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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
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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.
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
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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.
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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
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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. 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- α,
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-α 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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