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Causes of Recurrent Pregnancy Losses
and Treatments
Current medical
knowledge suggests that recurrent pregnancy loss (RPL)
causes are identified in only about 50% of patients.
The treatment of RPL is directed to the cause.
However, since incomplete testing results in no
definite cause in about half of the patients, there
is much controversy in what to do for this category
of patients. This has resulted in a number of
empirical treatment options, most of which remain to
be proven.
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Causes &
Treatments
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Chromosomal Abnormalities |
Unexplained
RPL
To
make an appointment, please call us TODAY at
615-321-8899.
|
Maternal Age |
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The chance of a miscarriage increases as a
woman ages. After age 40, more than half of
all pregnancies end in miscarriage. Most of
these embryos are aneuploidic. Another
factor leading to RPL in patients with
advanced reproductive age is granulosa and
luteal cell death. Granulosa (ovarian) cells
are responsible for maturing and ejecting
the oocyte at ovulation. Granulosa cell
death may lead to difficulties with
oogenesis and zygote development, thus
leading to embryonic demise and RPL.
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Treatment |
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Estradiol (E2) and Progesterone
(P4), hormones produced by luteal
cells in the ovaries after ovulation, are
necessary for endometrial development,
implantation and placentation. In patients
with increased maternal age low post-ovulatory
E2 and P4 levels,
called luteal phase deficiency, may cause
repeated miscarriages due to a weak
endometrium unreceptive to implantation and
placentation. Treatments may include
ovulation induction, E2 and P4
supplementation or injections of human
chorionic gonadotropin (HCG).
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Parental Chromosomal
Anomalies |
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In parents with RPL parental chromosomal
anomalies o rearrangements (i.e., reciprocal
inversions) occur in 3-6%. The most common
abnormality is a balanced translocation,
including reciprocal and Robertsonian
translocations resulting in unbalanced
translocations in the fetus.
Treatment:
In patients with chromosomal problems,
genetic counseling is important. Hence, a
clinical geneticist should be consulted. PGD
in our Center is a reasonable technology
that will accurately avoid the
transfer of an embryo with an unbalanced
karyotype that could result in a pregnancy
loss or a malformed live birth.
This karyotype
shows that a fragment of chromosome 9 has
been
moved
("translocated") from chromosome 9 to the
non-homologous chromosome 22. The balance of
genes is still normal (nothing has been
gained or lost) but can alter phenotype as
it places genes in a new environment. It can
also cause difficulties with egg or sperm
development and zygote development, thus
leading to RPL. |
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Treatment |
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Estradiol (E2) and Progesterone
(P4), hormones produced by luteal
cells in the ovaries after ovulation, are
necessary for endometrial development,
implantation and placentation. In patients
with increased maternal age low post-ovulatory
E2 and P4 levels,
called luteal phase deficiency, may cause
repeated miscarriages due to a weak
endometrium unreceptive to implantation and
placentation. Treatments may include
ovulation induction, E2 and P4
supplementation or injections of human
chorionic gonadotropin (HCG).
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Uterine Anomalies |
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Structural uterine anomalies occur in up to
10% of patients with a history of RPL. But
the incidence in the general population is
unknown. The mechanism of the pregnancy loss
in these patients is uncertain, but it may
be related to decreased placental
vascularization if placentation occurs on a
uterine septum or a submucous uterine
fibroid or in the presence of Asherman's
syndrome.
A uterus may have a normal
shape but it may have a septum in the center
dividing it into two cavities. This does not
need to be surgically corrected unless there
is recurrent pregnancy loss. A septate
uterus may also lead to premature labor and
breech presentation.
Ashermann's syndrome is the occlusion or
obliteration of the uterine cavity due to
damage to the lining of the cavity (endometrium).
