By Michele Evans,
15% of all pregnancies between 4 and 20 weeks of gestation
will end in a clinically recognized miscarriage (spontaneous
abortion). Recurrent pregnancy loss is classically defined
as 3 or more consecutive spontaneous miscarriages. This
occurs in 0.5-3% of women. Clinical studies indicate
that the risk of another miscarriage after 3 consecutive
pregnancy losses is 30-45%. Furthermore, without any
workup or treatment, the chance of a successful live
birth in a couple with a history of recurrent pregnancy
loss and no previous live birth is 55-60%. If the couple
has a history of recurrent pregnancy loss and has had
at least one previous normal pregnancy, the chance of
a subsequent live birth is 70%. These percentages are
based on studies of younger women, and it is important
to keep in mind that the miscarriage rate increases
with age. The causes of recurrent pregnancy loss can
be divided into 4 categories: genetic, anatomic, endocrine
(related to hormone abnormalities), and prothrombotic.
Current medical literature suggests that causes are
identified in only 50% of patients.
genetic abnormalities are noted in approximately 70%
of early miscarriages. In most cases, the couple has
normal chromosomes and the fetal abnormality is a random
event. In couples with recurrent pregnancy loss, an
initial workup should include a karyotype (chromosome
analysis) of the male and female partner. A karyotype
will reveal a genetic abnormality in 4% of couples.
The most common chromosome abnormality is a translocation
(balanced rearrangement of chromosomes). Other chromosome
abnormalities include chromosome inversions, X-chromosome
inactivation, sex chromosome mosaicism and ring chromosomes.
Single gene defects might also be responsible for multiple
miscarriages, but will not be detected by a karyotype.
recently, the only treatment for known genetic abnormalities
was the use of donor gametes (eggs or sperm). Currently,
preimplantation genetic diagnosis (PGD) can be utilized
to detect certain chromosome abnormalities in an early
embryo. PGD is performed in conjunction with in vitro
embryos are examined in the IVF laboratory, and only
those embryos that appear to be genetically normal are
transferred into the female patient's uterus in hopes
of achieving a successful pregnancy and live birth.
It is important to recognize that PGD has its limitations,
and therefore pregnant patients should still undergo
routine prenatal testing, including chorionic villus
sampling or amniocentesis, if indicated.
10-15% of women with recurrent pregnancy loss have a
uterine malformation. Uterine malformations include
mullerian anomalies (septate uterus, bicornuate uterus,
unicornuate uterus), leiomyomata (fibroids) and Asherman's
syndrome (intrauterine synechiae/scarring). Many of
these conditions can be diagnosed by sonohysterogram
(transvaginal ultrasound exam with saline instillation),
hysterosalpingogram (HSG) or office hysteroscopy.
with congenital or acquired uterine anomalies may be
predisposed to recurrent pregnancy loss because of inadequate
vascularity to the developing embryo and placenta or
reduced intrauterine volume. The septate uterus is the
most common congenital uterine abnormality associated
with recurrent miscarriages. Hysteroscopic resection
of the uterine septum (metroplasty) results in significantly
improved reproductive outcome. Surgical treatment is
not suggested for bicornuate or unicornuate uteri.
Asherman's syndrome is an acquired condition, which
is due to the presence of post-traumatic intrauterine
adhesions, often following a dilatation and curettage
with postoperative infection. These adhesions can partly
or completely obliterate the uterine cavity. The endometrium
is less responsive to steroid hormones in the areas
affected by adhesions. Successful surgical division
of adhesions without extensive fibrosis may restore
the endometrial responsivity. However, dense fibrosis
is associated with a poor prognosis.
fibroids may also affect implantation of an embryo.
There are three categories of uterine fibroids: submucosal
(distorting the endometrial cavity), intramural (within
the muscle layer of the uterus) and subserosal (in
the outermost layer of the uterus, away from the cavity).
number of retrospective and cohort studies have indicated
that there is good evidence to remove submucous fibroids
to reduce miscarriage, and there is some evidence
that removal of intramural fibroids also reduces miscarriage.
endocrine abnormalities have been cited as causes
of recurrent pregnancy loss, including hypersecretion
of luteinizing hormone (LH), high androgen levels,
hyperprolactinemia, thyroid disease and abnormal glucose
evidence suggests that only thyroid abnormalities, hyperprolactinemia
and poorly controlled Type I diabetes are positively
associated with recurrent miscarriage. An initial workup
for recurrent miscarriage should include a screening
test for thyroid disease with the measurement of thyrotropin
stimulating hormone (TSH) and a prolactin level. In
a healthy patient, laboratory evaluation of carbohydrate
metabolism is not suggested.
The presence of a luteal phase defect as a cause for
recurrent pregnancy loss is controversial. A luteal
phase defect is defined as inadequate secretory transformation
of the endometrium (uterine lining) resulting from a
deficient ovarian progesterone secretion. A luteal phase
defect can be diagnosed by out-of-phase endometrial
biopsies in 2 consecutive menstrual cycles. Studies
suggest that the majority of cases of luteal phase defect
are associated not with suboptimal progesterone but
with an abnormal response of the endometrium to progesterone.
Therefore, a recent study indicates that treatment should
be targeted at improving the endometrial responsivity
of progesterone by enhancing priming of the endometrium
in the follicular phase (first half of the menstrual
cycle). In the study cited, this was done by stimulating
the ovary with gonadotropins to increase estrogen production
in the follicular phase. Estrogen priming is associated
with normalization of endometrial development in the
syndrome is a well-recognized cause of recurrent miscarriage.
Antiphospholipid antibodies are directed to the negatively
charged phospholipids that are constituents of all cell
membranes. Lupus anticoagulant and anticardiolipin antibodies
are types of antiphospholipid antibodies. The diagnosis
of this syndrome, as related to recurrent pregnancy
loss, requires fulfillment of the following criteria:
three or more unexplained consecutive spontaneous miscarriages
before the 10th week of gestation, with all other causes
excluded. In addition, there must be a persistent abnormality
of one of the following tests when measured at least
twice, greater than 6 weeks apart: lupus anticoagulant
and/or anticardiolipin antibodies. The optimal treatment
is low dose aspirin and subcutaneous heparin.
pregnancy loss is very distressing for patients. A thorough
medical evaluation is critical, but often frustrating,
because a cause for the repeated pregnancy losses can
be identified in only 50% of cases. There are still
many unresolved questions about the causes and treatment
of recurrent miscarriage. Fortunately, the number of
publications on this topic have substantially increased
over the past 10 years, reflecting a growing interest
among clinicians and scientists.