EARLY PREGNANCY LOSS:
Pregnancy life is a significant event that could happen in a woman’s
life, and an emotional attachments that is to be acts as normal as the
pregnancy and developing baby may begin early in the first trimester. For most
women, experiencing a first trimester loss that is to be difficult and
vulnerable at the time. When it occurs,
the grief can be a profound as for any perinatal or other major loss. Spontaneous
abortion is among the most common complications of pregnancy. The risk factors
for spontaneous abortion are advanced maternal age, a previous spontaneous
abortion, and maternal smoking. Most spontaneous abortions are attributed to
structural or chromosomal abnormalities in the embryo.
INTRODUCTION
Early pregnancy loss is a
frustrating and heart-wrenching situation. Unfortunately, early pregnancy loss
is the most common complication of human gestation, occurring in at least 75%
of all women trying to conceive. Most of these losses are unrecognized and
occur before or with the expected next menses. Of those that are recognized, 15-20%
are spontaneous abortions (SABs) or ectopic pregnancies diagnosed after
clinical recognition of pregnancy. Approximately 5% of couples trying to
conceive have 2 consecutive miscarriages, and approximately 1% of couples have
3 or more consecutive losses.
Chemical pregnancy loss -
Loss of a biochemically evident pregnancy.
Early pregnancy
loss/abortion of the first trimester - Loss of a pregnancy recognized
histologically or by ultrasound.
Spontaneous abortion -
Pregnancy loss before 20 weeks gestation based on last menstrual period.
Stillbirth - Pregnancy loss
after 20 weeks gestation and neonatal loss is the death of live born fetus.
Habitual/recurrent abortion
- Three or more consecutive abortions.
INCIDENCE
Early pregnancy loss occurs at a rate of 114
cases per hour. Most studies quote a spontaneous miscarriage rate of 10-15%.
However, the true early pregnancy loss rate is closer to 50% because of the
high number of chemical pregnancies? That are not recognized in the two to four
weeks after conception. Most of these pregnancy failures are due to gamete
failure (eg, sperm, oocyte dysfunction). In a 1988 classic study by Wilcox et
al, 221 women were followed during 707 total menstrual cycles. A total of 198
pregnancies were achieved, of which 43 (22%) were lost before the onset of
menses, and another 20 (10%) were clinically recognized losses.
The recurrent miscarriage
rate is 3-5%. The chance for a subsequent abortion increases with each
successive abortion. Data from various studies indicate that after 1 SAB, the
couple has approximately the baseline risk of having another one (15%).
However, if 2 SABs occur, the subsequent risk increases to approximately 25%.
Several studies have estimated that the risk of pregnancy loss after 3
successive abortions is 30-45%. Controversy exists as to how many (ie, 2 or 3)
pregnancy losses a woman should experience before considering a diagnostic
evaluation. One could argue that the diagnostic evaluation should take place
after 2 losses because the diagnostic yield after 2 versus 3 miscarriages is
identical. In addition, it appears that an increase in the prevalence of
aneuploidy is noted when couples with 2 miscarriages are compared with normal
controls.
ETIOLOGY
The etiology of early
pregnancy loss is varied and often controversial. More than one etiologic
factor is often present. The most common causes of recurrent miscarriages are
as follows:
- Genetic balanced parental
translocation
- Mendelian
- Multifactorial
- Other
- Robertsonian
- Reciprocal
- Uterine congenital
- Müllerian anomaly
- Diethylstilbestrol-linked
- Acquired defects
- Iatrogenic
- Uterine septum
- Hemiuterus
- Double uterus
- Incompetent cervix
- Leiomyomas
- Asherman syndrome
- Immune autoimmune
- Alloimmune
- Humoral mediated
- Cellular immunity mediated
- Endocrine luteal phase
deficiency
- Other endocrine factors
- Antithyroid antibodies
- High luteinizing hormone
synthesis
- Infection
- Hematologic
- Environmental
The gestational age at the
time of the SAB can provide clues about the cause. For example,
antiphospholipid syndrome (APS) and cervical incompetence losses tend to occur
after the first trimester. It has been suggested that when a woman with a
history of retroperitoneal lymphadenectomy (RPL) carries a pregnancy past mid
gestation, her chances of having pregnancy complications, such as prematurity
and low-birth weight infants, may be somewhat higher than controls.
GENETIC CAUSES
Single miscarriage
Most spontaneous
miscarriages are caused by an abnormal karyotype of the embryo. At least 50% of
all first trimester SABs are cytogenetically abnormal. However, this figure
does not include abnormalities caused by single gene disorders (eg, Mendelian
disorders) or mutations at several loci (eg, polygenic or multifactorial
disorders) that are not detected by the evaluation of karyotypes. The highest
rate of cytogenetically abnormal concepti occurs earliest in gestation, with
rates declining after the embryonic period (>30 mm crown-rump length).
Cytogenetically abnormal
embryos usually are aneuploid because of sporadic events, such as meiotic
nondisjunction or polyploid from fertilization abnormalities. One half of the
cytogenetically abnormal abortuses in the first trimester involve autosomal
trisomy. Triploidy is found in 16% of abortions, with fertilization of a normal
haploid ovum by 2 sperm (dispermy) as the primary pathogenic mechanism.
Trisomies arise de novo because of meiotic nondisjunction during gametogenesis
in parents with a normal karyotype. For most trisomies, maternal meiosis I
errors have been implicated.
The incidence of trisomies
increases with age. Trisomy 16, which accounts for 30% of all trisomies, is the
most common. All chromosome trisomies have been reported in abortuses except
for trisomy 1. Interestingly, trisomy 1 has been reported in embryos obtained
with in vitro fertilization. This logically suggests that trisomy 1 is most
likely lethal at the preimplantation stage. Autosomal monosomies are rarely, if
ever, observed. In contrast, monosomy X (Turner syndrome) frequently is seen
and is the most common chromosomal abnormality observed in SABs. Turner
syndrome accounts for 20-25% of cytogenetically abnormal abortuses.
Approximately one third of Down syndrome (trisomy 21) fetuses survive to term.
The standard of care is to
offer genetic amniocentesis for all pregnant women of advanced maternal age,
which is defined as women older than 35 years. The risk of a woman having an
aneuploid fetus is 1 per 80 when she is older than 35 years, which is far
greater than the inherent risk of fetal loss after amniocentesis, which is 1
per 200.