Clinical situations that increase the chance
of Ashermann's Syndrome include overzealous
dilatation and curettage (especially for a
missed abortion, postpartum bleeding, or
septic abortion), intrauterine surgery to
remove fibroid tumors, uterine structural
defects (septum, bicornuate uterus, large
polyps), or at cesarean section infections
related to IUD use (or the placement of any
foreign object within the uterine cavity),
some uncommon infections of the uterus (such
as intrauterine tuberculosis or
Schistosomiasis) radium insertion into the
uterus for the treatment of gynecologic
cancers. The finding for Ashermann's
Syndrome on hysterosalpingogram (HSG) exam
is intrauterine filling defects. These are
irregular areas within the normally
triangular shaped cavity where the
distending media is excluded due to the
presence of the adhesions. Thin adhesions
may be primarily composed of fibroconnective
tissue with little blood supply.
Color Doppler reveals a
submucosal myoma with blood flow seen on
saline infusion sonohysterography that
resulted in previous miscarriages.
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Treatment |
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Congenital
uterine anomalies usually involves
metroplasty or resection of the septum with
a resectoscope. The incidence of RPL in
cases with a low grade uterine anomaly may
be as high as the incidence among cases with
more severe anomalies. There is a
significant improvement in maintaining
pregnancy after metroplasty. The removal of
uterine fibroids may significantly reduce
the fetal loss rate.
Ashermann's syndrome causes vascular and
muscular adhesions which are much more
difficult to repair and seemingly pose a
greater problem for fertility. A type of
operating hysteroscope called a resectoscope
allows the surgeon to apply electrical
current through a monopolar cutting
instrument attached as the operating element
of the hysteroscope and lysis (cutting) of
the adhesions can then be performed.
This hysterosalpingography
depicts a uterine cavity with multiple
filling defects consistent with Ashermann's
syndrome. Although less than 50% of the
uterine cavity is obliterated,
fibroconnective tissue obstructs the right
fallopian tube entrance resulting in Grade
III Ashermann's syndrome.
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Cervical Incompetence |
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Cervical incompetence is a common cause of
pregnancy losses in the second trimester.
Rarely may it be congenital following in-utero
exposure to diethylstilboestrol (DES). The
typical history is that of a sudden rupture
of fetal membranes in the second trimester,
followed by a painless miscarriage. There
are no truly diagnostic tests for cervical
incompetence. The diagnosis is most commonly
based on past obstetric history and, to a
lesser extent, clinical assessment of the
cervix during pregnancy by vaginal
examination or serial ultrasound
examination.
This graphic depicts
funneling of endocervical canal in a patient
with cervical incompetence that required a
cerclage because of cervical incompetence.
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Treatment |
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Cervical cerclage is used for cervical
incompetence. Cervical cerclage should be
offered to women with a clear history of
cervical incompetence or those at high risk
of midtrimester loss, such as those with a
history of three or more pregnancies ending
prematurely. Transabdominal cervicoisthmic
cerclage (TCC) may be used in a highly
selective group of women with anatomical
defects (e. g. following large/repeated cone
biopsy) of the cervix and previously failed
transvaginal cerclage associated with
cervical damage. In women who are at risk of
midtrimester loss but the diagnosis of
cervical incompetence is uncertain, serial
transvaginal ultrasonography from 14 weeks
onwards may be performed to measure the
length of the cervix (normal, 2. 5 cm) and
to exclude funneling of the upper cervical
canal which may precede shortening.
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Endocrinological Disorders |
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(a) Polycystic ovarian disease/Hypersecretion
of LH. There appears to be increasing
evidence of an association between
polycystic ovarian syndrome
(PCOS)
and RPL.
Ultrasonographic evidence of polycystic
ovaries occurs in 44-56% of patients with
RPL compared to 5% in the control
population.
(b) Hyperprolactinemia: Hyperprolactinemia
may be associated with unexplained
infertility and repeated miscarriages.
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Treatment |
For Polycystic ovarian disease/Hypersecretion
- Women with polycystic ovaries and high
luteinizing hormone levels may be treated
with:
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clomiphene citrate
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low dose gonadotropins
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pituitary desensitization (GnRHa and
gonadotropins)
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HCG support in early pregnancy
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E2
& P4
in early pregnancy
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metformin hydrochloride tablets (i.e.,
Glucophage ®, Glucophage XR®)
For Hyperprolactinemia - Bromocriptine has
been used with great success to medically
reduce prolactin concentrations to a normal
level and to restore fertility and prevent
miscarriages in hyperprolactinemic patients
(i.e., microprolactinomas, empty sella
syndrome).
