REVIEW

CURRENT
OPINION A new algorithm for the evaluation of recurrent
pregnancy loss redefining unexplained miscarriage:
review of current guidelines
Ralph S. Papas a and William H. Kutteh b,c

Purpose of review
Couples with recurrent pregnancy loss (RPL) are often referred to reproductive specialists to help determine
the reason for their repeated losses. This review will help to develop a strategy that is effective in providing
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a diagnosis, efficient to administer, and cost-effective to the healthcare system.

Recent findings
International societies have published different recommendations for the evaluation of RPL, they consider it
appropriate to initiate an evaluation after two (or three) clinical miscarriages. On the contrary, the clinician
who follows these guidelines will only be able to offer a possible explanation to fewer than half of the
couples being evaluated. Recently, genetic testing of miscarriage tissue using 24-chromosome microarray
(CMA) analysis at the time of the second pregnancy loss coupled with testing based on society guidelines
has been shown provide an explanation in more than 90% of cases.
Summary
New guidelines for the complete evaluation of RPL should consider adding 24-CMA testing on the
miscarriage tissue. Providing couples with an explanation for recurrent loss assists them in dealing with the
loss and discourages the clinician from instituting unproven therapies. Truly unexplained pregnancy loss
can be reduced to less than 10% with this new algorithm. Incorporation of these strategies will result in
significant cost savings to the healthcare system.
Keywords
24-chromosome microarray testing, antiphospholipid antibodies, genetic testing of miscarriage tissue, recurrent
miscarriage, recurrent pregnancy loss

INTRODUCTION maternal causes, this new algorithm involves elimi-

Recurrent pregnancy loss (RPL) occurs in up to 3% of
&&
reproductive age couples [1 ]. Over the past decade, a
consensus definition of RPL consisting of two or more
&&
pregnancy losses has emerged [2 ,3,4]. A recent
meta-analysis confirmed our earlier report that there
were no differences in abnormal findings when eval-
uating women with two or three or more pregnancy
&&
losses [1 ,5] However, current standards for the eval-
uation and management of this distressing disorder
for couples seeking to have children are insufficient,
with over 50% of RPL cases remaining unexplained.
This lack of an explanation has resulted in experi-
mental testing and treatment being requested by
patients and sometimes offered by physicians [6].
A newly devised algorithm for the evaluation
and management of RPL is presented in this review
suggesting an innovative approach to the manage-
ment of RPL. In addition to screening for the most
prevalent, known and potentially ‘treatable’
nating parental karyotype analysis from the initial
a
Infertility Division, Obstetrics & Gynecology Department, St George
Hospital – University Medical Center – University of Balamand, Beirut,
Lebanon, bDivision of Reproductive Endocrinology, Department of
Obstetrics and Gynecology, Vanderbilt University Medical Center and
c
Recurrent Pregnancy Loss Center, Fertility Associates of Memphis,
Memphis, Tennessee, USA
Correspondence to William H. Kutteh, MD, PhD, HCLD, Director of
Recurrent Pregnancy Loss Center, Fertility Associates of Memphis, 80
Humphreys Center, Suite 307, Memphis, TN 38139, USA.
Tel: +1 901 747 2229; fax: +1 901 747 4446;
e-mail: wkutteh@fertilitymemphis.com
Curr Opin Obstet Gynecol 2020, 32:371–379
DOI:10.1097/GCO.0000000000000647
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the work
provided it is properly cited. The work cannot be changed in any way or
used commercially without permission from the journal.

