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INTRODUCTION:
Recurrent miscarriage is traditionally defined as three or more
consecutive losses of pregnancy. This distressing problem
affects approximately 1% of all women. By contrast, sporadic
miscarriage affects 25% of all women who conceive a pregnancy.
As such, sporadic pregnancy loss is the commonest complication
of pregnancy and it is important to recognize that the causes of
sporadic and recurrent miscarriage are diverse.
GENETIC FACTORS AND RECURRENT MISCARRIAGES:
Chromosomal abnormalities of the embryo are
the most common cause of sporadic miscarriage. In women with a
history of recurrent miscarriage, chromosomal abnormalities of
the embryo occur much less frequently3. There is a tendency for
successive abortuses to be karyotypically normal or
karyotypically abnormal 4,5 suggesting that some couples are at
a risk of recurrent aneuploidy. However, the risk of a
subsequent miscarriage is higher when the index loss has a
normal karyotype 5.
Structural anomaly is seen in 3% of cytogenetically abnormal
conceptuses. The commonest type of structural chromosomal
anomaly is Robertsonian translocation. Structural chromosomal
anomalies are higher in couples with history of RSA as well as
past history of birth of anomalous or stillborn infants.
Recurrent aneuploidy & Recurrent Pregnancy Loss:
Chromosomal anomalies of the embryo are the
most common cause of early pregnancy loss. Couples in whom one
or other partner carries a chromosomal rearrangement are at risk
of RPL with loss of conceptus with an abnormal karyotype. An
increased number of chromosome breaks and eccentric fragments
and pericentric inversions are seen in recurrent abortion group.
ANATOMICAL CAUSES & R.S.A:
Congenital anomalies of the uterus have
been cited repeatedly as an important cause of recurrent
miscarriage, both in the midtrimester and in early pregnancy. In
order to cause early pregnancy loss, the embryo supposedly
implants in an avascular part of the endometrium, such as a
uterine septum, leading to arrested development and early
pregnancy failure.
The prevalence of uterine anomalies in
women with recurrent miscarriage has been reported to be in the
region of 10% 6,10.
The optimal treatment for uterine anomalies
is still a matter of debate. Open surgical correction of
congenital anomalies has been reported to give successful
subsequent pregnancy outcome. However the value of treatment of
these conditions in recurrent pregnancy loss is unclear.
Majority of studies of RPL on uterine anomalies are without
control, comparing miscarriage rates before and after treatment
in the same woman can give flawed interpretation of results..
CERVICAL INCOMPETENCE: Cervical
Incompetence is one acquired cause of recurrent pregnancy loss
that is well-described 14. Incidence of cervical incompetence
was put upto 0.5 % to 1% of all pregnancies 18. Cervical
incompetence as a cause of mid-trimester miscarriage has been
well described. Cervical cerclage is not associated with
significant difference in the fetal survival rate between the
cerclage and control groups. In addition, cerclage is associated
with increased obstetrics intervention and an increased
incidence of puerperal pyrexia.
Several avenues have been explored in an
effort to arrive at successful treatment of cervical
incompetence. By far the most effort has been expended on
surgical approaches to cervical incompetence, and this is at
present, the mainstay of treatment.
INFECTIONS & R.S.A:
Many infections of the genital tract have
been reported to be associated with sporadic pregnancy loss.
Bacterial vaginosis, a polymicrobial anaerobic infection, has
been implicated in the etiology of preterm labour 26-28, but its
role in recurrent pregnancy loss is doubtful. Maternal infection
with Toxoplasma gondii, cytomegalovirus, rubella and herpes
[TORCH] can cause sporadic pregnancy loss but evidence that
these organisms are associated with recurrent miscarriage is
lacking.
ENDOCRINE DYSFUNCTION & R.S.A:
Hyper secretion of luteinizing hormone:
Miscarriage rate was significantly higher in patients with high
LH levels than in those with normal LH levels. In contrast to
the normal population, who have a reported prevalence of PCO of
22% 36, the prevalence of PCO in women with a history of
recurrent early pregnancy loss was found to be 82% 37 and in
infertile women attending for in vitro fertilization (IVF) the
prevalence of PCO is as high as 50% 38.
IMMUNOLOGICAL CAUSES:
Autoimmune disease: The association between
raised circulating Antiphospholipid antibodies (APAs) and
recurrent pregnancy failure is now well established. Recurrent
spontaneous missed abortions, IUGR, recurrent stillbirths,
accidental hemorrhage and thromboembolism are some diverse
conditions that have this as its etiological factor. The primary
Antiphospholipid syndrome recurrent pregnancy loss, arterial and
venous thrombosis or thrombocytopenia in the absence of over
autoimmune disease, is now well documented. Diagnosis is also
helped by asking a history of allied complications of APA like
RSA of missed type, recurrent stillbirths 46, recurrent IUGR,
etc. The standard classification used for classifying APA cases
is: Negative ® < 10 GPL units , Low positive ®10-20 GPL units ,
Mod. Positive ®20-100 GPL units, Strong positive ®> 100 GPL
units. TREATMENT: Nearly 18 different protocols have been tried
over the period of years for the treatment of APA syndrome. But
the main stay is Heparin, Low dose Aspirin and corticosteroids.
We use the following protocol 51: In interval period:
® For low and moderate positive, Aspirin in a dose of 1.2
mg/kg./day for three months – Allow a conception – Restart
aspirin in the same dose upto 36 weeks.
® For High positive, Prednisolone in a dose of 10 mgms. /day for
3 months in the interval period; Allow conception- start aspirin
from 12 weeks upto 36 weeks
In Pregnancy: For these cases we give only the post-conception
protocol of aspirin specified above.
However, we now use aspirin and heparin
combination in refractory subjects and in subjects who test
positive for both ACA and LAC. Heparin is used in prophylactic
doses in the interval period of 1000 i.u. and later as soon as
pregnancy is diagnosed we give 5000 i.u of heparin daily till 36
weeks of pregnancy. This combination of aspirin and heparin
gives the best results.
Alloimmune causes: It has been suggested
that a necessary prerequisite for successful pregnancy involves
maternal recognition of the embryo, leading to a protective
immune response. Further a failure to mount the appropriate
maternal immune response will lead to recurrent pregnancy loss.
Based on this hypothesis, immunization treatment for recurrent
early miscarriage was developed the female partner is immunized
with paternal third-party or fetal material in order to
potentiate the maternal immune response. The most common method
of treatment utilized is paternal leukocyte immunization. That
an increased degree of human leukocyte antigen sharing between
the parents could be responsible for the lack of maternal immune
recognition is now strongly disputed52, 53 and most workers have
now abandoned human leukocyte antigen typing for couples
suffering from recurrent miscarriage. Only one randomized
controlled trial of immune therapy has shown benefit following
treatment 54. More recent randomized trials have failed to
confirm this finding 55,56, 57 - a striking feature being the
success rate in the control group of these studies. This
treatment must therefore be considered of no proven benefit.
SUMMARY:
The management of recurrent miscarriage can
be confusing and frustrating for both the women and her doctor,
frequently hindered by the bias of the investigating clinician
and the uncontrolled reports found in the literature. Using
systematic approach to screening, it is possible to identify a
probable cause for the repeated pregnancy losses in over 50% of
couples attending a specialized recurrent miscarriage clinic.
The importance of randomized controlled trials of new treatments
for women with recurrent miscarriage in the future cannot be
overstated.
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