First Trimester Miscarriage Evaluation

Ruth B. Lathi, M.D.,1 Florette K. Gray Hazard, M.D.,2

Amy Heerema-McKenney, M.D.,2 Joanne Taylor, M.S., C.G.C.,4
and Jane Tsung Chueh, M.D.3

ABSTRACT

Miscarriage is a relatively common occurrence for otherwise healthy women.

Despite its frequency, evaluation for cause is rare. The most common cause of miscarriage is
sporadic chromosome errors. Chromosomal analysis of the miscarriage offers an explan-
ation in at least 50% of cases. Conventional cytogenetic evaluation can only be done on

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fresh tissue, so it is critical that the treating physician consider genetic testing at the time of
the miscarriage. Ultrasound can estimate the gestational age at the time of miscarriage and
identify major abnormalities in some embryos. A careful pathological examination can add
to the evaluation by ruling out rare disorders with the highest recurrence risk. A multi-
disciplinary approach to miscarriage evaluation is essential to understanding the cause and
risk of recurrence. A thorough evaluation of a miscarriage, in combination with emotional
support, can often provide the necessary reassurance and confidence as the patient prepares
for her next pregnancy.

KEYWORDS: Miscarriage, ultrasound, aneuploidy, pathology, pregnancy loss

M iscarriage is defined as the loss of a pregnancy
before viability. Although it can occur at any gestational
age, most miscarriages occur in the first trimester. Even
within the first trimester, miscarriage is less frequent
with increasing gestational age. Patients experiencing a
miscarriage can benefit from understanding the cause,
and it often helps with the grieving process and planning
for future pregnancies. Therefore, when a miscarriage
occurs, evaluation for cause and risk factors is warranted.
Although most pregnancy losses in the first trimester are
due to sporadic chromosomal errors derived from the
fertilized oocyte, documenting gestational age, anoma-
lies, histological abnormalities, and genetic factors assists
in providing prognostic information for future pregnan-
cies. This review describes the essential components for
the evaluation of first trimester miscarriage.
Women are diagnosed with a miscarriage in one
of two ways, either based on human chorionic gonado-
tropin (hCG) testing or by ultrasound. A diagnosis of a
biochemical pregnancy loss consists of a positive serum
or urinary pregnancy test, usually combined with a
delayed period. At some point before her first physician
visit, she has bleeding and passage of tissue and the
pregnancy test becomes negative. In this case, it is
difficult to document the cause of miscarriage, but the
clinical history and/or hCG results can provide some
information about gestational age.
Fortunately, most women have access to
early pregnancy care and often seek medical attention
before passing miscarriage tissue. Whenever possible,
failing pregnancies should be evaluated with ultrasound,
quantitative hCG measurements, histopathology, and