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Reproductive endocrinology
KEY POINTS
 Couples with two or more pregnancy losses should be
evaluated for RPL.
 An evaluation including CMA on products of
conception with a modified American Society for
Reproductive Medicine work-up (deleting parental
chromosomes) will provide a proven or possible
explanation in about 90% of couples.
 Unexplained miscarriage will be reduced to
approximately 10% of cases; this group should be the
focus of future investigations into unknown causes of RPL.
 Knowing the cause(s) of miscarriage often provides
great psychological and emotional relief, as patients
often put the responsibility for the loss on themselves
when this is rarely the case.
 Adoption of this strategy for the evaluation and
management of RPL will result in a doubling of the
couples who have an explanation for their loss, and
will reduce the cost to the healthcare system by half.
&&
RPL work-up [2 ] and recommending a systematic
24-chromosome microarray (CMA) analysis of mis-
& ing for first trimester pregnancy losses (unless for
carriage tissue after the second or subsequent loss [7 ].
OVERVIEW OF CURRENT STANDARDS OF
PRACTICE
The Royal College of Obstetricians and Gynaecolo-
gists (RCOG) Green-top Guideline on recurrent mis-
carriage in 2011 uses quality of evidence to grade
their recommendations for evaluation of RPL from A
to D. Best practices included referral of patients to a
specialist clinic and an ultrasound for evaluation of
FIGURE 1. Results of the American Society for Reproductive Medicine Evaluation couples with recurrent pregnancy loss. A
total of 1398 couples with two or more documented early pregnancy losses of 1398 had a complete evaluation as
recommended by American Society for Reproductive Medicine [3]. More that 55% of couples had a normal evaluation and
were classified as unexplained recurrent pregnancy loss. Updated from [5].
372 www.co-obgyn.com
the uterus. Grade D recommendations included test-
ing for antiphospholipid syndrome (APS) and genetic
testing of products of conception (POC) after the
third and subsequent loss. The 2012 American Soci-
ety for Reproductive Medicine (ASRM) assessment of
RPL includes analyzing parental karyotypes, evaluat-
ing uterine anatomy, and screening for APS, thyroid
and prolactin abnormalities [3]. Karyotype analysis of
POC should only be used in the setting of ongoing
therapy for RPL [3]. The diagnostic results of the
ASRM evaluation based on our data from 1398 cases
(Fig. 1) reveal that over 50% will be left without an
explanation for their loss [5]. In 2018, the European
Society of Human Reproduction and Embryology
(ESHRE) published extensive guidelines using the
‘GRADE’ system with ‘strong’ recommendations to
test for APS, and thyroid abnormalities, as well as for
uterine anatomy assessment; whereas conditional
recommendations were given against the routine
use of parental karyotyping (to be carried out only
after individual risk assessment) and POC genetic
analysis (to be performed only for explanatory pur-
&&
poses) [2 ] (Table 1).
In addition, none of these guidelines support
the routine use of hereditary thrombophilia screen-
research or for women with additional risk factors
for thrombophilia) and male sperm DNA fragmen-
&&
tation (for explanatory purposes only) [2 ,3]. Fur-
thermore, ESHRE does not advise routine testing for
polycystic ovaries and insulin resistance, ovarian
&&
reserve, or luteal insufficiency [2 ].
Parental karyotyping
ASRM recommends parental karyotype analysis as a
balanced reciprocal or a Robertsonian translocation is
Volume 32  Number 5  October 2020
 New algorithm for recurrent pregnancy loss Papas and Kutteh

Table 1. Summary of the current guidelines from the Royal College of Obstetricians and Gynaecologists, American Society for
Reproductive Medicine, and European Society of Human Reproduction and Embryology compared with the new proposed
algorithm for the evaluation of recurrent pregnancy loss
Screening test Royal College 2011 ASRM 2012 ESHRE 2017 PROPOSED 2020

