/or systemic mechanisms have to play a key role in altering the immune response. An altered Th1/Th2 cytokine balance with Th2 predominance has been observed, indicating a possible mechanism for determining fetal survival in the womb.46 However, studies conducted in genetically deficient mice unable to secrete Th2 cytokines have not always reported miscarriages, suggesting that the former is not essential for a normal pregnancy.47 Thus, alloreactive Th1 cells must be differently blocked or regulated, for instance, by regulatory T cells (Tregs).

Modifications in different T cell subsets, particularly CD4+CD25+FoxP3+ Tregs, are essential to maintain maternal–fetal immune tolerance.48 ,49 Treg sensitisation from paternal antigens at the maternal–fetal interface is currently believed to avoid fetal allo-rejection by creating a ‘tolerant’ microenvironment particularly characterised by the expression of interleukin 10, transforming growth factor β and indoleamine 2–3 deoxygenase.48 ,50 Similarly, it has been proposed that progesterone, human chorionic gonadotropin (β-hCG) and human placental growth hormone may modulate maternal tolerance to fetal–paternal antigens, perhaps by means of a reduction in uterine natural killer (NK) cell activity, expanding Tregs, or both. Some authors have reported on the role played by different NK cell receptors, particularly killer cell immunoglobulin-like receptors (KIRs), their relationship with human leucocyte antigen C and fetal–maternal tolerance, and their possible pharmacological modulation.51 ,52

Other immunological factors

A correlation between maternal coeliac disease and recurrent miscarriage has been shown53; patients with proven coeliac disease should already be on a gluten-free diet.54 Thus, screening for antibody to transglutaminase IgA isotype in the recurrent miscarriage population could be warranted. However, in our clinical practice and after many years of testing women with recurrent miscarriage for coeliac disease, no data supporting that relationship have been obtained (unpublished results).

Inherited thrombophilic disorders

There is a large and contradictory literature on the association between maternal inherited thrombophilia and recurrent miscarriage. However, current studies have generally reported an association particularly for late fetal loss. The presumed mechanism seems to be the thrombosis of the uteroplacental circulation.

The most prevalent polymorphisms are the heterozygous variant of factor V Leiden and the abnormal heterozygous prothrombin gene (G20210A).55 Recurrent miscarriage has also been related to the presence of other mutations, such as 4G/5G plasminogen activator inhibitor and the homozygosity for methylenetetrahydrofolate reductase (MTHFR). The association with other deficiencies such as protein C or protein S is still debated.56 It has also been reported that the presence of combined thrombophilic disorders increases the rate of recurrent miscarriage, particularly late miscarriage. Finally, no studies associating recurrent miscarriage with paternal thrombophilia have been reported.

Infective agents

Infectious diseases are rarely a cause of early miscarriage. No factual association has been found between bacterial and viral organisms and recurrent miscarriage, although Chlamydia, Mycoplasma, Ureaplasma, Listeria, Toxoplasma, Rubella, cytomegalovirus, herpes virus and parvoviruses have been associated with spontaneous miscarriage.57

Lifestyle and environmental factors

The effects of environmental exposure on pregnancy, particularly in recurrent miscarriage, remain a matter of debate, since some confounding factors render it difficult to obtain reliable data. Cigarette smoking, alcohol and moderate-to-heavy caffeine and cocaine use58 ,59 may be associated with sporadic miscarriages; however, the relationship between these factors and recurrent miscarriage is unclear.

No high-quality evidence exists supporting a relationship between recurrent miscarriage and occupational factors, stress or low-level exposure to most environmental chemicals.2 Obesity (body mass index >29.9 kg/m2) is associated with a higher rate of miscarriage; its relationship with recurrent miscarriage, however, remains uncertain.60 Exercise does not appear to increase the rate of recurrent miscarriage.61

New risk factors: circulating microparticles, glycoproteins and leptin

Circulating microparticles represent subcellular elements for cell signalling and intercellular communication in inflammation and thrombosis, and are believed to induce coagulation. They are increased during pregnancy and in complicated pregnancy disorders.62 Recent studies found a correlation between circulating microparticles, including trophoblastic ones, and recurrent miscarriage.