Other abnormalities include
those related to abnormal fertilization (eg, tetraploidy, triploidy). These
abnormalities are not compatible with life. Tetraploidy occurs in approximately
8% of chromosomally abnormal abortions, resulting from failure of a very early
cleavage division in an otherwise normal diploid zygote.
Structural chromosomal
problems are a third category of abnormalities. Structural rearrangements occur
in approximately 3% of cytogenetically abnormal abortuses. It is thought that
structural chromosomal abnormalities are inherited more commonly from the
mother. Structural chromosomal problems that are found in men seem to lead to
lower sperm concentrations, male infertility, and, thus, a lesser chance of
pregnancy and miscarriage. The exception to this is the couple undergoing
assisted reproductive technologies, whereby selected sperm can be injected into
oocytes to force fertilization using potentially genetically abnormal sperm.
The incidence of
translocations increases with the number of abortions. In addition, women were
more frequently the carriers. Slightly more than one half of the unbalanced
rearrangements result from the abnormal segregation of Robertsonian
translocations (ie, fusion of 2 acrocentric chromosomes at the centromere). Approximately
one half of all unbalanced translocations arise de novo during gametogenesis.
Of the familial translocations, about two thirds are derived maternally, and
one third are paternal in origin. In 2-3% of couples who have had 2 or more
spontaneous miscarriages, one partner has a balanced translocation. In
addition, the rate is slightly higher (1.7-4.6%) in couples with a history of
both recurrent abortion and anomalous or stillborn infants. Other structural
rearrangements, such as inversions or ring chromosomes, are more rare.
The final group is gene
abnormalities. It is thought that there may be certain mutations of genes
involved with implantation that may predispose a patient to either infertility
or even miscarriage. An example of a single gene disorder associated with
recurrent pregnancy loss is myotonic dystrophy, an autosomal dominant disorder
with high penetrance.
This disorder is a
progressive, degenerative neuromuscular disease with an extremely variable
phenotype. The cause of the abortion is unknown but may be related to abnormal
gene interactions combined with disordered uterine function. Other presumed
autosomal dominant disorders that affect the fetus and are associated with
pregnancy loss include lethal skeletal dysplasias, such as thanatophoric
dysplasia and type II osteogenesis imperfecta. In these cases, the parents are
phenotypically normal because the mutation presumably occurs during
gametogenesis. The rare case of recurrence in these families is presumed to be
due to gonadal mosaicism in the ovary or the testes.
Maternal disease associated
with increased fetal wastage includes connective tissue disorders, such as
Marfan syndrome, Ehlers-Danlos syndrome, homocystinuria, and pseudoxanthoma
elasticum. Women with sickle cell anemia are at increased risk for fetal loss,
possibly because of placental bed microinfarcts. Other hematologic
abnormalities associated with recurrent pregnancy loss include
dysfibrinogenemia, factor XIII deficiency, and congenital hypofibrinogenemia
and afibrinogenemia.
Recurrent miscarriage may
result from 2 different chromosomal abnormalities, a structural abnormality
derived from one of the parents or the recurrence of a numerical abnormality,
which usually is not inherited. Studies have analyzed whether the presence of
karyotypic abnormalities in one abortus was predictive of a similar abnormality
in the next pregnancy. Warburton et al found that when the effects of maternal
age are taken into account, there is no increase in the risk of trisomy in a
second abortion following a trisomic abortion. There is no increased risk of
trisomy in a second abortion following a previous abortion with another
karyotype. Conversely, there is a significant increase in the risk of a
nontrisomic abnormal karyotype after a previous abortion with a similar
karyotype.
Genetic counseling after a
miscarriage
The study by Warburton et al
indicates that a routine karyotype analysis after one miscarriage is not
cost-effective or prognostic. However, after 2 miscarriages, analysis of the abortuses
is useful, a theory supported in a 1990 study by Drugan. This study sampled 305
women with 2 or more miscarriages, with either chorionic villus sampling or
amniocentesis. Drugan found a higher risk for fetal aneuploidy in couples with
recurrent miscarriages. The risk was 1.6, similar to the aneuploidy risk in a
woman older than 40 years. In a woman with a prior trisomic livebirth, an
approximately 1% increased risk exists for subsequent trisomic birth. The
recurrence risk probably is limited to only those trisomies compatible with
life, such as trisomies 13, 16, 18, and 21 or to parental trisomy mosaicism.
These couples should always have their karyotypes evaluated.
If the karyotype of both
parents is normal and the next pregnancy ends as a spontaneous miscarriage,
cytogenetic studies of the abortus should be preformed to provide prognostic
information and to assess the efficacy of treatments for other potential causes
of miscarriage. Because abnormalities caused by single gene mutations (eg,
Mendelian disorders) or mutations at several loci (eg, polygenic or
multifactorial disorders) are not detected by karyotype analysis, molecular
techniques are being used more frequently to complement standard cytogenetics.
The analysis of very small
structural deletions and rearrangements that are not detectable with standard
cytogenetic techniques can be identified with specialized methods, such as
fluorescence in situ hybridization (FISH). However, if a parental chromosome
abnormality is found, then this should be the starting point for familial
testing. If an inherited abnormality is found, then proper family counseling is
recommended. If an increased risk for future pregnancies is identified, then
each alternative should be discussed, including foregoing any attempts at
further conception, adoption, trying to conceive again with early prenatal
testing, sperm or oocyte donation, or preimplantation diagnosis (PGD).
PGD entails in vitro
fertilization (IVF), removal of a blastomere from the developing embryo for genetic
analysis, and then implantation into the uterus only those embryos that are
genetically normal. However, difficulties remain with this procedure. The
delivery rate for IVF is only 35% even if normal embryos are transferred. The
cost is $10,000-15,000 per treatment cycle. Of note, it is possible that all
the cells within the early embryo are not genetically similar and that a
so-called normal embryo actually may be abnormal.
