Hum. Reprod. Advance Access originally published online on May 17, 2006
Human Reproduction 2006 21(9):2216-2222; doi:10.1093/humrep/del150
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Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage
1 Academic Department of Obstetrics and Gynaecology, Royal Free and University College London Medical School, London 2 Department of Obstetrics and Gynaecology, Liverpool Women’s Hospital, Liverpool, UK 3 Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark and 4 Department of Obstetrics and Gynaecology, Spaarne Ziekenhuis, Hoofddorp, The Netherlands
5 To whom correspondence should be addressed at: Academic Department of Obstetrics and Gynaecology, University College London Medical School, 86-96 Chenies Mews, London WC1E 6HX, UK. E-mail: e.jauniaux{at}ucl.ac.uk
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Abstract |
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Recurrent miscarriage (RM;
3 consecutive early pregnancy losses) affects around 1% of fertile couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with recurrent miscarriage; however, in the vast majority of cases the pathophysiology remains unknown. We have updated the ESHRE Special Interest Group for Early Pregnancy (SIGEP) protocol for the investigation and medical management of RM. Based on the data of recently published large randomized controlled trials (RCTs) and meta-analyses, we recommend that basic investigations of a couple presenting with recurrent miscarriage should include obstetric and family history, age, BMI and exposure to toxins, full blood count, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), parental karyotype, pelvic ultrasound and/or hysterosalpingogram. Other investigations should be limited to particular cases and/or used within research programmes. Tender loving care and health advice are the only interventions that do not require more RCTs. All other proposed therapies, which require more investigations, are of no proven benefit or are associated with more harm than good.
Key words: early pregnancy/evidence-based/management/recurrent miscarriage/treatment
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Introduction |
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Recurrent miscarriage (RM) is traditionally defined as three or more consecutive miscarriages occurring before 20 weeks post-menstruation (Stirrat, 1990
; Berry et al., 1995; Bricker and Farquharson, 2002). Around 1% of fertile couples will experience recurrent early pregnancy losses (Berry et al., 1995). The risk of recurrence increases with the maternal age and number of successive losses (Brigham et al., 1999; Andersen et al., 2000). The prognosis is not better for couples with prior live birth (Clifford et al., 1997). Thus, the number of previous miscarriages and maternal age are the most important covariates, and they have to be taken into account when planning therapeutic trials. The ideal trial should have stratification for the number of previous miscarriages and maternal age, with randomization between control and experimental treatments, within each stratum as recently recommended (Christiansen et al., 2005).
Recurrent miscarriage has been directly associated with parental chromosomal anomalies (Franssen et al., 2005), maternal thrombophilic disorders (Rey et al., 2003) and structural uterine anomalies and indirectly with maternal immune dysfunction and endocrine abnormalities (Carrington et al., 2005). However, as the majority of RM cases following investigation are classified as idiopathic, that is, no identifiable cause in either partner, it is generally accepted that within the idiopathic group there is considerable heterogeneity and it is unlikely that one single pathological mechanism can be attributed to their RM history (Stirrat, 1990). Furthermore, there is considerable debate about the cause and association, as the exact pathophysiological mechanisms of most known etiologies have not been precisely elucidated. Current research is directed at theories on defects in nature’s quality control related to implantation, trophoblast invasion and placentation, as well as factors, which may be embryopathic (Quenby et al., 2002). Most women with recurrent pregnancy loss probably have several risk factors for miscarriage.
Although benefits have been reported for a variety of endocrinologic and immunologic treatment, many therapeutic approaches remain controversial, mainly because of wide variations in patient-selection criteria and treatment protocols. The small sizes of most individual studies, poor stratification bias and matching of cases and controls have limited the translation of results into clinical practice. New randomized controlled trials (RCTs) and meta-analyses have recently been published in the international literature. This has prompted the ESHRE Special Interest Group for Early Pregnancy (SIGEP) to update its protocol for the investigation and medical management of RM. The surgical treatment of uterine causes of RM and the value of preimplantation genetic screening (PGS) for the embryos of couples presenting with RM, being under the auspices of other SIGs, will not be included in this review.