1
Departments of Obstetrics and Gynecology, Recurrent Pregnancy
Loss Program; 2Pathology; 3Department of Obstetrics & Gynecology,
Maternal & Fetal Medicine, Stanford University; 4Department of
Perinatal Genetic Counseling, Lucile Packard Children’s Hospital at
Stanford, Stanford, California.
Address for correspondence and reprint requests: Ruth B. Lathi,
M.D., Department of Obstetrics and Gynecology, Recurrent Preg-
nancy Loss Program, Stanford University, 300 Pasteur Drive HH333,
Stanford, CA 94305 (e-mail: rlathi@stanford.edu).
Recurrent Early Pregnancy Loss; Guest Editor, Mary D. Stephenson,
M.D., M.Sc.
Semin Reprod Med 2011;29:463–469. Copyright # 2011 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1293200.
ISSN 1526-8004.
463
464 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6
cytogenetics. A thorough evaluation often provides an
explanation for the miscarriage and individualized prog-
nostic information.
ULTRASOUND EVALUATION
With the increased availability of ultrasound, patients
are receiving earlier sonographic diagnoses, and it is
more precise to describe unsuccessful or failed pregnan-
cies based on their sonographic appearance with ‘‘em-
bryonic demise’’ referring to cases where the ultrasound
clearly shows an ‘‘embryonic fetal pole’’ without cardiac
activity. Anembryonic miscarriage is defined by sonogra-
phy as an empty gestational sac at a gestational age where
one would expect to see a yolk sac or embryo with cardiac
activity.
When evaluating an early pregnancy by ultra-
sound, one must be familiar with the timing and
sequence of normal embryonic development. An embry-
onic pole with cardiac activity equates to a gestational
age of at least 6 weeks. If an embryonic pole is not seen,
the potential gestational sac should be examined for the
double decidual sac sign (double echogenic ring) within
the endometrial cavity, which can help differentiate a
true gestational sac from a pseudosac. This can be seen as
early as 4 weeks of gestation.1–3 If the sac lacks this sign
and appears as an endometrial fluid collection, one must
suspect a pseudogestational sac. In this case, the differ-
ential includes the nonpregnant state, a very early intra-
uterine pregnancy (IUP), or ectopic pregnancy, and the
ultrasound findings should be correlated with serial
quantitative hCG measurements. Theoretically, a
true gestational sac can be distinguished from a pseudo-
gestational sac by its appearance and location, and
should be confirmed with a mean sac diameter (MSD)
 10 mm.4,5 However, before clear visualization of this
sign, differentiation of a true versus pseudogestational
sac can be difficult. In the absence of symptoms suggest-
ing ectopic pregnancy, a follow-up ultrasound should be
considered to avoid terminating a potentially viable
pregnancy. Additionally, hCG levels can be helpful
in distinguishing between an early IUP and an ectopic
pregnancy, and hCG values between 1500 and 2000
mIU/mL are typically associated with a visible intra-
uterine gestational sac on transvaginal scan.6–8
As the pregnancy matures, a yolk sac becomes
visible on transvaginal scan by 8 mm MSD or by 20 mm
MSD on transabdominal scan.9 Cardiac activity is often
the earliest sign of the developing embryo and can
