BEST PRACTICE GUIDELINES - Investigation and Medical Treatment of Recurrent Miscarriage

Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage
 
Based on the Recommendation of the ESHRE Special Interest Group for Early Pregnancy (SIGEP) (2006)
 
And  RCOG green top guideline No. 17, (2003)

 

INTRODUCTION
 
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). 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.

 

 I. Evidence-based investigations for couples presenting with RM
 
Coagulation investigations

 

  • 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 APS syndrome.

  • The role of inherited thrombophilia (Factor V Leiden deficiency, activated

protein C resistance, prothrombin G20210A and protein S deficiency) is not clear and larger epidemiological studies are clearly needed to justify testing couples with RM for inherited thrombophilia in routine clinical practice.

 

Endocrinologic investigations

 

  • Early epidemiological data have shown an association between RM and hypothyroidism or diabetes mellitus.

  • Obesity is associated with a statistically significant increased risk of first trimester and recurrent miscarriage.

  • Other endocrinologic disorders, including hypersecretion of LH, high androgen levels, hyperprolactinaemia and luteal phase defects (LPD) have been associated with RM. Current evidence suggest however, that, as is the case for hypothyroidism, infertility is more likely a problem than pregnancy loss.

Immunologic investigations
 
Testing of peripheral blood NK cells and Mannan-binding lectin (MBL) (a C-type lectin) should not be performed routinely in the evaluation of miscarriage in general and RM in particular, except in the setting of a clinical trial.

 

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. It is thus advised to refer for parental karyotype only when the probability of carrier status is 2.2% or more. This risk calculation can be obtained from Probability tables (Franssen et al., 2005) recommended for this purpose.

 

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.

 

Anatomical investigations
 
The prevalence and impact on reproduction of uterine malformations in the general population have not been clearly established even though using 3Dultrasound, 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).

Other investigations

  • Investigation for Hyperhomocystinemia remains technically difficult and should not be performed outside a specific clinical context.

  • Toxoplasmosis, Rubella, cytomegalovirus, herpes (TORCH) screen is therefore
    of limited value in the investigation of RM, outside an acute infectious episode.

  • 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).

Table of recommendations for the testing of couple presenting with recurrent miscarriage

 

Basic investigations


Obstetric and family history, age, BMI, organic solvents, alcohol, mercury,lead, caffeine, hyperthermia, smoking


Full blood count (blood sugar level and thyroid function tests)


Antiphospholipid antibodies (LAC and aLC)


Parental karyotype (after 2 miscarriages???see Table I)

 
Pelvic ultrasound (SIS) and/or hysterosalpingogram and hysteroscopy and laparoscopy in case of inconclusive findings


Research investigations within the context of a trial

 

Feto-placental karyotypes


Testing of uterine and/or peripheral blood NK cells


Mannan-binding lectin (MBL) level


Luteal phase endometrial biopsy


Homocysteine/folic acid level


Thrombophilia screening

II. Evidence-based medical therapies for couples presenting with RM
 
Anticoagulants

  • 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).

  • The possible relationship between aspirin in early pregnancy and congenital defects remains controversial. A 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.

Progestational agents
 
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 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.

 

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).

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.

 

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).

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.

 

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).

 

Table on Recommendations for Treatment of Recurrent Miscarriage
 
Established Treatment
Tender loving care (TLC) and health advices (diet, coffee, smoking and alcohol)


Treatment requiring more RCTS


Aspirin and/or LMW heparins for women presenting with APS or (multiple) inherited thrombophilias


Progesterone in women presenting with unexplained early and late RM


IVIG in women presenting with unexplained secondary RM or late RM


Folic acid in women presenting with hyperhomocysteinaemia


Immunization with third-party donor leukocyte


Treatment of no proven benefit


Immunization with paternal leukocytes or trophoblast membranes


Multivitamins supplementation


Treatment associated with more harm than benefit


Daily corticoids during the first half of pregnancy

 
     

 
         
     

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