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Evidence-based investigations for couples presenting with RM |
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Coagulation investigations
Acquired maternal thrombophilia is a well-recognized cause of RM. All women with a history of three or more early pregnancy losses, that is, before 10 weeks, or 1 or more unexplained deaths at
10 weeks of a morphologically normal fetus, or 1 or more premature births at 
34 weeks with severe preeclampsia or placental insufficiency, should be offered a testing for lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), known collectively as antiphospholipid antibodies (APA), to exclude an antiphospholipid syndrome (APS) (Wilson et al., 1999). More recently, an increased incidence of early and recurrent fetal loss has also been suggested in women with inherited thrombophilia, including Factor V Leiden deficiency, activated protein C resistance, prothrombin G20210A and protein S deficiency (Dawood et al., 2003; Rey et al., 2003); however, other authors have found no association between maternal thrombophilia and pregnancy loss <10 weeks of gestation (Roque et al., 2004). Some studies reported a decreased risk of miscarriage in women with inherited thrombophilia (Carp et al., 2002; van Dunne et al., 2005), whereas one study reported that multiple genetic thrombophilic mutations in either partner seem to increase the risk of miscarriage in a subsequent pregnancy (Jivraj et al., 2006). Larger epidemiological studies are clearly needed to justify testing couples with RM for inherited thrombophilia in routine clinical practice (Robertson et al., 2006). Other coagulation abnormalities, including impaired fibrinolytic activity, factor XII deficiency and reduced activated partial thromboplastin time have also been reported to be associated with RM, but the corresponding epidemiological data are limited (Li et al., 2002), and the assay for these abnormalities should only be performed as part of prospective clinical studies.
Endocrinologic investigations
Early epidemiological data have shown an association between RM and hypothyroidism or diabetes mellitus. Although current evidence indicates that treated hypothyroidism and well-controlled diabetes are not associated with RM (RCOG, 1998), thyroid function tests and HbA1C measurements are accurate and inexpensive and can still be considered as part of the evaluation of RM (Christiansen et al., 2005). Furthermore, a low level of maternal thyroxin and poorly controlled maternal glucose levels in early pregnancy are associated with short- and long-term consequences for fetal development and should therefore be diagnosed and treated before conception.
Obesity is associated with a statistically significant increased risk of first trimester and recurrent miscarriage [odds ratios 1.2 and 3.5, 95% confidence interval (CI) 1.01–1.46 and 1.03–12.01, respectively] (Lashen et al., 2004). Obesity certainly has a wider impact on women’s health, and several studies have shown that the association between polycystic ovary syndrome (PCOS) and RM could be secondary to the association between obesity and miscarriage (Fedorcsak et al., 2000; Bellver et al., 2003). Weight loss should be considered as a first option for women who are infertile and overweight (Clark et al., 1998; Morikawa et al., 2004), and there is little doubt that the same concept applies to women with RM. Other endocrinologic disorders, including hypersecretion of LH, high androgen levels, hyperprolactinaemia and luteal phase defects (LPD) have been associated with RM. Current evidence suggest that, as is the case for hypothyroidism, infertility is more likely a problem than pregnancy loss. Further studies are required to examine the relationship between hyperandrogenism and RM (Christiansen et al., 2005).