In reciprocal
translocations, the chromosomes involved in the translocation together with
their normal homologues, form 1 quadrivalent instead of 2 bivalents. Alternate
segregation results in 1 gamete receiving both normal chromosomes and the other
gamete receiving both translocation chromosomes. The children created from
these gametes have normal and carrier karyotypes. Adjacent segregation results
in unbalanced distribution of the chromosomes involved in the translocation,
leading to partial trisomy for 1 chromosome and partial monosomy for the other
chromosome. The severity of the phenotype depends on the chromosomes involved
and the positions of their breakpoints. The risk is higher if the translocation
is carried by the female partner.
Chromosomes arising from
Robertsonian translocations are composed of 2 more or less complete acrocentric
chromosomes. Abnormal meiotic segregation results in either complete trisomies
or monosomies. Viable trisomies have been observed for chromosomes 13, 16, and
21.
With inversions, a loop is
formed during meiotic pairing. Crossing over within a loop yields 2 normal
chromosomes and 2 chromosomes showing duplication/deficiency. If the inversion
is paracentric, involving the centromere, 1 of the abnormal chromosomes is
dicentric and the other is acentric. Both are incompatible with life. In
pericentric inversion, not involving the centromere, abnormalities may lead to
offspring with congenital abnormalities.
AUTOIMMUNE CAUSES
An association exists
between recurrent pregnancy loss and autoimmune diseases. More specifically,
systemic erythematosus (SLE) has been implicated with an increased miscarriage
rate for many years, and pregnancy loss has been associated since 1954 with
antiphospholipid antibodies (APLAs). APLAs are specific antibodies that put
women with SLE at an increased risk for miscarriage. The median rate of
spontaneous miscarriage among patients with SLE is 10%, compared with the
general population. However, the median rate of late pregnancy loss (ie, second
and third trimesters) of 8% is considerably higher than that observed in the healthy
general population. Therefore, excess pregnancy loss in patients with SLE seems
to be isolated 75% of the time to fetal death in the second and third
trimesters. Most, if not all, fetal deaths in these women are associated with
the presence of APLAs.
Three other factors that are
predictive include disease before conception, onset of SLE during pregnancy,
and underlying renal disease. APLAs are antibodies that bind to negatively
charged phospholipids. At least 3 APLAs are well known as having important
clinical relevance, including lupus anticoagulant (LAC), anticardiolipin
antibodies (aCLs) and the biologically false-positive serologic test for
syphilis (FP-STS). Although found in otherwise healthy people, APLAs are
implicated in several other obstetric conditions, including preeclampsia,
intrauterine growth restriction, abnormal fetal heart rate tracings, preterm
deliveries, and pregnancy wastage.
Other medical conditions
associated with APLAs are arterial and venous thrombosis, autoimmune
thrombocytopenia, autoimmune hemolytic anemia, livedo reticularis, chorea,
pulmonary hypertension, and chronic leg ulcers. The diagnosis of APS, also
known as LAC and Hugh syndrome, is made when both clinical events (obstetric or
medical) are present and when specific levels of APLAs are present.
The International Consensus
Workshop in 1998 proposed preliminary classification criteria for APS that includes the following
clinical criteria:
Vascular thrombosis
One or more episodes of
arterial, venous, or small-vessel thrombosis in any tissue or organ that is
confirmed by imaging or Doppler studies or histopathology.
For histopathologic
confirmation, thrombosis should be present without significant evidence of inflammation
on the vessel wall.
Pregnancy morbidity
Three or more unexplained
consecutive miscarriages with anatomic, genetic, or hormonal causes excluded
One or more unexplained
deaths of a morphologically normal fetus at or after the 10th week of gestation
with fetal morphology documented by ultrasound or by direct examination of the
fetus
One or more premature births
of a morphologically normal neonate at or before the 34th week of gestation
associated with severe preeclampsia or severe placental insufficiency
Laboratory criteria
aCL: Immunoglobulin G (IgG)
and/or immunoglobulin M (IgM) isotype is present in medium or high titer on 2
or more occasions, 6 or more weeks apart.
The aCL is measured by a
standardized enzyme-linked immunosorbent assay (ELISA) for beta2-glycoprotein
I-dependent aCL LAC.
The abnormality is present
in plasma on 2 or more occasions, 6 or more weeks apart, and detected according
to the guidelines of the Scientific and Standardization Committee on lupus.
Anticoagulants/phospholipid-dependent
antibodies
Demonstration of a prolonged
phospholipid-dependent coagulation screening test (eg, activated partial
thromboplastin time [aPTT]) kaolin clotting time, dilute Russell viper venom
time, dilute prothrombin time [PT], and Textarin time.
Failure to correct the
prolonged screening test by mixing with normal platelet-poor plasma
Shortening or correction of
the prolonged d-screening test by the addition of excess phospholipid
Exclusion of other
coagulopathies as clinically indicated (eg, factor VIII inhibitor) and heparin
The demonstration of these
antibodies can be made with either ELISA or a coagulation test positive for
LAC. Therefore, the presence of the antibodies alone in the absence of other
clinical symptoms does not define the syndrome. APS is associated with systemic
autoimmune diseases and with various other connective tissue disorders; 7-30%
of women with SLE have APLAs. APLAs are found in less than 2% of apparently
healthy pregnant females, in less than 20% of apparently healthy females with
recurrent fetal loss, and in greater than 33% of women with SLE.
APLAs have not been shown
definitively to be a risk factor for pregnancy loss because most studies to
date implicating pregnancy loss with LACs and aCLs are case series. In contrast
to recurrent pregnancy loss, isolated miscarriages have not been associated
with APLA. Extensive placental infarction has been noted in some studies of
patients with APLAs and recurrent pregnancy loss; however, an underlying
pathophysiologic mechanism is still being sought for fetal loss and thrombosis.
Placentas obtained from patients with APLAs show accelerated atherosis and
vascular occlusion. In animal models, LAC and thrombocytopenia frequently
accompany pregnancy loss.
Anticoagulant treatments,
such as aspirin, heparin, intravenous immunoglobulin interleukin 3 (IL-3), and
ciprofloxacin, have been shown to be effective therapies. Ciprofloxacin is
thought to work through IL-3. IL-3 control animals have very large placentas
and fetuses; therefore, it is hypothesized that IL-3 acts as a placental growth
hormone and can make up for damaged placental tissue.