Parental karyotyping Not recommended Recommended Conditional Not Recommended

Unless POC reveals recommendation: Only Unless POC CMA reveals
unbalanced translocation after ‘individual risk unbalanced translocation
assessment’a
POC cytogenetic Recommended (after third Not recommended Conditional Recommend: Use CMA for
analysis and subsequent (karyotype analysis of recommendation: for the second and
miscarriage) POC explanatory purposes subsequent pregnancy
only in the setting of (strong recommendation loss
ongoing therapy for RPL) to use CMA when POC
genetic analysis is
performed)
Uterine anatomy Recommended: If Pelvic Recommended: 3D Strong recommendation: Recommend: 3D ultrasound
evaluation ultrasound abnormal get ultrasound (conditional
Hysteroscopy or 3D Hystero-salpingogram recommendation: prefer
ultrasound Hysteroscopy 3D ultrasound)
Antiphospholipid Recommended: lupus Recommended: lupus Strong recommendation: Recommend: lupus
antibodies anticoagulant and anticoagulant lupus anticoagulant and anticoagulant,
anticardiolipin Anticardiolipin antibodies anticardiolipin anticardiolipin
antibodies Antib2 glycoprotein I antibodies antibodies,
Good clinical practice: antiphosphtidyl serine
antib2 glycoprotein I antibodies
Thyroid function Recommended: TSH Recommended: TSH Strong recommendation: Recommend: TSH
Not recommended: TPO TSH and TPO antibodies TPO when TSH > 2.5 mIU/l
Prolactin Not discussed Recommended Conditional Recommended
recommendation: if
hyperprolactinemia
(oligo- or amenorrhea)
Hemoglobin A1c Recommended Recommended to evaluate Not recommended Recommended
for diabetes
Hereditary Not recommended for first Only recommended if a Conditional Only recommended if a
thrombophilia trimester (recommended personal or strong family recommendation: Only personal or strong family
for second trimester loss) history of thrombosis or in the context of research history of thrombosis or
thrombophilia or in women with thrombophilia
additional risk factorsa
Sperm DNA Not discussed Not recommended Conditional Not recommended
fragmentation Controversial data recommendation: only
for explanatory purposes
PCOS and insulin Insufficient evidence Not recommended Not recommended Not Recommended
resistance Controversial data
Luteal insufficiency Insufficient evidence Not recommended Not recommended Not Recommended
Ovarian reserve Not discussed Not recommended Not recommended Not recommended (use
testing only for explanatory
purposes)
Vitamin D deficiency Not discussed Not discussed General advice to consider Recommend to supplement
vitamin D vitamin D
supplementation

3D, three dimensional; ASRM, American Society for Reproductive Medicine; CMA, chromosomal microarray; ESHRE, European Society of Human Reproduction
and Embryology; POC, products of conception; RPL, recurrent pregnancy loss; TPO, thyroid peroxidase antibodies; TSH, thyroid stimulating hormone.
a
Individual risk assessment recommended (see text).

present in about 2–5% of RPL couples thus could
represent a major prognostic factor [3,8,9]. ESHRE
recommends testing only in couples at an increased
risk, evidenced by a prior child with congenital abnor-
malities, offspring with unbalanced chromosomes, or
&&
a translocation in POC [2 ,3]. RCOG advises parental
karyotypes when an unbalanced structural chromo-
some is found in POC and referral of the couple
for genetic counseling [4]. Recent studies have
shown that parental karyotyping for all RPL