Immunologic investigations
An excessive maternal immune response against paternal antigens resulting in abnormal immune cells and cytokine production has and is still thought to be one of the causes of RM (Laird et al., 2003). In particular, interest is currently focused on the relationship between RM and Natural Killer (NK) cells. Although much of the evidence is contradictory, these studies suggest differences in the peripheral blood NK-cell levels in women with RM. NK cells are also found in the endometrium and decidua, but the knowledge on their role in human placentation is limited. There are phenotypic and functional differences between peripheral and uterine NK cells, and tests to measure NK cells in peripheral blood give no useful information on uterine NK cells (Moffett et al., 2004). Furthermore, the percentage of CD56+ NK cells in peripheral blood of healthy individual varies from 5 to 29% and is affected by sex, stress, ethnicity and age. Within this context, testing of peripheral blood NK cells should not be performed routinely in the evaluation of miscarriage in general and RM in particular (Rai et al., 2005; Thum et al., 2005; Wold and Arici, 2005), outside research protocols. Similarly, there is no scientific basis for the introduction of peripheral cytokine level measurements into routine practice. Recent data have shown that a high number of uterine NK cells is found in the endometrium of women with RM and this could be reduced by therapy (Quenby et al., 2005). However, prospective trials are needed to evaluate the possible use of this finding, and currently endometrial sampling should only be offered to women within the context of research programmes.
Mannan-binding lectin (MBL) is a C-type lectin that participates in the innate immune defence by activating complement on the surfaces of micro-organisms. Two large case-controlled studies (Kilpatrick et al., 1995; Kruse et al., 2002) have shown that low levels of MBL are associated with RM and that low MBL is associated with a significantly (20%) higher miscarriage rate in the next pregnancy. However, most women with low MBL levels do not experience RM, suggesting that low MBL as a sole factor probably does not cause RM but may increase the risk of early pregnancy loss when found in conjunction with other immunological disturbances which remain to be investigated.
Parental cytogenetic investigation
The incidence of structural chromosome abnormalities, usually a balanced translocation is increased in couples with RM. All the four factors, namely low maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister and a history of two or more miscarriages in the parents of either partner increase the probability of carrier status (Franssen et al., 2005). A probability of carrier status is obtained when these four factors are combined (Franssen et al., 2005). After one miscarriage, it is generally accepted to refrain from karyotyping. The incidence of carrier status after one miscarriage is 2.2% (Braekeleer de and Dao, 1990). It is thus advised to refer for parental karyotype only when the probability of carrier status is 2.2% (see Table I).
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Histopathological and cytogenetic investigations
Whilst it is routine practice to send products of conception for histological examination, mainly to exclude a gestational trophoblastic disorder, the usefulness of histopathogical investigation of placental and/or fetal tissue in RM on future pregnancy management for an individual couple remains to be determined (Jauniaux et al., 1996
; Jauniaux and Burton, 2005). Overall, the inaccuracy of villous morphology and the limited clinical significance of the finding of an aneuploidy in a sporadic miscarriage have lead some authors to conclude that the histological classification is a valueless clinical exercise (Fox, 1993). New morphologic classifications continue to be proposed (Hakvoort et al., 2006). Overall, these retrospective studies are of academic interest in understanding the pathophysiology of early pregnancy failure, but their practical clinical role has never been demonstrated. In couples with RM, there are a few reports showing an increased incidence of thrombo-inflammatory lesions such as perivillous fibrin deposition, chronic villitis and deciduitis (Doss et al., 1995; Hustin et al., 1996), in particular, when the karyotype is normal (Redline et al., 1999). Although these lesions support the immunologic imbalance concept, the contribution of these histological findings to the management of RM is limited and has not been trialled prospectively.
The risk of live born trisomy following an aneuploidy in a sporadic early pregnancy failure is around 2% (Alberman, 1992). By contrast, chromosomal analyses of the products of conception in couples with RM indicate that a normal conceptus karyotype in a previous pregnancy is a predictor of subsequent miscarriage (Warburton et al., 1987; Ogasawara et al., 2000; Carp et al., 2001; Morikawa et al., 2004). Women <36 years of age with RM have a higher frequency of euploid miscarriage. When stratified for maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with RM compared with controls (Stephenson et al., 2002). The possibility that a miscarriage following treatment is the result of aneuploidy must be investigated particularly in efficacy trials. Without this information it is impossible to ascertain whether the pregnancy loss is the result of treatment failure or a de-novo chromosomal anomaly. The magnitude of the size of the treatment effect will be affected without correction for the aneuploidy factor (Christiansen et al., 2005). The cost benefit of performing systematic karyotyping of products of conception after one miscarriage on the overall management of RM needs to be investigated prospectively in large populations.