It is thought that the
thrombosis of APLA is caused by an increase in the thromboxane to prostacyclin
ratio, leading to thrombosis. Thromboxane production by the placenta could lead
to thrombosis at the uteroplacental interface and rationalizes the use of
low-dose aspirin therapy during pregnancies in women with APLA. Other studies
have proposed that the thrombosis is secondary to enhanced platelet aggregation,
decreased activation of protein C, increased expression of tissue factor, and
enhanced platelet-activating factor synthesis.
Clinically, pregnancy loss
in patients with APS frequently occurs after 10 weeks' gestation (as opposed to
the majority of SABs that tend to occur earlier). As mentioned previously, it
is thought that placental insufficiency is the causal agent.
The combination of higher
antibody titers and the IgG isotype has worse prognosis than does low titer and
the IgM isotype. In addition, it does not make any difference whether the APLA
is aCL, LAC, or antieta2-glycoprotein I. Treatment of patients with APS who
have suffered prior fetal losses seems to improve pregnancy rates, but fetal
loss may occur despite treatment. Preeclampsia, fetal distress, fetal growth
impairment, and premature delivery are common.
Treatment data are difficult
to analyze because most studies are not randomized and do not include
appropriate controls. In addition, the serologic criteria for APLA, the
clinical definitions of APS, and the dosing regimens for treatments vary
greatly among studies. Overall, most studies report increases in pregnancy
survival in women undergoing a treatment for APLA.
Treatment consists of
subcutaneous heparin low-dose aspirin, prednisone, immunoglobulins, or
combinations of the aforementioned drugs. Several well-controlled studies have
shown that subcutaneous heparin (5,000 U bid) with low-dose aspirin (81 mg/d)
increases fetal survival rates from 50% to 80% among women who have had at
least 2 losses and who have unequivocally positive tests for APLA. Treatment
started after pregnancy was confirmed and continued until the end of the
pregnancy (just before delivery). This therapy (low-dose aspirin and
subcutaneous heparin) has been shown to be equally effective and less toxic
than prednisone (40 mg/d) plus aspirin.
Cowchock et al showed that
women treated with prednisone plus aspirin had higher rates of hypertension,
weight gain, diabetes, and premature rupture of membranes. Babies had higher
incidences of amnionitis and prematurity. However, in women with secondary APS
and SLE, consider the use of prednisone as a treatment modality. With long-term
use of heparin, the physician must inform the patient about the risk of bone
loss, bleeding, and thrombocytopenia. Loss of bone mineral density (as much as
10%) has been reported in women treated with heparin for an entire pregnancy;
however, this loss of bone mineral density may be regained within 2 years.
In 1992, Branch et al
reviewed 82 consecutive pregnancies in 54 women with APS who were treated
during the pregnancy with the following: (1) prednisone and low-dose aspirin;
(2) heparin and low-dose aspirin; (3) prednisone, heparin, and low-dose
aspirin; and (4) other combinations of these medications or immunoglobulins.
The overall neonatal survival rate was 73%, excluding SABs, but treatment
failures (fetal and neonatal) occurred in all treatment groups. Patients with
successfully treated pregnancies had fewer previous fetal deaths than those
with unsuccessfully treated pregnancies. In addition, no significant
differences occurred in outcome among the 4 treatment groups.
Intravenous immunoglobulin
(IVIG) therapy has been shown to be effective with not only a decrease in fetal
loss but also a decrease in preeclampsia and fetal growth restriction. However,
to date, no properly controlled studies have been conducted. Intravenous
treatment with immunoglobulins is very expensive and should not be used as
first-line therapy until further data on its efficacy are available.
Antinuclear antibodies
(ANAs) have been associated with recurrent pregnancy loss, even in patients
without evidence of overt autoimmune disease. Elevated ANA titers (usually
>1:40) were found in 7-53% of women with recurrent fetal loss compared with
0-8% of pregnant and nonpregnant controls. However, other studies have refuted
the aforementioned study. In addition, the success rate in future pregnancies
in women with increased ANA titers and previous pregnancy losses was similar to
that in women with undetectable ANA. In most published studies, the ANA titers
in women with recurrent miscarriages were only mildly elevated. These mild
elevations are nonspecific and common in the general population (even in women
with no history of pregnancy loss). Therefore, it is difficult to extrapolate
this as a cause. Further studies are needed to prove or disprove ANA as a
causal agent in recurrent miscarriages and is not recommended as part of an
evaluation of recurrent miscarriage.
Unlike ANA, antithyroid
antibodies are independent markers for an increased risk of miscarriage.
Stagnaro-Green et al observed 500 consecutive women for the presence of thyroid
specific autoantibodies (specifically, antithyroglobulin and/or antithyroid
peroxidase) in the first trimester of pregnancy. Women with a positive test for
thyroid autoantibodies had a 17% rate of pregnancy loss compared with 8.4% for
women without evidence of thyroid autoantibodies. None of the women with
thyroid autoantibodies had clinically evident thyroid disease, and the increase
in pregnancy loss was not due to changes in thyroid hormone levels or APLA. The
pathophysiology involved in this phenomenon is unclear and probably represents
a generalized autoimmune defect rather than a thyroid induced abnormality.
However, the available data thus far do not support the use of thyroid
autoantibody testing in women with recurrent pregnancy loss.
ANATOMIC CAUSES
Anatomic uterine defects are
known to cause obstetric complications including recurrent pregnancy loss,
preterm labor and delivery, and malpresentation. A uterine malformation should
be considered in any woman experiencing recurrent pregnancy loss. However, not
all women with abnormal uteri have obstetric complications. Why some women have
difficulties while others do not is not known. The incidence of uterine
anomalies is estimated to be between 1 per 200 and 1 per 600, depending on the
method used for diagnosis. When manual exploration is preformed at the time of
delivery, uterine anomalies are found in approximately 3% of women. However, in
women with a history of pregnancy loss, uterine abnormalities are present in
approximately 27%.
The most common uterine
defects include septate, bicornuate, and didelphic uteri. The unicornuate
uterus is the least common.
When analyzing the different
studies about uterine anomalies and their role in miscarriage, great disparity
exists, caused by the lack of strict criteria in cataloging various types of
uterine malformations. The largest study to date was conducted in 1996 by
Acien. One hundred and seventy of the women had a prior pregnancy, of which
only 32 (18.8%) had normal deliveries at term, compared with 70% in the control
group and 0% in the hypoplastic uterus group. Sixty-two other patients with
uterine malformations (36.5%) had abnormal deliveries (eg, premature, breech).