typically be seen transvaginally when MSD 16 mm
or transabdominally when MSD 25 mm.10 Sono-
graphic diagnosis of embryonic demise can be made
when there is no cardiac activity in an embryo 5 mm
by transvaginal ultrasound or 9 mm by abdominal
ultrasound.11 Given the possibility of measurement
error, it is prudent to allow an additional 1 to 2 mm in
2011
gestational sac measurement before considering inter-
vention or repeat the ultrasound in 1 week if the
embryonic size is near this cutoff.11
Signs that may be associated with a higher rate of
embryonic demise include slow heart rate, small gesta-
tional sac size or abnormal shape, presence of subchor-
ionic hematoma, presence of embryonic anomalies, and
abnormalities in intervillous blood flow. Benson and
Doubilet found that 60% fetuses with heart rates <90
at <7 weeks of gestation died before the end of the first
trimester.12–16 Bromley et al found that 94% of embryos
with a small gestational sac (defined as the difference
between the mean sac diameter and crown rump
length [CRL] <5) resulted in miscarriage, despite the
presence of normal fetal cardiac rate.17 Ultrasound-
documented subchorionic hematomas also correlate
with miscarriage, with rates varying between 7.7% and
18.8%, depending on the size of the hematoma.18
Women who present with bleeding and a subchorionic
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hematoma at 8 weeks of gestation are at higher risk of
miscarriage than those with bleeding after 8 weeks of
gestation (13.7% versus 5.9%).19 Odeh et al compared
gestational sac volumes between normal pregnancies,
missed embryonic miscarriages, and anembryonic mis-
carriages. They found that gestational sac volume was
significantly smaller in both embryonic and anembryonic
miscarriages compared with normal pregnancies.20
Whether three-dimensional (3D) volumes offer advan-
tages over conventional ultrasound parameters in the
prediction of miscarriage remains to be tested by a large
prospective trial.
PATHOLOGICAL EVALUATION OF
THE MISCARRIAGE AND PLACENTA
The pathological evaluation of the first trimester
miscarriage includes assessment of the morphological
features of the gestational sac, embryo or fetus, and
placenta. An empty gestational sac does not allow
for embryo/fetal assessment; however, when embryo or
fetal examination is possible, developmental anomalies,
growth restriction or embryonic disorganization, and
isolated morphological defects may be detected. Pre-
evacuation imaging techniques such as embryoscopy or
high-resolution sonography can successfully augment
this evaluation. Whereas the initial pathologic assess-
ment should be used to confirm the presence or absence
of pregnancy tissue and identification of a molar preg-
nancy, perinatal pathologists have strived to add more
than a diagnosis of ‘‘products of conception.’’21–23 His-
topathology of the placental tissue commonly adds little
to determining an etiology of first trimester loss, with a
few rare but important exceptions. Diagnoses associated
with an increased recurrence risk include chronic inter-
villositis, villitis, massive perivillous fibrin deposition/
maternal floor infarction, and plasma cell deciduitis.