Anatomical investigations
The prevalence and impact on reproduction of uterine malformations in the general population have not been clearly established. Traditionally, laparoscopy, hysterosalpingography (HSG) and/or hysteroscopy have been used to diagnose these uterine malformations in women with RM. Ultrasound, and in particular 3D ultrasound, has become an accurate, reproducible, non-invasive, out-patient method for the diagnosis of congenital uterine anomalies (Salim et al., 2003a). Using 3D ultrasound, it has been reported that women with a subseptate uterus have a higher incidence of first trimester loss, whereas women with an arcuate uterus have a greater proportion of second trimester loss and preterm delivery (Woelfer et al., 2001). A large comparative study of the ultrasound morphology of congenital anomalies in women with and without RM has shown no difference in the relative frequency of various anomalies between the two groups of women (Salim et al., 2003b). However, with both arcuate and subseptate uteri, the length of the remaining cavity was shorter, and the size of the fundal distortion was higher in the RM group.
Other investigations
High level of homocysteine (hyperhomocysteinaemia) can be associated with RM (Nelen et al., 2000). Among the genetic causes of this condition, a common one is polymorphism at position 677 in the methyl tetrahydrofolate reductase (MTHFR) gene, which in the homozygous form leads to a thermolabile enzyme variant (Makris, 2000). Within this context, low plasma folate levels have been associated with an increased risk of first trimester miscarriage (George et al., 2002). Investigation for the above condition remains technically difficult and should not be performed outside a specific clinical context.
Infections with bacteria, viruses or parasites can all interfere with early pregnancy development, but none seems to be a significant cause of RM (Simpson et al., 1996). Toxoplasmosis, Rubella, cytomegalovirus, herpes (TORCH) screen is therefore of limited value in the investigation of RM, outside an acute infectious episode (Li et al., 2002).
A lot of information is available about environmental toxins. The association between miscarriage and ionizing radiation, organic solvents, alcohol, mercury and lead is confirmed, whilst an association to caffeine, hyperthermia and cigarette smoking is suspected (Gardella and Hill, 2000).
The recommended investigations are summarized in Table II.
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Evidence-based medical therapies for couples presenting with RM |
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Anticoagulants
Aspirin and/or heparins have become routine treatment for women with APS and inherited thrombophilias and a history of RM, on the basis of limited evidence. A recent meta-analysis of randomized and quasi-randomized RCTs on medical intervention in pregnant women with a history of RM has shown that overall combined unfractionated heparin and aspirin could reduce further pregnancy loss by 54% (Empson et al., 2005
). This conclusion was based on only two small non-blinded trials, and one of these lacked adequate allocation concealment. Furthermore, the trial by Farquharson et al. (2002), which was not included in the meta-analysis, could detect no effect of heparin/aspirin relative to aspirin alone.
When the data of low molecular weight heparin (LMWH) and unfractionated heparin (UFH) studies are pooled, there is only a 35% reduction in pregnancy loss and premature delivery (Empson et al., 2005). No head-to-head study comparing LMWH and UFH met the inclusion criteria of the systematic review. There is no advantage in high dose over low dose of UFH and aspirin combined with LMWH, and aspirin alone has shown a variable effect in recent studies. The authors of this systematic review also concluded that large RCTs with adequate allocation concealment are needed to further evaluate therapeutic differences between UFH and LMWH (Empson et al., 2005). There is a need for an international collaborative RCT to evaluate the type and duration of thromboprophylaxis in APS, before this treatment is used systematically in routine clinical practice (Table III).