Again, 59 (35%) had only reproductive losses (1 or more), including early
abortions in 19.4%, late abortions in 4.7%, and immature deliveries in 10.6%.
These loss rates were significantly higher than the control group.
The highest rate of only
reproductive losses was that of bicornuate uterus (47%), whereas the lowest was
that of unicornuate uterus (17%). Women with unicornuate and didelphys had the
highest rate of abnormal deliveries, while women with uterine septums had a 26%
risk of reproductive loss.
Unicornuate uterus results
from arrested or defective development of one of the müllerian ducts. The
uterus often is deviated markedly to either side and is shaped like a banana.
Although the studies on uterine anomalies are scarce, nearly all agree that the
pregnancy outcome in women with unicornuate uteri is poor. Fetal survival rates
for women with the unicornuate uterus average approximately 40%. Approximately
45% of pregnancies are lost within the first 2 trimesters.
In addition to fetal loss,
prematurity occurs in 20% of all pregnancies and is thought to be due to the
reduced capacity that does not allow for proper gestational growth and the
possibility of cervical incompetence. Malpresentation and fetal growth
restriction are other complications faced by women with unicornuate uteri.
Fetal growth restriction is thought to be secondary to vascular anomalies in
the distribution of the uterine artery.
The imaging studies of
choice include hysterosalpingography and high-resolution ultrasonography. A
bananalike cavity with a single fallopian tube is the most common finding.
Approximately 65% of unicornuate uteri contain a rudimentary horn.
Approximately one third contain endometrial tissue, and one half of these
communicate with the main uterine cavity. A rudimentary horn without an
endometrial cavity is present in approximately 34% of cases, and it is thought
that pregnancies with rudimentary horns had a greater chance of delivering at
or near full term. Fedele reported that the incidence of rudimentary horn
pregnancy is approximately 12.5% because of the transmigration of sperm.
Excision of the rudimentary horn is advised because of the high risk of morbidity
secondary to intraperitoneal hemorrhage. However, removal of a solid
rudimentary horn is not necessary because little evidence suggests that there
is an adverse affect on pregnancy outcome in a solid (nonfunctioning) horn.
Prophylactic cervical cerclage
should be considered in patients with a unicornuate uterus. Some authors
support expectant management in these patients with serial assessments of
cervical lengths by digital and ultrasonographic examinations. Uterine
didelphys results from failed fusion of the paired müllerian ducts. A uterus
didelphys consists of 2 endometrial cavities, each with a uterine cervix that
is fused in the area of the lower uterine segment. A longitudinal vaginal
septum running between the 2 cervices is present in most cases.
INFECTIOUS CAUSES
The theory that microbial
infections can cause miscarriage has been present in the literature as early as
1917, when DeForest et al observed recurrent abortions in humans exposed to
farm animals with brucellosis. Although infection has been cited as a cause of
pregnancy loss, few studies exist, and results are inconsistent. Numerous
organisms have been implicated in the sporadic cause of miscarriage, but common
microbial causes generally have not been confirmed. In fact, infection is
viewed as a rare cause of recurrent miscarriage.
Those organisms implicated
with SAB include the following:
- Bacteria
- Listeria monocytogenes
- Chlamydia trachomatis
- Ureaplasma urealyticum
- Mycoplasma hominis
- Bacterial vaginosis
- Viruses
- Cytomegalovirus
- Rubella
- Herpes simplex virus (HSV)
- Human immunodeficiency virus
(HIV)
- Parvovirus
- Parasites
- Toxoplasmosis gondii
- Plasmodium falciparum
- Spirochetes - Treponema
pallidum
Different theories have been
postulated to explain exactly how an infectious agent leads to miscarriage and
include the following:
Toxic metabolic byproducts,
endotoxin, exotoxin or cytokines could have a direct effect on the uterus or
the fetoplacental unit.
Fetal infection could cause
fetal death or severe malformation incompatible with fetal viability.
Placental infection could
result in placental insufficiency, with subsequent fetal death.
Chronic infection of the
endometrium from ascending spread of organisms (eg, Mycoplasma hominis,
Chlamydia, Ureaplasma urealyticum, HSV) from the lower genital tract could
interfere with implantation.
Amnionitis in the first
trimester could play a role similar to chorioamnionitis in the third trimester,
resulting in preterm labor (various common gram-positive and gram-negative
bacteria, Listeria monocytogenes).
Induction of a genetically
and anatomically altered embryo or fetus by viral infection (eg, rubella,
parvovirus B19, cytomegalovirus, coxsackievirus B, varicella-zoster, chronic
cytomegalovirus [CMV], HSV, syphilis, Lyme disease) during early gestation.
Any patient undergoing
infertility workup should be treated for any recognized vaginitis or
cervicitis. In addition, chronic genital infection may be the most obvious initial
manifestation of a general health problem. Chronic vulvovaginitis is known to
be associated with both diabetes, other endocrinopathies, and, possibly, lupus
erythematosus. In addition, elimination of both gonorrhea and chlamydia should
take place before infertility workup (eg, hysterosalpingograms) for fear of
spreading the infection to the upper genital tract. A recent review failed to
find sufficient evidence for the notion that any type of infection could be
identified as a causal factor for recurrent miscarriage. Most patients with a
history of recurrent miscarriage will not benefit from an extensive infection
workup. Exposure to a microbe that can establish chronic infection that can
spread to the placenta in a patient who is immunocompromised is probably the
most obvious risk situation in recurrent abortions.
Specific pathogens are as
follows:
Gonorrhea:
This is
associated with premature rupture of membranes and chorioamnionitis.
Chlamydia trachomatis: No
association exists between a prior chlamydial infection and fetal loss in women
with recurrent abortion. However, neonatal conjunctivitis and pneumonia are
known sequelae.
Women who are in high-risk
groups are the only patients who should be screened. Serologic studies have
suggested an association between C trachomatis and recurrent abortion, and
routine C trachomatis screening has been recommended for all infertility
patients. However, microbiologic testing for endocervical chlamydial infection
during pregnancy has failed to confirm the association with recurrent abortion.