Chronic Intervillositis
Chronic intervillositis is a very rare disorder, present in
<1% of first trimester miscarriage specimens and even
more rarely in the second and third trimester.24 Patients
with this disorder tend to have recurrent miscarriage
or pregnancies complicated by severe growth restriction
or fetal demise. The etiology of this disorder is un-
known.25,26 The pathological hallmark is the presence of
dense sheeting aggregates of histiocytes in the maternal
blood space between villi, with or without the presence
of perivillous fibrin deposition. The absence of villous
inflammation and large number of histiocytes in chronic
intervillositis distinguishes this lesion from chronic
lymphohistiocytic villitis with perivillous extension
and fibrin deposition. The intensity of the intervillous
histiocytic burden increases with gestational age. In a
recent series of 69 pregnancies complicated by chronic
intervillositis, 21 had liveborn infants, 13 of whom
weighed less than the 3rd percentile for age. These 69
pregnancies occurred in 50 patients, 9 of whom had at
least one recurrence of chronic intervillositis.25
Massive Perivillous Fibrin Deposition/Maternal
Floor Infarction
Massive perivillous fibrin deposition/maternal floor in-
farction has some overlap with changes from prolonged
retention of the conceptus after embryo-fetal demise.
The diagnosis of massive perivillous fibrin deposition/
maternal floor infarction is made in the mature placenta
when the parenchyma is firm and marbled appearing on
gross examination because of markedly increased fibrin
or there is a thick rind of fibrin on the maternal surface.
This disorder has significant recurrent potential in sub-
sequent pregnancies with complications of fetal growth
retardation and demise.27 In some cases it may be due to
a maternal thrombophilia leading to increased fibrin
deposition at the villous maternal–fetal interface. In
addition, compromised villous trophoblast integrity ex-
poses tissue factor and activates the clotting cascade
locally on the villous surface. Various disorders could
damage syncytiotrophoblast including extrinsic factors
like antiphospholipid antibodies or intrinsic factors
such as fetal long chain fatty acid deficiency.28 Cases of
massive perivillous fibrin deposition can be identified in
midgestation, but the specificity of this finding in first
trimester miscarriages is not entirely clear. Placental
pathologists look for an extravillous trophoblast prolifer-
ation embedded within the fibrin in true cases of massive
perivillous fibrin deposition/maternal floor infarction,
to help distinguish the entity.29 However, the presence
of diffuse increased perivillous fibrin with a similar
histologic appearance might also reflect prolonged bleed-
ing or the presence of a severely macerated fetus.30,31
Also difficult to interpret is the significance of
hemorrhage and ischemic necrosis at the implantation
FIRST TRIMESTER MISCARRIAGE EVALUATION/LATHI ET AL 465
margins and the decidua basalis. Although one might
like to speculate about a possible disorder of coagulation,
the mechanism of miscarriage always involves separation
of the conceptus from the decidua and hemorrhage.
The various clinical associations with this finding sug-
gest that the morphology is a final common pathway
of syncytiotrophoblast injury or degeneration, with sub-
sequent activation of the coagulation pathway at the
villous surface, or possibly a balance that favors excessive
coagulation at the villous surface due to an inherited
thrombophilia.
Chronic Villitis
Chronic villitis is a histologic pattern of chronic inflam-
mation of the villous parenchyma most commonly seen
in the third trimester, less commonly seen in the second
or first trimester placenta. Approximately 10% of cases
are associated with a known infectious etiology, most
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commonly cytomegalovirus, Treponema pallidum, and
Toxoplasma gondii in the United States. Rubella-associ-
ated chronic villitis is rarely seen due to vaccination. In
the vast majority of cases, no infectious etiology can be
identified and the inflammation is termed villitis of
unknown etiology (VUE). Most authors now consider
these cases an aberrant maternal cell-mediated immune
response to fetal villous antigens. Chronic villitis is rarely
manifested in the first trimester spontaneous abortion
with very rare exceptions.32 In some women, VUE
appears to have no clinical significance. In others, the
disorder gets progressively worse in subsequent pregnan-
cies and is associated with recurrent pregnancy loss.33,34
Earlier studies describing VUE and recurrent pregnancy
loss did not distinguish between chronic intervillositis
and chronic villitis. Patterns with chronic intervillositis
were associated with recurrent loss, as expected. Also,
chronic villitis with increased perivillous fibrin deposi-
tion was more frequently associated with recurrent loss.
The increased perivillous fibrin deposition suggests more
chronicity to the lesions, but whether or not this is a
distinct pathogenetic category of chronic villitis is un-
clear. In the Redline study,33 a significant number of the
women had associated abnormalities of uterine anatomy
or placentation, suggesting an important role of the
decidua in mediating proper immunostasis.
Plasma Cell Deciduitis
Lymphocytes and natural killer cells are normal constit-
uents of the gestational endometrium, but plasma cells
are not. Detection of plasma cells in the endometrium on
endometrial biopsy is a diagnostic marker of chronic
endometritis. Chronic endometritis has been associated