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The data on the use of anticoagulants for the treatment of RM in women without APS is too limited to recommend their routine use within this context (Di Nisio et al., 2005
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The possible relationship between aspirin in early pregnancy and congenital defects remains controversial. Initial reports such as the Collaborative Perinatal Project which surveyed 14 864 mother–child pairs, exposed to aspirin during the first trimester, found no evidence of a teratogenic effect (Slone et al., 1976). The Food and Drug Administration (FDA) surveillance study involving 1709 newborns exposed to aspirin during the first trimester presented similar conclusions (Briggs, 1998). A more recent meta-analysis has found that the overall risk of congenital malformations in offspring of women exposed to aspirin in early pregnancy is not significantly higher than that in control subjects (Kozer et al., 2002). However, a significant increase in the risk of fetal gastroschisis (odds ratio 2.37, 95% CI 1.44–3.88) was found. A similar risk (odds ratio 2.70, 95% CI 1.20–5.90) was also found in a retrospective study of maternal use during the first trimester of pregnancy of over-the-counter cough/cold/analgesics including aspirin and other non-steroidal anti-inflammatory drugs (NSAID) (Werler et al., 2002). An association between NSAID use in the first trimester and an increased risk of miscarriage has also been reported, in particular when used around the time of conception (Nielsen et al., 2001; Li et al., 2003). The risk is higher when NSAIDs were used for longer than a week, which indicates a dose–response relationship, though no precise dose information was available (Li et al., 2003). The study by Nielsen et al. (2001) can be criticized on the basis of incomplete ascertainment of both miscarriages and NSAID use during pregnancy and lack of information on important confounders including the reasons for NSAID use. By contrast, the study by Li et al. (2003) identified indications for use of the different drugs, controlled for confounding factors, and evaluated the effect of timing and duration of use. These authors concluded that the association between NSAID use and miscarriage is unlikely to be because of the underlying indications for use of NSAIDs or aspirin.
There is no reported fetal side-effect of heparin use during pregnancy, but osteopenia has been a major concern of long-term heparin therapy, in particular with UFH (Pettila et al., 2002; Hawkins and Evans, 2005). In women with RM, a small decrease of 3.7% of lumbar spine and 0.9% of the neck of femur bone mineral density (BMD) has been reported in one study using both LMWH and UFH (Backos et al., 1999). There was no significant difference in BMD changes, in this uncontrolled study, between the two heparin preparations. A more recent prospective, controlled study has shown that bone loss associated with the use of long-term LMWH for RM and thrombophilia is not significantly different from physiological losses during pregnancy (Carlin et al., 2004). Overall, the decrease in BMD seems to be similar in heparin-treated and untreated pregnant women (Holmberg-Marttila et al., 2000). Fondaparinux sodium, a new indirect activated factor VII inhibitor, does not have a negative effect on BMD and could therefore be a safe and effective alternative to UFH and LMWH (Hawkins and Evans, 2005). Treatment-related thrombocytopenia was not reported in a recent systematic review of 64 studies of LMWH use in pregnancy (Greer and Nelson-Piercy, 2005). Minor local skin reactions are observed in about one-third of RM patients (Deruelle et al., 2005).
Progestational agents
Progesterone has been administered orally, intramuscularly and vaginally for more than five decades in an attempt to prevent miscarriage in early-to-mid pregnancy. Overall, the use of progestational agents during the first and second trimester of pregnancy is not associated with adverse effects in mothers. However, Carmichael et al. (2005) have recently reported that maternal intake of progestins in early pregnancy is associated with an increased risk of hypospadia in the male offspring (odds ratio 3.7, 95% CI 2.3–6.0).
Overall, despite considerable medical use, there is currently insufficient information to allow recommendations regarding optimal dose, route and timing of progesterone supplementation. A recent systematic review found no evidence to support the routine use of progesterone in the first trimester to prevent miscarriage (Oates-Whitehead et al., 2005). The meta-analysis indicated that in a subgroup analysis of three trials involving women with RM, progesterone treatment showed a statistically significant decrease in miscarriage rate compared with placebo or no treatment (odds ratio 0.39, 95% CI 0.17–0.91). The route of administration did not influence the results. All trials were more than 40 years old, and a modern prospective RCT of sufficient power to determine the efficacy of progesterone supplementation in women with RM is needed to confirm these results (Table III).
