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

1
Departments of Obstetrics and Gynecology, Recurrent Pregnancy Stanford, CA 94305 (e-mail: rlathi@stanford.edu).
Loss Program; 2Pathology; 3Department of Obstetrics & Gynecology, Recurrent Early Pregnancy Loss; Guest Editor, Mary D. Stephenson,
Maternal & Fetal Medicine, Stanford University; 4Department of M.D., M.Sc.
Perinatal Genetic Counseling, Lucile Packard Children’s Hospital at Semin Reprod Med 2011;29:463–469. Copyright # 2011 by Thieme
Stanford, Stanford, California. Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
Address for correspondence and reprint requests: Ruth B. Lathi, USA. Tel: +1(212) 584-4662.
M.D., Department of Obstetrics and Gynecology, Recurrent Preg- DOI: http://dx.doi.org/10.1055/s-0031-1293200.
nancy Loss Program, Stanford University, 300 Pasteur Drive HH333, ISSN 1526-8004.
463
464 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6 2011

cytogenetics. A thorough evaluation often provides an gestational sac measurement before considering inter-
explanation for the miscarriage and individualized prog- vention or repeat the ultrasound in 1 week if the
nostic information. 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-
ULTRASOUND EVALUATION tional sac size or abnormal shape, presence of subchor-
With the increased availability of ultrasound, patients ionic hematoma, presence of embryonic anomalies, and
are receiving earlier sonographic diagnoses, and it is abnormalities in intervillous blood flow. Benson and
more precise to describe unsuccessful or failed pregnan- Doubilet found that 60% fetuses with heart rates <90
cies based on their sonographic appearance with ‘‘em- at <7 weeks of gestation died before the end of the first
bryonic demise’’ referring to cases where the ultrasound trimester.12–16 Bromley et al found that 94% of embryos
clearly shows an ‘‘embryonic fetal pole’’ without cardiac with a small gestational sac (defined as the difference
activity. Anembryonic miscarriage is defined by sonogra- between the mean sac diameter and crown rump
phy as an empty gestational sac at a gestational age where length [CRL] <5) resulted in miscarriage, despite the
one would expect to see a yolk sac or embryo with cardiac presence of normal fetal cardiac rate.17 Ultrasound-
activity. documented subchorionic hematomas also correlate
When evaluating an early pregnancy by ultra- with miscarriage, with rates varying between 7.7% and
sound, one must be familiar with the timing and 18.8%, depending on the size of the hematoma.18
sequence of normal embryonic development. An embry- Women who present with bleeding and a subchorionic