Some proteins appear to be downregulated in patients who have early recurrent miscarriages. Examples include hCG, glycodelin (glycoproteins secreted in high amounts by the trophoblast or the decidualised endometrium mainly during the first trimester of pregnancy), and galectin-1 expression in the syncytiotrophoblast.63 Furthermore, low serum leptin levels were observed in women suffering spontaneous miscarriage in the first trimester of pregnancy.64 The promising results of preliminary studies, as mentioned previously, showing the role played by the diverse KIRs expressed by NK cells in recurrent miscarriage and in recurrent IVF failure require further assessment.52 ,65

Evaluation and management of recurrent miscarriage

Couples suffering recurrent miscarriage need empathy, since for them this is a traumatic experience. Evaluation can be frustrating and difficult because the aetiology may not be established. Couples should be (table 2) informed that the prognosis of recurrent miscarriage is favourable, even without any intervention,72 although most couples do not accept the conservative approach.

Box 3

Suggested regimens for the treatment of APS in pregnancy*

(A) Women with APS without previous thrombosis and recurrent early (pre-embryonic or embryonic) miscarriage: LDA together with either prophylactic unfractionated heparin (5000–7500 IU SC/12 h) or LMWH (enoxaparin, tinzaparin, bemiparin or dalteparin, in usual prophylactic doses SC/24 h) (Grade 1B). After delivery, postpartum thromboprophylaxis with warfarin or better, LMWH, is indicated for 6 weeks.

(B) Women with APS without previous thrombosis and isolated or recurrent fetal death (more than 10 weeks’ gestation) or previous early delivery (<34 weeks’ gestation) due to early severe pre-eclampsia or placental insufficiency: LDA plus prophylactic or intermediate-unfractionated heparin (7500–10 000 IU SC every 12 h, or every 8–12 h adjusted to maintain the mid-interval aPTT 1.5 times the control mean) or LMWH (usual low or intermediate prophylactic doses, eg, enoxaparin 40 mg or 60 mg SC/24 h). After delivery, postpartum thromboprophylaxis with warfarin or better, LMWH, is indicated for 6 weeks.

(C) Women with APS and previous thrombosis: LDA plus therapeutic unfractionated heparin (SC every 8–12 h adjusted to maintain the mid-interval aPTT or heparin concentration anti-factor Xa activity in the therapeutic range) or LMWH (therapeutic dose, ie, enoxaparin 1 mg/kg SC, or dalteparin 100 U/kg SC/12 h, or enoxaparin 1.5 mg/kg/day SC, or dalteparin 200 U/kg/day SC)§. After delivery, thromboprophylaxis (secondary) with warfarin or LMWH (therapeutic dose) is indicated for life.

*Modified from Bates et al.66

†Lactation is not a contraindication to warfarin or heparin use.

‡Women without a lupus anticoagulant in whom the aPTT is normal can be monitored with the aPTT. Women with lupus anticoagulant should be monitored with anti-factor Xa activity.

§Need for dose adjustments over the course of pregnancy remains controversial. Some experts argue that, in the absence of better evidence, it is prudent to monitor anti-factor Xa LMWH concentrations 4–6 h after injection, with dose adjustment to maintain a therapeutic anti-factor Xa concentration (0.6–1.1 U/mL) if a twice-daily regimen is used, and slightly higher if a once-daily regimen is chosen.

APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin time; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin; SC, subcutaneously.

Table 1

Proposed evaluation of women with recurrent miscarriage*

Table 2

Some evidence-based guidelines for diagnosis and management of recurrent miscarriage

Figure 3

Suggested management of patients with recurrent miscarriage. G-CSF, granulocyte colony-stimulating factor; IVIG, intravenous immunoglobulin; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin; PCOS, polycystic ovary syndrome; TNF-α, tumour necrosis factor α. *Do not use between 5th and 12th week of gestation. Adapted from Alijotas-Reig and Garrido-Gimenez.67

First, a complete medical history should be obtained, with special attention paid to personal or family history of thrombosis, poor obstetric outcomes, autoimmune disease or endocrinological disorders. The history should include knowledge of gestational age at fetal loss, since recurrent miscarriage typically occurs at a similar gestational age in consecutive pregnancies and the aetiology could vary in early and late miscarriages. Physical examination should include a general assessment with attention to signs of endocrinopathy (eg, hirsutism, galactorrhoea), autoimmune disease (eg, malar blushing, telangiectasia) and pelvic organ abnormalities (eg, uterine malformation, cervical laceration). The most useful tests should then be analysed separately in the evaluation of recurrent miscarriage (tables 1 and 2).