1040-872X Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-obgyn.com 373
Reproductive endocrinology
couples is simply not cost-effective [10,11] and
that there is no overall difference in live birth
rate when comparing Preimplantation Genetic
Testing (PGT) to natural conception in those cases
[11,12].
Products of conception cytogenetic analysis
The RCOG issued a Grade D recommendation to
obtain cytogenetic analysis on POC after the third
or subsequent consecutive miscarriage. They state
that knowledge of the POC karyotype provides
prognostic value to the clinician in counseling
the couple on subsequent successful pregnancies
[4].
The ASRM Practice Committee recommended
against the use of karyotype analysis of the POC
except in the setting of ongoing therapy for RPL [3].
According to the committee, ‘if the evaluation iden-
tifies a remediable cause, cytogenetic analysis of
subsequent losses can be employed to evaluate
whether the event was random and not a treatment
failure per se.’ ASRM acknowledges the probable
psychological value for RPL couples.
The 2017 ESHRE Guidelines issued a conditional
recommendation against the routine use of POC
genetic analysis but issued a strong recommenda-
tion in favor of using microarray CMA whenever
genetic analysis was performed on POC for explan-
&&
atory purposes [2 ,13]. Furthermore, ESHRE recog-
nized that the ‘genetic analysis of pregnancy tissue
has the benefit of providing the patient with a
reason for the pregnancy loss and may help to
determine whether further investigations or treat-
&&
ments are required’ [2 ].
The ASRM and RCOG positions on POC genetic
testing for RPL were based on the then current
standard of conventional G-banding karyotype
analysis [3,4]. ESHRE recommends CMA as the pre-
ferred modality for POC genetic testing because it is
not limited by tissue culture failure or false negative
results secondary to maternal cell contamination
&&
[2 ]. Up to 50% of ‘46, XX normal’ reports from
POC testing result from maternal cell contamina-
tion, so methods to ensure the correct results are
&
required [14 ,15–17]. A recent report on CMA of
26 101 miscarriages had a successful read in over
86% of samples, detected 59% with a chromosomal
anomaly that could explain a pregnancy loss, but
reported 13% of total results were due to maternal
&
cell contamination [14 ]. Conventional cytogenetic
results of 5457 consecutive POC samples yielded
only 75% culture successes [16]. Limitations of
CMA technology include the inability to detect
balanced structural chromosomal rearrangements
and low-level mosaicism [16–18].
374 www.co-obgyn.com
Benefits of recurrent pregnancy loss
evaluation based on products of conception
cytogenetic analysis
When the ASRM guidelines were published, we and
others proposed a new algorithm for the evaluation
and management of RPL based on the results of
cytogenetic analysis of POC by G-banding [19] or
CMA [20] at the time of the second or subsequent
first trimester miscarriage. Following this original
algorithm, if the cytogenetic analysis revealed aneu-
ploid POC, no further evaluation or treatment was
recommended. If an unbalanced chromosomal
translocation or inversion was identified, then
parental karyotyping and genetic counseling was
advised. Finally, if the miscarriage tissue was found
to be euploid and maternal cell contamination had
been ruled out, a full 2012 ASRM RPL work-up was
recommended [19,20].
To clinically validate that this algorithm would
be more effective and cost-efficient than the ASRM
RPL evaluation alone (Table 1), Popescu et al. [7 ]
&
prospectively evaluated RPL patients using the full
ASRM workup (parental chromosomal abnormali-
ties, uterine anomalies, endocrine imbalances, auto-
&
immune factors) as well as CMA analysis of POC [7 ].
Results indicated that in over 90% of cases, at least
one potential explanation for the miscarriage could
be identified when CMA analysis of POC was added
to the standard ASRM RPL evaluation. Moreover,
this algorithm was found to be significantly more
cost-effective, producing savings of over 50% for the
&
health system based on US numbers [7 ]. We here
present additional data on a total of 378 RPL cases in
which POC CMA was performed. This large cohort
confirms that in 91.8% of cases an explanation for
miscarriage can be identified when combining the
ASRM work-up with POC CMA (Fig. 2).
Based on our experience, we agree with RCOG,
ASRM, and ESHRE statements that there is a psycho-
logical benefit to the couples experiencing RPL
when they learn that the pregnancy loss was the
result of an abnormal chromosome complement.
Clinically we have observed a great sense of relief
in many couples, alleviating some feelings of guilt
once they have an explanation for their loss.
NEW PROPOSED EVALUATION FOR
RECURRENT PREGNANCY LOSS
It is appropriate to remember that human reproduc-
tion is an extremely inefficient process. Approxi-
mately 70% of human conceptions never achieve
viability, and nearly 50% spontaneously fade before
ever being noticed [21,22]. Spontaneous miscarriage
is ultimately the most common complication of
pregnancy. Of clinically recognized pregnancies
Volume 32  Number 5  October 2020
 New algorithm for recurrent pregnancy loss Papas and Kutteh

FIGURE 2. Three strategies for identifying the cause of recurrent pregnancy loss including American Society for Reproductive
Medicine 2012 evaluation (left panel), products of conception chromosome microarray (right panel), and a combination of
both (center panel). As shown on the left, only 42.9% of patients who were evaluated for recurrent pregnancy loss using the
American Society for Reproductive Medicine recommendations had an explanation for their loss. When using only
chromosomal microarray on products of conception as shown on the right, 57.7% of pregnancy losses were aneuploid and
the couples had an explanation for their loss. When using the new strategy proposed in this article of combining chromosomal
microarray on products of conception after the second or subsequent loss with a modified American Society for Reproductive
Medicine evaluation (deleting parental chromosome analysis), 91.8% of couples had a possible or proven explanation for
their loss (center panel).