with recurrent pregnancy loss. It is assumed that chronic
endometritis in the nonpregnant endometrium and
chronic deciduitis of the decidua basalis or parietalis
466 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6
are a continuum of the same process.35 However, a
definite association has not been proven. The presence
of plasma cells in the decidua of an early pregnancy loss
remains an abnormal finding, not known to be associated
with prolonged retention. Plasma cell deciduitis should
be documented and further clinical correlation done.
Their presence may indicate the presence of chronic
endometritis with or without bacterial vaginosis,
which are potentially treatable risk factors for recurrent
miscarriage.
Acute Inflammation and Other
Histopathological Changes of Unclear
Significance
The significance of acute inflammation is unclear in this
setting. Infection could be a mechanism of loss when
acute inflammation is present.23 However, one rarely
sees acute inflammation of the villous parenchyma or
chorion. The acute infiltrates are often adjacent to
necrotic foci in the decidua, and they may be part of
the miscarriage process. One early study demonstrated
an association of acute inflammation of the decidua and
placenta in first trimester miscarriages with the presence
of genital Mycoplasma organisms. Although all cases
with a positive culture had inflammation present, not
all cases with inflammation present had a positive
culture.36 The presence of acute inflammation is worth
noting in the pathology report, with clinical consider-
ation given to a possible infectious process. It is unclear
what percentage of recurrent pregnancy loss is associated
with infections, but some reports suggest the number is
significant.37,38 However, the mechanism may be more
complex than an active infection damaging the preg-
nancy or decidua.
Embryo Evaluation
The evaluation of an intact embryo by the pathologist
following uterine evacuation is rare. Most embryos are
submitted to the pathologist fragmented following en-
dometrial curettage. This fragmentation may preclude
definitive assessment of the CRL and other subtle
external features. The use of pre-evacuation embryo-
scopy enables visualization of the intact miscarried
embryo in situ before manipulation. With this techni-
que, an endoscope is inserted through either the uterine
cervix or the abdomen and the chorion is incised; the
embryo is then viewed directly through the amnion.39
Phillip and colleagues reported a series of embryoscopic
observations of abnormal miscarried embryos under a
variety of clinical circumstances. They report growth
disorganization in 48 of 154 (31%) missed miscarriages
from unassisted pregnancies40 and 11 of 22 (50%)
visualized missed miscarriages from in vitro fertiliza-
tion.41 Embryoscopy can also be used to detect isolated
2011
developmental anomalies such as neural tube defects,
microcephaly, and craniorachischisis.42 It has also been
successfully used to characterize the embryonic features
of various chromosomal abnormalities such as 45,X,43
triploidies,44 and a variety of syndromes.39 The use of
embryoscopy allows for a more complete examination of
the intact embryo, particularly its external features. It
also underscores the fact that miscarriage can result from
a variety of causes including, but not limited to, growth
disorganization, isolated developmental defects, and
chromosomal anomalies.
Like the embryo, when a fetus is evaluated fol-
lowing miscarriage, the CRL and the crown-heel length
can provide a useful guide to the overall growth (i.e.,
whether it is normal or restricted). The external fetal
examination should focus on developmental anomalies
and dysmorphisms that provide insight into the cause of
the miscarriage. Although these anomalies may occur in
isolation, they may also arise as part of a constellation of
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anomalies and possible genetic syndromes. Cytogenetic
testing is complementary to the autopsy because there
may be fetuses affected by chromosomal abnormalities
even when external examination does not reveal typical
stigmata.45
GENETIC EVALUATION OF
THE MISCARRIAGE
Ultrasound and pathologic evaluation are the most
common tests done in a miscarriage, but neither can
confirm the chromosomal status of the developing em-
bryo. In every case of miscarriage, especially when there
are developmental anomalies, chromosomal analysis of
the miscarriage should be performed. Although the most
common cause of first trimester miscarriage is a numeric
chromosome error, it fortunately does not confer an
increased risk of miscarriage in subsequent pregnancies.
If chromosome testing is done on the second miscarriage
and the result is aneuploid or polyploidy, it can eliminate
the need for a costly and time-consuming evaluation.
Additionally, patients will have an explanation that may
help lessen anxiety about causes associated with recur-
rent pregnancy loss. Studies have suggested a 75%
success rate in future pregnancies after a documented
numeric chromosome error.46 Therefore, knowing the
chromosome results of the miscarried embryo/fetus is
important, particularly for parents struggling with fer-
tility or recurrent miscarriage.
The most common numeric chromosome errors
identified in first trimester miscarriages are monosomy
X, followed by trisomy 16. Numeric errors of all chro-
mosomes have been reported for all 24 chromosomes.
The most frequent reason for such errors is meiotic
nondisjunction, which is most commonly a random
event occurring in the fertilized oocyte and therefore
not a reflection of an abnormal oocyte pool. The rate of