Genetic abnormalities

Genetic counselling is important when a genetic factor is identified. However, peripheral karyotyping is expensive and does not always provide valuable information on recurrent miscarriage; thus, this test could be avoided in many couples, although current guidelines still recommend parental karyotyping.

In couples with recurrent miscarriage, some experts recommend conceptus karyotype analysis, albeit controversial, since it can offer useful information73—that is, an aneuploid conceptus indicates a better chance of success in a subsequent pregnancy.74 Preimplantation genetic screening of biopsied blastomeres during IVF has not shown any improvement in clinical outcomes,19 and thus its use is debateable in couples with recurrent miscarriage, except in those who are carriers of Robertsonian translocations involving chromosome 21.

Endocrine abnormalities

Routine screening for diabetes mellitus should be limited to women with clinical manifestations of the disease. Neither routine screening nor medical treatment of thyroid dysfunctions in euthyroid pregnant women is recommended.75 However, thyroid antibodies should be evaluated in women with recurrent miscarriage, including those with aPLs, since there is an apparent interaction between them.25 ,76 Women with overt hypothyroidism or hyperthyroidism obviously require treatment, but this is less clear for women with subclinical hypothyroidism and thyroid autoimmunity.77 To date, the only prospective randomised controlled trial evaluating treatment in euthyroid women with positive thyroid antibodies was performed by Negro et al,78 showing a statistically significant reduction in miscarriages in women who received levothyroxine. Furthermore, thyroid-stimulating hormone (TSH) levels should be kept below 2.5–3 IU, as one study concluded that there is a higher incidence of miscarriage when TSH levels are above this range.79 The treatment of subclinical hyperthyroidism during pregnancy is currently considered to be unwarranted, since it is not associated with adverse pregnancy outcomes.

The use of metformin for women with anovulatory PCOS showed no benefit with respect to enhancing either fertility or live birth rates; thus, its routine use is not recommended.80

No clear evidence exists to support the routine use of exogenous progesterone supplementation during the first trimester to prevent miscarriage. However, although randomised studies in this setting are lacking, there appears to be evidence of benefit in women with a history of recurrent miscarriage.68 A large randomised, double-blind, placebo-controlled multicentre trial (PROMISE; http://www.medscinet.net/promise) is currently underway to assess the benefit of progesterone supplementation in women with unexplained recurrent miscarriage.

Data supporting an association between alterations in prolactin levels and recurrent miscarriage are lacking; however, in cases of detected hyperprolactinaemia, it may be appropriate to treat with cabergoline or bromocriptine.28

Anatomical factors

Gynaecological ultrasound is recommended in women with recurrent miscarriage, since it is an available, non-invasive and cost-effective method for detecting uterine disorders, while the systematic use of hysteroscopy, CT, MRI or hysterosalpingography is not justified.

In patients with recurrent miscarriage and structural uterine malformations, re-establishing the normal anatomy seems to improve gestational prognosis.81 Observational studies found an improvement in gestational outcomes in patients with uterine septum following hysteroscopic metroplasty.82 Furthermore, it seems that myomectomy of submucous leiomyomata before conception reduces the rate of miscarriage;33 however, it is less clear when fibroids do not distort the uterine cavity.83 The clinical management of miscarriage in patients with Asherman's syndrome/intrauterine synechiae or uterine polyps is controversial, and there is no conclusive evidence that surgical treatment reduces the risk of miscarriage.36

For women with late recurrent miscarriage or three or more early preterm births who have risk factors for cervical insufficiency, cervical cerclage is indicated. Measurement of cervical length with transvaginal ultrasound during pregnancy could detect patients with a short cervix (<25 mm) before 24 weeks, and vaginal progesterone administration or cervical pessary could reduce the risk of late miscarriage or preterm birth.84

Immune factors

Women with recurrent miscarriage should also be tested for lupus anticoagulant, aCLs and β2-glycoprotein I antibodies (IgG/IgM isotypes) using standard assays. The tests should be performed twice, 12 weeks apart, since transient positive levels can be due to infections or drugs and spontaneously revert to normal.43

The recommended therapy in women with aPL/APS-related recurrent miscarriage consists of prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA), which was found to be superior to treatment with LDA alone (74.2% vs 55.8% live birth rate)66 ,85 (box 3). The use of LMWH is preferable because of its greater safety and efficacy compared with unfractionated heparin; however, unfractionated heparin remains an acceptable alternative. In cases of refractory obstetric APS (20–25% of cases), promising results have been obtained with the addition of hydroxychloroquine or low-dose prednisolone to standard treatment.71 Similarly, other therapeutic regimens have been proposed, such as vitamin D, fondaparinux or pentoxifylline;86 however, they should be tested in well-designed clinical trials before their general use is approved.