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onic pole with cardiac activity equates to a gestational hematoma at 8 weeks of gestation are at higher risk of
age of at least 6 weeks. If an embryonic pole is not seen, miscarriage than those with bleeding after 8 weeks of
the potential gestational sac should be examined for the gestation (13.7% versus 5.9%).19 Odeh et al compared
double decidual sac sign (double echogenic ring) within gestational sac volumes between normal pregnancies,
the endometrial cavity, which can help differentiate a missed embryonic miscarriages, and anembryonic mis-
true gestational sac from a pseudosac. This can be seen as carriages. They found that gestational sac volume was
early as 4 weeks of gestation.1–3 If the sac lacks this sign significantly smaller in both embryonic and anembryonic
and appears as an endometrial fluid collection, one must miscarriages compared with normal pregnancies.20
suspect a pseudogestational sac. In this case, the differ- Whether three-dimensional (3D) volumes offer advan-
ential includes the nonpregnant state, a very early intra- tages over conventional ultrasound parameters in the
uterine pregnancy (IUP), or ectopic pregnancy, and the prediction of miscarriage remains to be tested by a large
ultrasound findings should be correlated with serial prospective trial.
quantitative hCG measurements. Theoretically, a
true gestational sac can be distinguished from a pseudo-
gestational sac by its appearance and location, and PATHOLOGICAL EVALUATION OF
should be confirmed with a mean sac diameter (MSD) THE MISCARRIAGE AND PLACENTA
 10 mm.4,5 However, before clear visualization of this The pathological evaluation of the first trimester
sign, differentiation of a true versus pseudogestational miscarriage includes assessment of the morphological
sac can be difficult. In the absence of symptoms suggest- features of the gestational sac, embryo or fetus, and
ing ectopic pregnancy, a follow-up ultrasound should be placenta. An empty gestational sac does not allow
considered to avoid terminating a potentially viable for embryo/fetal assessment; however, when embryo or
pregnancy. Additionally, hCG levels can be helpful fetal examination is possible, developmental anomalies,
in distinguishing between an early IUP and an ectopic growth restriction or embryonic disorganization, and
pregnancy, and hCG values between 1500 and 2000 isolated morphological defects may be detected. Pre-
mIU/mL are typically associated with a visible intra- evacuation imaging techniques such as embryoscopy or
uterine gestational sac on transvaginal scan.6–8 high-resolution sonography can successfully augment
As the pregnancy matures, a yolk sac becomes this evaluation. Whereas the initial pathologic assess-
visible on transvaginal scan by 8 mm MSD or by 20 mm ment should be used to confirm the presence or absence
MSD on transabdominal scan.9 Cardiac activity is often of pregnancy tissue and identification of a molar preg-
the earliest sign of the developing embryo and can nancy, perinatal pathologists have strived to add more
typically be seen transvaginally when MSD 16 mm than a diagnosis of ‘‘products of conception.’’21–23 His-
or transabdominally when MSD 25 mm.10 Sono- topathology of the placental tissue commonly adds little
graphic diagnosis of embryonic demise can be made to determining an etiology of first trimester loss, with a
when there is no cardiac activity in an embryo 5 mm few rare but important exceptions. Diagnoses associated
by transvaginal ultrasound or 9 mm by abdominal with an increased recurrence risk include chronic inter-
ultrasound.11 Given the possibility of measurement villositis, villitis, massive perivillous fibrin deposition/
error, it is prudent to allow an additional 1 to 2 mm in maternal floor infarction, and plasma cell deciduitis.
FIRST TRIMESTER MISCARRIAGE EVALUATION/LATHI ET AL 465

Chronic Intervillositis margins and the decidua basalis. Although one might
Chronic intervillositis is a very rare disorder, present in like to speculate about a possible disorder of coagulation,
<1% of first trimester miscarriage specimens and even the mechanism of miscarriage always involves separation
more rarely in the second and third trimester.24 Patients of the conceptus from the decidua and hemorrhage.
with this disorder tend to have recurrent miscarriage The various clinical associations with this finding sug-
or pregnancies complicated by severe growth restriction gest that the morphology is a final common pathway
or fetal demise. The etiology of this disorder is un- of syncytiotrophoblast injury or degeneration, with sub-
known.25,26 The pathological hallmark is the presence of sequent activation of the coagulation pathway at the
dense sheeting aggregates of histiocytes in the maternal villous surface, or possibly a balance that favors excessive
blood space between villi, with or without the presence coagulation at the villous surface due to an inherited
of perivillous fibrin deposition. The absence of villous thrombophilia.
inflammation and large number of histiocytes in chronic
intervillositis distinguishes this lesion from chronic
lymphohistiocytic villitis with perivillous extension Chronic Villitis
and fibrin deposition. The intensity of the intervillous Chronic villitis is a histologic pattern of chronic inflam-
histiocytic burden increases with gestational age. In a mation of the villous parenchyma most commonly seen
recent series of 69 pregnancies complicated by chronic in the third trimester, less commonly seen in the second
intervillositis, 21 had liveborn infants, 13 of whom or first trimester placenta. Approximately 10% of cases
weighed less than the 3rd percentile for age. These 69 are associated with a known infectious etiology, most