In 1992, Witkin and Ledger reviewed the relationship between high-titer IgG
antibodies to C trachomatis and recurrent SAB. They found that high-titer IgG
antibodies to C trachomatis were associated with recurrent SABs. They proposed
the mechanism to be reactivation of a latent chlamydial infection, endometrial
damage from past chlamydial infection, or an immune response to an epitope
shared by a chlamydial and a fetal antigen.
Bacterial vaginosis:
This is
associated with preterm labor, intrauterine growth retardation
chorioamnionitis, and late miscarriage; however, no studies have investigated
its role in women with recurrent miscarriages. Most women are screened at their
first prenatal visit and more frequently if there is a history of late
miscarriages or preterm delivery.
Genital mycoplasma:
Mycoplasma hominis and Ureaplasma are isolated from the vagina in as many as
70% of pregnant women. Although these organisms are found more frequently in
women with recurrent miscarriages, their elimination has not improved
subsequent pregnancy outcome. Therefore, it is not recommended to screen for
mycoplasma and ureaplasma in the typical patient with a history of recurrent
miscarriage.
L monocytogenes:
Typically,
this produces asymptomatic colonization of the maternal lower genital tract,
although symptomatic maternal listeriosis characterized by bacteremia and
influenzalike symptoms may occur. Symptomatic listerial infection typically is
described as a complication of the third trimester, resulting from ingestion of
unpasteurized milk or cheese. Asymptomatic genital Listeria colonization may
result in high perinatal mortality and morbidity if the organism is spread to
the fetus during labor and delivery. However, no evidence suggests that
Listeria plays a role in patients with a history of recurrent pregnancy loss.
Chronic genital infection with L monocytogenes, which could lead to recurrent
abortion, would occur in patients who were immunocompromised, and, because of
its low prevalence, screening for listeria during pregnancy or in routine cases
of recurrent miscarriage is not recommended.
Treponema pallidum:
This is
known to cause stillbirth and abortion in the second trimester. The timing of
death is probably associated with the maturation of the fetal immune system at
the 20th week of gestation. However, it is unlikely that syphilis contributes
significantly to the general problem of recurrent miscarriage.
Borrelia burgdorferi:
Lyme
disease can result in stillbirth and fetal infection. Obtain serology if the
patient relates a history suspicious for infection with Lyme disease; however,
it is unlikely that Lyme disease contributes significantly to the general
problem of recurrent abortion.
CMV:
This is associated with
random miscarriage but not recurrent miscarriage. A large study conducted by
Stagno et al observed 3712 pregnant patients and documented only 21 per 3712
cases of primary maternal CMV during pregnancy. Only 11 of the 21 showed
neonatal infection, and SABs did not occur in this group.
HSV:
Primary HSV has been
associated with SAB, and chronic HSV is a possible cause of recurrent abortion
(especially in a patient who is immunocompromised). The risk for in utero HSV
transmission from chronic maternal disease is low (about 0-3% of pregnancies).
Therefore, recurrent abortion secondary to chronic HSV is extremely low in the
general population and does not warrant routine screening in patients with
recurrent pregnancy loss.
P falciparum:
Malaria during
pregnancy is associated with SAB, stillbirth, low birth weight, and
prematurity. Screening is only important in those women where the disease is
endemic or in symptomatic patients who have traveled to endemic countries.
Toxoplasmosis:
Primary
infection with toxoplasmosis can lead to miscarriage and stillbirth. However,
if the infection develops during the first trimester, the risk is less than 5%.
In addition, repeated infections in subsequent pregnancies are unlikely, unless
chronic infection develops in patients who are immunocompromised.
HIV:
Studies have failed to
show an increase in miscarriage rates for asymptomatic patients with HIV.
ENVIRONMENTAL, HORMONAL, AND
THROMBOPHILIC CAUSES
Environmental causes: Such
causes of human malformation account for approximately 10% of malformations,
and less than 1% of all human malformations are related to prescription drug
exposure, chemicals, or radiation. It is important to recognize these
preventable exposures. For example, the relationship between exposure to trace
concentrations of waste anesthetic gases in the operating room and the possible
development of adverse health effects has been a concern for many years.
However, the studies that showed an increase incidence of miscarriage and
congenital anomalies had many flaws.
Maternal exposure to tobacco
and its effect on reproductive outcomes has been the subject of many studies.
Cigarette smoke contains hundreds of toxic compounds. Nicotine is thought to
have vasoactive actions, and thought to reduce placental and fetal circulation.
Carbon monoxide depletes both fetal and maternal oxygen supplies, and lead is a
known neurotoxin. Maternal smoking appears to only slightly increase the risk
of SABs.
Endocrine factors:
Ovulation,
implantation, and the early stages of pregnancy are dependent on an integral
maternal endocrine regulatory system. Historically, most attention has been
directed on maternal systemic endocrine disorders, luteal phase abnormalities,
and hormonal events that follow conception, particularly progesterone levels in
early pregnancy.
Diabetes mellitus:
Women
with diabetes mellitus who have good metabolic control are no more likely to
miscarry than are women without diabetes. However, women with diabetes with high
glycosylated A1c levels in the first trimester are at a significantly higher
risk of both miscarriage and fetal malformation. Insulin-dependent women with
inadequate glucose control have a 2- to 3-fold higher rate of SAB than the
general population of women. There is no value to screening for occult diabetes
in asymptomatic women unless a random glucose is elevated. For a patient with
an unexplained loss in the second trimester or with clinical signs of diabetes
mellitus, investigation is needed.
Thyroid dysfunction:
No
direct evidence suggests that thyroid disease is associated with recurrent
miscarriages. However, the presence of antithyroid antibodies is and may
represent a generalized autoimmune abnormality rather than a specific thyroid
dysfunction. Screening for thyroid disease is not useful unless the patient is
symptomatic.
Low progesterone levels:
Progesterone is the principal factor responsible for the conversion of a
proliferative to a secretory endometrium, rendering the endometrium receptive
for embryo implantation. In 1929, Allen and Corner published their classic
results on physiologic properties of the corpus luteum, and, since then, it has
been assumed that low progesterone levels are associated with miscarriage.