that ultimately miscarry, 60% contain a chromo-
&
somal anomaly that can explain the loss [13,14 ]. In
spite of this high rate of aneuploidy, it is important
to realize that genetic factors alone cannot be the
only causative factor for miscarriages in many RPL
&&
cases [1 ,5].
Based on our data summarized in Fig. 2, we now
propose an updated algorithm for the evaluation
and management of RPL. This proposal includes
CMA analysis of POC after the second or subsequent
loss combined with a modified ASRM evaluation
that omits parental karyotypes.
MATERIALS AND METHODS
The retrospective cohort and the prospective studies
were approved by the Institutional Review Boards at
the University of Tennessee Health Sciences Center
and Rhodes College, respectively, for exempt status
because the research included the collection and
study of existing data recorded by the investigators
in such a manner that the subjects could not be
identified directly or indirectly through identifiers
&
linked to the subjects [5,7 ]. The original prospective
study has been expanded for this report.
Patients included women with two or more
consecutive, clinically documented pregnancy
losses. Pregnancy loss was defined as any natural
miscarriage occurring at or before 20 weeks of ges-
tation or with a fetal weight of 500 g or less [3]. For
this study, patients who had losses after 20 weeks,
ectopic pregnancies, molar pregnancies, and preg-
nancy terminations were excluded. All women were
included regardless of socioeconomic status or race.
Laboratory and uterine cavity evaluation as well as
interpretation of normal and abnormal results has
been described in detail elsewhere [5].
The average age of patients at the time of the loss
for inclusion in this report was 33.4  4.6. The esti-
mated gestational age at the time of loss was
8.2  3.5 weeks with 96% occurring before 13 weeks
of gestation. Primary RPL occurred in 68% of women
(951/1398) whereas secondary RPL was diagnosed in
the remaining women (447/1398; 32%). The major-
ity of women had two losses (747/1398; 53.4%) or
three losses (393/1398; 28.1%), while fewer had four
or more losses (258/1398; 18.5%). It has previously
been reported that the frequency of abnormal find-
ings does not differ in women who had two, three,
&&
or four or more losses [1 ,5].
EVALUATION AND MANAGEMENT
Initial considerations
Couples who have experienced RPL want their med-
ical team to provide compassionate care and clear
information on the causes and treatments of RPL
[23,24]. Healthcare providers should support,
understand, and acknowledge the pregnancy losses
are significant life events [24]. Furthermore, in keep-
ing with ASRM, RCOG, and ESHRE guidelines,