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pregnancies occurred in 50 patients, 9 of whom had at commonly cytomegalovirus, Treponema pallidum, and
least one recurrence of chronic intervillositis.25 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
Massive Perivillous Fibrin Deposition/Maternal identified and the inflammation is termed villitis of
Floor Infarction unknown etiology (VUE). Most authors now consider
Massive perivillous fibrin deposition/maternal floor in- these cases an aberrant maternal cell-mediated immune
farction has some overlap with changes from prolonged response to fetal villous antigens. Chronic villitis is rarely
retention of the conceptus after embryo-fetal demise. manifested in the first trimester spontaneous abortion
The diagnosis of massive perivillous fibrin deposition/ with very rare exceptions.32 In some women, VUE
maternal floor infarction is made in the mature placenta appears to have no clinical significance. In others, the
when the parenchyma is firm and marbled appearing on disorder gets progressively worse in subsequent pregnan-
gross examination because of markedly increased fibrin cies and is associated with recurrent pregnancy loss.33,34
or there is a thick rind of fibrin on the maternal surface. Earlier studies describing VUE and recurrent pregnancy
This disorder has significant recurrent potential in sub- loss did not distinguish between chronic intervillositis
sequent pregnancies with complications of fetal growth and chronic villitis. Patterns with chronic intervillositis
retardation and demise.27 In some cases it may be due to were associated with recurrent loss, as expected. Also,
a maternal thrombophilia leading to increased fibrin chronic villitis with increased perivillous fibrin deposi-
deposition at the villous maternal–fetal interface. In tion was more frequently associated with recurrent loss.
addition, compromised villous trophoblast integrity ex- The increased perivillous fibrin deposition suggests more
poses tissue factor and activates the clotting cascade chronicity to the lesions, but whether or not this is a
locally on the villous surface. Various disorders could distinct pathogenetic category of chronic villitis is un-
damage syncytiotrophoblast including extrinsic factors clear. In the Redline study,33 a significant number of the
like antiphospholipid antibodies or intrinsic factors women had associated abnormalities of uterine anatomy
such as fetal long chain fatty acid deficiency.28 Cases of or placentation, suggesting an important role of the
massive perivillous fibrin deposition can be identified in decidua in mediating proper immunostasis.
midgestation, but the specificity of this finding in first
trimester miscarriages is not entirely clear. Placental
pathologists look for an extravillous trophoblast prolifer- Plasma Cell Deciduitis
ation embedded within the fibrin in true cases of massive Lymphocytes and natural killer cells are normal constit-
perivillous fibrin deposition/maternal floor infarction, uents of the gestational endometrium, but plasma cells
to help distinguish the entity.29 However, the presence are not. Detection of plasma cells in the endometrium on
of diffuse increased perivillous fibrin with a similar endometrial biopsy is a diagnostic marker of chronic
histologic appearance might also reflect prolonged bleed- endometritis. Chronic endometritis has been associated
ing or the presence of a severely macerated fetus.30,31 with recurrent pregnancy loss. It is assumed that chronic
Also difficult to interpret is the significance of endometritis in the nonpregnant endometrium and
hemorrhage and ischemic necrosis at the implantation chronic deciduitis of the decidua basalis or parietalis
466 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6 2011

are a continuum of the same process.35 However, a developmental anomalies such as neural tube defects,
definite association has not been proven. The presence microcephaly, and craniorachischisis.42 It has also been
of plasma cells in the decidua of an early pregnancy loss successfully used to characterize the embryonic features
remains an abnormal finding, not known to be associated of various chromosomal abnormalities such as 45,X,43
with prolonged retention. Plasma cell deciduitis should triploidies,44 and a variety of syndromes.39 The use of
be documented and further clinical correlation done. embryoscopy allows for a more complete examination of
Their presence may indicate the presence of chronic the intact embryo, particularly its external features. It
endometritis with or without bacterial vaginosis, also underscores the fact that miscarriage can result from
which are potentially treatable risk factors for recurrent a variety of causes including, but not limited to, growth
miscarriage. disorganization, isolated developmental defects, and
chromosomal anomalies.
Like the embryo, when a fetus is evaluated fol-
Acute Inflammation and Other lowing miscarriage, the CRL and the crown-heel length
Histopathological Changes of Unclear can provide a useful guide to the overall growth (i.e.,
Significance whether it is normal or restricted). The external fetal
The significance of acute inflammation is unclear in this examination should focus on developmental anomalies
setting. Infection could be a mechanism of loss when and dysmorphisms that provide insight into the cause of
acute inflammation is present.23 However, one rarely the miscarriage. Although these anomalies may occur in
sees acute inflammation of the villous parenchyma or isolation, they may also arise as part of a constellation of