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Immunological Factors |
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Autoantibodies are more common in patients
with RPL in comparison with control
populations. Autoantibodies are found in
18-43% of patients with RPL. The antibodies
commonly identified include antiphospholipid
antibodies (14%), and antinuclear antibodies
(7%) and anti-thyroid antibodies (7%).
Thyroid antibodies:
Prevalence of
thyroid auto-antibodies, including
thyroglobulin or peroxidase (anti-microsomal)
antibodies is significantly increased in
women with RPL. The association between RPL
and thyroid antibodies may be a result of;
> direct effect of these autoantibodies
on fetal tissue, or
> the
presence of thyroid antibodies represent
an underlying more generalized defect in
autoimmunity
The presence of thyroid autoantibodies in
the non-pregnant state in women with RPL is
associated with an increased risk of
miscarriage in a subsequent pregnancy.
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Treatment |
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While the determination of thyroid
antibodies should be included in the list of
auto-antibodies tested in the protocol for
investigation of women with RPL, it is
uncertain what treatment, if any is of
benefit. It is now recognized that women
with thyroid auto-antibodies are at risk of
developing subclinical hypothyroidism.
Hence, close monitoring with thyroxine
function test and TSH levels is necessary. A
logical (empirical) treatment consists of a
low dose thyroxine (e. g. 50 µg) especially
in those with a highest normal TSH level.
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Coagulation Disorder |
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Apart from lupus anticoagulation which is a
prothrombotic state, other coagulation
disorders have also been associated with RPL,
including an impaired fibrinolytic capacity
and factor XII deficiency. Women who have
lupus coagulant or high antiphospholipid
antibodies have been treated with
acetylsalicylic acid (aspirin) 50-100 mg
daily, corticosteroids (prednisolone 10 mg
daily) and heparin 10,000 i. u. daily,
either individually or in combination
without any obvious side effects in treated
mothers or their babies. Heparin, in
in-vitro studies, appears to inhibit the
binding of antiphospholipid antibodies to
phospholipids.
Hypercoagulable states (i.
e., Systemic Lupus Erythematosus,
thrombophilia) may lead to thrombosis,
placental infarctions, and embryonic demise
and pregnancy losses.
When a patient has a tendency to form blood
clots, the condition is called thrombophilia.
Physicians may suspect thrombophilia when
patients have a blocked blood vessel at a
young age or have a strong family history of
clotting disorders (such as stroke,
pulmonary embolism, or deep venous
thrombosis). Recent research suggests a
possible correlation between inherited
thrombophilia and RPL. Genetic markers for
these clotting factors include factor V
Leiden mutation and prothrombin G20210A
mutation. These two mutations are the most
common causes of inherited thrombophilia.
These markers, as well as several others
that have also been associated with RPL, can
be detected through simple blood tests.
Other indicators of thrombophilia (prothrombin
mutation, activated protein C or S
resistance, and antithrombin III deficiency)
are also more prevalent among women
experiencing frequent miscarriages. The PCOS
patient and Thrombophilia patients with PCOS
have an increased risk of miscarriage. It
used to be thought that high levels of serum
luteinizing hormone (LH) associated with
PCOS caused chromosomally abnormal eggs,
leading to an increased risk of miscarriage.
While the exact cause remains unknown,
clotting factor abnormalities associated
with insulin resistance (PAI-1 level and
activity) are important to consider.
Elevated levels of insulin interfere with
the normal clotting balance causing abnormal
uterine blood flow. |
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Treatment |
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Treatment regimens used to manage
thrombophilia may include heparin or Lovenox
(low molecular weight heparin) injections,
and baby aspirin or metformin (for insulin
resistant patients with elevated PAI-1).
Thrombocythemia has also been reported to be
a cause of RPL.
Empirical treatment with subcutaneous
heparin/clexane during pregnancy may be
considered. There is a clear need for a
clinical trial of thromboprophylaxis for RPL
associated with thrombophilia. Long term
heparin therapy, however, may be associated
with side effects such as osteoporosis and
severe hypertriglyceridemia due to
lipoprotein lipase deficiency.