Immunosuppressant and immunomodulator agents
The use of intravenous immunoglobulin (IVIG), anti-TNF
, glucocorticoids or cellular therapies in order to prevent or reduce an ‘excessive immune response’ and/or abrogate maternal–fetal incompatibility in women with RM remains controversial. IVIG is a pooled blood product, which can be rarely associated with anaphylactic response, fever, flushing, muscle pain, nausea and headache. IVIG preparations may be derived from tens of thousands of donations, and thus there is also the possibility of iatrogenic Creutzfeldt–Jakob disease (CJD), but there is so far no evidence that CJD has been diagnosed following IVIG therapy. Overall, the only downside of IVIG is its high price (Sapir et al., 2005). By contrast, anti-TNF agents have been reported to be associated with the development of granulomatous disease, lymphoma, systemic lupus erythematosus-like syndromes, congestive cardiac failure and demyelinating diseases (Claudepierre et al., 2005). Multiple courses of glucocorticoids during pregnancy are associated with serious side effects including an increased risk of preterm birth because of premature rupture of membranes and the development of preeclampsia and gestational diabetes (Empson et al., 2002).
In women presenting with RM associated with APA, IVIG shows no reduction in subsequent pregnancy loss (Empson et al., 2005). In these patients, the association of IVIG, heparin and aspirin is associated with an increased risk of pregnancy loss or premature delivery when compared with UFH or LMWH combined with aspirin (relative risk 2.51; 95% CI 1.27–4.95). Similarly, prednisone and aspirin resulted in a significant increase in premature delivery and gestational diabetes in comparison with a placebo, aspirin alone or aspirin combined with heparin (Empson et al., 2005). A small benefit of IVIG in women with RM and APS cannot be excluded on the basis of available studies. Furthermore, IVIG might also be of benefit to women with unexplained RM (Christiansen et al., 2004), but within this context, its use should only occur as part of an RCT. IVIG could be more efficacious in women presenting with secondary RM or repeated second trimester intrauterine fetal deaths (Christiansen and Nielsen, 2005).
The majority of trials using cellular treatment for RM have failed to find any beneficial effect. The most common of these are transfusions of paternal leukocytes before conception. So far, meta-analyses have shown no significant benefit of paternal leukocytes, third-party donor leukocytes or trophoblast membranes on pregnancy outcome when compared with placebo (Scott, 2003; Porter et al., 2005); however, in the three small trials that tested third-party donor leukocytes, the pooled odds ratio for live birth was 1.39 (95% CI 0.68–2.82) in the treatment group compared with the placebo group, emphasizing that this treatment should be further tested in RCTs (Table III).
Other treatments
A small number of non-randomized studies have reported that psychological support, that is, tender loving care (TLC) in early pregnancy, decreases miscarriage rates in women with unexplained RM. Stray-Pedersen and Stray-Pedersen (1984) found that among the RM couples with no abnormal findings, women receiving specific antenatal counselling and psychological support had a subsequent pregnancy success rate of 86%, as compared with a success rate of 33% observed in women who were given no specific antenatal care. Clifford et al. (1997) found that supportive care in early pregnancy conferred a significant beneficial effect on pregnancy outcome with those who attended the early pregnancy clinic having a 26% miscarriage rate in the next pregnancy, compared with 51% for those who did not attend the clinic.
Vitamin supplementation has been advocated in the context of an association between poor dietary intake of vitamins and an increased risk of miscarriage. A recent meta-analysis has shown that taking vitamin supplements, alone or in combination with other vitamins, before conception or in early pregnancy does not change the risk of early or late miscarriage (Rumbold et al., 2005). Currently, the data on individual vitamin supplementation in women with RM are insufficient to perform any meaningful analyses (Table III).
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Submitted on April 5, 2006; accepted on April 7, 2006.
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