Luteal support remains critical until about the seventh week of gestation at
which time the trophoblast has acquired enough steroidogenic ability to support
the pregnancy. In patients where the corpus luteum is removed before the
seventh week, miscarriage results. If progesterone is given to these patients,
the pregnancy is salvaged. Recent developments with RU486 (an antiprogestin)
have shown that these can effectively terminate a pregnancy up to 56 days from
the last menstrual period.
Luteal phase defects (LPD):
In 1943, Jones first discussed the concept of insufficient luteal progesterone
resulting in either infertility or early pregnancy loss. This disorder was
characterized by inadequate endometrial maturation resulting from a qualitative
or quantitative disorder in corpus luteal function, which has been reported in
23-60% of women with recurrent miscarriage. Unfortunately, no reliable method
is available to diagnose this disorder, and controversy exists due to the
inconsistencies in the method of diagnosis.
Methods used to diagnose
luteal phase defects include basal body temperature records, progesterone
concentrations, and histologic dating of endometrial biopsy specimens. The
criterion standard has been an endometrial biopsy taken in the luteal phase.
However, significant interobservational and intraobservational discrepancies
exist using the standard histologic criteria. This criteria uses development of
stromal and glandular cells to determine how many days after ovulation the
patient was at the time of the biopsy. A delay of more than 2 days in
maturation compared to where the patient exactly was based on her luteinizing
hormone (LH) surge is defined as LPD.
Most studies use the patient
subsequent menses as a reference point, assuming the patient has a normal
28-day cycle. This accounts for many of the discrepancies in the literature.
Consequently, as many as 31% of normally fertile women have a luteal phase
defect by serial endometrial biopsies. In one of the few prospective studies
evaluating women with 3 or more consecutive miscarriages, LPD was believed to
be the cause in 17% of them. The biopsy samples were dated accurately by the
pathologist using LH assays to pinpoint the time of ovulation. In this study,
luteal phase serum progesterone levels were normal in the women with LPD.
Luteal phase deficiency is most likely the result of an abnormal response of
the endometrium to progesterone than a subnormal production of progesterone by
the corpus luteum. This is evident in the fact that as many as 50% of women
with histologic defined LPD have normal serum progesterone levels.
In treating LPD, it is
important to realize that postimplantation failure or a very early nonviable
pregnancy is associated with low serum progesterone levels. Only 1 randomized
trial has shown treatment with progesterone supplementation to have a
beneficial effect on pregnancy outcome. Most studies have opposite results,
failing to show that any type of support (eg, progesterone, HCG) to have
beneficial results.
Therefore, the physician must be selective in deciding who
should be screened for LPD. One approach is to screen patients with either a
history of recurrent miscarriages or recurrent failures at infertility therapy.
In addition, it would be most accurate if the histology is reviewed by the same
pathologist, and the day of ovulation should be based on LH levels as opposed
to subsequent menses. The dose of progesterone should be adequate enough to
stimulate luteinization of the endometrium with the fewest adverse effects.
Endocrine modulation of decidual
immunity:
The transformation of endometrium to decidua affects all of the cell
types present in the uterine mucosa. These morphologic and functional changes
facilitate implantation but also help in controlling trophoblast migration and
in preventing over invasion in maternal tissue. Attention focuses on the
interaction between extravillous trophoblast and the leukocyte populations
infiltrating the uterine mucosa.
Most of these cells are large granular
lymphocytes (LGL) and macrophages; very few T and B cells are present. The LGL
population is unusual, staining strongly for natural killer (NK) cell marker
CD56, but the cells do not express the CD16 and CD3 NK markers. NK cells with
this distinct phenotype are found in high numbers, primarily in the progesterone檏rimed endometrium of the
uterus. The CD56 cells are low in the proliferative phase endometrium, increase
midluteal, and peak in the late secretory phase, suggesting that recruitment of
LGLs is under hormonal control.
Progesterone is essential since
LGLs are not found before menarche or after menopause or in conditions
associated with unopposed estrogen, such as endometrial hyperplasia or
carcinoma. In women who have been oophorectomized, LGLs appear only after
treatment with both estrogen and progesterone. The increase in NK cells at the
implantation site in the first trimester suggest its role in pregnancy
maintenance.
They preferentially kill target cells with little or no HLA
expression. Extravillous trophoblast (which expresses modified forms of 1 HLA)
is resistant to lysis by decidual NK cells under most circumstances, allowing
invasion needed for normal placentation. These CD56 cells probably
differentiate in utero from precursor cells, since serum levels are negligible.
The only cytokine that has
been able to induce proliferation of these cells is interleukin 2 (IL-2). IL-2
also transforms NK cells into lymphokine-activated killer (LAK) cells, which
are capable of lysing first trimester trophoblast cells in vitro. As expected,
IL-2 has not been found in vivo at uterine implantation sites; otherwise,
stimulation of decidual NK cells would cause widespread destruction of
trophoblast. Trophoblast HLA expression is increased by interferon, a
phenomenon that may offer protection from LAK cell lysis. Therefore, an
equilibrium exists between the level of HLA expression on trophoblast and the
amount of lymphokine activation of NK cells, leading to the concept of fine
regulation of trophoblast invasion.
Thrombophilic defects:
Many cases
of recurrent miscarriages are characterized by defective placentation and the
presence of microthrombi in the placental vasculature. Various components of
the coagulation and fibrinolytic pathways are important in embryonic
implantation, trophoblast invasion, and placentin. Because the association
between APLA and recurrent miscarriage are now firmly established, interest has
been fueled regarding the possible role of other hemostatic defects in
pregnancy loss.
Pregnancy is a
hypercoagulable state because of the following: (1) an increase in the levels
of procoagulant factors, (2) a decrease in the levels of naturally occurring
anticoagulants, and (3) a decrease in fibrinolysis. The levels of factors VII,
VIII, X, and fibrinogen increase during a normal pregnancy, as early as 12
weeks' gestation.
This increase in factors is
not balanced by an increase in anticoagulants, antithrombin III and proteins C
and S. In fact, protein S decreases by 40-50%. Antithrombin III and protein C
remain constant. Fibrinolytic activity also is altered, with levels of
plasminogen activator inhibitors 1 and 2 increasing progressively during
pregnancy. PAI-1 is produced by endothelial cells and inhibits release of
plasminogen activator. PAI-2 is produced by the trophoblast and helps regulate
placental growth. An increase occurs in platelet activation, which contributes
to the prothrombic state of pregnancy reflected by an increase in platelet
production of thromboxane and decreased platelet sensitivity to the
antiaggregatory effects of prostacyclin. The hemostatic changes in pregnancy
favor coagulation.