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chorion. The acute infiltrates are often adjacent to anomalies and possible genetic syndromes. Cytogenetic
necrotic foci in the decidua, and they may be part of testing is complementary to the autopsy because there
the miscarriage process. One early study demonstrated may be fetuses affected by chromosomal abnormalities
an association of acute inflammation of the decidua and even when external examination does not reveal typical
placenta in first trimester miscarriages with the presence stigmata.45
of genital Mycoplasma organisms. Although all cases
with a positive culture had inflammation present, not
all cases with inflammation present had a positive GENETIC EVALUATION OF
culture.36 The presence of acute inflammation is worth THE MISCARRIAGE
noting in the pathology report, with clinical consider- Ultrasound and pathologic evaluation are the most
ation given to a possible infectious process. It is unclear common tests done in a miscarriage, but neither can
what percentage of recurrent pregnancy loss is associated confirm the chromosomal status of the developing em-
with infections, but some reports suggest the number is bryo. In every case of miscarriage, especially when there
significant.37,38 However, the mechanism may be more are developmental anomalies, chromosomal analysis of
complex than an active infection damaging the preg- the miscarriage should be performed. Although the most
nancy or decidua. common cause of first trimester miscarriage is a numeric
chromosome error, it fortunately does not confer an
increased risk of miscarriage in subsequent pregnancies.
Embryo Evaluation If chromosome testing is done on the second miscarriage
The evaluation of an intact embryo by the pathologist and the result is aneuploid or polyploidy, it can eliminate
following uterine evacuation is rare. Most embryos are the need for a costly and time-consuming evaluation.
submitted to the pathologist fragmented following en- Additionally, patients will have an explanation that may
dometrial curettage. This fragmentation may preclude help lessen anxiety about causes associated with recur-
definitive assessment of the CRL and other subtle rent pregnancy loss. Studies have suggested a 75%
external features. The use of pre-evacuation embryo- success rate in future pregnancies after a documented
scopy enables visualization of the intact miscarried numeric chromosome error.46 Therefore, knowing the
embryo in situ before manipulation. With this techni- chromosome results of the miscarried embryo/fetus is
que, an endoscope is inserted through either the uterine important, particularly for parents struggling with fer-
cervix or the abdomen and the chorion is incised; the tility or recurrent miscarriage.
embryo is then viewed directly through the amnion.39 The most common numeric chromosome errors
Phillip and colleagues reported a series of embryoscopic identified in first trimester miscarriages are monosomy
observations of abnormal miscarried embryos under a X, followed by trisomy 16. Numeric errors of all chro-
variety of clinical circumstances. They report growth mosomes have been reported for all 24 chromosomes.
disorganization in 48 of 154 (31%) missed miscarriages The most frequent reason for such errors is meiotic
from unassisted pregnancies40 and 11 of 22 (50%) nondisjunction, which is most commonly a random
visualized missed miscarriages from in vitro fertiliza- event occurring in the fertilized oocyte and therefore
tion.41 Embryoscopy can also be used to detect isolated not a reflection of an abnormal oocyte pool. The rate of
FIRST TRIMESTER MISCARRIAGE EVALUATION/LATHI ET AL 467

trisomies increases with maternal age; thus the propor- The one exception to the low recurrence risk of
tion of miscarriages with numeric chromosome errors chromosome errors is the discovery of an unbalanced
increases with maternal age. Other chromosome errors, structural chromosome rearrangement in the miscar-
such as triploidy and tetraploidy, account for 8% riage. Although some translocations found in miscar-
of miscarriages with numeric chromosome errors.47 Ma- riages are sporadic, 77% are inherited from one of the
ternal age is the major risk factor for trisomic pregnancies. parents who carries a balanced form of the rearrange-
Other factors, such as diminished ovarian reserve, pre- ment.50 If a structural chromosome rearrangement is
mature ovarian insufficiency, and recurrent miscarriage, found in the miscarriage tissue, the partners should have
have been proposed, but further study is needed. their peripheral blood karyotyped. If a partner is found to
Most cytogenetic laboratories use metaphase have a balanced structural chromosome rearrangement,
karyotyping as their primary method of testing. This then genetic counseling is indicated because these cou-
testing gives a clear view of both chromosome number ples are at increased risk of miscarriage51,52 There is also
and arrangement, and it is available in most hospital an increased risk of an unbalanced structural chromo-
settings. Although this is the gold standard for evaluat- some rearrangement that could result in miscarriage or
ing chromosomal abnormalities, it has several limita- an ongoing pregnancy with major congenital anomalies.
tions, including requirements for tissue culture and the This risk depends on mode of ascertainment, the sex of
possibility of maternal cell contamination. To ensure the transmitting parent, and the size of the unbalanced
the highest yield, tissue from the miscarriage needs to segments. The chance of having an abnormal liveborn
be gathered and sent to the cytogenetics laboratory as ranges from 0% to 30%.51 Following two or three