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Infections |
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Associations of RPL with high titers of
immunoglobulin G (IgG) antibody to Chlamydia
have been reported. Furthermore,
colonization of the reproductive tract by
pathogens (i.e., Ureaplasma Urealyticum,
Chlamydia Trachomatis) may lead to
hyper-activation of local immune cells that
become giant cells (i.e., macrophages)
releasing stress hormones (i.e.,
Prostaglandins) and cytokines that interfere
with implantation and placentation, thus,
leading to RPL. Infection is an occasional
cause of sporadic spontaneous abortion and,
consistent with statistical probability, RPL
due to pelvic infection should be less
likely than with other etiologies.
The picture on the left shows
a conventional microscopic view of
Ureaplasma Urealyticum. On the right there
is an electron microscopic view of an
Ureaplasma colony that has been implicated
in causing recurrent pregnancy losses.
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Treatment |
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Most patients with a history of RPL will not
benefit from an extensive infection workup.
Chorioamnionitis may be a cause of premature
labor and midtrimester loss. Bacterial
vaginosis (BV) is a condition associated
with a complex (quantitative) alteration in
vaginal flora involving mobiluncus species,
bacteroides species, peptostreptococci,
ureaplasma urealyticum and mycoplasma
hominis, in addition to Gardnerella
vaginalis. These changes are accompanied by
depletion in vaginal lactobacilli. BV is
thought to be associated with sexual
activity. Unlike other infection which
depends primarily on bacteriological study,
the diagnosis of BV is based on composite
criteria in which 3 out of 4 should be
present:
a. vaginal pH more than 4. 5
b. a grey homogenous (malodorous,
fishy-smelling) vaginal discharge
c. the presence of clue cells in a wet mount
preparation of vaginal fluid
d. the amine test, in which a fishy odor is
released after the addition of 10% potassium
hydroxide to vaginal fluid
It should be noted that routine
High vaginal swab (HVS)
to look for infection
may show only "commensals" or "no
pathogens". If BV is to be excluded, HVS
alone is not the appropriate test. BV is
associated with second trimester loss,
preterm premature rupture of membranes and
preterm labor. However, BV has not been
found to be associated with first trimester
miscarriage.
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Maternal Chronic Conditions
& Diseases |
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Maternal chronic diseases including diabetes
mellitus, systemic lupus erythematosus,
thyroid disease, chronic essential
hypertension and renal diseases appear to
have an increase risk for RPL.
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Treatment |
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Identifiable
treatment is not available at this time.
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Metabolic Abnormalities |
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Poorly controlled diabetes increases the
risk of miscarriage. Women with diabetes
improve pregnancy outcomes if blood sugars
are controlled before conception. Women who
have insulin resistance, such as obese women
and many who have PCOS, also have higher
rates of miscarriage. |
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Treatment |
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There is still not enough evidence to know
if medications that improve insulin
sensitivity lower miscarriage risks in women
with PCOS.
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Other Factors |
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(a) Exposure to pentachlorophenol (PCP)
present in certain types of timber
preservative has been reported as a possible
cause of miscarriage. Serum PCP level may be
measured and should not exceed 25 Ng/I.
(b) Selenium deficiency detected by a
reduction of serum selenium level has been
reported to be associated with first
trimester miscarriage in a study in South
Wales.
(c) Hyperhomocysteinemia, an inborn error of
metabolism is associated with RPL.
Hyperhomocysteinemia is associated also with
neural tube defect, placental infarcts,
fetal growth retardation, placenta abortion
and thrombophilia. It interferes with
embryonic development as well as with
vascular function. The metabolic defect may
be overcome with folate administration.
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Treatment |
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For hyperhomocysteinemia, treatment with
subcutaneous heparin or clexane is advisable
to reduce the risk of venous thrombosis.
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>>
Causes &
Treatments
|
Chromosomal Abnormalities |
Unexplained
RPL
To
make an appointment, please call us TODAY at
615-321-8899.
|