1040-872X Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-obgyn.com 375
Reproductive endocrinology
couples should be informed of the negative impacts
of smoking, excessive alcohol intake and weight
extremes on general health as well as on their repro-
ductive potential, and referred to qualified providers
&&
if necessary [2 ,3,4] (Fig. 3, Box 1, item 1).
Modified evaluation of patients with
recurrent pregnancy loss
In this new algorithm, all known, prevalent, and
potentially treatable abnormalities in first trimester
loss RPL cases, whether anatomic, immunologic,
and/or endocrine, are to be addressed regardless of
POC cytogenetic analysis results (Fig. 3, Box. 1). This
recommendation differs from the original proposals
of Bernardi et al. [19] who suggested that the results
of G-banding karyotypes on POC or Brezina and
Kutteh [20] who suggested that the results of 24-
CMA on POC be used to direct testing. Because it has
been shown that approximately 25% of women with
an aneuploid result on POC CMA analysis will also
have a treatable cause of RPL a modified ASRM
&
workup is necessary [7 ] (Fig. 3, Box 1, items 2–4).
The modified evaluation omits parental karyo-
type analysis from the initial work-up, replacing
that with systematic CMA evaluation of miscarriage
tissue. The frequency of abnormal parental karyo-
types is 2–5% and the self-pay cost for a karyotype
analysis is $800. Thus, cost for each couple to obtain
a karyotype is $1600. Conversely, the self-pay cost
for a 24-CMA is $249, which will provide an expla-
nation for the miscarriage in almost 60% of cases
& &
[7 ,14 ,15,17]. Potentially treatable maternal causes
that will be found in about 40% of cases recognized
by RCOG, ASRM, or ESHRE include uterine abnor-
malities, APS, and thyroid and prolactin endocrine
&& &&
disorders [1 ,2 ,3–5].
The updated algorithm recommends that the
uterine cavity be evaluated for all RPL women
(Table 1), given such anomalies are common but
also simply treatable. ESHRE prefers three dimen-
sional transvaginal ultrasound to assess the uterine
cavity in RPL given its high sensitivity and specific-
ity and its cost-effectiveness compared with hyster-
&&
oscopy [2 ]. ASRM accepts sonohysterography,
hysteroscopy, and/or hysterosalpingography as suit-
able methods [3]. RCOG suggests a pelvic ultrasound
on all women with RPL followed by hysteroscopy or
three dimensional ultrasonography if a uterine
anomaly is suspected [4]. An ESHRE committee con-
cluded that three dimensional ultrasound technol-
ogy has an accuracy of 97.6% (confidence interval
94.3–100) for the diagnosis of female genital tract
anomalies when compared with hysterosco-
py  laparoscopy [25]. The prevalence of congenital
and acquired uterine tract anomalies has been
376 www.co-obgyn.com
estimated to be 16.7% in RPL as compared with
6.7% in the general population [26].
The updated proposal recommends screening
for APS as a potentially treatable and prevalent
&&
(15–20%) diagnosis in RPL women [2 ,3,4,27,28].
All three societies recommend testing for APS using
lupus anticoagulant, IgG and IgM anticardiolipin in
&&
all patients with RPL (Table 1) [2 ,3,4]. The Inter-
national Congress on APS recommends adding anti-
phosphatidyl serine antibody testing to identify an
additional 5% of women with APS who would oth-
erwise not be detected [28]. The clinical value of
such an approach goes beyond miscarriage preven-
tion, given that treatment has been shown to reduce
late pregnancy complications [29]. ASRM adds test-
ing for IgG and IgM antib2 glycoprotein I antibod-
ies, however, RCOG and ESHRE guidelines consider
&&
the association weaker [2 ,3,4]. A general consensus
recommends low-dose aspirin (75–100 mg/day)
beginning before conception and a prophylactic
dose of heparin starting with a positive pregnancy
&&
test and continuing to delivery [2 ,3,4,27,30,31].
In the newly proposed algorithm, all cases are to
be evaluated for thyroid and prolactin abnormalities
along with elevation of HgbA1c. In our current
protocol, when thyroid stimulating hormone
(TSH) levels are above 2.5 mIU/l, especially in com-
bination with positive thyroid peroxidase (TPO)
antibodies, we initiate low-dose levothyroxine.
There have been various published recommenda-
tions from ESHRE, ASRM, and RCOG for hormonal
testing including TSH, TPO antibodies, prolactin,
HgbA1c, diabetes, insulin resistance, and ovarian
&&
reserve (refer to Table 1 for comparisons) [2 ,3,4].
We do not routinely recommend ovarian reserve
testing; however, a recent meta-analysis correlated
low-ovarian reserve in some women with unex-
plained RPL [32]. Vitamin D deficiency has been
shown to be associated with several obstetric com-
plications including miscarriage [33] and ESHRE
issued a recommendation to consider vitamin D
supplementation for all cases as part of preconcep-
&&
tion counseling [2 ]. We believe it judicious to
consider Vitamin D supplementation for all women
with RPL.
Management based on initial evaluation
results including products of conception
chromosome microarray
Typically at the initial referral for RPL evaluation, the
chromosomal status of the previous pregnancy mis-
carriage is not available. Studies based on G-banding
karyotype analysis, suggest that POC results from the
first miscarriage (euploid or aneuploid) are associated
with a similar genetic outcome in 65% of second
Volume 32  Number 5  October 2020
 New algorithm for recurrent pregnancy loss Papas and Kutteh

FIGURE 3. Proposed evaluation for recurrent pregnancy loss.