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quickly as possible in either culture media or saline to pregnancy losses, there is a 3 to 5% chance that one
ensure adequate cell growth. Tissue from either a spon- member of the couple carries a chromosome rearrange-
taneous miscarriage or following surgical evacuation of ment.53 Approximately 50% of these rearrangements are
the uterus can be used. However, if tissue is exposed to balanced reciprocal translocations, 24% are Robertsonian
formalin, it cannot be used. translocations, and the remainder are inversions, mosa-
Maternal cell contamination is a concern with icism, and other sporadic abnormalities. Females are
conventional cytogenetic analysis because maternal and twice as likely as males to have a structural rearrange-
pregnancy cells are both expelled or collected together. ment.54,55 Carriers of balanced translocations should be
The risk of maternal cell contamination of tissue culture offered preconception genetic counseling and prenatal
can be reduced if the chorionic villi are carefully diagnosis through chorionic villus sampling (CVS) or
dissected from the maternal decidua. Unfortunately, amniocentesis.
because the chromosomes are analyzed with G-banding If miscarriage chromosome testing is not avail-
only, differentiating maternal 46, XX from pregnancy able, parental karyotypes are indicated after two or more
46, XX cannot be accomplished. Studies examining the first trimester miscarriages. Conversely, parental karyo-
rate of maternal cell contamination with metaphase types are not indicated when sporadic numeric chromo-
karyotypes have reported that a third to half of reported some errors are found in the miscarriage. Likewise, such
46, XX results are false negatives due to maternal cell errors are not an indication for diagnostic testing
contamination.48,49 through CVS or amniocentesis in future pregnancies.
Other methods of analyzing miscarriage tissue
include array comparative genomic hybridization
(CGH), single nucleotide polymorphism (SNP) micro- CONCLUSION
arrays, and florescence in situ hybridization. These A combination of genetic, pathological, and ultrasound
techniques can be performed either on fresh tissue or examination of miscarriage can help describe the timing
preserved (formalin-fixed or paraffin-embedded) tissue. of loss and identify the cause of the miscarriage. With a
CGH detects aneuploidy or an unbalanced structural comprehensive multidisciplinary approach to miscar-
chromosome rearrangement but cannot detect balanced riage, the patient and her partner can often be given
translocations, triploidy, or tetraploidy. Although CGH an explanation of the cause of their miscarriage and
is more expensive than conventional cytogenetics and individualized prognostic information. Regardless of the
not readily available in all settings, it could be considered cause of miscarriage or the prognosis, women need
when conventional cytogenetic analysis fails. CGH has emotional support during and after a miscarriage. Post-
the same limitation of cytogenetics in that maternal cells partum depression can occur in up to 20% of women
cannot be differentiated from pregnancy. SNP micro- experiencing a miscarriage and is more common in
arrays can differentiate maternal and paternal SNPs from women with multiple miscarriages.56 Recognizing both
maternal SNPs and therefore readily identify maternal the medical and emotional needs of patients experienc-
contamination and triploidy. Similar to CGH, SNP ing miscarriage is critical to her long-term health and
microarrays cannot detect balanced structural chromo- willingness to embark on another pregnancy. As pro-
some rearrangements or tetraploidy. viders, we need to offer answers, support, and realistic
468 SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 29, NUMBER 6 2011

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