Urokinase plasminogen (uPA)
activator is active around the time of implantation. It triggers the localized
production of plasmin, which catalyzes the destruction of the extracellular
matrix, facilitating implantation. uPA also is found in the maternal venous
sinuses and, therefore, plays a role in maintaining the patency of these
channels. uPA receptors also are expressed on first trimester human trophoblast
cells, primarily those that are not actively invasive, which serves to
facilitate generation of plasmin at the interface of these cells with maternal
plasma, thereby limiting deposition of fibrin within the intervillous spaces.
PAI-1 and PAI-2 have been
localized to invasive trophoblast. Therefore, trophoblast implantation and
invasion seemingly are regulated to some extent by the balance between
plasminogen activators and inactivators. Indeed, defective trophoblast invasion
of the spiral arteries has been a common finding in placental bed biopsies
obtained from women who miscarry and from those patients with preeclampsia or
intrauterine growth restriction.
In the normal placenta,
important components of the hemostatic, fibrinolytic, and protein C
anticoagulant (factor V Leiden) pathways are present and responsible for
maintenance of hemostasis. Abnormal gestations are associated with an abnormal
distribution of fibrin, and the production of certain factors (eg, cytokines)
may convert a thrombo-resistant endothelium to one that is more thrombogenic.
In support of this theory, fibrin deposition has been seen in chorionic villi
that make allogenic contact with maternal tissue, which contains many factors
and products of the hemostatic pathway. Endothelial cells in these areas appear
to be deficient in the thrombin-thrombomodulin anticoagulant pathway and,
therefore, are prone to clot formation. Normal villi have this pathway.
Compelling evidence suggests
that women with a history of recurrent miscarriage are in a procoagulant state
even when not pregnant. A large study of 116 nonpregnant women with recurrent
miscarriages, who tested negative for LAC and aCLs, reported that 64% of these
women had at least 1 abnormal fibrinolysis-related test, most commonly a high
PAI-1. No abnormal defects were found in the control group, which consisted of
90 fertile women with no history of miscarriage. In 1994, in another study by
Patrassi and colleagues, 67% of patients, regardless of whether they were aCL
positive, had a defect in their fibrinolytic pathway.
Evidence also suggests that
just before a miscarriage, defects in hemostatic variables are present.
Tulpalla and coworkers revealed that in women with a history of recurrent
miscarriages, an abundance of thromboxane production at 4-6 weeks' gestation
and a decrease in prostacyclin production at 8-11 weeks exists, compared with
women without such history. This shift in the thromboxane-to-prostacyclin ratio
can lead to vasospasms and platelet aggregation, causing microthrombi and
placental necrosis. A decrease seemingly occurs in the level of protein C and
fibrinopeptide A just prior to miscarriage, suggesting an activation of the
coagulation cascade.
Activated protein C (APC)
resistance: Resistance to the anticoagulant effects of APC is inherited as an
autosomal dominant trait and is the most important cause of thrombosis and
familial thrombophilia. In more than 90% of cases, it is due to single-point
mutation (glutamine for arginine) at nucleotide position 1691 in the factor V
gene. This mutated gene is known as factor V Leiden. APC cleaves and
inactivates coagulation factors Va and VIIIa in the presence of cofactor
protein S. The mutated factor V is resistant to inactivation by APC, resulting
in increased thrombin production and a hypercoagulable state. Its prevalence is
3-5%. In those with a prior venous thrombosis, the prevalence is as high as
40%.
In 1995, Rai and colleagues
evaluated 120 women with a history of recurrent miscarriages. All women were
negative for thrombosis history, LAC, and aCL. The prevalence of APC resistance
was higher in those women who had had a second trimester miscarriage (20%)
versus those with a first trimester loss (5.7%).
In normal pregnancies, a
natural decrease in APC resistance occurs; however, it is those women with APC
resistance prior to pregnancy who tend to have an even further drop in
resistance. The best way to detect APC resistance is both a coagulation based
assay and the DNA test to detect the actual mutation. They complement each
other since one is a genetic test and one is a functional test.
Coagulation inhibitors:
Little data exist evaluating deficiencies of antithrombin III, protein S, or
protein C, and pregnancy loss.
Specific coagulation factor
deficiencies: The deficiency is factor XII (Hageman) and is associated with
both systemic and placental thrombosis and has been reported to be associated
with recurrent miscarriage in up to 22% of patients evaluated. Again, data are
limited.
Abnormal homocysteine
metabolism: Homocysteine is an amino acid formed during the conversion of
methionine to cysteine. Hyperhomocystinemia, which may be congenital or
acquired, is associated with thrombosis and premature vascular disease. This
condition also is associated with pregnancy loss; in one study, 21% of women were
observed with recurrent pregnancy loss. The gene for the inherited form is
transmitted in an autosomal recessive form. The most common acquired form is
folate deficiency. In these patients, folic acid replacement achieves normal
homocysteine levels within a few days.
Therapy for coagulation
disorders: Low-dose aspirin (60-150 mg/d) irreversibly inhibits the enzyme
cyclooxygenase in platelets and macrophages. This leads to a shift in
arachidonic acid metabolism toward the lipoxygenase pathway, resulting in inhibition
of thromboxane synthesis without affecting prostacyclin production. It also
stimulates leukotrienes, which, in turn, stimulates production of IL-3 that is
essential for implantation and placental growth. Heparin inhibits blood
coagulation by 2 mechanisms. At conventional doses, it increases the inhibitory
action of antithrombin III on activated coagulation factors XII, XI, IX, X, and
thrombin. At high doses, it catalyzes the inactivation of thrombin by heparin
cofactor 2. Heparin does not cross the placenta; therefore, no risk to the
fetus is present.
The primary adverse effects
are osteopenia if therapy is prolonged (usually therapeutic doses) and
thrombocytopenia, which usually occurs within a few weeks of starting heparin
(even low prophylactic doses). Osteopenia is reversed upon discontinuation of
heparin, and platelet levels should be checked routinely.