trisomies increases with maternal age; thus the propor-
tion of miscarriages with numeric chromosome errors
increases with maternal age. Other chromosome errors,
such as triploidy and tetraploidy, account for 8%
of miscarriages with numeric chromosome errors.47 Ma-
ternal age is the major risk factor for trisomic pregnancies.
Other factors, such as diminished ovarian reserve, pre-
mature ovarian insufficiency, and recurrent miscarriage,
have been proposed, but further study is needed.
Most cytogenetic laboratories use metaphase
karyotyping as their primary method of testing. This
testing gives a clear view of both chromosome number
and arrangement, and it is available in most hospital
settings. Although this is the gold standard for evaluat-
ing chromosomal abnormalities, it has several limita-
tions, including requirements for tissue culture and the
possibility of maternal cell contamination. To ensure
the highest yield, tissue from the miscarriage needs to
be gathered and sent to the cytogenetics laboratory as
quickly as possible in either culture media or saline to
ensure adequate cell growth. Tissue from either a spon-
taneous miscarriage or following surgical evacuation of
the uterus can be used. However, if tissue is exposed to
formalin, it cannot be used.
Maternal cell contamination is a concern with
conventional cytogenetic analysis because maternal and
pregnancy cells are both expelled or collected together.
The risk of maternal cell contamination of tissue culture
can be reduced if the chorionic villi are carefully
dissected from the maternal decidua. Unfortunately,
because the chromosomes are analyzed with G-banding
only, differentiating maternal 46, XX from pregnancy
46, XX cannot be accomplished. Studies examining the
rate of maternal cell contamination with metaphase
karyotypes have reported that a third to half of reported
46, XX results are false negatives due to maternal cell
contamination.48,49
Other methods of analyzing miscarriage tissue
include array comparative genomic hybridization
(CGH), single nucleotide polymorphism (SNP) micro-
arrays, and florescence in situ hybridization. These
techniques can be performed either on fresh tissue or
preserved (formalin-fixed or paraffin-embedded) tissue.
CGH detects aneuploidy or an unbalanced structural
chromosome rearrangement but cannot detect balanced
translocations, triploidy, or tetraploidy. Although CGH
is more expensive than conventional cytogenetics and
not readily available in all settings, it could be considered
when conventional cytogenetic analysis fails. CGH has
the same limitation of cytogenetics in that maternal cells
cannot be differentiated from pregnancy. SNP micro-
arrays can differentiate maternal and paternal SNPs from
maternal SNPs and therefore readily identify maternal
contamination and triploidy. Similar to CGH, SNP
microarrays cannot detect balanced structural chromo-
some rearrangements or tetraploidy.
FIRST TRIMESTER MISCARRIAGE EVALUATION/LATHI ET AL 467
The one exception to the low recurrence risk of
chromosome errors is the discovery of an unbalanced
structural chromosome rearrangement in the miscar-
riage. Although some translocations found in miscar-
riages are sporadic, 77% are inherited from one of the
parents who carries a balanced form of the rearrange-
ment.50 If a structural chromosome rearrangement is
found in the miscarriage tissue, the partners should have
their peripheral blood karyotyped. If a partner is found to
have a balanced structural chromosome rearrangement,
then genetic counseling is indicated because these cou-
ples are at increased risk of miscarriage51,52 There is also
an increased risk of an unbalanced structural chromo-
some rearrangement that could result in miscarriage or
an ongoing pregnancy with major congenital anomalies.
This risk depends on mode of ascertainment, the sex of
the transmitting parent, and the size of the unbalanced
segments. The chance of having an abnormal liveborn
ranges from 0% to 30%.51 Following two or three
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pregnancy losses, there is a 3 to 5% chance that one
member of the couple carries a chromosome rearrange-
ment.53 Approximately 50% of these rearrangements are
balanced reciprocal translocations, 24% are Robertsonian
translocations, and the remainder are inversions, mosa-
icism, and other sporadic abnormalities. Females are
twice as likely as males to have a structural rearrange-
ment.54,55 Carriers of balanced translocations should be
offered preconception genetic counseling and prenatal
diagnosis through chorionic villus sampling (CVS) or
amniocentesis.
If miscarriage chromosome testing is not avail-
able, parental karyotypes are indicated after two or more
first trimester miscarriages. Conversely, parental karyo-
types are not indicated when sporadic numeric chromo-
some errors are found in the miscarriage. Likewise, such
errors are not an indication for diagnostic testing
through CVS or amniocentesis in future pregnancies.
CONCLUSION
A combination of genetic, pathological, and ultrasound
examination of miscarriage can help describe the timing
of loss and identify the cause of the miscarriage. With a
comprehensive multidisciplinary approach to miscar-
riage, the patient and her partner can often be given
an explanation of the cause of their miscarriage and
individualized prognostic information. Regardless of the
cause of miscarriage or the prognosis, women need
emotional support during and after a miscarriage. Post-
partum depression can occur in up to 20% of women
experiencing a miscarriage and is more common in
women with multiple miscarriages.56 Recognizing both
the medical and emotional needs of patients experienc-
ing miscarriage is critical to her long-term health and
willingness to embark on another pregnancy. As pro-
viders, we need to offer answers, support, and realistic
468 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6
optimism for our patients experiencing miscarriage be-
cause most patients will eventually achieve a successful
pregnancy.
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