Inherited thrombophilic disorders

Routine testing for inherited thrombophilias in women with recurrent miscarriages is not currently recommended. Screening may be clinically justified when a history of thromboembolism with no risk factors, such as surgery or late recurrent miscarriages, does exist.70

Consensus on whether or not to treat cases of recurrent miscarriage with associated congenital thrombophilia using aspirin, heparin or both is lacking.87

Infective agents

Routine cervical cultures, vaginal evaluation for bacterial vaginosis, and toxoplasmosis serology are not useful in the evaluation of recurrent miscarriage in otherwise healthy women. Although some authors, including a Cochrane review,88 support them, these screening tests are currently not recommended.

Unexplained recurrent miscarriage

If no cause for recurrent miscarriage is established, a lifestyle modification should be recommended. Epidemiological studies suggest that lifestyle modifications can increase fertility, although they have not been definitively tested in randomised trials. These modifications include eliminating toxic habits and caffeine, following a well-balanced diet, and reducing body mass index in obese women.89

Furthermore, there seems to be a rationale for the use of a combination of LDA and prophylactic heparin in the treatment of unexplained recurrent miscarriage.67 Several trials have emphasised the benefit of LMWH,90 although some studies found no advantages of its use.91 Despite this, and taking into account its probable benefit and small potential risk, LMWH could be considered an experimental drug for patients with recurrent miscarriages until further conclusive data from controlled clinical trials become available.

Although no alloimmune mechanism has been proven to cause recurrent miscarriage, some immune-modulating therapies have been used to treat these women. However, systematic reviews have consistently found no beneficial effect of immunotherapy for treating unexplained recurrent miscarriage. Therapy with paternal leucocyte immunisation and intravenous immunoglobulins (IVIGs) has been used in this field, but results have been controversial.69 ,92 Anti-tumour necrosis factor α (anti-TNF-α) drugs may offer a novel, safe and effective approach, but evidence is still scarce.93 Furthermore, the combination of heparin with IVIGs or anti-TNF-α inhibitor seems to improve live birth rates;94 however, further controlled trials are required to confirm these optimistic results. Data on the effectiveness of granulocyte colony-stimulating factor in the treatment of both unexplained recurrent miscarriage and recurrent in vitro implantation failure are now available.95 ,96 However, the paucity of well-designed studies does not support the use of these therapies in routine clinical practice.

Glucocorticoids have several anti-inflammatory effects, including suppression of NK cell number and activity in the endometrium; however, the high rate of adverse effects (eg, gestational diabetes and hypertension) renders their use for recurrent miscarriage controversial (figure 3).97 ,98

Summary

Recurrent miscarriage can be evaluated after two clinical pregnancy losses. Assessment of recurrent miscarriage focuses on medical history, physical examination and recommended laboratory tests; however, up to 50% of cases will not have a clearly defined aetiology. The prognosis of subsequent pregnancies is generally good even without treatment, and patients should be informed that solid evidence is lacking to support several commonly used interventions and treatments for recurrent miscarriage.

Main messages

  • Approximately 5% and 2–3% of couples trying to conceive have, respectively, two or three consecutive miscarriages.

  • Recurrent miscarriage typically occurs at a similar gestational age in consecutive pregnancies.

  • Systematic parental karyotyping, karyotype screening of the conceptus and preimplantation genetic screening are not recommended.

  • Routine screening for thyroid dysfunction is recommended. If subclinical hypothyroidism is detected, levothyroxine treatment must be offered.

  • Assessment of uterine anatomy with pelvic ultrasound is widely recommended.

  • The benefits of myomectomy (for non-submucous myomas) and metroplasty are uncertain, and more information is required before a surgical therapeutic approach can be recommended.

  • Testing for lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I and anti-thyroid autoantibodies is recommended.

  • Currently, women with unexplained recurrent miscarriage, particularly in the first trimester, should not be tested for inherited thrombophilia.

  • Patients with antiphospholipid syndrome must be treated with low-dose aspirin (LDA) plus low-molecular-weight heparin (LMWH). In refractory cases, drugs such as hydroxychloroquine or low-dose prednisone are being tested, but preliminary results are controversial.