1040-872X Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-obgyn.com 377
Reproductive endocrinology
miscarriages [34]. Using CMA analysis of POC
revealed similar aneuploidy rates in pregnancy losses
from natural conceptions (56.8%), conceptions from
IVF (53.6%), women with one prior loss (54.4%), and
women with three or more losses (52.1%) [35]. POC
aneuploidy is extremely common, and its presence
does not rule out the presence of any of the known
treatable RPL causes, which could have caused the
loss of the previous pregnancy. Indeed, we believe all
RPL cases deserve to be assessed for all potentially
treatable causes (Fig. 3, Box. 1). One key feature of this
new algorithm makes use of POC cytogenetic analysis
to direct management toward what would poten-
tially be the most appropriate approach, without
making assumptions regarding the chromosomal
status of previous miscarriages (Fig. 3, Box 1, item
5 and Box 2).
If the POC CMA reveals an unbalanced transloca-
tion or an inversion, then a karyotype analysis of both
parents should be performed. In addition to genetic
counseling, expectant management versus IVF with
PGT should be considered and discussed [4,8].
The POC CMA will reveal aneuploidy in about 55%
&
of cases [7 ,35] (Fig. 2). In a patient who has been
evaluated and treated for all of the known causes
(according to Fig. 3, Box 1), no further testing is
generally recommended. Approximately 25% of
women with POC aneuploidy by CMA will have
at least one concomitant abnormal finding on the
&
ASRM evaluation [7 ] and should benefit from treat-
ment in any subsequent pregnancy. For women
with a normal ASRM work-up with aneuploid
POC as the sole identified cause of at least the last
miscarriage, we optimistically counsel the couple
about the chances of a future live born child based
on the maternal age and number of prior losses [36].
When POC are euploid on cytogenetic analysis
(42.3%) (Fig. 2) over 80% of these women will have
&
an abnormal ASRM test result [7 ]. Overall a euploid
POC and an abnormal ASRM work-up occur in 28%
&
of all cases [7 ]. Given that at least one of the known
and treatable causes would have been addressed, no
further testing is recommended at this point for
those specific cases.
RPL cases with a normal ASRM evaluation and
euploid POC account for 8.2% of 378 cases (Fig. 2).
Thus, a new definition for ‘unexplained RPL’ arises
when incorporating systematic POC cytogenetic
analysis as a routine part of the RPL evaluation.
For these specific cases, additional testing can be
considered if indicated and appropriate (Fig. 3, Box.
2) by the managing medical team, availability of
given test and/or for research purposes. The patient
should be counseled that expectant management is
also appropriate and that successful outcomes are
frequent [36,37].
378 www.co-obgyn.com
Management of subsequent miscarriage
Management of a subsequent pregnancy loss should
be based on the prior investigation (Fig. 3, Box 3). If
no testing has been performed, evaluation should
begin according to the new algorithm including
POC cytogenetic analysis and modified ASRM
workup (starting with Fig. 3, Box 1). POC CMA
testing should be performed on the present miscar-
riage tissue as it could provide an explanation for the
loss and be relevant to any prior treatment. Addi-
tional testing, which is available and appropriate,
should be considered potentially beneficial in spe-
cific cases such as when repeated losses are euploid
(Fig. 3, Box 2). In cases of repetitive POC aneuploidy,
when all possible causes have previously been
addressed, IVF with PGT of embryos for aneuploidy
remains an unproven option with potential benefit
but may offer no benefit over expectant manage-
ment [38,39] (Fig. 3, Box 3).
CONCLUSION
We have designed an updated strategy for a more
effective and cost-efficient diagnosis and treatment
of RPL. The combination of a genetic evaluation on
miscarriage tissue with an evidence-based evalua-
tion of RPL will provide a probable or definitive
explanation for the loss in 90% of couples and less
than 10% of couples with RPL will remain unex-
plained. In addition to doubling the numbers of
couples that will be given an explanation for their
pregnancy loss, this new strategy for the manage-
ment of RPL results in an estimated 50% cost savings
&
to the healthcare system [7 ] (Fig. 3).
These results compare very favorably to the use of
RCOG, ASRM, or ESHRE guidelines where over 50%
of couples will be categorized as unexplained RPL.
This should decrease the tendency for clinicians and
patients to move toward unproven therapies out of
desperation. This small remaining group of patients
with unexplained RPL would be ideal candidates for
new research studies and therapies. In our opinion,
future studies on novel treatments for RPL should
include mandatory testing of POC using CMA.
Couples with RPL want to know the reason for
their pregnancy losses. The evaluation and treat-
ment of RPL should be based on the cause(s) of
the loss. Explanation of test results and emotional
support are very important components of therapy.
Realistic expectations for future success should be
based on maternal age, numbers of prior losses, and
the results of the evaluation. Finally, knowing the
cause(s) of miscarriage may provide great psycho-
logical and emotional relief, as patients often put
the responsibility for the loss on themselves when
this is rarely the case.
Volume 32  Number 5  October 2020

Acknowledgements
Author contribution: R.S.P. – writing and review of
article. W.H.K. – data collection, analysis, revision
and review of article.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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