  • It seems reasonable to use prophylactic LMWH in combination with LDA for patients with recurrent miscarriage. Currently, immunotherapy and glucocorticoids are not yet recommended as treatments for unexplained recurrent miscarriage.

Current research questions

  • Could patients with recurrent miscarriage and elevated circulating microparticle levels benefit from low-molecular-weight heparin and/or low-dose aspirin during pregnancy?

  • What is the role of the complement pathway, uterine Tregs and natural killer cells, killer cell immunoglobulin-like receptors, and cytokines in unexplained recurrent miscarriage?

  • What is the most accurate thromboprophylaxis schedule for women with inherited thrombophilia and recurrent first-trimester miscarriage?

  • Can immunotherapy, particularly maternal sensitisation with paternal-derived cells and treatment with granulocyte colony-stimulating factor, be an effective treatment for recurrent miscarriage?

Key references

  • Alijotas-Reig J, Garrido-Gimenez C. Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv 2013;68:445–66.

  • American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. Int J Gynaecol Obstet 2002;78:179–90.

  • Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy. In: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S–736S.

  • Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J Med 2010;363:1740–7.

  • Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006;2:CD000112.

  • Royal College of Obstetricians and Gynaecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green-top Guidelines No 17, April 2011.

Self assessment questions

  1. Which of the following statements regarding miscarriage is false?

    1. Approximately 5% of couples trying to conceive have two consecutive miscarriages, and approximately 2% of couples have three or more consecutive losses.

    2. The aetiology is not established in up to 50% of cases.

    3. The term ‘early miscarriage’ means involuntary pregnancy loss before the 12th week of gestation.

    4. The American Society for Reproductive Medicine 2008 expert committee defines recurrent miscarriage as the loss of three or more failed pregnancies.

  2. Which of the following statements regarding recurrent miscarriage is false?

    1. Genetic factors are the most common cause (50% and 60%) of early spontaneous miscarriages, and translocations are the most common types of structural abnormality.

    2. The higher the number of miscarriages, the more probable they are related to chromosomal anomalies.

    3. Preimplantation genetic screening of biopsied blastomeres during IVF has not produced any improvement in clinical outcomes.

    4. Parental karyotyping is expensive and does not always provide valuable information on recurrent miscarriage.

  3. Which of the following statements regarding the aetiology of recurrent miscarriage is true?

    1. Women with diabetes mellitus have more miscarriages, regardless of metabolic control.

    2. In cases of detected hyperprolactinaemia, it may be appropriate to give treatment with cabergoline or bromocriptine.

    3. Subclinical hyperthyroidism is associated with increased risk of recurrent miscarriage, so treatment of these patients is recommended.

    4. Women with high levels of anti-thyroid antibodies suffer more miscarriages than those with low concentrations of antibodies.

  4. Which of the following statements regarding immunology of recurrent miscarriage is false?

    1. Antiphospholipid syndrome (APS) is diagnosed in 15-20% of women with recurrent miscarriage.

    2. Alloimmune factors may play a role in recurrent miscarriage.

    3. Women with antiphospholipid antibody-related obstetric morbidity should be treated with metformin.

    4. The combination of low-dose aspirin (LDA) plus prophylactic heparin increases fetal–maternal outcomes in recurrent miscarriage related to antiphospholipid antibody positivity.

  5. Which of these statements regarding the future treatment of women with recurrent miscarriage is true?

    1. Hydroxychloroquine and low-dose prednisolone plus low-molecular-weight heparin (LMWH) may have success in the treatment of refractory obstetric APS.

    2. The recommended therapy in women with recurrent miscarriage related to APS is prophylactic LMWH plus LDA plus granulocyte colony-stimulating factor.

    3. Currently, treatment with human chorionic gonadotropin shows clear benefits compared with a placebo group.

    4. Therapy with paternal leucocyte immunisation is the new approved treatment for idiopathic recurrent miscarriage

Answers

  1. D.

  2. B.

  3. B.

  4. C.

  5. A.

Acknowledgments

We thank Ms Christine O'Hara for reviewing and correcting the style and grammar of the manuscript. An extensive review by us67 on this topic ‘Current concepts and new trends in the diagnosis and management of recurrent miscarriage’ was published in Obstetrical and Gynecological Survey in 2013; the present paper is published with permission of the publishers.

References

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Footnotes

  • Contributors CG-G and JA-R contributed to the conception and design of this research, drafting the article and critically revising it, and final approval of the version to be published.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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